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

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.

• Authors: Jimin Xu, Judith Berastegui-Cabrera, Na Ye, Marta Carretero-Ledesma, Jerónimo Pachón-Díaz, Haiying Chen, Maria Eugenia Pachón-Ibáñez, Javier Sánchez-Céspedes, Jia Zhou
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 21 Pg. 12830-12852 (11 12 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 33112138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-chloro-2-hydroxybenzamide
• Antiviral Agents
• Benzamides

Topics

• Adenoviruses, Human (drug effects, physiology)
• Animals
• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Benzamides (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cricetinae
• Drug Evaluation, Preclinical
• Humans
• Lethal Dose 50
• Structure-Activity Relationship
• Virus Internalization (drug effects)
• Virus Replication (drug effects)