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Mg- and Mn-MOFs Boost the Antibiotic Activity of Nalidixic Acid

  • Vânia André*
    Vânia André
    Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, Lisbon 1049-001, Portugal
    *E-mail: [email protected]
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    Orcidhttp://orcid.org/0000-0001-5599-8355
    • , 
  • André Ramires Ferreira da Silva
    André Ramires Ferreira da Silva
    Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, Lisbon 1049-001, Portugal
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    • , 
  • Auguste Fernandes
    Auguste Fernandes
    Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, Lisbon 1049-001, Portugal
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    • , 
  • Raquel Frade
    Raquel Frade
    Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisbon 1649-003, Portugal
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    • , 
  • Catarina Garcia
    Catarina Garcia
    Centre Research for Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Lisbon 1749-024, Portugal
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    • , 
  • Patrícia Rijo
    Patrícia Rijo
    Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisbon 1649-003, Portugal
    Centre Research for Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Lisbon 1749-024, Portugal
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    • , 
  • Alexandra M. M. Antunes
    Alexandra M. M. Antunes
    Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, Lisbon 1049-001, Portugal
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    • , 
  • João Rocha
    João Rocha
    University of Aveiro, Department of Chemistry, CICECO-Aveiro Institute of Materials, Aveiro 3810-193, Portugal
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    Orcidhttp://orcid.org/0000-0002-0417-9402
    • , and 
  • M. Teresa Duarte
    M. Teresa Duarte
    Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, Lisbon 1049-001, Portugal
    More by M. Teresa Duarte
    Orcidhttp://orcid.org/0000-0003-0994-1352
Cite this: ACS Appl. Bio Mater. 2019, 2, 6, 2347–2354
Publication Date (Web):May 8, 2019
https://doi.org/10.1021/acsabm.9b00046
Copyright © 2019 American Chemical Society
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Abstract

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The development of metal–organic frameworks (MOFs) enclosing active pharmaceutical ingredients is of considerable interest, as their use in controlled drug release and delivery is very promising. Although nalidixic acid is an antibiotic with a broad spectrum of biological applications, effective mainly against Gram-negative infections, its oral bioavailability is low due to a poor solubility and slow dissolution. Herein, we report new metal–organic frameworks (BioMOFs) comprising nalidixic acid and divalent magnesium and manganese ions. These compounds showed an adequate cytotoxicity and improved antimicrobial activity, especially against Gram-negative bacteria. These BioMOFS are among the first examples containing active pharmaceutical ingredients as linkers. Importantly, it is shown that a remarkable increase of the antimicrobial activity of certain antibiotics may be achieved by delivering them in the form of BioMOFs.

KEYWORDS:

Introduction

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Infections and infectious diseases are among the major causes of worldwide morbidity and mortality, and therefore, it is essential to develop effective antimicrobial agents. Bactericidal agents, including antibiotics, have drastically reduced the number of deaths caused by infections over the last 70 years. However, due to their misuse and abuse, many microorganisms have developed resistance mechanisms to most available antibiotics. The United States Centers for Disease Control and Prevention estimates that highly antibiotic-resistant bacteria are responsible for 2 million illnesses, resulting in 23 000 deaths every year in the United States. In Europe, such infections are responsible for some 25 000 deaths per year and represent an economic burden of over 1.5 billion euros. Many of these infections are caused by Gram-negative bacteria, which are responsible for a wide spectrum of diseases, including pneumonia, bloodstream infections, wound or surgical site infections, meningitis, urinary tract, bloodstream, airway, venereal, and other health care-associated infections. Although the fast and global dissemination of antimicrobial-resistant organisms in recent years has been unprecedented, only a few new antibiotics targeting Gram-negative bacteria are in development.(1)
Metal–organic frameworks (MOFs) display fascinating architectures and may be used in many different applications, such as gas storage, luminescence, separation, catalysis, drug delivery,(2−8) and cancer therapy.(9,10) As shown here, they can also be advantageous in the quest for more efficient antibiotic forms.
We disclose here one example in which nalidixic acid MOFs present benefits. Nalidixic acid (NALD) is a first generation drug of the quinolone family with a broad spectrum of biological activity, such as antimicrobial, anti-inflammatory, and antitumor.(11−16) It is bacteriostatic at low concentrations and bactericidal at higher doses. However, nalidixic acid has a low oral bioavailability due to its poor solubility and slow dissolution rate.(17) Moreover, microorganisms developed resistance mechanisms against quinolone antibiotics.(18) To overcome these drawbacks, new quinazolone derivatives of nalidixic acid have been prepared(19) and nanotechnological approaches have been explored.(20,21) For example, nanoformulations of nalidixic acid-based diacyl and sulfonyl acyl hydrazide derivatives were reported has having promising antimicrobial activity.(20) Also the formation of peptide–nalidixic acid conjugates led to an improved antibacterial activity.(22)
Several metal-based nalidixic acid complexes have been synthesized in the past few years as binary or ternary complexes with one or more O- (water, methanol) or N-bearing donor ligands or coligands (pyridine, 2,2′-bipyridine, 1R,2R-diaminocyclo-hexane, etc.). This activity was prompted by the synergetic effect of a metal ion to quinolone drugs with an improved pharmacological activity, including potential as anticancer agents.(13−16,23−27) Very recently, André et al. reported a coordination network with Zn2+ showing a higher water solubility.(28) Herein, we report two new BioMOFs with divalent magnesium and manganese ions.
Magnesium is the fourth most abundant metal in the human body, and it is partially responsible for countless aspects of good health, being essential, for example, in the regulation of over 300 biological reactions due to the role of its ions as anzyme cofactores, and in the reactions that generate and use adenosine triphosphate (ATP). Magnesium further contributes for healthy muscle and nerve functions, a steady heart rhythm, normal blood pressure, regulated blood sugar levels, strong bones, and hormonal activity.(29−34) R. Blower et al.(35) and Wohlkonig, A. et al.(36) have shown that a magnesium ion bridges the enzymes (topoisomerase IV or gyrase) and fluoroquinolones, being essential for the activity of these antibiotics. This is owed to its stabilizing effect on DNA topology and its ability to chelate with quinolones keto and carboxylate groups.
Manganese plays a role, for example, in keeping bones healthy, alleviating the premenstrual syndrome, and assisting in the vitamin absorption in the digestive tract.(37−39)
Mechanochemistry is a solvent-free synthetic technique increasingly used for the synthesis of organic solids of pharmaceutical interest, luminescent and photo- or termoactive materials, coordination polymers, and MOFs and in studies of biomolecular recognition, asymmetric catalysis, interlocked systems, and racemic resolution.(40−56) Several variations of the technique may be employed: in neat grinding, no liquid is added; liquid-assisted grinding uses catalytic amounts of solvent; in ion- and liquid-assisted grinding, catalytic amounts of solvent and an ionic salt are added; polymer-assisted grinding was recently reported.(49,50,55,57−59) Ball milling is one of the techniques in the portfolio of pharmaceutical particle technologies used to improve the poor solubility of drugs by reducing the particle size.(60)
Herein, we report the preparation of novel BioMOFs comprising nalidixic acid and divalent manganese or magnesium ions by mechanochemistry, exhibiting a water solubility increase over nalidixic acid. Moreover, the material with Mg2+ showed a remarkable increase in the antibacterial activity mostly against the Escherichia coli strain. We, thus, demonstrate that BioMOFs may be used to change the properties of currently used antibiotics, such as solubility, and most importantly to enhance their bactericidal activity. To the best of our knowledge, this is the first example of a BioMOF built from an active pharmaceutical ingredient showing such an increase in the bactericidal properties.

Results and Discussion

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Two metal coordination frameworks of nalidixic acid were obtained by reacting with Mg(NO3)2·6H2O and MnCl2·4H2O and were characterized by single-crystal and powder X-ray diffraction, infrared spectroscopy, elemental analyses, and (Mg-form) solid-state nuclear magnetic resonance. The thermal stability of these compounds was evaluated by thermal analyses. The solubility of the materials and their toxicity and bactericidal effect were also assessed.
Liquid-assisted grinding was used in the synthesis of both compounds reported herein. Different synthetic approaches, such as solution and solvothermal, were unsuccessfully explored, leading to mixtures that were not possible to separate and characterize.

Structural Characterization

Due to their similarity, the crystal structures of both BioMOFs will be discussed in parallel and only the differences highlighted. The asymmetric unit of these compounds consists of a metal center coordinated to one deprotonated nalidixic acid moiety and three water molecules, and the charge balance is ensured by a counterion, nitrate for Mg-MOF and chloride for Mn-MOF. The metal centers display an octahedral geometry, coordinating to three water molecules and two nalidixic acid moieties. One nalidixic acid molecule acts as a bidentate ligand coordinating via the carbonyl group and one of the carboxylate oxygen atoms, while the other nalidixic acid molecule coordinates to the metal through the remaining carboxylate’s oxygen (Figure 1). These structures are similar to the previously reported network with Zn.(28)

Figure 1

Figure 1. Nalidixic acid coordination modes scheme (a) and details on the octahedral geometry in the coordination sphere of the metal centers (b).

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Metal complexes of quinolones have been extensively studied by many authors.(61) The coordination is established via the carbonyl and carboxylic/carboxylate groups and the metal center. Focusing on examples with magnesium, the most common is the bidentate coordination mode involving the carbonyl and one of the carboxylate oxygen atoms, originating complexes.(62−64) The extended frameworks presented here are due to the coordination of the second oxygen of the carboxylate moiety, besides the common bidentate mode.
At a supramolecular level, zigzag chains are formed in the bc plane (Figure 2a). These chains stack along the b axis in a parallel fashion, and the counterions (nitrate in Mg-MOF and chloride in Mn-MOF) reside in the voids between the chains (Figure 2b).

Figure 2

Figure 2. Crystal structure details of Mg- and Mn-MOFs viewed along the a (a) and b (b) axes.

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Concerning crystal packing, the same description applies to both MOFs, even if the counterions are different and the networks are not isostructural, showing some conformational differences (Figure 3).

Figure 3

Figure 3. Overlap of Mg-MOF (yellow) and Mn-MOF (blue), showing conformational differences in the 2D network.

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Water molecules are involved in hydrogen bonding, stabilizing the crystal packing (Table 1). The water coordinated in one of the equatorial positions is involved in hydrogen bonds within the chains (O2w–H2w···O1 2.721(2) Å for Mg-MOF and 2.765(4) Å for Mn-MOF). One of the axial water molecules establishes the interaction between parallel chains (O3w–H4w···N2 2.910(2) Å for Mg-MOF and 2.939(4) Å for Mn-MOF). All of the other interactions involving water molecules are established with the counterions.
Table 1. Hydrogen Bond Parameters for the Most Relevant Interactions in Mg- and Mn-MOFs
Mg-MOF
sym opD–H···Ad(H···A) (Å)d(D···A) (Å)(DHA) (deg)
x, 1/2 – y, 1/2 + zO1w–H6w···O62.58(2)3.282(2)135(2)
2 – x, 1 – y, 1 – zO2w–H1w···O61.917(16)2.833(2)173(2)
1 – x, 1/2 + y, 3/2 – zO2w–H2w···O11.854(16)2.721(2)158(2)
1 – x, 1 – y, 1 – zO3w–H3w···O41.866(15)2.770(2)170(2)
1 −x, 1 −y, 1 – zO3w–H3w···O52.47(2)3.146(2)131(2)
1 – x, 1 – y, 1 – zO3w–H4w···N22.015(15)2.910(2)170(2)
2 – x, 1 −y, 1 – zO1w–H5w···O52.002(16)2.817(2)148(2)
x, 1/2 – y, 1/2 + zO1w–H6w···O41.867(15)2.765(2)170(2)
Mn-MOF
–x, –1/2 + y, 1/2 – zO2w–H1w···Cl12.189(19)3.115(3)178(4)
1 – x, –1/2 + y, 1/2 – zO2w–H2w···O11.88(2)2.765(4)159(4)
1 – x, –1/2 + y, 1/2 – zO3w–H3w···Cl12.17(2)3.120(3)174(3)
1 – x, 1 – y, 1 – zO3w–H4w···N22.06(2)2.939(4)155(3)
–x, −1/2 + y, 1/2 – zO1w–H5w···Cl12.33(2)3.174(3)152(3)
x, y, zO1w–H6w···Cl12.188(18)3.114(3)170(3)
The intermolecular interactions of the compounds were also explored by Hirshfeld surface analysis. This is a graphical tool for visualization and further understanding of intermolecular interactions. The red spots over the surface (Figure 4) depict the strong hydrogen bonds between the water molecules and the nalidixic acid moieties and counterions. Lighter spots correspond to weaker interactions among the molecules and H···H contacts.

Figure 4

Figure 4. Hirshfeld surfaces for the Mg-MOF.

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The contribution of the different intermolecular contacts for the Hishfeld surfaces is represented in two-dimensional fingerprint plots (see the Supporting Information). Only in the Mn-MOF, the interaction to the metal (O–M) has some contribution to these surfaces, even if minimal (2.4%). The H–H intercontacts show large surfaces in both structures, whereas the O···H/H···O contacts show the two characteristic wings of hydrogen bonds. N···H/H···N interactions are represented by two sharp spikes pointing toward the upper and lower left of the plots corresponding to the hydrogen bonds. The relative contributions of the different interactions to the Hirshfeld surfaces are summarized in Figure 5.

Figure 5

Figure 5. Hirshfeld surface: percentage of various intermolecular contacts contributing to the Hirshfeld surfaces for Mg- and Mn-MOFs.

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Powder X-ray diffraction shows that both MOFs are obtained as pure phases (see the Supporting Information).
Infrared spectroscopy supports the crystal structure determined by single-crystal X-ray diffraction. Indeed, the characteristic nalidixic acid bands at 1715 and 1620 cm–1 (C═O stretching ascribed to, respectively, carboxylic and carbonyl groups) are absent in the Mg-MOF spectrum, while new bands appear at 1640 and 1390 cm–1, characteristic of carboxylate groups (see the Supporting Information). The Mn-MOF shows similar results.
Concerning Mg-MOF, 13C solid-state NMR confirmed the presence of nalidixic acid (see the Supporting Information).
Concerning Mg-MOF, 13C solid-state NMR confirmed the presence of nalidixic acid (see the Supporting Information) and 1H NMR solution NMR data suggest that the Mg coordination to carbonyl groups was maintained in solution (see the Supporting Information).

Thermal Stability

The Mg-MOF is stable until ca. 100 °C. Above this temperature and up to 207 °C, two endothermic peaks are observed corresponding to a total mass loss of 14.9%, i.e., the release of the three water molecules (Figure 6a).

Figure 6

Figure 6. Differential scanning calorimetry (black line) and thermogravimetry (blue line) curves of Mg-MOF (a) and Mn-MOF (b).

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The Mn-MOF is stable up to 80 °C, followed by a 9.5% mass loss until 175 °C, associated with two endothermic peaks. These events correspond to the loss of two water molecules, with the third water molecule being released above 230 °C (Figure 6b).
These data show that both Mg- and Mn-MOFs are stable up to temperatures well above 37 °C, with the Mg material being more stable than the Mn one.

Stability under Ambient Conditions and at 77% Room Humidity

As witnessed by powder X-ray diffraction, both BioMOFs are stable for, at least, five months on the shelf under ambient conditions (20–25 °C, 35–40% room humidity) and at 77% room humidity (20–25 °C) (see the Supporting Information).

Solubility Tests

The solubility of Mg- and Mn-MOFs was determined by high-performance liquid chromatography at 25 °C in water, in a phosphate buffered saline solution (PBS) (pH 7.40) and in an HCl solution (pH 1.52). The MOFs solubility is higher than the solubility of nalidixic acid (3.76 × 10–4 M): 6.78 × 10–4 M for Mg-MOF and 6.15 × 10–4 M for Mn-MOF. In phosphate buffered saline solution, nalidixic acid is more soluble (1.52 × 10–3 M) than the BioMOFs (5.78 × 10–4 M for Mg-MOF, 4.68 × 10–4 M for Mn-MOF), while in acidic media all solubility values are similar (7.97 × 10–5 M for nalidixic acid, 7.81 × 10–5 M for Mg-MOF, and 8.71 × 10–5 M for Mn-MOF). The increased solubility of MOFs when compared with the free ligand might be explained on the basis of the carboxylate character of MOFs.

Cytotoxicity

BioMOF cytotoxicity was assessed using human colorectal adenocarcinoma CaCo-2 cells, a model common in this type of studies because in a differentiated state it resembles the human intestinal epithelium. As the cells were grown in an aqueous culture medium, the compounds tested must be water-soluble. Unfortunately, only Mg-MOF could be dissolved in the aqueous cell culture medium attaining the concentration required for these tests.
A stock solution of NALD-Mg MOF was prepared in ethanol and then diluted with the cell culture medium in order to attain ≤1% organic solvent in contact with the CaCo-2 cell monolayer. Concentrations up to 45 μM were tested. Cytotoxicity was determined by the MTT assay after 24 h exposure. (Figure 7). Mg-MOF does not affect significantly the cell viability, and thus, it is probably not cytotoxic to the human epithelium. However, other in vitro models should be tested to assess its impact on humans.

Figure 7

Figure 7. MTT cytotoxicity and cell viability study (where error bars represent the standard deviation).

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Antimicrobial Activity

Antimicrobial tests (Table 2) were carried out against Gram-positive (Staphylococcus aureus and Enterococcus faecalis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and yeasts strains (Candida albicans and Saccharomyces cerevisiae). Notable growth inhibitory activity is observed against the Gram-negative bacteria E. coli. Mg-MOF has shown significant bactericidal effect against the Gram-negative bacteria, whereas Mn-MOF induces a bacteriostatic effect. The antimicrobial activity of both BioMOFs is higher than the nalidixic acid activity. Lower, or similar, minimum inhibitory concentration (MIC) values are observed for Mg- and Mn-MOFs on yeasts, when compared to nalidixic acid. The latter exhibits an overall bactericidal effect, in contrast with the BioMOFs, showing a tendency for bacteriostatic behavior. In short, Mg- and Mn-MOFs have a greater inhibitory activity against Gram-positive and Gram-negative bacteria and yeasts than nalidixic acid.
Table 2. Minimum Inhibitory and Bactericidal Concentrations, MIC and MBC (or Minimum Fungicidal Concentration, MFC) Values, of the Compounds Obtained by the Microdilution Method against Gram-Negative and Gram-Positive Bacteria and Yeasts Strains in μg/mLa
 S. aureusE. faecalisP. aeruginosaE. coliC. albicansS. cerevisiae
compoundMICMBCMICMBCMICMBCMICMBCMICMBCMICMBC
NA1255001255001255003.9131.262.562.5125125
Mg-MOF31.350031.32501255000.981.9562.525031.3250
Mn-MOF31.325031.32502505000.987.8131.312531.3125
positive controlb7.82ntc1.95ntc<0.48ntc0.98ntc0.98ntc0.98ntc
a

Results represent a median of at least three independent experiments.

b

Vancomycin for S. aureus and E. faecalis. Norfloxacin for P. aeruginosa and E. coli. Nystatin for C. albicans and S. cerevisiae.

c

Not tested (nt).

Experimental Section

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Synthesis

All reagents were purchased from Sigma and used without further purification.

Mg-MOF

An equimolar (0.6 mmol) mixture of nalidixic acid and Mg(NO3)2·6H2O was milled with 50 μL of water and 100 μL of ammonium hydroxide to turn the media basic and facilitate the reaction, making use of a Retsch MM400 ball mill with two stainless steel balls (7 mm diameter), at 29.5 rpm for 5 min. Ethanol was used to wash the powder and eliminate the ammonium nitrate (secondary product). The resulting powder was then dissolved in a water/ethanol (1:1) solution with droplets of ammonium hydroxide, and colorless single crystals of Mg-MOF were grown by slow evaporation of the solvent after 3 days at room temperature.

Mn-MOF

An equimolar (0.5 mmol) mixture of nalidixic acid and MgCl2·4H2O was manually ground for 2 min with 50 μL of water and 100 μL of ammonium hydroxide using an agate mortar and pestle. Ethanol was used to wash the powder and eliminate the ammonium chloride (secondary product). The resulting powder was then dissolved in a water/ethanol (1:1) solution with droplets of ammonium hydroxide, and colorless single crystals of Mn-MOF were grown by slow evaporation of the solvent after 5 days at room temperature.

Single-Crystal X-ray Diffraction

Data were acquired on Bruker AXS-KAPPA APEX II and Bruker AXS-KAPPA D8 QUEST diffractometers at 293 K, with graphite-monochromated radiation (Mo K, = 0.71069 Å). Further details are given in the Supporting Information. Table 3 summarizes data collection and refinement details. Crystallographic data of Mg- and Mn-MOF were deposited at the Cambridge Crystallographic Data Centre (CCDC nos. 1885221 and 1885222).
Table 3. Crystallographic Data and Experimental Details for Mg- and Mn-MOFs
 Mg-MOFMn-MOF
chemical formulaC12H17N3O9MgC12H17N2O6MnCl
formula weight371.59375.67
temperature (K)293(2)293(2)
wavelength (Å)0.710 690.710 69
crystal form, colorblock, colorlessplate, colorless
crystal size (mm)0.20 × 0.12 × 0.100.20 × 0.10 × 0.04
crystal systemmonoclinicmonoclinic
space groupP21/cP21/c
a (Å)8.4071(7)7.7602(6)
b (Å)9.3706(9)9.4603(7)
c (Å)20.5857(18)21.1818(18)
α (deg)90.0090.00
β (deg)93.473(3)91.906(3)
γ (deg)90.0090.00
V (Å3)1618.8(2)1554.2(2)
Z44
d (mg cm–3)1.5251.605
μ (mm–1)0.1641.050
θ range (deg)1.982–29.4962.626–28.490
reflections collected/unique17 528/449921 829/3188
Rint0.06910.0880
GoF1.0181.120
final R indicesa,b [I > 2(I)]R1 = 0.0462, wR2 = 0.1106R1 = 0.0510, wR2 = 0.1298
a

R1 = ||F0| – |Fc||/|F0|.

b

wR2 = [[w(F02 – Fc2)2]/[w(F02)2]]1/2.

Powder X-ray Diffraction

Patterns were collected on a D8 Advance Bruker AXS θ-2θ diffractometer, with a copper radiation source (Cu Kα, λ = 1.5406 Å) and a secondary monochromator, operated at 40 kV and 30 mA. The program Mercury 3.10.3(65) was used to obtain the diffraction patterns calculated from single-crystal data. The purity of the bulk was always verified by comparing the calculated and observed powder X-ray diffraction patterns.

Solid-State NMR

1H–13C cross-polarization magic angle spinning NMR spectra were recorded at 100.6 MHz on a 9.4 T widebore (400 MHz, 1 H Larmor frequency) Bruker Avance III 400 spectrometer, on a 4 mm double-resonance MAS probe. Samples were spun at 14 kHz on ZrO2 rotors. Spectra were recorded using a ramp step (varying from 100% to 50% in amplitude using 100 points), 3.0 ms contact time, 1H 90° 2.5 μ s excitation pulse, 5 s recycle delay. 1H and 13C radio frequency field strengths for cross-polarization were set to 87 and 68 kHz, respectively. TPPM-15 decoupling was employed during the signal acquisition, using a 4.75 μ s pulse length for the basic TPPM pulse unit on the 1H channel (field strength = 100 kHz).

Solution NMR

1H NMR spectra were recorded at 37 °C on a Bruker Avance III 500, operating at 500 MHz, using a 5 mm BBO probe. Samples were dissolved in D2O and analyzed by 1H NMR with and without water resonance presaturation, performed with standard pulse programs.

Infrared Spectroscopy

Data for samples diluted in KBr (1:100 w/w) were acquired on a Nexus-Thermo Nicolet spectrometer (64 scans; resolution of 4 cm–1) from 4000 to 400 cm–1.

Elemental Analysis

Data were obtained at the elemental analysis service of Instituto Superior Técnico (IST) on a Fisons Instrument Mod EA-1108. Anal. Calcd for C12H17N3O9Mg: C, 38.79%; H, 4.61%; N, 11.31%. Found: C, 38.035%; H, 4.55%; N, 11.23%. Anal. Calcd for C12H17N2O6MnCl: C, 38.37%; H, 4.56%; N, 7.46%. Found: C, 37.94%; H, 4.53%; N, 7.58%.

Differential Scanning Calorimetry and Thermogravimetry

Combined measurements were carried out on a SETARAM TG-DTA 92 thermobalance under a nitrogen flow with a heating rate of 10 °C min–1. The sample masses were in the range from 5 to 10 mg.

Stability Tests

Shelf Stability

Samples were kept under ambient conditions (20–25 °C, 35–40% room humidity) over 5 months and analyzed weekly by powder X-ray diffraction to confirm the shelf stability.

Stability under 77% Room Humidity

Samples were kept inside a desiccator with a saturated solution of NaCl to maintain 77% room humidity (20–25 °C). Samples were analyzed on a weekly basis for five months to confirm their stability.

Solubility Tests

Slurry suspensions of nalidixic acid and Mg- and Mn-MOFs were left stirring for 24 h in water, in a phosphate buffered saline solution (PBS) (pH 7.40) and in a HCl solution (pH 1.52). The filtered solutions were used to calculate the solubility of the novel BioMOFs and nalidixic acid using HPLC.

High-Performance Liquid Chromatography (HPLC)

Data were acquired at room temperature using Dionex equipment with an Ultimate 3000 pump, a photodiode detector (DAD, Ultimate 3000), and a RP-18e reverse phase column (Luna C18(2) from Phenomenex, 250 mm × 4.6 mm, 5 μm) with a flow of 1 mL min–1. An isocratic elution was used, with acetonitrile and 1% aqueous formic acid solution (30%:70% v/v) as a mobile phase, with a flow of 1 mL min–1 (sample volume = 20 μL, run time = 30 min). Nalidixic acid was identified at 256.7 nm, with a 20.5 min retention time. Standard solutions of the drug were prepared in order to determine the calibration curve and the compound solubility. For solubility studies, the calibration curve method was used.

Cell Culture

Colorectal adenocarcinoma CaCo-2 cells (ATCC) were grown in RPMI- 1640 medium (R8758, Sigma), supplemented with 10% fetal bovine serum (FBS) and an antibiotic antimycotic solution at 37 °C in a humidified 5% CO2 atmosphere.

Cytotoxic Assay

CaCo-2 cells were seeded on 96-well plates and cultured until reaching confluence. Stock solutions of the compounds were diluted with the cell culture medium and added to the cells for 24 h (percentage of the organic solvent ≤ 1%). The medium was removed from the plate, and cells were washed with phosphate buffer saline solution (PBS). Then, fresh medium with the colorimetric reagent MTT (0.1 g/L) was added to the plate and left for 4 h. The medium was removed; the plate was washed with PBS, and DMSO was added to dissolve the purple formazam crystals. The plate was gently shaken and read in a plate reader at 570 nm. Each experimental condition was done in triplicate. Presented error bars are the standard deviation of the 3 replicates.

Antimicrobial Activity

The minimum inhibitory and bactericidal concentrations (MIC and MBC) were determined by the microdilution method.(66) Briefly, a volume of 100 μL was added to all of the wells containing the appropriate culture medium (Mueller-Hinton for bacteria and Sabouraud for yeasts), and 100 μL of the samples at a concentration of 1 mg/mL were added to the first well. Serial dilutions were made in a proportion of 1:2, and 10 μL of the bacterial (Gram-negative and -positive) or yeast suspension was added to each well. The plates were then incubated for 24 h at 37 °C. MBC determination followed MIC assignment, by swabbing a solution of each well within the range concentrations lower than its MIC, onto a Petri plate with the adequate solid culture medium. These microplates were then incubated using the conditions already stated. MBC corresponds to the lowest concentration with no visible bacterial or fungal growth.

Conclusions

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Mg- and Mn-MOFs were mechanochemically obtained, as this was the most efficient synthetic technique leading to the isolation of the pure compounds. Compared with other approaches, previously explored, concerning the improvement of the antimicrobial activity of nalidixic acid, our procedure is much simpler and faster. BioMOFs were structurally characterized, and their properties were assessed, namely, the shelf stability, solubility, bioavailability, cytotoxicity, and bactericidal activity. The results witness a clear potential of these materials for pharmaceutical applications. Importantly, both compounds have proven to increase the nalidixic acid antimicrobial activity in the assays using S. aureus, E. faecalis, E. coli, C. albicans, and S. cerevisiae, with the effect against E. coli being the most relevant. The emergence of Gram-negative E. coli multidrug resistance is of global concern, and BioMOFs may provide a viable alternative to the present antibiotics, due to their increased bactericidal activity.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsabm.9b00046.

  • Single-crystal X-ray diffraction experimental details, bulk purity, infrared spectroscopy, solid-state NMR, and shelf stability at 77% room humidity (PDF)

Author Contributions

The authors contributed equally.

The authors declare no competing financial interest.

Terms & Conditions

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Acknowledgments

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The authors acknowledge Fundação para a Ciência e a Tecnologia (FCT, Portugal) (PEst-OE/QUI/UI0100/2013) and FEDER to the project PTDC/QUI-OUT/30988/2017 for funding. We also wish to thank the European Union, QREN, FEDER through Programa Operacional Factores de Competitividade (COMPETE), and CICECO–Aveiro Institute of Materials, POCI-01-0145-FEDER-007679 (FCT ref no. UID/CTM/50011/2013), financed by national funds through the FCT/MEC and when appropriate cofinanced by FEDER under the PT2020 Partnership Agreement. The authors further acknowledge Ms. C. Iolanda Santos for the use of the HPLC.

References

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  15. 15
    Lee, S. S.; Jung, O. S.; Lee, C. O.; Choi, S. U.; Jun, M. J.; Sohn, Y. S. Cationic diamineplatinum(II) complexes of nalidixic acid. Inorg. Chim. Acta 1995, 239 (1–2), 133– 138,  DOI: 10.1016/0020-1693(95)04734-4
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    15
    Cationic diamineplatinum(II) complexes of nalidixic acid
    Lee, Sung Sil; Jung, Ok-Sang; Lee, Chong Ock; Choi, Sang Un; Jun, Moo-Jin; Sohn, Youn Soo
    Inorganica Chimica Acta (1995), 239 (1-2), 133-8CODEN: ICHAA3; ISSN:0020-1693. (Elsevier)
    The reaction of cis-A2PtCl2 with Na nalidixate (nal) leads to the cationic Pt complexes cis-[A2Pt(nal)]+X-; 1 A2 = ethylenediamine (en), X = Cl; 2 A2 = (1R,2R)-diaminocyclohexane (dach), X = Cl; 3 A2 = 1,1-bis(aminomethyl)cyclohexane (bamch), X = Cl; 4 A = cyclopropylamine (cpa), X = Cl; 5 A = NH3, X = nal. The complexes were characterized by elemental anal., cond., spectroscopic methods and x-ray anal. The crystal structure of 5·5H2O (space group P‾1; a 10.558(3), b 11.351(5), c 14.803(10) Å, α 110.16(5), β 99.73(3), γ 110.77(2)°, Z = 2, R = 0.053) discloses that one nalidixate ion is chelated to the Pt atom via its carboxylate and ring carbonyl groups whereas the other nalidixate is a counter anion. These Pt complexes are stable in H2O, but are changed to Me2SO adducts in DMSO soln. Among the title complexes, 2 and 5 showed good antitumor activity for further study.
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  16. 16
    Kljun, J.; Bytzek, A. K.; Kandioller, W.; Bartel, C.; Jakupec, M. A.; Hartinger, C. G.; Keppler, B. K.; Turel, I. Physicochemical Studies and Anticancer Potency of Ruthenium eta(6)-p-Cymene Complexes Containing Antibacterial Quinolones. Organometallics 2011, 30 (9), 2506– 2512,  DOI: 10.1021/om101180c
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    16
    Physicochemical Studies and Anticancer Potency of Ruthenium η6-p-Cymene Complexes Containing Antibacterial Quinolones
    Kljun, Jakob; Bytzek, Anna K.; Kandioller, Wolfgang; Bartel, Caroline; Jakupec, Michael A.; Hartinger, Christian G.; Keppler, Bernhard K.; Turel, Iztok
    Organometallics (2011), 30 (9), 2506-2512CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    With the aim of exploring the anticancer properties of organometallic compds. with bioactive ligands, Ru(arene) compds. of the antibacterial quinolones nalidixic acid (2) and cinoxacin (3) were synthesized, and their physicochem. properties were compared to those of chlorido(η6-p-cymene)(ofloxacinato-κ2O,O)ruthenium(II) (1). All compds. undergo a rapid ligand exchange reaction from chlorido to aqua species. 2 And 3 are significantly more stable than 1 and undergo minor conversion to an unreactive [(cym)Ru(μ-OH)3Ru(cym)]+ species (cym = η6-p-cymene). In the presence of human serum albumin 1-3 form adducts with this transport protein within 20 min of incubation. With GMP (5'-GMP; as a simple model for reactions with DNA) very rapid reactions yielding adducts via its N7 atom were obsd., illustrating that DNA is a possible target for this compd. class. A moderate capacity of inhibiting tumor cell proliferation in vitro was obsd. for 1 in CH1 ovarian cancer cells, whereas 2 and 3 turned out to be inactive.
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    Mallick, S.; Sahu A Fau - Pal, K.; Pal, K. Dissolution behaviour of nalidixic acid solid dispersions using water soluble dispersion carriers. Acta Polym. Pharm. 2004, 61, 21– 30
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    Drlica, K.; Hiasa, H.; Kerns, R.; Malik, M.; Mustaev, A.; Zhao, X. L. Quinolones: Action and Resistance Updated. Curr. Top. Med. Chem. 2009, 9 (11), 981– 998,  DOI: 10.2174/156802609789630947
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    Quinolones: action and resistance updated
    Drlica, Karl; Hiasa, Hiroshi; Kerns, Robert; Malik, Muhammad; Mustaev, Arkady; Zhao, Xilin
    Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2009), 9 (11), 981-998CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
    A review. The quinolones trap DNA gyrase and DNA topoisomerase IV on DNA as complexes in which the DNA is broken but constrained by protein. Early studies suggested that drug binding occurs largely along helix-4 of the GyrA (gyrase) and ParC (topoisomerase IV) proteins. However, recent X-ray crystallog. shows drug intercalating between the -1 and +1 nucleotides of cut DNA, with only one end of the drug extending to helix-4. These two models may reflect distinct structural steps in complex formation. A consequence of drug-enzyme-DNA complex formation is reversible inhibition of DNA replication; cell death arises from subsequent events in which bacterial chromosomes are fragmented through two poorly understood pathways. In one pathway, chromosome fragmentation stimulates excessive accumulation of highly toxic reactive oxygen species that are responsible for cell death. Quinolone resistance arises stepwise through selective amplification of mutants when drug concns. are above the MIC and below the MPC, as obsd. with static agar plate assays, dynamic in vitro systems, and exptl. infection of rabbits. The gap between MIC and MPC can be narrowed by compd. design that should restrict the emergence of resistance. Resistance is likely to become increasingly important, since three types of plasmid-borne resistance have been reported.
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    Grover, G.; Kini, S. G. Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents. Eur. J. Med. Chem. 2006, 41 (2), 256– 262,  DOI: 10.1016/j.ejmech.2005.09.002
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    19
    Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents
    Grover, Gaurav; Kini, Suvarna G.
    European Journal of Medicinal Chemistry (2006), 41 (2), 256-262CODEN: EJMCA5; ISSN:0223-5234. (Elsevier B.V.)
    In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivs. having quinazolones moiety were synthesized to achieve enhanced biol. activity and wide spectrum of activity. Nalidixic acid was first converted into its acid chloride using thionyl chloride as an acylating agent at lab. temp. Later it was converted to Me ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a Me ester of nalidixic acid. The ester on addn. of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form benzoxazine/acetanthranil. 5-Iodo deriv. of anthranilic acid was prepd. and also utilized to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitrobenzoxazine/acetanthranil was obtained by nitration of acetanthranil using conc. H2SO4 and fuming HNO3. Equimolar proportions of the appropriate synthesized acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesize quinazolones. Elemental anal. and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compds. obtained have been established on the basis of spectral (IR, 1H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar diln. and Punch well diffusion method) of synthesized quinazolone derivs. bearing nalidixic acid moiety on randomly collected microbial strains. Some derivs. showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhea in children as well as adults. One deriv. was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesized derivs. against Coagulase neg. Staphylococcus. One deriv. was found to show very high activity against the Candida colonies and another deriv. was also found to exhibit inhibitory activity against Candida albicans; a normal flora of the human body which plays an important role in causing opportunistic infections in immunocompromised hosts. Proteus vulgaris, a gram-neg. bacteria included in our study, was found to be inhibited.
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    Pandey, A.; Aggarwal, N.; Adholeya, A.; Kochar, M. Resurrection of Nalidixic Acid: Evaluation of Water-Based Nanoformulations as Potential Nanomedicine. Nanoscale Res. Lett. 2018, 13, 298,  DOI: 10.1186/s11671-018-2718-8
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    20
    Resurrection of Nalidixic Acid: Evaluation of Water-Based Nanoformulations as Potential Nanomedicine
    Pandey Alka; Adholeya Alok; Kochar Mandira; Aggarwal Nisha
    Nanoscale research letters (2018), 13 (1), 298 ISSN:1931-7573.
    Resistance to quinolone antibiotics has been a serious problem ever since nalidixic acid was introduced into clinical medicine. Over time, resistance of pathogenic microbes to nalidixic acid led to the design of novel variants to revive its potential application. In the present work, a series of eight nanoformulations of nalidixic acid-based diacyl and sulfonyl acyl hydrazine derivatives were prepared. All nanoformulations were found to be stable at different storage temperatures. Antibacterial and anticandida activity of the eight nanoformulations presented encouraging results when compared with their non-nano parent counterparts. The nanoformulations of chloro, furanyl, and sulfonyl acyl substituted derivatives of nalidixic acid displayed most promising results (MIC ranging from 50 to 100 μg mL(-1)) against the tested bacteria and yeast. Among the screened bacteria, Acinetobacter baumannii displayed maximum sensitivity to the above nanoformulations. Biosafety study on the mammalian model-wax moth, Galleria mellonella-showed that all eight prepared nanoformulations were absolutely nontoxic to the larvae and subsequent pupae and hence may likely have no or low toxicity against mammalian systems.
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    Zhu, X.; Radovic-Moreno, A. F.; Wu, J.; Langer, R.; Shi, J. J. Nanomedicine in the management of microbial infection - Overview and perspectives. Nano Today 2014, 9 (4), 478– 498,  DOI: 10.1016/j.nantod.2014.06.003
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    Nanomedicine in the management of microbial infection - Overview and perspectives
    Zhu, Xi; Radovic-Moreno, Aleksandar F.; Wu, Jun; Langer, Robert; Shi, Jinjun
    Nano Today (2014), 9 (4), 478-498CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)
    A review. For more than 2 billion years, microbes have reigned on our planet, evolving or outlasting many obstacles they have encountered. In the 20th century, this trend took a dramatic turn with the introduction of antibiotics and vaccines. Nevertheless, since then, microbes have progressively eroded the effectiveness of previously successful antibiotics by developing resistance, and many infections have eluded conventional vaccine design approaches. Moreover, the emergence of resistant and more virulent strains of bacteria has outpaced the development of new antibiotics over the last few decades. These trends have had major economic and health impacts at all levels of the socioeconomic spectrum - we need breakthrough innovations that could effectively manage microbial infections and deliver solns. that stand the test of time. The application of nanotechnologies to medicine, or nanomedicine, which has already demonstrated its tremendous impact on the pharmaceutical and biotechnol. industries, is rapidly becoming a major driving force behind ongoing changes in the antimicrobial field. Here we provide an overview on the current progress of nanomedicine in the management of microbial infection, including diagnosis, antimicrobial therapy, drug delivery, medical devices, and vaccines, as well as perspectives on the opportunities and challenges in antimicrobial nanomedicine.
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    Ahmed, M.; Kelley, S. O. Enhancing the Potency of Nalidixic Acid toward a Bacterial DNA Gyrase with Conjugated Peptides. ACS Chem. Biol. 2017, 12 (10), 2563– 2569,  DOI: 10.1021/acschembio.7b00540
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    22
    Enhancing the Potency of Nalidixic Acid toward a Bacterial DNA Gyrase with Conjugated Peptides
    Ahmed, Marya; Kelley, Shana O.
    ACS Chemical Biology (2017), 12 (10), 2563-2569CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    Quinolones and fluoroquinolones are widely used antibacterial agents. Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and mol. charge prepd. by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and mol. charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide contg. cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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    Behrens, N. B.; Diaz, G. M.; Goodgame, D. M. L. etal-complexes of the antibiotic nalidixic acid. Inorg. Chim. Acta 1986, 125 (1), 21– 26,  DOI: 10.1016/S0020-1693(00)85478-X
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    Mendozadiaz, G.; Martinezaguilera, L. M. R.; Perezalonso, R.; Solans, X.; Moreno-Esparza, R. Synthesis and characterization of mixed-ligand complexes of copper with nalidixic acid and (N-N) donors - crystal-structure of Cu(PHEN)(NAL)-(H2O)NO3.3H2O. Inorg. Chim. Acta 1987, 138 (1), 41– 47,  DOI: 10.1016/S0020-1693(00)81179-2
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    Arjmand, F.; Yousuf, I.; Afzal, M.; Toupet, L. Design and synthesis of new Zn(II) nalidixic acid-DACH based Topo-II inhibiting molecular entity: Chemotherapeutic potential validated by its in vitro binding profile, pBR322 cleavage activity and molecular docking studies with DNA and RNA molecular targets. Inorg. Chim. Acta 2014, 421, 26– 37,  DOI: 10.1016/j.ica.2014.05.015
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    Design and synthesis of new Zn(II) nalidixic acid-DACH based Topo-II inhibiting molecular entity: Chemotherapeutic potential validated by its in vitro binding profile, pBR322 cleavage activity and molecular docking studies with DNA and RNA molecular targets
    Arjmand, Farukh; Yousuf, Imtiyaz; Afzal, Mohd.; Toupet, Loic
    Inorganica Chimica Acta (2014), 421 (), 26-37CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
    Nalidixic acid-DACH based Zn(II) mol. entity I was synthesized and thoroughly characterized by spectroscopic techniques (FT-IR, 1H and 13C NMR, ESI-MS) and single crystal x-ray crystallog. as a potential chemotherapeutic drug candidate. The comparative in vitro binding studies of complex I with targets like CT-DNA and yeast tRNA were carried out by employing UV-Vis, emission spectroscopy, CD and viscosity which revealed higher binding affinity of I towards yeast tRNA as compared to CT-DNA. Complex cleaves pBR322 plasmid via hydrolytic pathway (validated by T4 religation assay); in addn., I also exhibited significant inhibitory effects on the catalytic activity of Topo-II at a concn. of 30 μM. Further, validation of the interaction studies was accomplished by carrying out mol. docking studies with DNA, RNA and Topo-II targets. This work also advances the knowledge for the development and design of small RNA targeted therapeutic mols. which were relatively under exploited drug targets.
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    Arjmand, F.; Yousuf, I.; ben Hadda, T.; Toupet, L. Synthesis, crystal structure and antiproliferative activity of Cu(II) nalidixic acid-DACH conjugate: Comparative in vitro DNA/RNA binding profile, cleavage activity and molecular docking studies. Eur. J. Med. Chem. 2014, 81, 76– 88,  DOI: 10.1016/j.ejmech.2014.04.080
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    Synthesis, crystal structure and antiproliferative activity of Cu(II) nalidixic acid-DACH conjugate: Comparative in vitro DNA/RNA binding profile, cleavage activity and molecular docking studies
    Arjmand, Farukh; Yousuf, Imtiyaz; Hadda, Taibi ben; Toupet, Loic
    European Journal of Medicinal Chemistry (2014), 81 (), 76-88CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    Nalidixic acid-DACH conjugate Cu(II) mol. entity (I) was synthesized, thoroughly characterized by spectroscopic techniques (FT-IR, EPR and ESI-MS) and single crystal x-ray diffraction technique as a potential chemotherapeutic drug candidate for cancer oncol. Complex I was a potent drug-like mol. entity in confirmation with Lipinski rules. 1R,2R-diaminocyclohexane (DACH) ligand scaffold (which reduces the drawbacks of cisplatin analogs) and nalidixic acid pharmacophore make it a suitable drug entity targeting nucleic acids. To evaluate the chemotherapeutic potential of complex I comparative in vitro DNA/RNA interaction studies have been investigated by employing various biophys. techniques (UV-vis, fluorescence, CD, viscosity, cyclic voltammetry and FT-IR), cleavage activity and Topo-II inhibition assay. Further, mechanistic investigation revealed the efficiency of complex I to cleave pBR322 DNA strands by an oxidative pathway involving the generation of ROS and preferential selectivity towards the A-T region of DNA major groove. Antiproliferative activity in conjugation with flow cytometry anal. of complex I against human osteoblastoma cell line (U2OS) suggested a cell cycle arrest at S phase. This work further advances the authors knowledge for the development and design of small RNA targeted therapeutic mols. which are under exploited drug targets.
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    Yousuf, I.; Usman, M.; Ahmad, M.; Tabassum, S.; Arjmand, F. Single X-ray crystal structure, DFT studies and topoisomerase I inhibition activity of a tailored ionic Ag(I) nalidixic acid-piperazinium drug entity specific for pancreatic cancer cells. New J. Chem. 2018, 42 (1), 506– 519,  DOI: 10.1039/C7NJ03602G
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    27
    Single X-ray crystal structure, DFT studies and topoisomerase I inhibition activity of a tailored ionic Ag(I) nalidixic acid-piperazinium drug entity specific for pancreatic cancer cells
    Yousuf, Imtiyaz; Usman, Mohammad; Ahmad, Musheer; Tabassum, Sartaj; Arjmand, Farukh
    New Journal of Chemistry (2018), 42 (1), 506-519CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
    Novel ionic Ag(I)-piperazinium nalidixic acid conjugate 1 was synthesized as a potential antitumor agent and was thoroughly characterized by elemental anal., FT-IR, 1H and 13C NMR and single X-ray crystal diffraction studies. Complex 1 crystd. in the triclinic space group P1 and comprises a dipiperazinium-Ag(I) cationic unit, two nalidixate (naI-) anionic moieties and a nitrate ion. The Ag(I) ion adopted a linear configuration upon coordination with two nitrogen atoms of piperazinium cations (pipzH+) arranged in a trans fashion. The d. functional theory (DFT) studies of 1 revealed the HOMO and LUMO to be localized on the metal center viz., the dx2-y2 orbital and partially localized on the C27, C28, C29, C30, C31, C32, N7 and N6 atoms of the piperazinium moiety. Non covalent interaction (NCI) calcns. were carried out to identify the weak non-covalent interactions from the topol. anal. and reduced gradient of the electron d. of complex 1. Our results revealed significant inter- and intramol. non-covalent interactions between the naI- and [Ag(pip)2]2+ units. Furthermore, an anal. of Hirshfeld surfaces and fingerprint plots were carried out to ascertain a comparison between intermol. interactions which provide interesting supramol. architectures involving combinations of N-H···O, O-H···O and C-H···O linkages into a two-dimensional framework. In vitro binding studies of 1 with ct-DNA and tRNA revealed higher binding propensity for tRNA which was evidenced from its higher intrinsic binding const., Kb and binding const., K values and the mode of binding was found to be groove binding in nature. The catalytic activity of topoisomerase I enzyme in the presence of complex 1 was ascertained by gel electrophoretic assay which demonstrated significant inhibitory effects at a low concn. of 25 μM. The cytotoxicity activity of 1 was detd. by SRB assay on MIA-PA-CA-2, HepG2, HeLa and MCF7 human cancer cell lines; these results exhibited specific and selective antitumor activity for the MIA-PA-CA-2 cancer cell line with a GI50 value <10.
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    Andre, V.; Galego, F.; Martins, M. Mechanochemical Assembly of Nalidixic Acid Bioinspired Metal-Organic Compounds and Complexes toward Improved Solubility. Cryst. Growth Des. 2018, 18 (4), 2067– 2081,  DOI: 10.1021/acs.cgd.7b01523
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    Mechanochemical assembly of nalidixic acid Bioinspired Metal-organic compounds and complexes toward improved solubility
    Andre, Vania; Galego, Filipa; Martins, Marta
    Crystal Growth & Design (2018), 18 (4), 2067-2081CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Nalidixic acid is an antibiotic from the quinolones family whose bioavailability is limited due to its low soly. The development of complexes and bioinspired metal-org. frameworks has been explored as a way to achieve controlled drug delivery and release, and we demonstrate that they can also be used to tune drugs' physicochem. properties, such as soly. Herein we disclose a series of complexes and frameworks of nalidixic acid and Zn. One of these frameworks duplicates the soly. of nalidixic acid, and it is stable on the shelf and to 77% room humidity. The incorporation of a second ligand into the frameworks is also presented, showing the possibility to develop extended networks with further potential applications.
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    Rios, F. J.; Montezano, A. C.; Touyz, R. M.; Collins, J. F. Magnesium, Vascular Function, and Hypertension. Molecular, genetic, and nutritional aspects of major and trace minerals 2017, 353– 364,  DOI: 10.1016/B978-0-12-802168-2.00029-4
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    Schmitz, C.; Perraud, A.-L.; Collins, J. F. Magnesium and the Immune Response. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 319– 331,  DOI: 10.1016/B978-0-12-802168-2.00026-9
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    Biological role of magnesium
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    A review of the biol. role of Mg based chiefly upon Russian scientific literature.
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    Nielsen, F. H.; Collins, J. F. Magnesium: Basic Nutritional Aspects. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 307– 317,  DOI: 10.1016/B978-0-12-802168-2.00025-7
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    Komiya, Y.; Runnels, L. W.; Collins, J. F. Magnesium and Embryonic Development. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 343– 351,  DOI: 10.1016/B978-0-12-802168-2.00028-2
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    He, K.; Tsinovoi, C. L.; Collins, J. F. Magnesium Intake and Chronic Disease in Humans. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 333,  DOI: 10.1016/B978-0-12-802168-2.00027-0
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    Blower, T. R.; Williamson, B. H.; Kerns, R. J.; Berger, J. M. Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. U. S. A. 2016, 113 (7), 1706– 1713,  DOI: 10.1073/pnas.1525047113
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    Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis
    Blower, Tim R.; Williamson, Benjamin H.; Kerns, Robert J.; Berger, James M.
    Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (7), 1706-1713CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Mycobacterium tuberculosis (Mtb) infects one-third of the world's population and in 2013 accounted for 1.5 million deaths. Fluoroquinolone antibacterials, which target DNA gyrase, are crit. agents used to halt the progression from multidrug-resistant tuberculosis to extensively resistant disease; however, fluoroquinolone resistance is emerging and new ways to bypass resistance are required. To better explain known differences in fluoroquinolone action, the crystal structures of the WT Mtb DNA gyrase cleavage core and a fluoroquinolone-sensitized mutant were detd. in complex with DNA and five fluoroquinolones. The structures, ranging from 2.4- to 2.6-Å resoln., show that the intrinsically low susceptibility of Mtb to fluoroquinolones correlates with a redn. in contacts to the water shell of an assocd. magnesium ion, which bridges fluoroquinolone-gyrase interactions. Surprisingly, the structural data revealed few differences in fluoroquinolone-enzyme contacts from drugs that have very different activities against Mtb. By contrast, a stability assay using purified components showed a clear relationship between ternary complex reversibility and inhibitory activities reported with cultured cells. Collectively, our data indicate that the stability of fluoroquinolone/DNA interactions is a major determinant of fluoroquinolone activity and that moieties that have been appended to the C7 position of different quinolone scaffolds do not take advantage of specific contacts that might be made with the enzyme. These concepts point to new approaches for developing quinolone-class compds. that have increased potency against Mtb and the ability to overcome resistance.
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    Wohlkonig, A.; Chan, P. F.; Fosberry, A. P.; Homes, P.; Huang, J.; Kranz, M.; Leydon, V. R.; Miles, T. J.; Pearson, N. D.; Perera, R. L.; Shillings, A. J.; Gwynn, M. N.; Bax, B. D. Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance. Nat. Struct. Mol. Biol. 2010, 17, 1152,  DOI: 10.1038/nsmb.1892
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    Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance
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    Nature Structural & Molecular Biology (2010), 17 (9), 1152-1153CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
    Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion. This provides a mol. basis for the quinolone inhibition mechanism, resistance mutations and invariant quinolone antibacterial structural features.
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    Peres, T. V.; Aschner, M.; Collins, J. F. Nutritional, Genetic, and Molecular Aspects of Manganese Intoxication. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 367– 376,  DOI: 10.1016/B978-0-12-802168-2.00030-0
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    Strukil, V.; Igrc, M. D.; Eckert-Maksic, M.; Friscic, T. Click Mechanochemistry: Quantitative Synthesis of ″Ready to Use″ Chiral Organocatalysts by Efficient Two-Fold Thiourea Coupling to Vicinal Diamines. Chem. - Eur. J. 2012, 18 (27), 8464– 8473,  DOI: 10.1002/chem.201200632
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    Click Mechanochemistry: Quantitative Synthesis of "Ready to Use" Chiral Organocatalysts by Efficient Two-Fold Thiourea Coupling to Vicinal Diamines
    Strukil, Vjekoslav; Igrc, Marina D.; Eckert-Maksic, Mirjana; Friscic, Tomislav
    Chemistry - A European Journal (2012), 18 (27), 8464-8473, S8464/1-S8464/42CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Mechanochem. methods of neat grinding and liq.-assisted grinding have been applied to the synthesis of mono- and bis(thiourea)s by using the click coupling of arom. and aliph. diamines with arom. isothiocyanates. The ability to modify the reaction conditions allowed the optimization of each reaction, leading to the quant. formation of chiral bis(thiourea)s with known uses as organocatalysts or anion sensors. Quant. reaction yields, combined with the fact that mechanochem. reaction conditions avoid the use of bulk solvents, enabled soln.-based purifn. methods (such as chromatog. or recrystn.) to be completely avoided. Importantly, by using selected model reactions, we also show that the described mechanochem. reaction procedures can be readily scaled up to at least the one-gram scale. In that way, mechanochem. synthesis provides a facile method to fully transform valuable enantiomerically pure reagents into useful products that can immediately be applied in their designed purpose. This was demonstrated by using some of the mechanochem. prepd. reagents as organocatalysts in a model Morita-Baylis-Hillman reaction and as cyanide ion sensors in org. solvents. The use of electronically and sterically hindered ortho-phenylenediamine revealed that mechanochem. reaction conditions can be readily optimized to form either the 1:1 or the 1:2 click-coupling product, demonstrating that reaction stoichiometry can be more efficiently controlled under these conditions than in soln.-based syntheses. In this way, it was shown that excellent stoichiometric control by mechanochem., previously established for mechanochem. syntheses of cocrystals and coordination polymers, can also be achieved in the context of covalent-bond formation.
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    Nichols, P. J.; Raston, C. L.; Steed, J. W. Engineering of porous pi-stacked solids using mechanochemistry. Chem. Commun. 2001, (12), 1062– 1063,  DOI: 10.1039/b103411c
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    Engineering of porous π-stacked solids using mechanochemistry
    Nichols, Peter J.; Raston, Colin L.; Steed, Jonathan W.
    Chemical Communications (Cambridge, United Kingdom) (2001), (12), 1062-1063CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Charge-assisted π-stacking interactions gave large porous arrays formed from the inclusion of metal tris(phenanthroline) cations into p-sulfonatocalix[4]arene anions. Thus, aq. [Ni(phen)3](NO3)2 was treated with Na5L (H5L = p-sulfonatocalix[4]arene) to give [Ni(phen)3]HL.nH2O (I) and [Na(H2O4)(phen)][Ni(phen)3]4(HL)L.nH2O (II). I is triclinic, space group P‾1, Z = 2, R1 = 0.1322, wR2 =0.4148. II is monoclinic, space group C2/c, Z = 8, R1 = 0.0739, wR2 = 0.2236.
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    Martins, I.; Martins, M.; Fernandes, A.; Andre, V.; Duarte, M. T. An insight into dapsone co-crystals: sulfones as participants in supramolecular interactions. CrystEngComm 2013, 15 (40), 8173– 8179,  DOI: 10.1039/c3ce41323c
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    An insight into dapsone co-crystals: sulfones as participants in supramolecular interactions
    Martins, Ines; Martins, Marta; Fernandes, Auguste; Andre, Vania; Duarte, M. Teresa
    CrystEngComm (2013), 15 (40), 8173-8179CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
    The authors disclose a new pathway for the design of dapsone co-crystals exploring the formation of N-H···O/N interactions using amide and pyridinic derivs. as potential co-formers. Two new co-crystals of dapsone, a sulfonamide antibiotic, with ε-caprolactam and 4,4'-bipyridine were synthesized preferentially by traditional soln. techniques, but mechanochem. also was addressed. The full structural characterization of these forms is discussed and shows that: (a) in the co-crystal with ε-caprolactam the typical NNH2···OSO2 interactions of dapsone mols. and the cages formed between them are disrupted by a new NNH2···OCONH interaction, in which ε-caprolactam mols. further form amide···amide R22(8) synthons and (b) in the co-crystal with 4,4'-bipyridine, the NNH2···OSO2 interactions between dapsone mols. are maintained and addnl. NNH2···Npyridine interactions are responsible for the formation of 4,4'-bipyridine channels between dapsone cages. Also, the thermal stability of these co-crystals is also discussed, showing that the co-formers leave the structure and hence the reported melting corresponds to the melting of pure dapsone.
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    Braga, D.; Maini, L.; Grepioni, F. Mechanochemical preparation of co-crystals. Chem. Soc. Rev. 2013, 42 (18), 7638– 7648,  DOI: 10.1039/c3cs60014a
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    Mechanochemical preparation of co-crystals
    Braga, Dario; Maini, Lucia; Grepioni, Fabrizia
    Chemical Society Reviews (2013), 42 (18), 7638-7648CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. The prepn. of co-crystals via mechanochem. combines the quest for clean and green processes with the investigation of multicomponent new materials, among the currently most fashionable systems in the crystal engineering field: the physico-chem. properties of the components add, merge or transform when co-crystals are formed, giving rise to potentially improved performance in "old" solid-state chem. fields, as in the pharmaceutical industry field, where they represent a way to obtain new formulations and to improve the properties (soly., thermal stability, compressibility, etc.) of both new and existing drugs.
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    André, V.; Quaresma, S. Bio-inspired metalorganic frameworks in the pharmaceutical world: a brief review. Metal-Organic Frameworks 2016, 135– 156,  DOI: 10.5772/64027
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    Bio-inspired metal-organic frameworks in the pharmaceutical world: a brief review
    Andre, Vania; Quaresma, Silvia
    Metal-Organic Frameworks (2016), (), 135-156CODEN: 69VUTH ISSN:. (InTech)
    One of the great challenges in the pharmaceutical industry is the search for more efficient and cost-effective ways to store and deliver existing drugs. Bio-inspired metalorg. frameworks (BioMOFs) are groundbreaking materials that have recently been explored for drug storage, delivery and controlled release as well as for applications in imaging and sensing for therapeutic and diagnostic. This review presents a brief overview on these materials, and by alluding to a few reported examples, it intends to clearly show the extremely important role that BioMOFs have been playing in the pharmaceutical field.
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    Andini, S.; Bolognese, A.; Formisano, D.; Manfra, M.; Montagnaro, F.; Santoro, L. Mechanochemistry of ibuprofen pharmaceutical. Chemosphere 2012, 88 (5), 548– 553,  DOI: 10.1016/j.chemosphere.2012.03.025
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    Mechanochemistry of ibuprofen pharmaceutical
    Andini, Salvatore; Bolognese, Adele; Formisano, Domenico; Manfra, Michele; Montagnaro, Fabio; Santoro, Luciano
    Chemosphere (2012), 88 (5), 548-553CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)
    In this paper mechanochem. has been studied in view of possible application to detoxification of expired pharmaceuticals. The expts. have been carried out with a com. medication contg. ibuprofen ((RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid) which has been submitted to prolonged milling up to 40 h. When Al(OH)3 is used as co-reagent, the first degrdn. step induced by the mechanochem. treatment is an acid-base reaction with the ibuprofen carboxylic acid group. The subsequent degrdn. follows a complex pathway leading to 1-(4-isobutylphenyl)ethanone, 1-isobutyl-4-vinylbenzene and 2-(4-(3-methylbutan-2-yl)phenyl)propan-1-ol after 10 h milling and, in addn., 1-(4-acetylphenyl)-2-methylpropan-1-one, 1-(4-(1-hydroxy-2-methylpropyl)phenyl)ethanone and 1-(4-(2-hydroxy-2-methylpropyl)phenyl)ethanone after 40 h milling. The degrdn. reaction path and products have been identified by means of FT-IR spectroscopy, thin layer chromatog., NMR spectroscopy, mass spectroscopy and elemental anal. The obsd. ibuprofen decarboxylation makes the drug simultaneously lose both its pharmaceutical activity and toxicity.
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    Chow, E. H. H.; Strobridge, F. C.; Friscic, T. Mechanochemistry of magnesium oxide revisited: facile derivatisation of pharmaceuticals using coordination and supramolecular chemistry. Chem. Commun. 2010, 46 (34), 6368– 6370,  DOI: 10.1039/c0cc01337d
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    Mechanochemistry of magnesium oxide revisited: facile derivatisation of pharmaceuticals using coordination and supramolecular chemistry
    Chow, Ernest H. H.; Strobridge, Fiona C.; Friscic, Tomislav
    Chemical Communications (Cambridge, United Kingdom) (2010), 46 (34), 6368-6370CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Liq.-assisted grinding allows the rapid, waste-free and one-pot synthesis of a variety of magnesium drug derivs. directly from the excipient MgO; such reactivity is relevant for the behavior of ibuprofen formulations involving MgO and can be used for oxide-based mechanosynthesis of metal-org. salts, discrete complexes and carboxylate clusters involving magnesium and pharmaceutically active ingredients.
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    Andre, V.; Quaresma, S.; Silva, J. L. F.; Duarte, M. T. Exploring mechanochemistry to turn organic bio-relevant molecules into metal-organic frameworks: a short review. Beilstein J. Org. Chem. 2017, 13, 2416– 2427,  DOI: 10.3762/bjoc.13.239
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    Exploring mechanochemistry to turn organic bio-relevant molecules into metal-organic frameworks: a short review
    Andre, Vania; Quaresma, Silvia; Ferreira da Silva, Joao Luis; Duarte, M. Teresa
    Beilstein Journal of Organic Chemistry (2017), 13 (), 2416-2427CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
    Mechanochem. is a powerful and environmentally friendly synthetic technique successfully employed in different fields of synthetic chem. Application spans from org. to inorg. chem. including the synthesis of coordination compds. Metal-org. frameworks (MOFs) are a class of compds. with numerous applications, from which we highlight herein their application in the pharmaceutical field (BioMOFs), whose importance has been growing and is now assuming a relevant and promising domain. The need to find cleaner, greener and more energy and material-efficient synthetic procedures led to the use of mechanochem. into the synthesis of BioMOFs.
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    Craig, Stephen L.
    Nature (London, United Kingdom) (2012), 487 (7406), 176-177CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    A review. The effect of force on a chem. reaction was visited in three different mol. environments. The results reveal a unifying framework that enables predictions of force-induced reactivity.
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    James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Friscic, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse, W. C.; Steed, J. W.; Waddell, D. C. Mechanochemistry: opportunities for new and cleaner synthesis. Chem. Soc. Rev. 2012, 41 (1), 413– 447,  DOI: 10.1039/C1CS15171A
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    Mechanochemistry: opportunities for new and cleaner synthesis
    James, Stuart L.; Adams, Christopher J.; Bolm, Carsten; Braga, Dario; Collier, Paul; Friscic, Tomislav; Grepioni, Fabrizia; Harris, Kenneth D. M.; Hyett, Geoff; Jones, William; Krebs, Anke; Mack, James; Maini, Lucia; Orpen, A. Guy; Parkin, Ivan P.; Shearouse, William C.; Steed, Jonathan W.; Waddell, Daniel C.
    Chemical Society Reviews (2012), 41 (1), 413-447CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. The aim of this crit. review is to provide a broad but digestible overview of mechanochem. synthesis, i.e. reactions conducted by grinding solid reactants together with no or minimal solvent. Although mechanochem. has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concg. on recent advances, this article covers industrial aspects, inorg. materials, org. synthesis, cocrystn., pharmaceutical aspects, metal complexes (including metal-org. frameworks), supramol. aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed.
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    New opportunities for materials synthesis using mechanochemistry
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    Journal of Materials Chemistry (2010), 20 (36), 7599-7605CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)
    Mechanochem. synthesis is experiencing a dynamic re-discovery in the areas of org. and metal-org. materials. Emerging mechanochem. methods, such as liq.-assisted grinding (LAG) or ion- and liq.-assisted grinding (ILAG) achieve enhanced mol. mobility through the addn. of near-stoichiometric amts. of a liq. phase to a solid-state reaction, and are aided by catalytic and templating effects. This article highlights the exciting areas of application for these mild mechanochem. methods: one-pot assembly of "soft" metal-org. and org. materials, and the rapid room-temp. synthesis of porous metal-org. frameworks directly from a metal oxide.
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    Beldon, P. J.; Fabian, L.; Stein, R. S.; Thirumurugan, A.; Cheetham, A. K.; Friscic, T. Rapid Room-Temperature Synthesis of Zeolitic Imidazolate Frameworks by Using Mechanochemistry. Angew. Chem., Int. Ed. 2010, 49 (50), 9640– 9643,  DOI: 10.1002/anie.201005547
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    Rapid Room-Temperature Synthesis of Zeolitic Imidazolate Frameworks by Using Mechanochemistry
    Beldon, Patrick J.; Fabian, Laszlo; Stein, Robin S.; Thirumurugan, A.; Cheetham, Anthony K.; Friscic, Tomislav
    Angewandte Chemie, International Edition (2010), 49 (50), 9640-9643, S9640/1-S9640/30CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Porous and nonporous zeolitic imidazolate frameworks (ZIFs) Zn(Im)2, Zn(MeIm)2 and Zn(EtIm)2 were prepd. by direct and topol. selective conversion of ZnO at room-temp. reaction with imidazole (HIm), 2-methylimidazole (HMeIm) and 2-ethylimidazole (HEtIm) using mechanochem.
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    Delori, A.; Friscic, T.; Jones, W. The role of mechanochemistry and supramolecular design in the development of pharmaceutical materials. CrystEngComm 2012, 14 (7), 2350– 2362,  DOI: 10.1039/c2ce06582g
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    The role of mechanochemistry and supramolecular design in the development of pharmaceutical materials
    Delori, Amit; Friscic, Tomislav; Jones, William
    CrystEngComm (2012), 14 (7), 2350-2362CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
    The development of modern pharmaceutical solid forms, including solvates, polymorphs, salts or cocrystals, is related to the design and control of mol. self-assembly processes. Mechanochem. has emerged as an excellent exptl. approach to rapidly and efficiently screen for and synthesize such pharmaceutical materials. This is particularly the case for pharmaceutical cocrystals which are of considerable interest in the area of modern solid-state pharmaceutical materials science. Mechanochem. has also been demonstrated as a successful technique to screen and synthesize metal-org. pharmaceutical derivs. (herein addressed as metallopharmaceuticals) as well as metallodrugs. The quant. yields and high crystallinity of products obtained via mechanochem. synthesis enables the efficient coupling of solvent-free screening and structure detn. from powder X-ray diffraction data to provide rapid advances in systematic studies and the structural understanding of pharmaceutical forms based on hydrogen bonding interactions or coordination bonds. In this review, we describe how mechanochem. methods have improved the development of new solid forms and their structural understanding, as well as the development of supramol. strategies for the crystal engineering of pharmaceutical solid forms.
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    Zhang, P.; Li, H.; Veith, G. M.; Dai, S. Soluble Porous Coordination Polymers by Mechanochemistry: From Metal-Containing Films/Membranes to Active Catalysts for Aerobic Oxidation. Adv. Mater. 2015, 27 (2), 234– 239,  DOI: 10.1002/adma.201403299
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    Soluble Porous Coordination Polymers by Mechanochemistry: From Metal-Containing Films/Membranes to Active Catalysts for Aerobic Oxidation
    Zhang, Pengfei; Li, Haiying; Veith, Gabriel M.; Dai, Sheng
    Advanced Materials (Weinheim, Germany) (2015), 27 (2), 234-239CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Soln. and solid state synthesis, surface areas and soly. of a family of 1-dimensional porous transition metal coordination polymers with the highly contorted and rigid ligand 5,5,6,6-tetrahydroxy-3,3,3,3-tetramethyl-1,1'-spirobisindane is reported. The oxidn. of β-isophorone by atm. oxygen is catalyzed by the sol. porous coordination polymers (SPCPs). Hybrid SPCPs with tetrafluoroterephthalonitrile are also prepd.
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    Garay, A. L.; Pichon, A.; James, S. L. Solvent-free synthesis of metal complexes. Chem. Soc. Rev. 2007, 36 (6), 846– 855,  DOI: 10.1039/b600363j
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    Supramolecular concepts and new techniques in mechanochemistry: cocrystals, cages, rotaxanes, open metal-organic frameworks
    Friscic, Tomislav
    Chemical Society Reviews (2012), 41 (9), 3493-3510CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Mechanochem. reactions effected by milling or grinding are an attractive means to conduct chem. reactions dependent on mol. recognition and to systematically explore different modes of mol. self-assembly. The natural relation between milling mechanochem. and supramol. chem. arises primarily from the ability to avoid bulk solvent, which simultaneously avoids limitations of soln.-based chem., such as soly., solvent complexation, or solvolysis, and makes the resulting process highly environmentally friendly. This tutorial review highlights the use of mechanochem. for the synthesis of supramol. targets in the solid state, such as mol. hydrogen- or halogen-bonded complexes, mol. and supramol. cages, open frameworks and interlocked architectures. Also the mol. self-assembly phenomena that are well-established in soln. chem., such as reversible binding through covalent or non-covalent bonds, thermodn. equilibration and structure templating, are also accessible in milling mechanochem. through recently developed highly efficient methodologies such as liq.-assisted grinding (LAG) or ion- and liq.-assisted grinding (ILAG). Also highlighted are the new opportunities arising from the marriage of concepts of supramol. and mechanochem. synthesis, including organocatalysis, deracemization and discovery of new mol. recognition motifs.
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    Mechanochem. reactions of Bi2O3 with salicylic acid (H2sal) were investigated with and without ion- and liq.-assisted grinding (ILAG), i.e., addn. of NH4NO3 or KNO3, and water. Quant. and selective conversions to different forms of bismuth salicylate were found, including formation of the pharmaceutical ingredient bismuth subsalicylate, [BiO(Hsal)]. Bismuth disalicylate hydrate, [Bi(sal)(Hsal)(H2O)]n, without auxiliary org. ligands, was characterized by powder XRD as 2-dimensional sheets. Bismuth trisalicylate was also isolated from product mixts. Recrystn. of bismuth disalicylate from DMF afforded cuboctahedral cluster [Bi38O64(Hsal)26(H2O)4(DMF)18], which was characterized by single-crystal x-ray crystallog.
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    Mechanochem. an environment-friendly synthetic technique has been successfully used in the search for new metallopharmaceuticals, metallodrugs and bio-inspired metal-org. frameworks. These materials recently became highly promising on the pharmaceutical and medical field due to their ability to function as drug carriers, allowing a controlled drug delivery and release in addn. to potential applications in imaging and magnetic resonance imaging for diagnostic and therapy. Here we refer to some of our previous results on Ag and Ni with piracetam and 4-aminosalicylic acid complexes as well as on the bismuth salicylates metallodrugs. Our results on bioinspired gabapentin networks are also discussed. Furthermore we disclose herein novel metallopharmaceuticals with flufenamic acid and a bio-inspired framework with muconic acid. The synthesis and structural characterization of these materials is described and their thermal and on-shelf stability was assessed, showing that they are stable under the relevant temp. range for pharmaceutical applications.
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    Despite the great interest that cocrystals are currently gaining for their application to the design of new supramol. structures with desired functional properties, studies concerning new exptl. strategies capable of controlling polymorphism phenomena of a given system are scarcely reported. We propose herein the use of polymer-assisted grinding (POLAG) as a new method for the selective control of the product polymorphic form in a mechanochem. cocrystn. reaction. Specifically, to the model system selected in this study formed by caffeine and glutaric acid, we demonstrate that the polymorphic outcome can be controlled by modifying the no. of monomer units of the catalyst from the shortest dimer to a polymer with chains of approx. 1000 units. The characteristics of each polymorphic form were investigated by low-dose high-resoln. TEM, and the mechanistic aspects of the cocrystal formation were studied through a series of ex situ and interconversion expts. The results suggest that for this system the modification of the catalyst chain length and, consequently, modification of polarity drives cocrystal formation toward the more stable polymorph. The approach proposed in this paper can be readily applied to each system, where polarity is the main issue for polymorph control without the risk of solvate formation.
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    Mechanochem. is an effective method for the prepn. of multicomponent crystal systems. In the present work, we propose an alternative to the established liq.-assisted grinding (LAG) approach. Polymer-assisted grinding (POLAG) is demonstrated to provide a new class of catalysts for improving reaction rate and increasing product diversity during mechanochem. cocrystn. reactions. We demonstrate that POLAG provides advantages comparable to the conventional liq.-assisted process, while eliminating the risk of unwanted solvate formation as well as enabling control of resulting particle size. It represents a new approach for the development of functional materials through mechanochem., and possibly opens new routes toward the understanding of the mechanisms and pathways of mechanochem. cocrystal formation.
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  • Abstract

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    Figure 1

    Figure 1. Nalidixic acid coordination modes scheme (a) and details on the octahedral geometry in the coordination sphere of the metal centers (b).

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    Figure 2

    Figure 2. Crystal structure details of Mg- and Mn-MOFs viewed along the a (a) and b (b) axes.

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    Figure 3

    Figure 3. Overlap of Mg-MOF (yellow) and Mn-MOF (blue), showing conformational differences in the 2D network.

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    Figure 4

    Figure 4. Hirshfeld surfaces for the Mg-MOF.

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    Figure 5

    Figure 5. Hirshfeld surface: percentage of various intermolecular contacts contributing to the Hirshfeld surfaces for Mg- and Mn-MOFs.

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    Figure 6

    Figure 6. Differential scanning calorimetry (black line) and thermogravimetry (blue line) curves of Mg-MOF (a) and Mn-MOF (b).

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    Figure 7

    Figure 7. MTT cytotoxicity and cell viability study (where error bars represent the standard deviation).

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      Miller, Stuart R.; Heurtaux, Daniela; Baati, Tarek; Horcajada, Patricia; Greneche, Jean-Marc; Serre, Christian
      Chemical Communications (Cambridge, United Kingdom) (2010), 46 (25), 4526-4528CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A new metal org. framework (MOF) built up from non-toxic iron and the therapeutically active linker nicotinic acid, with pellagra-curative, vasodilating, and antilipemic properties, has been isolated and characterized via single crystal methods. The release of the therapeutic agent, which is a constituent of the framework, is achieved through the degrdn. of the hybrid phase, under simulated physiol. conditions, allowing for the delivery of the bioactive mol.
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    5. 5
      Li, S.; Huo, F. Metal-organic framework composites: from fundamentals to applications. Nanoscale 2015, 7 (17), 7482– 7501,  DOI: 10.1039/C5NR00518C
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      Metal-organic framework composites: from fundamentals to applications
      Li, Shaozhou; Huo, Fengwei
      Nanoscale (2015), 7 (17), 7482-7501CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      A review. Metal-org. frameworks (MOFs) are a class of crystd. porous polymeric materials consisting of metal ions or clusters linked together by org. bridging ligands. Due to their permanent porosity, rich surface chem. and tuneable pore sizes, MOFs have emerged as one type of important porous solid and have attracted intensive interests in catalysis, gas adsorption, sepn. and storage over the past two decades. When compared with pure MOFs, the combination of MOFs with functional species or matrix materials not only shows enhanced properties, but also broadens the applications of MOFs in new fields, such as bio-imaging, drug delivery and elec. catalysis, owing to the interactions of the functional species/matrix with the MOF structures. Although the synthesis, chem. modification and potential applications of MOFs have been reviewed previously, there is an increasing awareness on the synthesis and applications of their composites, which have rarely been reviewed. This review aims to fill this gap and discuss the fabrication, properties, and applications of MOF composites. The remaining challenges and future opportunities in this field, in terms of processing techniques, maximizing composite properties, and prospects for applications, have also been indicated.
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    6. 6
      Lee, J.; Farha, O. K.; Roberts, J.; Scheidt, K. A.; Nguyen, S. T.; Hupp, J. T. Metal-organic framework materials as catalysts. Chem. Soc. Rev. 2009, 38 (5), 1450– 1459,  DOI: 10.1039/b807080f
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      Metal-organic framework materials as catalysts
      Lee, Jeong Yong; Farha, Omar K.; Roberts, John; Scheidt, Karl A.; Nguyen, Son Binh T.; Hupp, Joseph T.
      Chemical Society Reviews (2009), 38 (5), 1450-1459CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review; a crit. review of the emerging field of MOF-based catalysis is presented. Discussed are examples of: (a) opportunistic catalysis with metal nodes, (b) designed catalysis with framework nodes, (c) catalysis by homogeneous catalysts incorporated as framework struts, (d) catalysis by MOF-encapsulated mol. species, (e) catalysis by metal-free org. struts or cavity modifiers, and (f) catalysis by MOF-encapsulated clusters.
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    7. 7
      Sun, C.-Y.; Qin, C.; Wang, X.-L.; Su, Z.-M. Metal-organic frameworks as potential drug delivery systems. Expert Opin. Drug Delivery 2013, 10 (1), 89– 101,  DOI: 10.1517/17425247.2013.741583
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      Metal-organic frameworks as potential drug delivery systems
      Sun, Chun-Yi; Qin, Chao; Wang, Xin-Long; Su, Zhong-Min
      Expert Opinion on Drug Delivery (2013), 10 (1), 89-101CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)
      A review. Introduction: Metal-org. frameworks (MOFs) are a unique class of hybrid porous solids based on metals and org. linkers. Compared to traditional porous materials, they possess predominance of large surface areas, tunable pore size and shape, adjustable compn. and functionalized pore surface, which enable them unique advantages and promises for applications in adsorption and release of therapeutic agents. Areas covered: This review addresses MOFs as a new avenue for drug delivery and exhibits their ability to efficiently deliver various kinds of therapeutic agents. It also details the requirements that MOFs need to satisfy for biomedical application, such as toxicol. compatibility, stability, particle size, and surface modification. In addn., several approaches used to enhance encapsulation efficiency are summarized and parameters influencing delivery efficiency are also discussed. Expert opinion: Benefiting from the unique advantages of MOFs materials, efficient delivery of various kinds of drugs has been achieved in some MOF materials. However, it is only the outset of MOFs in drug delivery system, and numerous work need to be done before clin. applications, for example, studying their in vivo toxicity, exploring degrdn. mechanisms so as to establish real stability of MOFs in body's liq., providing appropriated surface modification avenue for MOFs, and researching in vivo efficiency and pharmacokinetics of drug-loaded MOFs.
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      Wang, S.; Wang, X. Multifunctional Metal-Organic Frameworks for Photocatalysis. Small 2015, 11 (26), 3097– 3112,  DOI: 10.1002/smll.201500084
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      Multifunctional Metal-Organic Frameworks for Photocatalysis
      Wang, Sibo; Wang, Xinchen
      Small (2015), 11 (26), 3097-3112CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Metal-org. frameworks (MOFs) have attracted significant research attention in diverse areas due to their unique phys. and chem. characteristics that allow their innovative application in various research fields. Recently, the application of MOFs in heterogeneous photocatalysis for water splitting, CO2 redn., and org. transformation have emerged, aiming at providing alternative solns. to address the world-wide energy and environmental problems by taking advantage of the unique porous structure together with ample physicochem. properties of the metal centers and org. ligands in MOFs. In this review, the latest progress in MOF-involved solar-to-chem. energy conversion reactions are summarized according to their different roles in the photoredox chem. systems, e.g., photocatalysts, co-catalysts, and hosts. The achieved progress and existing problems are evaluated and proposed, and the opportunities and challenges of MOFs and their related materials for their advanced development in photocatalysis are discussed and anticipated.
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    9. 9
      Wuttke, S.; Braig, S.; Preiss, T.; Zimpel, A.; Sicklinger, J.; Bellomo, C.; Raedler, J. O.; Vollmar, A. M.; Bein, T. MOF nanoparticles coated by lipid bilayers and their uptake by cancer cells. Chem. Commun. 2015, 51 (87), 15752– 15755,  DOI: 10.1039/C5CC06767G
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      MOF nanoparticles coated by lipid bilayers and their uptake by cancer cells
      Wuttke, Stefan; Braig, Simone; Preiss, Tobias; Zimpel, Andreas; Sicklinger, Johannes; Bellomo, Claudia; Raedler, Joachim O.; Vollmar, Angelika M.; Bein, Thomas
      Chemical Communications (Cambridge, United Kingdom) (2015), 51 (87), 15752-15755CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      We report the synthesis of [email protected] nanoparticles as a versatile and powerful novel class of nanocarriers based on metal-org. frameworks (MOFs). We show that the [email protected] system can effectively store dye mols. inside the porous scaffold of the MOF while the lipid bilayer prevents their premature release. Efficient uptake of the [email protected] nanoparticles by cancer cells makes these nanocarriers promising for drug delivery and diagnostic purposes.
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    10. 10
      Wang, X. G.; Dong, Z. Y.; Cheng, H.; Wan, S. S.; Chen, W. H.; Zou, M. Z.; Huo, J. W.; Deng, H. X.; Zhang, X. Z. A multifunctional metal-organic framework based tumor targeting drug delivery system for cancer therapy. Nanoscale 2015, 7 (38), 16061– 16070,  DOI: 10.1039/C5NR04045K
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      A multifunctional metal-organic framework based tumor targeting drug delivery system for cancer therapy
      Wang, Xiao-Gang; Dong, Zhi-Yue; Cheng, Hong; Wan, Shuang-Shuang; Chen, Wei-Hai; Zou, Mei-Zhen; Huo, Jia-Wei; Deng, He-Xiang; Zhang, Xian-Zheng
      Nanoscale (2015), 7 (38), 16061-16070CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-org. framework (MOF) based tumor targeting DDS developed by a one-pot, and org. solvent-free "green" post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects.
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    11. 11
      Barry, A. L.; Jones, R. N.; Thornsberry, C.; Ayers, L. W.; Gerlach, E. H.; Sommers, H. M. Antibacterial activities of ciprofloxacin, oxolinic acid, cinoxacin, and nalidixic acid. Antimicrob. Agents Chemother. 1984, 25 (5), 633– 637,  DOI: 10.1128/AAC.25.5.633
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      11
      Antibacterial activities of ciprofloxacin, norfloxacin, oxolinic acid, cinoxacin, and nalidixic acid
      Barry, A. L.; Jones, R. N.; Thornsberry, C.; Ayers, L. W.; Gerlach, E. H.; Sommers, H. M.
      Antimicrobial Agents and Chemotherapy (1984), 25 (5), 633-7CODEN: AMACCQ; ISSN:0066-4804.
      In vitro studies were performed comparing ciprofloxacin (Bay o 9867) and norfloxacin with 3 related org. acids. Ciprofloxacin was 2-8 fold more active than norfloxacin against 658 bacterial isolates representing 30 species. For all species tested, ciprofloxacin min. inhibitory concns. for 90% inhibition were ≤2.0 μg/mL. Addnl. tests with 5994 isolates detected only 37 (0.6%) strains resistant to 2.0 μg of ciprofloxacin per mL and 106 (1.8%) resistant to 1.0 μg/mL. Only 6 (0.1%) of the 5994 strains were resistant to 16 μg of norfloxacin per mL, and 129 (2.1%) were resistant to 4.0 μg/mL. The majority of resistant strains were streptococci or Pseudomonas species. Resistance among the Enterobacteriaceae was extremely rare (i.e., >99.8% susceptible to both drugs).
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    12. 12
      Akahane, K.; Sekiguchi, M.; Une, T.; Osada, Y. Structure-epileptogenicity relationships of quinolones with special reference to their interaction with gamma-aminobutyric acid receptor sites. Antimicrob. Agents Chemother. 1989, 33 (10), 1704– 1708,  DOI: 10.1128/AAC.33.10.1704
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      Structure-epileptogenicity relationship of quinolones with special reference to their interaction with γ-aminobutyric acid receptor sites
      Akahane, Kouichi; Sekiguchi, Masayasu; Une, Tsutomu; Osada, Yasuaki
      Antimicrobial Agents and Chemotherapy (1989), 33 (10), 1704-8CODEN: AMACCQ; ISSN:0066-4804.
      The relationship between the chem. structure and epileptogenic activity of quinolones was investigated. When the quinolones were administered i.v. to mice concomitantly with oral biphenylacetic acid, a major metabolite of the nonsteroidal antiinflammatory drug fenbufen, enoxacin, norfloxacin, ciprofloxacin, and pipemidic acid, which have an unsubstituted piperazine moiety at the 7 position of their parent nuclei, provoked clonic convulsions and subsequent death at ≥6.25 mg/kg in a dose-dependent manner. AM-1091 and T-3262, which have an unsubstituted aminopyrrolidine moiety at their 7 positions, were less epileptogenic than the compds. listed above were. In contrast, ofloxacin, AT-4140, and nalidixic acid, which have piperazine substituted with Me group(s) or no piperazine moiety at their 7 positions, never induced convulsions, even at doses of 100 mg/kg. Lomefloxacin, which has a 3-Me piperazine, however, provoked convulsions at ≥6.25 mg/kg. In the presence of biphenylacetic acid, all the test quinolones except nalidixic acid competitively inhibited [3H]muscimol binding to receptor sites for GABA in vitro. Nalidixic acid did not inhibit the binding at all, even at the highest concn. tested, i.e., 10-4M. The 50% inhibition doses for [3H]muscimol binding varied within 4 orders of magnitude or more, between 10-8 to >10-4M for various compds., and there was a close correlation between the epileptogenic activities of quinolones and their inhibitory potencies for [3H]muscimol binding to GABA receptor sites. Thus, the epileptogenic activity of quinolones possibly relates to the GABA-like structures of substituents at their 7 positions, which act as antagonists of GABA receptors.
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    13. 13
      Kljun, J.; Bratsos, I.; Alessio, E.; Psomas, G.; Repnik, U.; Butinar, M.; Turk, B.; Turel, I. New Uses for Old Drugs: Attempts to Convert Quinolone Antibacterials into Potential Anticancer Agents Containing Ruthenium. Inorg. Chem. 2013, 52 (15), 9039– 9052,  DOI: 10.1021/ic401220x
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      13
      New Uses for Old Drugs: Attempts to Convert Quinolone Antibacterials into Potential Anticancer Agents Containing Ruthenium
      Kljun, Jakob; Bratsos, Ioannis; Alessio, Enzo; Psomas, George; Repnik, Urska; Butinar, Miha; Turk, Boris; Turel, Iztok
      Inorganic Chemistry (2013), 52 (15), 9039-9052CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      Continuing the study of the physicochem. and biol. properties of Ru-quinolone adducts, four novel complexes [Ru([9]aneS3)(DMSO-κS)(quinolonato-κ2O,O)](PF6), contg. the quinolones levofloxacin (1), nalidixic acid (2), oxolinic acid (3), and cinoxacin (4), were prepd. and characterized in solid state as well as in soln. Contrary to their organoruthenium analogs, these complexes are generally relatively stable in aq. soln. as substitution of the DMSO ligand is slow and not quant., and a minor release of the quinolonato ligand is obsd. only in the case of 4. The complexes bind to serum proteins displaying relatively high binding consts. DNA binding was studied using UV-visible spectroscopy, cyclic voltammetry, and performing viscosity measurements of CT DNA solns. in the presence of complexes 1-4. The Ru complexes interact with DNA via intercalation. Possible electrostatic interactions occur in the case of compd. 4, which also shows the most pronounced rate of hydrolysis. Compds. 2 and 4 also exhibit a weak inhibition of cathepsins B and S, which are involved in the progression of a no. of diseases, including cancer. Also, complex 2 displayed moderate cytotoxicity when tested on the HeLa cell line.
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    14. 14
      Hudej, R.; Kljun, J.; Kandioller, W.; Repnik, U.; Turk, B.; Hartinger, C. G.; Keppler, B. K.; Miklavcic, D.; Turel, I. Synthesis and Biological Evaluation of the Thionated Antibacterial Agent Nalidixic Acid and Its Organoruthenium(II) Complex. Organometallics 2012, 31 (16), 5867– 5874,  DOI: 10.1021/om300424w
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      14
      Synthesis and Biological Evaluation of the Thionated Antibacterial Agent Nalidixic Acid and Its Organoruthenium(II) Complex
      Hudej, Rosana; Kljun, Jakob; Kandioller, Wolfgang; Repnik, Urska; Turk, Boris; Hartinger, Christian G.; Keppler, Bernhard K.; Miklavcic, Damijan; Turel, Iztok
      Organometallics (2012), 31 (16), 5867-5874CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      The thionated deriv. of the antibacterial agent nalidixic acid and its organoruthenium complex were prepd., and their crystal structures were detd. The aq. stability of the complex was studied and, unlike the case for the nalidixicato complex, increased stability of the Ru complex in aq. soln. was obsd. with only a minor degree of thionalidixicato ligand dissocd. within 1 wk. While the derivatization caused the antibacterial activity of the ligand against E. coli to decrease, the cytotoxicity of the complex against three cancer cell lines was significantly increased and the inhibitory potency against two enzymes of the cathepsin family was increased by 10-fold.
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    15. 15
      Lee, S. S.; Jung, O. S.; Lee, C. O.; Choi, S. U.; Jun, M. J.; Sohn, Y. S. Cationic diamineplatinum(II) complexes of nalidixic acid. Inorg. Chim. Acta 1995, 239 (1–2), 133– 138,  DOI: 10.1016/0020-1693(95)04734-4
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      15
      Cationic diamineplatinum(II) complexes of nalidixic acid
      Lee, Sung Sil; Jung, Ok-Sang; Lee, Chong Ock; Choi, Sang Un; Jun, Moo-Jin; Sohn, Youn Soo
      Inorganica Chimica Acta (1995), 239 (1-2), 133-8CODEN: ICHAA3; ISSN:0020-1693. (Elsevier)
      The reaction of cis-A2PtCl2 with Na nalidixate (nal) leads to the cationic Pt complexes cis-[A2Pt(nal)]+X-; 1 A2 = ethylenediamine (en), X = Cl; 2 A2 = (1R,2R)-diaminocyclohexane (dach), X = Cl; 3 A2 = 1,1-bis(aminomethyl)cyclohexane (bamch), X = Cl; 4 A = cyclopropylamine (cpa), X = Cl; 5 A = NH3, X = nal. The complexes were characterized by elemental anal., cond., spectroscopic methods and x-ray anal. The crystal structure of 5·5H2O (space group P‾1; a 10.558(3), b 11.351(5), c 14.803(10) Å, α 110.16(5), β 99.73(3), γ 110.77(2)°, Z = 2, R = 0.053) discloses that one nalidixate ion is chelated to the Pt atom via its carboxylate and ring carbonyl groups whereas the other nalidixate is a counter anion. These Pt complexes are stable in H2O, but are changed to Me2SO adducts in DMSO soln. Among the title complexes, 2 and 5 showed good antitumor activity for further study.
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    16. 16
      Kljun, J.; Bytzek, A. K.; Kandioller, W.; Bartel, C.; Jakupec, M. A.; Hartinger, C. G.; Keppler, B. K.; Turel, I. Physicochemical Studies and Anticancer Potency of Ruthenium eta(6)-p-Cymene Complexes Containing Antibacterial Quinolones. Organometallics 2011, 30 (9), 2506– 2512,  DOI: 10.1021/om101180c
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      16
      Physicochemical Studies and Anticancer Potency of Ruthenium η6-p-Cymene Complexes Containing Antibacterial Quinolones
      Kljun, Jakob; Bytzek, Anna K.; Kandioller, Wolfgang; Bartel, Caroline; Jakupec, Michael A.; Hartinger, Christian G.; Keppler, Bernhard K.; Turel, Iztok
      Organometallics (2011), 30 (9), 2506-2512CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      With the aim of exploring the anticancer properties of organometallic compds. with bioactive ligands, Ru(arene) compds. of the antibacterial quinolones nalidixic acid (2) and cinoxacin (3) were synthesized, and their physicochem. properties were compared to those of chlorido(η6-p-cymene)(ofloxacinato-κ2O,O)ruthenium(II) (1). All compds. undergo a rapid ligand exchange reaction from chlorido to aqua species. 2 And 3 are significantly more stable than 1 and undergo minor conversion to an unreactive [(cym)Ru(μ-OH)3Ru(cym)]+ species (cym = η6-p-cymene). In the presence of human serum albumin 1-3 form adducts with this transport protein within 20 min of incubation. With GMP (5'-GMP; as a simple model for reactions with DNA) very rapid reactions yielding adducts via its N7 atom were obsd., illustrating that DNA is a possible target for this compd. class. A moderate capacity of inhibiting tumor cell proliferation in vitro was obsd. for 1 in CH1 ovarian cancer cells, whereas 2 and 3 turned out to be inactive.
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      Mallick, S.; Sahu A Fau - Pal, K.; Pal, K. Dissolution behaviour of nalidixic acid solid dispersions using water soluble dispersion carriers. Acta Polym. Pharm. 2004, 61, 21– 30
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      Drlica, K.; Hiasa, H.; Kerns, R.; Malik, M.; Mustaev, A.; Zhao, X. L. Quinolones: Action and Resistance Updated. Curr. Top. Med. Chem. 2009, 9 (11), 981– 998,  DOI: 10.2174/156802609789630947
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      Quinolones: action and resistance updated
      Drlica, Karl; Hiasa, Hiroshi; Kerns, Robert; Malik, Muhammad; Mustaev, Arkady; Zhao, Xilin
      Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2009), 9 (11), 981-998CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
      A review. The quinolones trap DNA gyrase and DNA topoisomerase IV on DNA as complexes in which the DNA is broken but constrained by protein. Early studies suggested that drug binding occurs largely along helix-4 of the GyrA (gyrase) and ParC (topoisomerase IV) proteins. However, recent X-ray crystallog. shows drug intercalating between the -1 and +1 nucleotides of cut DNA, with only one end of the drug extending to helix-4. These two models may reflect distinct structural steps in complex formation. A consequence of drug-enzyme-DNA complex formation is reversible inhibition of DNA replication; cell death arises from subsequent events in which bacterial chromosomes are fragmented through two poorly understood pathways. In one pathway, chromosome fragmentation stimulates excessive accumulation of highly toxic reactive oxygen species that are responsible for cell death. Quinolone resistance arises stepwise through selective amplification of mutants when drug concns. are above the MIC and below the MPC, as obsd. with static agar plate assays, dynamic in vitro systems, and exptl. infection of rabbits. The gap between MIC and MPC can be narrowed by compd. design that should restrict the emergence of resistance. Resistance is likely to become increasingly important, since three types of plasmid-borne resistance have been reported.
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      Grover, G.; Kini, S. G. Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents. Eur. J. Med. Chem. 2006, 41 (2), 256– 262,  DOI: 10.1016/j.ejmech.2005.09.002
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      19
      Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents
      Grover, Gaurav; Kini, Suvarna G.
      European Journal of Medicinal Chemistry (2006), 41 (2), 256-262CODEN: EJMCA5; ISSN:0223-5234. (Elsevier B.V.)
      In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivs. having quinazolones moiety were synthesized to achieve enhanced biol. activity and wide spectrum of activity. Nalidixic acid was first converted into its acid chloride using thionyl chloride as an acylating agent at lab. temp. Later it was converted to Me ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a Me ester of nalidixic acid. The ester on addn. of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form benzoxazine/acetanthranil. 5-Iodo deriv. of anthranilic acid was prepd. and also utilized to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitrobenzoxazine/acetanthranil was obtained by nitration of acetanthranil using conc. H2SO4 and fuming HNO3. Equimolar proportions of the appropriate synthesized acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesize quinazolones. Elemental anal. and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compds. obtained have been established on the basis of spectral (IR, 1H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar diln. and Punch well diffusion method) of synthesized quinazolone derivs. bearing nalidixic acid moiety on randomly collected microbial strains. Some derivs. showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhea in children as well as adults. One deriv. was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesized derivs. against Coagulase neg. Staphylococcus. One deriv. was found to show very high activity against the Candida colonies and another deriv. was also found to exhibit inhibitory activity against Candida albicans; a normal flora of the human body which plays an important role in causing opportunistic infections in immunocompromised hosts. Proteus vulgaris, a gram-neg. bacteria included in our study, was found to be inhibited.
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    20. 20
      Pandey, A.; Aggarwal, N.; Adholeya, A.; Kochar, M. Resurrection of Nalidixic Acid: Evaluation of Water-Based Nanoformulations as Potential Nanomedicine. Nanoscale Res. Lett. 2018, 13, 298,  DOI: 10.1186/s11671-018-2718-8
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      20
      Resurrection of Nalidixic Acid: Evaluation of Water-Based Nanoformulations as Potential Nanomedicine
      Pandey Alka; Adholeya Alok; Kochar Mandira; Aggarwal Nisha
      Nanoscale research letters (2018), 13 (1), 298 ISSN:1931-7573.
      Resistance to quinolone antibiotics has been a serious problem ever since nalidixic acid was introduced into clinical medicine. Over time, resistance of pathogenic microbes to nalidixic acid led to the design of novel variants to revive its potential application. In the present work, a series of eight nanoformulations of nalidixic acid-based diacyl and sulfonyl acyl hydrazine derivatives were prepared. All nanoformulations were found to be stable at different storage temperatures. Antibacterial and anticandida activity of the eight nanoformulations presented encouraging results when compared with their non-nano parent counterparts. The nanoformulations of chloro, furanyl, and sulfonyl acyl substituted derivatives of nalidixic acid displayed most promising results (MIC ranging from 50 to 100 μg mL(-1)) against the tested bacteria and yeast. Among the screened bacteria, Acinetobacter baumannii displayed maximum sensitivity to the above nanoformulations. Biosafety study on the mammalian model-wax moth, Galleria mellonella-showed that all eight prepared nanoformulations were absolutely nontoxic to the larvae and subsequent pupae and hence may likely have no or low toxicity against mammalian systems.
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      Zhu, X.; Radovic-Moreno, A. F.; Wu, J.; Langer, R.; Shi, J. J. Nanomedicine in the management of microbial infection - Overview and perspectives. Nano Today 2014, 9 (4), 478– 498,  DOI: 10.1016/j.nantod.2014.06.003
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      Nanomedicine in the management of microbial infection - Overview and perspectives
      Zhu, Xi; Radovic-Moreno, Aleksandar F.; Wu, Jun; Langer, Robert; Shi, Jinjun
      Nano Today (2014), 9 (4), 478-498CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)
      A review. For more than 2 billion years, microbes have reigned on our planet, evolving or outlasting many obstacles they have encountered. In the 20th century, this trend took a dramatic turn with the introduction of antibiotics and vaccines. Nevertheless, since then, microbes have progressively eroded the effectiveness of previously successful antibiotics by developing resistance, and many infections have eluded conventional vaccine design approaches. Moreover, the emergence of resistant and more virulent strains of bacteria has outpaced the development of new antibiotics over the last few decades. These trends have had major economic and health impacts at all levels of the socioeconomic spectrum - we need breakthrough innovations that could effectively manage microbial infections and deliver solns. that stand the test of time. The application of nanotechnologies to medicine, or nanomedicine, which has already demonstrated its tremendous impact on the pharmaceutical and biotechnol. industries, is rapidly becoming a major driving force behind ongoing changes in the antimicrobial field. Here we provide an overview on the current progress of nanomedicine in the management of microbial infection, including diagnosis, antimicrobial therapy, drug delivery, medical devices, and vaccines, as well as perspectives on the opportunities and challenges in antimicrobial nanomedicine.
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      Ahmed, M.; Kelley, S. O. Enhancing the Potency of Nalidixic Acid toward a Bacterial DNA Gyrase with Conjugated Peptides. ACS Chem. Biol. 2017, 12 (10), 2563– 2569,  DOI: 10.1021/acschembio.7b00540
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      22
      Enhancing the Potency of Nalidixic Acid toward a Bacterial DNA Gyrase with Conjugated Peptides
      Ahmed, Marya; Kelley, Shana O.
      ACS Chemical Biology (2017), 12 (10), 2563-2569CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      Quinolones and fluoroquinolones are widely used antibacterial agents. Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and mol. charge prepd. by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and mol. charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide contg. cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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      Behrens, N. B.; Diaz, G. M.; Goodgame, D. M. L. etal-complexes of the antibiotic nalidixic acid. Inorg. Chim. Acta 1986, 125 (1), 21– 26,  DOI: 10.1016/S0020-1693(00)85478-X
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      Mendozadiaz, G.; Martinezaguilera, L. M. R.; Perezalonso, R.; Solans, X.; Moreno-Esparza, R. Synthesis and characterization of mixed-ligand complexes of copper with nalidixic acid and (N-N) donors - crystal-structure of Cu(PHEN)(NAL)-(H2O)NO3.3H2O. Inorg. Chim. Acta 1987, 138 (1), 41– 47,  DOI: 10.1016/S0020-1693(00)81179-2
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      Arjmand, F.; Yousuf, I.; Afzal, M.; Toupet, L. Design and synthesis of new Zn(II) nalidixic acid-DACH based Topo-II inhibiting molecular entity: Chemotherapeutic potential validated by its in vitro binding profile, pBR322 cleavage activity and molecular docking studies with DNA and RNA molecular targets. Inorg. Chim. Acta 2014, 421, 26– 37,  DOI: 10.1016/j.ica.2014.05.015
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      Design and synthesis of new Zn(II) nalidixic acid-DACH based Topo-II inhibiting molecular entity: Chemotherapeutic potential validated by its in vitro binding profile, pBR322 cleavage activity and molecular docking studies with DNA and RNA molecular targets
      Arjmand, Farukh; Yousuf, Imtiyaz; Afzal, Mohd.; Toupet, Loic
      Inorganica Chimica Acta (2014), 421 (), 26-37CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
      Nalidixic acid-DACH based Zn(II) mol. entity I was synthesized and thoroughly characterized by spectroscopic techniques (FT-IR, 1H and 13C NMR, ESI-MS) and single crystal x-ray crystallog. as a potential chemotherapeutic drug candidate. The comparative in vitro binding studies of complex I with targets like CT-DNA and yeast tRNA were carried out by employing UV-Vis, emission spectroscopy, CD and viscosity which revealed higher binding affinity of I towards yeast tRNA as compared to CT-DNA. Complex cleaves pBR322 plasmid via hydrolytic pathway (validated by T4 religation assay); in addn., I also exhibited significant inhibitory effects on the catalytic activity of Topo-II at a concn. of 30 μM. Further, validation of the interaction studies was accomplished by carrying out mol. docking studies with DNA, RNA and Topo-II targets. This work also advances the knowledge for the development and design of small RNA targeted therapeutic mols. which were relatively under exploited drug targets.
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      Arjmand, F.; Yousuf, I.; ben Hadda, T.; Toupet, L. Synthesis, crystal structure and antiproliferative activity of Cu(II) nalidixic acid-DACH conjugate: Comparative in vitro DNA/RNA binding profile, cleavage activity and molecular docking studies. Eur. J. Med. Chem. 2014, 81, 76– 88,  DOI: 10.1016/j.ejmech.2014.04.080
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      Synthesis, crystal structure and antiproliferative activity of Cu(II) nalidixic acid-DACH conjugate: Comparative in vitro DNA/RNA binding profile, cleavage activity and molecular docking studies
      Arjmand, Farukh; Yousuf, Imtiyaz; Hadda, Taibi ben; Toupet, Loic
      European Journal of Medicinal Chemistry (2014), 81 (), 76-88CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      Nalidixic acid-DACH conjugate Cu(II) mol. entity (I) was synthesized, thoroughly characterized by spectroscopic techniques (FT-IR, EPR and ESI-MS) and single crystal x-ray diffraction technique as a potential chemotherapeutic drug candidate for cancer oncol. Complex I was a potent drug-like mol. entity in confirmation with Lipinski rules. 1R,2R-diaminocyclohexane (DACH) ligand scaffold (which reduces the drawbacks of cisplatin analogs) and nalidixic acid pharmacophore make it a suitable drug entity targeting nucleic acids. To evaluate the chemotherapeutic potential of complex I comparative in vitro DNA/RNA interaction studies have been investigated by employing various biophys. techniques (UV-vis, fluorescence, CD, viscosity, cyclic voltammetry and FT-IR), cleavage activity and Topo-II inhibition assay. Further, mechanistic investigation revealed the efficiency of complex I to cleave pBR322 DNA strands by an oxidative pathway involving the generation of ROS and preferential selectivity towards the A-T region of DNA major groove. Antiproliferative activity in conjugation with flow cytometry anal. of complex I against human osteoblastoma cell line (U2OS) suggested a cell cycle arrest at S phase. This work further advances the authors knowledge for the development and design of small RNA targeted therapeutic mols. which are under exploited drug targets.
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    27. 27
      Yousuf, I.; Usman, M.; Ahmad, M.; Tabassum, S.; Arjmand, F. Single X-ray crystal structure, DFT studies and topoisomerase I inhibition activity of a tailored ionic Ag(I) nalidixic acid-piperazinium drug entity specific for pancreatic cancer cells. New J. Chem. 2018, 42 (1), 506– 519,  DOI: 10.1039/C7NJ03602G
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      Single X-ray crystal structure, DFT studies and topoisomerase I inhibition activity of a tailored ionic Ag(I) nalidixic acid-piperazinium drug entity specific for pancreatic cancer cells
      Yousuf, Imtiyaz; Usman, Mohammad; Ahmad, Musheer; Tabassum, Sartaj; Arjmand, Farukh
      New Journal of Chemistry (2018), 42 (1), 506-519CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
      Novel ionic Ag(I)-piperazinium nalidixic acid conjugate 1 was synthesized as a potential antitumor agent and was thoroughly characterized by elemental anal., FT-IR, 1H and 13C NMR and single X-ray crystal diffraction studies. Complex 1 crystd. in the triclinic space group P1 and comprises a dipiperazinium-Ag(I) cationic unit, two nalidixate (naI-) anionic moieties and a nitrate ion. The Ag(I) ion adopted a linear configuration upon coordination with two nitrogen atoms of piperazinium cations (pipzH+) arranged in a trans fashion. The d. functional theory (DFT) studies of 1 revealed the HOMO and LUMO to be localized on the metal center viz., the dx2-y2 orbital and partially localized on the C27, C28, C29, C30, C31, C32, N7 and N6 atoms of the piperazinium moiety. Non covalent interaction (NCI) calcns. were carried out to identify the weak non-covalent interactions from the topol. anal. and reduced gradient of the electron d. of complex 1. Our results revealed significant inter- and intramol. non-covalent interactions between the naI- and [Ag(pip)2]2+ units. Furthermore, an anal. of Hirshfeld surfaces and fingerprint plots were carried out to ascertain a comparison between intermol. interactions which provide interesting supramol. architectures involving combinations of N-H···O, O-H···O and C-H···O linkages into a two-dimensional framework. In vitro binding studies of 1 with ct-DNA and tRNA revealed higher binding propensity for tRNA which was evidenced from its higher intrinsic binding const., Kb and binding const., K values and the mode of binding was found to be groove binding in nature. The catalytic activity of topoisomerase I enzyme in the presence of complex 1 was ascertained by gel electrophoretic assay which demonstrated significant inhibitory effects at a low concn. of 25 μM. The cytotoxicity activity of 1 was detd. by SRB assay on MIA-PA-CA-2, HepG2, HeLa and MCF7 human cancer cell lines; these results exhibited specific and selective antitumor activity for the MIA-PA-CA-2 cancer cell line with a GI50 value <10.
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      Andre, V.; Galego, F.; Martins, M. Mechanochemical Assembly of Nalidixic Acid Bioinspired Metal-Organic Compounds and Complexes toward Improved Solubility. Cryst. Growth Des. 2018, 18 (4), 2067– 2081,  DOI: 10.1021/acs.cgd.7b01523
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      Mechanochemical assembly of nalidixic acid Bioinspired Metal-organic compounds and complexes toward improved solubility
      Andre, Vania; Galego, Filipa; Martins, Marta
      Crystal Growth & Design (2018), 18 (4), 2067-2081CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Nalidixic acid is an antibiotic from the quinolones family whose bioavailability is limited due to its low soly. The development of complexes and bioinspired metal-org. frameworks has been explored as a way to achieve controlled drug delivery and release, and we demonstrate that they can also be used to tune drugs' physicochem. properties, such as soly. Herein we disclose a series of complexes and frameworks of nalidixic acid and Zn. One of these frameworks duplicates the soly. of nalidixic acid, and it is stable on the shelf and to 77% room humidity. The incorporation of a second ligand into the frameworks is also presented, showing the possibility to develop extended networks with further potential applications.
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      Rios, F. J.; Montezano, A. C.; Touyz, R. M.; Collins, J. F. Magnesium, Vascular Function, and Hypertension. Molecular, genetic, and nutritional aspects of major and trace minerals 2017, 353– 364,  DOI: 10.1016/B978-0-12-802168-2.00029-4
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      Schmitz, C.; Perraud, A.-L.; Collins, J. F. Magnesium and the Immune Response. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 319– 331,  DOI: 10.1016/B978-0-12-802168-2.00026-9
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      Pleshchitser, A. L. BIOLOGICAL ROLE OF MAGNESIUM. Clinical Chemistry 1958, 4 (6), 429– 450
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      Biological role of magnesium
      Pleshchitser, A. Ya.
      (1958), 4 (), 429-51 ISSN:.
      A review of the biol. role of Mg based chiefly upon Russian scientific literature.
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      Nielsen, F. H.; Collins, J. F. Magnesium: Basic Nutritional Aspects. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 307– 317,  DOI: 10.1016/B978-0-12-802168-2.00025-7
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      Komiya, Y.; Runnels, L. W.; Collins, J. F. Magnesium and Embryonic Development. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 343– 351,  DOI: 10.1016/B978-0-12-802168-2.00028-2
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      He, K.; Tsinovoi, C. L.; Collins, J. F. Magnesium Intake and Chronic Disease in Humans. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 333,  DOI: 10.1016/B978-0-12-802168-2.00027-0
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      Blower, T. R.; Williamson, B. H.; Kerns, R. J.; Berger, J. M. Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. U. S. A. 2016, 113 (7), 1706– 1713,  DOI: 10.1073/pnas.1525047113
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      Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis
      Blower, Tim R.; Williamson, Benjamin H.; Kerns, Robert J.; Berger, James M.
      Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (7), 1706-1713CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Mycobacterium tuberculosis (Mtb) infects one-third of the world's population and in 2013 accounted for 1.5 million deaths. Fluoroquinolone antibacterials, which target DNA gyrase, are crit. agents used to halt the progression from multidrug-resistant tuberculosis to extensively resistant disease; however, fluoroquinolone resistance is emerging and new ways to bypass resistance are required. To better explain known differences in fluoroquinolone action, the crystal structures of the WT Mtb DNA gyrase cleavage core and a fluoroquinolone-sensitized mutant were detd. in complex with DNA and five fluoroquinolones. The structures, ranging from 2.4- to 2.6-Å resoln., show that the intrinsically low susceptibility of Mtb to fluoroquinolones correlates with a redn. in contacts to the water shell of an assocd. magnesium ion, which bridges fluoroquinolone-gyrase interactions. Surprisingly, the structural data revealed few differences in fluoroquinolone-enzyme contacts from drugs that have very different activities against Mtb. By contrast, a stability assay using purified components showed a clear relationship between ternary complex reversibility and inhibitory activities reported with cultured cells. Collectively, our data indicate that the stability of fluoroquinolone/DNA interactions is a major determinant of fluoroquinolone activity and that moieties that have been appended to the C7 position of different quinolone scaffolds do not take advantage of specific contacts that might be made with the enzyme. These concepts point to new approaches for developing quinolone-class compds. that have increased potency against Mtb and the ability to overcome resistance.
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      Wohlkonig, A.; Chan, P. F.; Fosberry, A. P.; Homes, P.; Huang, J.; Kranz, M.; Leydon, V. R.; Miles, T. J.; Pearson, N. D.; Perera, R. L.; Shillings, A. J.; Gwynn, M. N.; Bax, B. D. Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance. Nat. Struct. Mol. Biol. 2010, 17, 1152,  DOI: 10.1038/nsmb.1892
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      Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance
      Wohlkonig, Alexandre; Chan, Pan F.; Fosberry, Andrew P.; Homes, Paul; Huang, Jianzhong; Kranz, Michael; Leydon, Vaughan R.; Miles, Timothy J.; Pearson, Neil D.; Perera, Rajika L.; Shillings, Anthony J.; Gwynn, Michael N.; Bax, Benjamin D.
      Nature Structural & Molecular Biology (2010), 17 (9), 1152-1153CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
      Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion. This provides a mol. basis for the quinolone inhibition mechanism, resistance mutations and invariant quinolone antibacterial structural features.
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      Peres, T. V.; Aschner, M.; Collins, J. F. Nutritional, Genetic, and Molecular Aspects of Manganese Intoxication. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 367– 376,  DOI: 10.1016/B978-0-12-802168-2.00030-0
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      Juttukonda, L. J.; Skaar, E. P.; Collins, J. F. Manganese and Nutritional Immunity. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 377– 387,  DOI: 10.1016/B978-0-12-802168-2.00031-2
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      Gunter, T. E.; Collins, J. F. Manganese and Mitochondrial Function. Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals 2017, 389– 396,  DOI: 10.1016/B978-0-12-802168-2.00032-4
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      Strukil, V.; Igrc, M. D.; Eckert-Maksic, M.; Friscic, T. Click Mechanochemistry: Quantitative Synthesis of ″Ready to Use″ Chiral Organocatalysts by Efficient Two-Fold Thiourea Coupling to Vicinal Diamines. Chem. - Eur. J. 2012, 18 (27), 8464– 8473,  DOI: 10.1002/chem.201200632
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      Click Mechanochemistry: Quantitative Synthesis of "Ready to Use" Chiral Organocatalysts by Efficient Two-Fold Thiourea Coupling to Vicinal Diamines
      Strukil, Vjekoslav; Igrc, Marina D.; Eckert-Maksic, Mirjana; Friscic, Tomislav
      Chemistry - A European Journal (2012), 18 (27), 8464-8473, S8464/1-S8464/42CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Mechanochem. methods of neat grinding and liq.-assisted grinding have been applied to the synthesis of mono- and bis(thiourea)s by using the click coupling of arom. and aliph. diamines with arom. isothiocyanates. The ability to modify the reaction conditions allowed the optimization of each reaction, leading to the quant. formation of chiral bis(thiourea)s with known uses as organocatalysts or anion sensors. Quant. reaction yields, combined with the fact that mechanochem. reaction conditions avoid the use of bulk solvents, enabled soln.-based purifn. methods (such as chromatog. or recrystn.) to be completely avoided. Importantly, by using selected model reactions, we also show that the described mechanochem. reaction procedures can be readily scaled up to at least the one-gram scale. In that way, mechanochem. synthesis provides a facile method to fully transform valuable enantiomerically pure reagents into useful products that can immediately be applied in their designed purpose. This was demonstrated by using some of the mechanochem. prepd. reagents as organocatalysts in a model Morita-Baylis-Hillman reaction and as cyanide ion sensors in org. solvents. The use of electronically and sterically hindered ortho-phenylenediamine revealed that mechanochem. reaction conditions can be readily optimized to form either the 1:1 or the 1:2 click-coupling product, demonstrating that reaction stoichiometry can be more efficiently controlled under these conditions than in soln.-based syntheses. In this way, it was shown that excellent stoichiometric control by mechanochem., previously established for mechanochem. syntheses of cocrystals and coordination polymers, can also be achieved in the context of covalent-bond formation.
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      Nichols, P. J.; Raston, C. L.; Steed, J. W. Engineering of porous pi-stacked solids using mechanochemistry. Chem. Commun. 2001, (12), 1062– 1063,  DOI: 10.1039/b103411c
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      Engineering of porous π-stacked solids using mechanochemistry
      Nichols, Peter J.; Raston, Colin L.; Steed, Jonathan W.
      Chemical Communications (Cambridge, United Kingdom) (2001), (12), 1062-1063CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Charge-assisted π-stacking interactions gave large porous arrays formed from the inclusion of metal tris(phenanthroline) cations into p-sulfonatocalix[4]arene anions. Thus, aq. [Ni(phen)3](NO3)2 was treated with Na5L (H5L = p-sulfonatocalix[4]arene) to give [Ni(phen)3]HL.nH2O (I) and [Na(H2O4)(phen)][Ni(phen)3]4(HL)L.nH2O (II). I is triclinic, space group P‾1, Z = 2, R1 = 0.1322, wR2 =0.4148. II is monoclinic, space group C2/c, Z = 8, R1 = 0.0739, wR2 = 0.2236.
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      Martins, I.; Martins, M.; Fernandes, A.; Andre, V.; Duarte, M. T. An insight into dapsone co-crystals: sulfones as participants in supramolecular interactions. CrystEngComm 2013, 15 (40), 8173– 8179,  DOI: 10.1039/c3ce41323c
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      An insight into dapsone co-crystals: sulfones as participants in supramolecular interactions
      Martins, Ines; Martins, Marta; Fernandes, Auguste; Andre, Vania; Duarte, M. Teresa
      CrystEngComm (2013), 15 (40), 8173-8179CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
      The authors disclose a new pathway for the design of dapsone co-crystals exploring the formation of N-H···O/N interactions using amide and pyridinic derivs. as potential co-formers. Two new co-crystals of dapsone, a sulfonamide antibiotic, with ε-caprolactam and 4,4'-bipyridine were synthesized preferentially by traditional soln. techniques, but mechanochem. also was addressed. The full structural characterization of these forms is discussed and shows that: (a) in the co-crystal with ε-caprolactam the typical NNH2···OSO2 interactions of dapsone mols. and the cages formed between them are disrupted by a new NNH2···OCONH interaction, in which ε-caprolactam mols. further form amide···amide R22(8) synthons and (b) in the co-crystal with 4,4'-bipyridine, the NNH2···OSO2 interactions between dapsone mols. are maintained and addnl. NNH2···Npyridine interactions are responsible for the formation of 4,4'-bipyridine channels between dapsone cages. Also, the thermal stability of these co-crystals is also discussed, showing that the co-formers leave the structure and hence the reported melting corresponds to the melting of pure dapsone.
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      Braga, D.; Maini, L.; Grepioni, F. Mechanochemical preparation of co-crystals. Chem. Soc. Rev. 2013, 42 (18), 7638– 7648,  DOI: 10.1039/c3cs60014a
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      Mechanochemical preparation of co-crystals
      Braga, Dario; Maini, Lucia; Grepioni, Fabrizia
      Chemical Society Reviews (2013), 42 (18), 7638-7648CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. The prepn. of co-crystals via mechanochem. combines the quest for clean and green processes with the investigation of multicomponent new materials, among the currently most fashionable systems in the crystal engineering field: the physico-chem. properties of the components add, merge or transform when co-crystals are formed, giving rise to potentially improved performance in "old" solid-state chem. fields, as in the pharmaceutical industry field, where they represent a way to obtain new formulations and to improve the properties (soly., thermal stability, compressibility, etc.) of both new and existing drugs.
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      André, V.; Quaresma, S. Bio-inspired metalorganic frameworks in the pharmaceutical world: a brief review. Metal-Organic Frameworks 2016, 135– 156,  DOI: 10.5772/64027
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      Bio-inspired metal-organic frameworks in the pharmaceutical world: a brief review
      Andre, Vania; Quaresma, Silvia
      Metal-Organic Frameworks (2016), (), 135-156CODEN: 69VUTH ISSN:. (InTech)
      One of the great challenges in the pharmaceutical industry is the search for more efficient and cost-effective ways to store and deliver existing drugs. Bio-inspired metalorg. frameworks (BioMOFs) are groundbreaking materials that have recently been explored for drug storage, delivery and controlled release as well as for applications in imaging and sensing for therapeutic and diagnostic. This review presents a brief overview on these materials, and by alluding to a few reported examples, it intends to clearly show the extremely important role that BioMOFs have been playing in the pharmaceutical field.
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      Andini, S.; Bolognese, A.; Formisano, D.; Manfra, M.; Montagnaro, F.; Santoro, L. Mechanochemistry of ibuprofen pharmaceutical. Chemosphere 2012, 88 (5), 548– 553,  DOI: 10.1016/j.chemosphere.2012.03.025
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      Mechanochemistry of ibuprofen pharmaceutical
      Andini, Salvatore; Bolognese, Adele; Formisano, Domenico; Manfra, Michele; Montagnaro, Fabio; Santoro, Luciano
      Chemosphere (2012), 88 (5), 548-553CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)
      In this paper mechanochem. has been studied in view of possible application to detoxification of expired pharmaceuticals. The expts. have been carried out with a com. medication contg. ibuprofen ((RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid) which has been submitted to prolonged milling up to 40 h. When Al(OH)3 is used as co-reagent, the first degrdn. step induced by the mechanochem. treatment is an acid-base reaction with the ibuprofen carboxylic acid group. The subsequent degrdn. follows a complex pathway leading to 1-(4-isobutylphenyl)ethanone, 1-isobutyl-4-vinylbenzene and 2-(4-(3-methylbutan-2-yl)phenyl)propan-1-ol after 10 h milling and, in addn., 1-(4-acetylphenyl)-2-methylpropan-1-one, 1-(4-(1-hydroxy-2-methylpropyl)phenyl)ethanone and 1-(4-(2-hydroxy-2-methylpropyl)phenyl)ethanone after 40 h milling. The degrdn. reaction path and products have been identified by means of FT-IR spectroscopy, thin layer chromatog., NMR spectroscopy, mass spectroscopy and elemental anal. The obsd. ibuprofen decarboxylation makes the drug simultaneously lose both its pharmaceutical activity and toxicity.
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      Chow, E. H. H.; Strobridge, F. C.; Friscic, T. Mechanochemistry of magnesium oxide revisited: facile derivatisation of pharmaceuticals using coordination and supramolecular chemistry. Chem. Commun. 2010, 46 (34), 6368– 6370,  DOI: 10.1039/c0cc01337d
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      Mechanochemistry of magnesium oxide revisited: facile derivatisation of pharmaceuticals using coordination and supramolecular chemistry
      Chow, Ernest H. H.; Strobridge, Fiona C.; Friscic, Tomislav
      Chemical Communications (Cambridge, United Kingdom) (2010), 46 (34), 6368-6370CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Liq.-assisted grinding allows the rapid, waste-free and one-pot synthesis of a variety of magnesium drug derivs. directly from the excipient MgO; such reactivity is relevant for the behavior of ibuprofen formulations involving MgO and can be used for oxide-based mechanosynthesis of metal-org. salts, discrete complexes and carboxylate clusters involving magnesium and pharmaceutically active ingredients.
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      Andre, V.; Quaresma, S.; Silva, J. L. F.; Duarte, M. T. Exploring mechanochemistry to turn organic bio-relevant molecules into metal-organic frameworks: a short review. Beilstein J. Org. Chem. 2017, 13, 2416– 2427,  DOI: 10.3762/bjoc.13.239
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      Exploring mechanochemistry to turn organic bio-relevant molecules into metal-organic frameworks: a short review
      Andre, Vania; Quaresma, Silvia; Ferreira da Silva, Joao Luis; Duarte, M. Teresa
      Beilstein Journal of Organic Chemistry (2017), 13 (), 2416-2427CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
      Mechanochem. is a powerful and environmentally friendly synthetic technique successfully employed in different fields of synthetic chem. Application spans from org. to inorg. chem. including the synthesis of coordination compds. Metal-org. frameworks (MOFs) are a class of compds. with numerous applications, from which we highlight herein their application in the pharmaceutical field (BioMOFs), whose importance has been growing and is now assuming a relevant and promising domain. The need to find cleaner, greener and more energy and material-efficient synthetic procedures led to the use of mechanochem. into the synthesis of BioMOFs.
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      Craig, S. L. Mechanochemistry: A tour of force. Nature 2012, 487 (7406), 176– 177,  DOI: 10.1038/487176a
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      Mechanochemistry: A tour of force
      Craig, Stephen L.
      Nature (London, United Kingdom) (2012), 487 (7406), 176-177CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      A review. The effect of force on a chem. reaction was visited in three different mol. environments. The results reveal a unifying framework that enables predictions of force-induced reactivity.
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      James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Friscic, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse, W. C.; Steed, J. W.; Waddell, D. C. Mechanochemistry: opportunities for new and cleaner synthesis. Chem. Soc. Rev. 2012, 41 (1), 413– 447,  DOI: 10.1039/C1CS15171A
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      Mechanochemistry: opportunities for new and cleaner synthesis
      James, Stuart L.; Adams, Christopher J.; Bolm, Carsten; Braga, Dario; Collier, Paul; Friscic, Tomislav; Grepioni, Fabrizia; Harris, Kenneth D. M.; Hyett, Geoff; Jones, William; Krebs, Anke; Mack, James; Maini, Lucia; Orpen, A. Guy; Parkin, Ivan P.; Shearouse, William C.; Steed, Jonathan W.; Waddell, Daniel C.
      Chemical Society Reviews (2012), 41 (1), 413-447CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. The aim of this crit. review is to provide a broad but digestible overview of mechanochem. synthesis, i.e. reactions conducted by grinding solid reactants together with no or minimal solvent. Although mechanochem. has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concg. on recent advances, this article covers industrial aspects, inorg. materials, org. synthesis, cocrystn., pharmaceutical aspects, metal complexes (including metal-org. frameworks), supramol. aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed.
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      Friscic, T. New opportunities for materials synthesis using mechanochemistry. J. Mater. Chem. 2010, 20 (36), 7599– 7605,  DOI: 10.1039/c0jm00872a
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      New opportunities for materials synthesis using mechanochemistry
      Friscic, Tomislav
      Journal of Materials Chemistry (2010), 20 (36), 7599-7605CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)
      Mechanochem. synthesis is experiencing a dynamic re-discovery in the areas of org. and metal-org. materials. Emerging mechanochem. methods, such as liq.-assisted grinding (LAG) or ion- and liq.-assisted grinding (ILAG) achieve enhanced mol. mobility through the addn. of near-stoichiometric amts. of a liq. phase to a solid-state reaction, and are aided by catalytic and templating effects. This article highlights the exciting areas of application for these mild mechanochem. methods: one-pot assembly of "soft" metal-org. and org. materials, and the rapid room-temp. synthesis of porous metal-org. frameworks directly from a metal oxide.
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      Beldon, P. J.; Fabian, L.; Stein, R. S.; Thirumurugan, A.; Cheetham, A. K.; Friscic, T. Rapid Room-Temperature Synthesis of Zeolitic Imidazolate Frameworks by Using Mechanochemistry. Angew. Chem., Int. Ed. 2010, 49 (50), 9640– 9643,  DOI: 10.1002/anie.201005547
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      Rapid Room-Temperature Synthesis of Zeolitic Imidazolate Frameworks by Using Mechanochemistry
      Beldon, Patrick J.; Fabian, Laszlo; Stein, Robin S.; Thirumurugan, A.; Cheetham, Anthony K.; Friscic, Tomislav
      Angewandte Chemie, International Edition (2010), 49 (50), 9640-9643, S9640/1-S9640/30CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Porous and nonporous zeolitic imidazolate frameworks (ZIFs) Zn(Im)2, Zn(MeIm)2 and Zn(EtIm)2 were prepd. by direct and topol. selective conversion of ZnO at room-temp. reaction with imidazole (HIm), 2-methylimidazole (HMeIm) and 2-ethylimidazole (HEtIm) using mechanochem.
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      Delori, A.; Friscic, T.; Jones, W. The role of mechanochemistry and supramolecular design in the development of pharmaceutical materials. CrystEngComm 2012, 14 (7), 2350– 2362,  DOI: 10.1039/c2ce06582g
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      The role of mechanochemistry and supramolecular design in the development of pharmaceutical materials
      Delori, Amit; Friscic, Tomislav; Jones, William
      CrystEngComm (2012), 14 (7), 2350-2362CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
      The development of modern pharmaceutical solid forms, including solvates, polymorphs, salts or cocrystals, is related to the design and control of mol. self-assembly processes. Mechanochem. has emerged as an excellent exptl. approach to rapidly and efficiently screen for and synthesize such pharmaceutical materials. This is particularly the case for pharmaceutical cocrystals which are of considerable interest in the area of modern solid-state pharmaceutical materials science. Mechanochem. has also been demonstrated as a successful technique to screen and synthesize metal-org. pharmaceutical derivs. (herein addressed as metallopharmaceuticals) as well as metallodrugs. The quant. yields and high crystallinity of products obtained via mechanochem. synthesis enables the efficient coupling of solvent-free screening and structure detn. from powder X-ray diffraction data to provide rapid advances in systematic studies and the structural understanding of pharmaceutical forms based on hydrogen bonding interactions or coordination bonds. In this review, we describe how mechanochem. methods have improved the development of new solid forms and their structural understanding, as well as the development of supramol. strategies for the crystal engineering of pharmaceutical solid forms.
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      Zhang, P.; Li, H.; Veith, G. M.; Dai, S. Soluble Porous Coordination Polymers by Mechanochemistry: From Metal-Containing Films/Membranes to Active Catalysts for Aerobic Oxidation. Adv. Mater. 2015, 27 (2), 234– 239,  DOI: 10.1002/adma.201403299
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      Soluble Porous Coordination Polymers by Mechanochemistry: From Metal-Containing Films/Membranes to Active Catalysts for Aerobic Oxidation
      Zhang, Pengfei; Li, Haiying; Veith, Gabriel M.; Dai, Sheng
      Advanced Materials (Weinheim, Germany) (2015), 27 (2), 234-239CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Soln. and solid state synthesis, surface areas and soly. of a family of 1-dimensional porous transition metal coordination polymers with the highly contorted and rigid ligand 5,5,6,6-tetrahydroxy-3,3,3,3-tetramethyl-1,1'-spirobisindane is reported. The oxidn. of β-isophorone by atm. oxygen is catalyzed by the sol. porous coordination polymers (SPCPs). Hybrid SPCPs with tetrafluoroterephthalonitrile are also prepd.
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      Garay, A. L.; Pichon, A.; James, S. L. Solvent-free synthesis of metal complexes. Chem. Soc. Rev. 2007, 36 (6), 846– 855,  DOI: 10.1039/b600363j
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      Solvent-free synthesis of metal complex
      Garay, Ana Lazuen; Pichon, Anne; James, Stuart L.
      Chemical Society Reviews (2007), 36 (6), 846-855CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Avoiding the use of solvents in synthesis can reduce environmental contamination and even be more convenient than using solvent-based synthesis. In this tutorial review the authors focus on recent research into the use of mechanochem. (grinding) to synthesize metal complex in the absence of solvent. The authors include synthesis of mononuclear complex, coordination clusters, spacious coordination cages, and 1-, 2- and 3-dimensional coordination polymers (metal org. frameworks) which can even exhibit microporosity. Remarkably, in many cases, mechanochem. synthesis is actually faster and more convenient than the original solvent-based methods. Examples of solvent-free methods other than grinding are also briefly discussed, and the pos. outlook for this growing topic is emphasized.
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      Friscic, T. Supramolecular concepts and new techniques in mechanochemistry: cocrystals, cages, rotaxanes, open metal-organic frameworks. Chem. Soc. Rev. 2012, 41 (9), 3493– 3510,  DOI: 10.1039/c2cs15332g
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      Supramolecular concepts and new techniques in mechanochemistry: cocrystals, cages, rotaxanes, open metal-organic frameworks
      Friscic, Tomislav
      Chemical Society Reviews (2012), 41 (9), 3493-3510CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Mechanochem. reactions effected by milling or grinding are an attractive means to conduct chem. reactions dependent on mol. recognition and to systematically explore different modes of mol. self-assembly. The natural relation between milling mechanochem. and supramol. chem. arises primarily from the ability to avoid bulk solvent, which simultaneously avoids limitations of soln.-based chem., such as soly., solvent complexation, or solvolysis, and makes the resulting process highly environmentally friendly. This tutorial review highlights the use of mechanochem. for the synthesis of supramol. targets in the solid state, such as mol. hydrogen- or halogen-bonded complexes, mol. and supramol. cages, open frameworks and interlocked architectures. Also the mol. self-assembly phenomena that are well-established in soln. chem., such as reversible binding through covalent or non-covalent bonds, thermodn. equilibration and structure templating, are also accessible in milling mechanochem. through recently developed highly efficient methodologies such as liq.-assisted grinding (LAG) or ion- and liq.-assisted grinding (ILAG). Also highlighted are the new opportunities arising from the marriage of concepts of supramol. and mechanochem. synthesis, including organocatalysis, deracemization and discovery of new mol. recognition motifs.
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      Andre, V.; Hardeman, A.; Halasz, I.; Stein, R. S.; Jackson, G. J.; Reid, D. G.; Duer, M. J.; Curfs, C.; Duarte, M. T.; Friscic, T. Mechanosynthesis of the Metallodrug Bismuth Subsalicylate from Bi2O3 and Structure of Bismuth Salicylate without Auxiliary Organic Ligands. Angew. Chem., Int. Ed. 2011, 50 (34), 7858– 7861,  DOI: 10.1002/anie.201103171
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      Mechanosynthesis of the Metallodrug Bismuth Subsalicylate from Bi2O3 and Structure of Bismuth Salicylate without Auxiliary Organic Ligands
      Andre, Vania; Hardeman, Andrew; Halasz, Ivan; Stein, Robin S.; Jackson, Graham J.; Reid, David G.; Duer, Melinda J.; Curfs, Caroline; Duarte, M. Teresa; Friscic, Tomislav
      Angewandte Chemie, International Edition (2011), 50 (34), 7858-7861, S7858/1-S7858/19CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Mechanochem. reactions of Bi2O3 with salicylic acid (H2sal) were investigated with and without ion- and liq.-assisted grinding (ILAG), i.e., addn. of NH4NO3 or KNO3, and water. Quant. and selective conversions to different forms of bismuth salicylate were found, including formation of the pharmaceutical ingredient bismuth subsalicylate, [BiO(Hsal)]. Bismuth disalicylate hydrate, [Bi(sal)(Hsal)(H2O)]n, without auxiliary org. ligands, was characterized by powder XRD as 2-dimensional sheets. Bismuth trisalicylate was also isolated from product mixts. Recrystn. of bismuth disalicylate from DMF afforded cuboctahedral cluster [Bi38O64(Hsal)26(H2O)4(DMF)18], which was characterized by single-crystal x-ray crystallog.
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      Quaresma, S.; Andre, V.; Fernandes, A.; Duarte, M. T. Mechanochemistry - a green methodology leading to metallodrugs, metallopharmaceuticals and bio-inspired metal-organic frameworks. Inorg. Chim. Acta 2017, 455, 309– 318,  DOI: 10.1016/j.ica.2016.09.033
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      Mechanochemistry - A green synthetic methodology leading to metallodrugs, metallopharmaceuticals and bio-inspired metal-organic frameworks
      Quaresma, Silvia; Andre, Vania; Fernandes, Auguste; Duarte, M. Teresa
      Inorganica Chimica Acta (2017), 455 (Part_2), 309-318CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
      Mechanochem. an environment-friendly synthetic technique has been successfully used in the search for new metallopharmaceuticals, metallodrugs and bio-inspired metal-org. frameworks. These materials recently became highly promising on the pharmaceutical and medical field due to their ability to function as drug carriers, allowing a controlled drug delivery and release in addn. to potential applications in imaging and magnetic resonance imaging for diagnostic and therapy. Here we refer to some of our previous results on Ag and Ni with piracetam and 4-aminosalicylic acid complexes as well as on the bismuth salicylates metallodrugs. Our results on bioinspired gabapentin networks are also discussed. Furthermore we disclose herein novel metallopharmaceuticals with flufenamic acid and a bio-inspired framework with muconic acid. The synthesis and structural characterization of these materials is described and their thermal and on-shelf stability was assessed, showing that they are stable under the relevant temp. range for pharmaceutical applications.
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      Hasa, D.; Carlino, E.; Jones, W. Polymer-Assisted Grinding, a Versatile Method for Polymorph Control of Cocrystallization. Cryst. Growth Des. 2016, 16 (3), 1772– 1779,  DOI: 10.1021/acs.cgd.6b00084
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      Polymer-Assisted Grinding, a Versatile Method for Polymorph Control of Cocrystallization
      Hasa, Dritan; Carlino, Elvio; Jones, William
      Crystal Growth & Design (2016), 16 (3), 1772-1779CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Despite the great interest that cocrystals are currently gaining for their application to the design of new supramol. structures with desired functional properties, studies concerning new exptl. strategies capable of controlling polymorphism phenomena of a given system are scarcely reported. We propose herein the use of polymer-assisted grinding (POLAG) as a new method for the selective control of the product polymorphic form in a mechanochem. cocrystn. reaction. Specifically, to the model system selected in this study formed by caffeine and glutaric acid, we demonstrate that the polymorphic outcome can be controlled by modifying the no. of monomer units of the catalyst from the shortest dimer to a polymer with chains of approx. 1000 units. The characteristics of each polymorphic form were investigated by low-dose high-resoln. TEM, and the mechanistic aspects of the cocrystal formation were studied through a series of ex situ and interconversion expts. The results suggest that for this system the modification of the catalyst chain length and, consequently, modification of polarity drives cocrystal formation toward the more stable polymorph. The approach proposed in this paper can be readily applied to each system, where polarity is the main issue for polymorph control without the risk of solvate formation.
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      Hasa, D.; Rauber, G. S.; Voinovich, D.; Jones, W. Cocrystal Formation through Mechanochemistry: from Neat and Liquid-Assisted Grinding to Polymer-Assisted Grinding. Angew. Chem., Int. Ed. 2015, 54 (25), 7371– 7375,  DOI: 10.1002/anie.201501638
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      Cocrystal Formation through Mechanochemistry: from Neat and Liquid-Assisted Grinding to Polymer-Assisted Grinding
      Hasa, Dritan; Schneider Rauber, Gabriela; Voinovich, Dario; Jones, William
      Angewandte Chemie, International Edition (2015), 54 (25), 7371-7375CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Mechanochem. is an effective method for the prepn. of multicomponent crystal systems. In the present work, we propose an alternative to the established liq.-assisted grinding (LAG) approach. Polymer-assisted grinding (POLAG) is demonstrated to provide a new class of catalysts for improving reaction rate and increasing product diversity during mechanochem. cocrystn. reactions. We demonstrate that POLAG provides advantages comparable to the conventional liq.-assisted process, while eliminating the risk of unwanted solvate formation as well as enabling control of resulting particle size. It represents a new approach for the development of functional materials through mechanochem., and possibly opens new routes toward the understanding of the mechanisms and pathways of mechanochem. cocrystal formation.
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      Khadka, P.; Ro, J.; Kim, H.; Kim, I.; Kim, J. T.; Kim, H.; Cho, J. M.; Yun, G.; Lee, J. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. Asian J. Pharm. Sci. 2014, 9 (6), 304– 316,  DOI: 10.1016/j.ajps.2014.05.005
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      Turel, I. The interactions of metal ions with quinolone antibacterial agents. Coord. Chem. Rev. 2002, 232 (1–2), 27– 47,  DOI: 10.1016/S0010-8545(02)00027-9
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      The interactions of metal ions with quinolone antibacterial agents
      Turel, Iztok
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      A review of selected crystal structures of quinolone-metal compds. and the results of different physicochem. methods (thermal anal., potentiometric measurements, IR, UV-visible, NMR spectroscopy) as well as some results of bioactivity tests. The quinolones are a group of synthetic antibacterial agents structurally related to nalidixic acid. The absorption of quinolone drugs is lowered when they are consumed simultaneously with Mg or Al antacids. Many other ions found in pharmaceuticals cause similar effect. The proposed reason for such behavior is the chelate bonding of the quinolone to the metal.
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      Chen, Z. F.; Xiong, R. G.; Zuo, J. L.; Guo, Z. J.; You, X. Z.; Fun, H. K. X-Ray crystal structures of Mg2+ and Ca2+ dimers of the antibacterial drug norfloxacin. Journal of the Chemical Society-Dalton Transactions 2000, (22), 4013– 4014,  DOI: 10.1039/b006806n
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      Xiao, D. R.; Wang, E. B.; An, H. Y.; Su, Z. M.; Li, Y. G.; Gao, L.; Sun, C. Y.; Xu, L. Rationally designed, polymeric, extended metal-ciprofloxacin complexes. Chem. - Eur. J. 2005, 11 (22), 6673– 6686,  DOI: 10.1002/chem.200500548
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      Rationally designed, polymeric, extended metal-ciprofloxacin complexes
      Xiao, Dong-Rong; Wang, En-Bo; An, Hai-Yan; Su, Zhong-Min; Li, Yang-Guang; Gao, Lei; Sun, Chun-Yan; Xu, Lin
      Chemistry - A European Journal (2005), 11 (22), 6673-6686CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Reactions of the antimicrobial fluoroquinolone ciprofloxacin (cfH) with metal salts in the presence of arom. polycarboxylate ligands or under basic conditions produce fourteen new metal-cfH complexes, namely, [Ba2(cf)2(1,4-bdc)(H2O)2].H2O (1), [Sr6(cf)6(1,4-bdc)3(H2O)6].2H2O (2), [M2(cfH)2(bptc)(H2O)2].8H2O (M = Mn (3) and Cd(4)), [M(cfH)(1,3-bdc)] (M = Mn (5), Co (6), and Zn (7)), [Zn2(cfH)4(1,4-bdc)](1,4-bdc).13H2O (8), [Ca(cfH)2(1,2-Hbdc)2].2H2O (9) and [M(cf)2].2.5H2O (M = Mn (10), Co (11), Zn (12), Cd (13), and Mg (14)) (1,4-bdc = 1,4-benzenedicarboxylate, bptc = 3,3',4,4'-benzophenonetetracarboxylate, 1,3-bdc = 1,3-benzenedicarboxylate, 1,2-bdc = 1,2-benzenedicarboxylate). Their structures were detd. by single-crystal x-ray diffraction analyses and further characterized by elemental analyses, IR spectra, and thermogravimetric analyses. The structures of 1 and 2 consist of unique two-dimensional arm-shaped layers. Compds. 3 and 4 are isostructural and feature 1-dimensional structures formed from the interconnection of [M2(cfH)2(H2O)2] dimers with bptc ligands. Compds. 5-7 are isostructural and contain double-chain-like ribbons constructed from [M2(cfH)2(CO2)2] dimers and 1,3-bdc. Compd. 8 consists of a pair of [Zn(cfH)2]2+ fragments bridged by a 1,4-bdc into a dinuclear dumbbell structure. Compd. 9 is a neutral monomeric complex. To the best of the authors' knowledge, compds. 1-9 are the first examples of metal-quinolone complexes that contain arom. polycarboxylate ligands. Compds. 10-14 are isostructural and exhibit interesting two-dimensional rhombic grids featuring large cavities with dimensions of 13.6 × 13.6 Å. Polymeric extended metal-cfH complexes have never been reported.
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      Turel, I.; Zivec, P.; Pevec, A.; Tempelaar, S.; Psomas, G. Compounds of antibacterial agent ciprofloxacin and magnesium - Crystal structures and molecular modeling calculations. Eur. J. Inorg. Chem. 2008, 2008 (23), 3718– 3727,  DOI: 10.1002/ejic.200800338
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      Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. Mercury CSD 2.0 - new features for the visualization and investigation of crystal structures. J. Appl. Crystallogr. 2008, 41, 466– 470,  DOI: 10.1107/S0021889807067908
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      Mercury CSD 2.0 - new features for the visualization and investigation of crystal structures
      Macrae, Clare F.; Bruno, Ian J.; Chisholm, James A.; Edgington, Paul R.; McCabe, Patrick; Pidcock, Elna; Rodriguez-Monge, Lucia; Taylor, Robin; van de Streek, Jacco; Wood, Peter A.
      Journal of Applied Crystallography (2008), 41 (2), 466-470CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)
      The program Mercury, developed by the Cambridge Crystallog. Data Center, is designed primarily as a crystal structure visualization tool. A new module of functionality has been produced, called the Materials Module, which allows highly customizable searching of structural databases for intermol. interaction motifs and packing patterns. This new module also includes the ability to perform packing similarity calcns. between structures contg. the same compd. In addn. to the Materials Module, a range of further enhancements to Mercury has been added in this latest release, including void visualization and links to ConQuest, Mogul and IsoStar.
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      Siopa, F.; Figueiredo, T.; Frade, R. F. M.; Neto, I.; Meirinhos, A.; Reis, C. P.; Sobral, R. G.; Afonso, C. A. M.; Rijo, P. Choline-Based Ionic Liquids: Improvement of Antimicrobial Activity. Chemistryselect 2016, 1 (18), 5909– 5916,  DOI: 10.1002/slct.201600864
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      Choline-Based Ionic Liquids: Improvement of Antimicrobial Activity
      Siopa, Filipa; Figueiredo, Teresa; Frade, Raquel F. M.; Neto, Iris; Meirinhos, Ana; Reis, Catarina P.; Sobral, Rita G.; Afonso, Carlos A. M.; Rijo, Patricia
      ChemistrySelect (2016), 1 (18), 5909-5916CODEN: CHEMUD; ISSN:2365-6549. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Antibiotic resistance is a global public health concern. The choline-based ionic liqs. (ILs) have raised particular attention in the design of "greener" ILs and can exert a broad-spectrum of antimicrobial activity. To improve antimicrobial chemotherapy, the authors herein tested the antimicrobial activity and toxicity of a wide range of choline-based ILs. Two series of compds. were synthesized -dimethylethanolamine monoquaternary ammonium salts (Series A) and -Me diethanolamine, diethanolamine and triethanolamine monoquaternary ammonium salts (Series B). The antimicrobial screening revealed that compds. N-(2-hydroxyethyl)-N,N-dimethyl-1-tetradecanaminium bromide ([N1,1,14,2(OH)]Br), N-(2-hydroxyethyl)-N,N-dimethyl-1-hexadecanaminium bromide ([N1,1,16,2(OH)]Br) and N-(2-hydroxyethyl)-N,N-dimethyl-1-octadecanaminium bromide ([N1,1,18,2(OH)]Br) are potent antimicrobial agents. The presence of a hydroxyethyl group and as mention previously in the literature, the C14 to C16 linker in a choline compd. improves the antimicrobial activity and lowers the cytotoxic properties of this class of compds.
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