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Título: | Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors |
Autor: | Xu, Jimin; Berastegui-Cabrera, Judith CSIC; Ye, Na; Carretero-Ledesma, Marta CSIC ORCID; Pachón, Jerónimo CSIC ORCID; Chen, Haiying; Pachón-Ibáñez, M. E. CSIC ORCID; Sánchez-Céspedes, Javier CSIC ORCID; Zhou, Jia | Fecha de publicación: | 28-oct-2020 | Editor: | American Chemical Society | Citación: | Journal of Medicinal Chemistry 63(21): 12830-12852 (2020) | Resumen: | An effective therapy for human adenovirus (HAdV) infections in immunocompromised patients and healthy individuals with community-acquired pneumonia remains an unmet medical need. We herein reported a series of novel substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds 6, 15, 29, 40, 43, 46, 47, and 54 exhibited increased selectivity indexes (SI > 100) compared to the lead compound niclosamide, while maintaining sub-micromolar to low micromolar potency against HAdV. The preliminary mechanistic studies indicated that compounds 6 and 43 possibly target the HAdV DNA replication process, while compounds 46 and 47 suppress later steps of HAdV life cycle. Notably, among these derivatives, compound 15 showed improved anti-HAdV activity (IC50 = 0.27 μM), significantly decreased cytotoxicity (CC50 = 156.8 μM), and low in vivo toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further in vivo efficacy studies for the treatment of HAdV infections. | Versión del editor: | http://doi.org/10.1021/acs.jmedchem.0c01226 | URI: | http://hdl.handle.net/10261/237203 | DOI: | 10.1021/acs.jmedchem.0c01226 | Identificadores: | doi: 10.1021/acs.jmedchem.0c01226 e-issn: 1520-4804 issn: 0022-2623 |
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