Discovery of Novel Substituted <i>N</i>-(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 <i>N</i>-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds <b>6</b>, <b>15</b>, <b>29</b>, <b>40</b>, <b>43</b>, <b>46</b>, <b>47</b>, and <b>54</b> 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 <b>6</b> and <b>43</b> possibly target the HAdV DNA replication process, while compounds <b>46</b> and <b>47</b> suppress later steps of HAdV life cycle. Notably, among these derivatives, compound <b>15</b> showed improved anti-HAdV activity (IC₅₀ = 0.27 μM), significantly decreased cytotoxicity (CC₅₀ = 156.8 μM), and low <i>in vivo</i> toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further <i>in vivo</i> efficacy studies for the treatment of HAdV infections.