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

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 -(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds , , , , , , , and 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 and possibly target the HAdV DNA replication process, while compounds and suppress later steps of HAdV life cycle. Notably, among these derivatives, compound showed improved anti-HAdV activity (IC = 0.27 μM), significantly decreased cytotoxicity (CC = 156.8 μM), and low toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further efficacy studies for the treatment of HAdV infections.