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

Jimin Xu, Judith Berastegui-Cabrera, Na Ye, Marta Carretero-Ledesma, Jerónimo Pachón-Díaz, Haiying Chen, Maria Eugenia Pachón-Ibáñez, Javier Sánchez-Céspedes, Jia Zhou

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)12830-12852
Number of pages23
JournalJournal of medicinal chemistry
Volume63
Issue number21
DOIs
StatePublished - Nov 12 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors'. Together they form a unique fingerprint.

Cite this