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Serinol-Based Benzoic Acid Esters as New Scaffolds for the Development of Adenovirus Infection Inhibitors: Design, Synthesis, and In Vitro Biological Evaluation

  • Sarah Mazzotta
    Sarah Mazzotta
    Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, Profesor García González 2, E-41071 Seville, Spain
    Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy
  • Judith Berastegui-Cabrera
    Judith Berastegui-Cabrera
    Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, E41013 Seville, Spain
  • Gabriele Carullo
    Gabriele Carullo
    Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy
    Department of Biotechnology, Chemistry and Pharmacy, DoE 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
  • Margarita Vega-Holm*
    Margarita Vega-Holm
    Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, Profesor García González 2, E-41071 Seville, Spain
    *Email: [email protected]
  • Marta Carretero-Ledesma
    Marta Carretero-Ledesma
    Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, E41013 Seville, Spain
  • Lara Mendolia
    Lara Mendolia
    Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, Profesor García González 2, E-41071 Seville, Spain
  • Francesca Aiello
    Francesca Aiello
    Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy
  • Fernando Iglesias-Guerra*
    Fernando Iglesias-Guerra
    Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, Profesor García González 2, E-41071 Seville, Spain
    *Email: [email protected]
  • Jerónimo Pachón
    Jerónimo Pachón
    Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, E41013 Seville, Spain
    Department of Medicine, University of Seville, E-41009 Seville, Spain
  • José Manuel Vega-Pérez
    José Manuel Vega-Pérez
    Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, Profesor García González 2, E-41071 Seville, Spain
  • , and 
  • Javier Sánchez-Céspedes*
    Javier Sánchez-Céspedes
    Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, E41013 Seville, Spain
    *Email: [email protected]
Cite this: ACS Infect. Dis. 2021, 7, 6, 1433–1444
Publication Date (Web):October 19, 2020
https://doi.org/10.1021/acsinfecdis.0c00515
Copyright © 2020 American Chemical Society

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    Abstract

    Abstract Image

    Over the years, human adenovirus (HAdV) has progressively been recognized as a significant viral pathogen. Traditionally associated with self-limited respiratory, gastrointestinal, and conjunctival infections, mainly in immunocompromised patients, HAdV is currently considered to be a pathogen presenting significant morbidity and mortality in both immunosuppressed and otherwise healthy individuals. Currently available therapeutic options are limited because of their lack of effectivity and related side effects. In this context, there is an urgent need to develop effective anti-HAdV drugs with suitable therapeutic indexes. In this work, we identified new serinol-derived benzoic acid esters as novel scaffolds for the inhibition of HAdV infections. A set of 38 compounds were designed and synthesized, and their antiviral activity and cytotoxicity were evaluated. Four compounds (13, 14, 27, and 32) inhibited HAdV infection at low micromolar concentrations (2.82–5.35 μM). Their half maximal inhibitory concentration (IC50) values were lower compared to that of cidofovir, the current drug of choice. All compounds significantly reduced the HAdV DNA replication process, while they did not block any step of the viral entry. Our results showed that compounds 13, 14, and 32 seem to be targeting the expression of the E1A early gene. Moreover, all four derivatives demonstrated a significant inhibition of human cytomegalovirus (HCMV) DNA replication. This new scaffold may represent a potential tool useful for the development of effective anti-HAdV drugs.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00515.

    • Full description of the chemical characterization of compounds 950; copies of NMR spectra of compounds 950, Figures S1–S39 (PDF)

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    Cited By

    This article is cited by 7 publications.

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    2. María Balsera-Manzanero, Francesca Ghirga, Ana Ruiz-Molina, Mattia Mori, Jerónimo Pachón, Bruno Botta, Elisa Cordero, Deborah Quaglio, Javier Sánchez-Céspedes. Inhibition of adenovirus transport from the endosome to the cell nucleus by rotenone. Frontiers in Pharmacology 2024, 14 https://doi.org/10.3389/fphar.2023.1293296
    3. Chong Liang, Wei Zhao, Xutang Liu, Fei Wang, Zhijie Jiang. Controllable selectivity of carboxylic acids produced by H 3+n [PMo 12‐n V n O 40 ]‐catalyzed oxidation of lignite and its oxidative mechanism analysis. ChemistrySelect 2023, 8 (43) https://doi.org/10.1002/slct.202303563
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    5. Gabriele Carullo, Simona Saponara, Amer Ahmed, Beatrice Gorelli, Sarah Mazzotta, Alfonso Trezza, Beatrice Gianibbi, Giuseppe Campiani, Fabio Fusi, Francesca Aiello. Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels. Marine Drugs 2022, 20 (8) , 515. https://doi.org/10.3390/md20080515
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    7. Sarah Mazzotta, Judith Berastegui-Cabrera, Margarita Vega-Holm, María del Rosario García-Lozano, Marta Carretero-Ledesma, Francesca Aiello, José Manuel Vega-Pérez, Jerónimo Pachón, Fernando Iglesias-Guerra, Javier Sánchez-Céspedes. Design, synthesis and in vitro biological evaluation of a novel class of anti-adenovirus agents based on 3-amino-1,2-propanediol. Bioorganic Chemistry 2021, 114 , 105095. https://doi.org/10.1016/j.bioorg.2021.105095

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