Nitrogen-Containing Flavonoids—Preparation and Biological Activity

In this work, we report the application of Buchwald–Hartwig amination for the preparation of new derivatives of quercetin and luteolin. Our investigation delves into the impact of aniline moiety on antioxidant, and anti-inflammatory activity, cytotoxicity, and the ability of flavonoids to modulate drug-resistance mechanisms in bacteria. The anti-inflammatory activity disappeared after the introduction of aniline into the flavonoids and the cytotoxicity remained low. Although the ability of quercetin and luteolin to modulate bacterial resistance to antibiotics has already been published, this is the first report on the molecular mechanism of this process. Both flavonoids attenuate erythromycin resistance by suppressing the ribosomal methyltransferase encoded by the ermA gene in Staphylococcus aureus. Notably, 4-(trifluoromethyl)anilino quercetin emerged as a potent ErmA inhibitor, likely by interacting with the RNA-binding pocket of ErmA. Additionally, both 4-fluoroanilino derivatives effectively impended the staphylococcal efflux system. All the prepared derivatives exhibited superior activity in modulating gentamicin resistance in S. aureus compared to the parent compounds. Overall, the incorporation of substituted anilines into the flavonoid core significantly enhanced its ability to combat multidrug resistance in bacteria.

NO production IL-6 production TNFα production   "/" means that there isn't any binding pose in that pocket.

Figure S1 .
Figure S1.The observed differences in SAM orientation are attributed to the presence of water HOH-949.

Table S4 .
Cytotoxicity of the prepared derivatives is measured as the ability of flavonoids to halve the viability of immortalized human keratinocytes (HaCaT) and human dermal fibroblasts (HDF).

Table S6 .
Mode of antimicrobial action of quercetin, luteolin and their derivatives with gentamicin against methicilin-resistant Staphylococcus aureus 3596 strain positive for the presence of the aadD gene encoding 4′,4″-adenyltransferase and the strain 1584 positive for the presence of the aac(6')/aph(2') gene encoding bifunctional aminoglycoside-modifying enzyme with acetylation and phosphotransferase activities.

Table S7 .
quercetin (4), luteolin (10), and their selected derivatives into the model of ribosomal methyltransferase (encoded by the ermC gene).The table illustrates the best free energy of binding score ΔG (kcal/mol) value.