Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 3; pp. 744 - 749
• Main Authors: Dai, Dongcheng, Burgeson, James R., Gharaibeh, Dima N., Moore, Amy L., Larson, Ryan A., Cerruti, Natasha R., Amberg, Sean M., Bolken, Tove’ C., Hruby, Dennis E.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.02.2013; Elsevier
• Subjects: Animals; Antiviral; Antiviral activity; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; antiviral properties; Arenavirus; Arenavirus - drug effects; Benzimidazole; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Broad-spectrum inhibitor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cores; Disease Models, Animal; Drug Discovery; Entry inhibitor; Envelopes; genes; Glycoproteins; Guinea Pigs; high-throughput screening; Lassa fever; Lassa virus; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Ribavirin; SAR; Science & Technology; screening; Small Molecule Libraries; Lassa fever; Entry inhibitor; SAR; Broad-spectrum inhibitor; Antiviral; Lassa virus; Arenavirus; FUSION; IDENTIFICATION; FEVER
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.11.095

A chemically diverse library of about 400,000 small molecules was screened for antiviral activity against lentiviral pseudotypes with the Lassa virus envelope glycoprotein (LASV GP) gene incorporated. High-throughput screening resulted in discovery of a hit compound (ST-37) possessing a benzimidazole core which led to a potent compound series. Herein, we report SAR studies which involved structural modifications to the phenyl rings and methylamino linker portion attached to the benzimidazole core. Many analogs in this study possessed single digit nanomolar potency against LASV pseudotypes. Compounds in this benzimidazole series also exhibited nanomolar antiviral activity against pseudotypes generated from other arenavirus envelopes indicating the potential for development of a broad-spectrum inhibitor. Ultimately, lead compound ST-193 was identified and later found to be efficacious in a lethal LASV guinea pig model showing superior protection compared to ribavirin treatment.