Lead optimization of an acylhydrazone scaffold possessing antiviral activity against Lassa virus

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 21; pp. 5840 - 5843
• Main Authors: Burgeson, James R., Gharaibeh, Dima N., Moore, Amy L., Larson, Ryan A., Amberg, Sean M., Bolken, Tove’ C., Hruby, Dennis E., Dai, Dongcheng
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2013; Elsevier
• Subjects: Acylation; Antiviral; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; antiviral properties; Arenaviridae; Arenavirus; benzimidazole; chemical analysis; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Discovery; glycoproteins; Humans; Hydrazones - chemistry; Hydrazones - pharmacology; Lassa fever; Lassa Fever - drug therapy; Lassa virus; Lassa virus - drug effects; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; SAR; Science & Technology; screening; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; stereochemistry; viruses; Antiviral; Lassa fever; Lassa virus; SAR; Arenavirus; ACTIVATION; DESIGN; ACID; RECEPTOR; DISCOVERY; POTENT; BENZIMIDAZOLE; INHIBITORS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.08.103

SAR analysis and optimization of an acylhydrazone-linked scaffold for potential treatment of arenavirus derived hemorrhagic fever. Previously we reported the optimization of antiviral scaffolds containing benzimidazole and related heterocycles possessing activity against a variety of arenaviruses. These series of compounds were discovered through an HTS campaign of a 400,000 small molecule library using lentivirus-based pseudotypes incorporated with the Lassa virus envelope glycoprotein (LASV GP). This screening also uncovered an alternate series of very potent arenavirus inhibitors based upon an acylhydrazone scaffold. Subsequent SAR analysis of this chemical series involved various substitutions throughout the chemical framework along with assessment of the preferred stereochemistry. These studies led to an optimized analog (ST-161) possessing subnanomolar activity against LASV and submicromolar activity against a number of other viruses in the Arenaviridae family.