2. Academic Validation
  3. Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors

Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors

  • J Med Chem. 2020 Nov 12;63(21):12830-12852. doi: 10.1021/acs.jmedchem.0c01226.
Jimin Xu 1,  Judith Berastegui-Cabrera 2,  Na Ye 1,  Marta Carretero-Ledesma 2,  Jerónimo Pachón-Díaz 2 3,  Haiying Chen 1,  Maria Eugenia Pachón-Ibáñez 2,  Javier Sánchez-Céspedes 2,  Jia Zhou 1
Affiliations

Affiliations

  • 1 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
  • 2 Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, E-41013 Seville, Spain.
  • 3 Department of Medicine, University of Seville, E-41009 Seville, Spain.
PMID: 33112138 DOI: 10.1021/acs.jmedchem.0c01226
Abstract

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.

Figures