title: Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole.
abstract: 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.
authors.affiliation: SIGA Technologies, Inc., 4575 SW Research Way, Suite 230, Corvallis, OR 97333, USA. ddai@siga.com
authors.forename: Dongcheng
authors.initials: D
authors.lastname: Dai
authors.forename: James R
authors.initials: JR
authors.lastname: Burgeson
authors.forename: Dima N
authors.initials: DN
authors.lastname: Gharaibeh
authors.forename: Amy L
authors.initials: AL
authors.lastname: Moore
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Larson
authors.forename: Natasha R
authors.initials: NR
authors.lastname: Cerruti
authors.forename: Sean M
authors.initials: SM
authors.lastname: Amberg
authors.forename: Tove' C
authors.initials: TC
authors.lastname: Bolken
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hruby
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018050:Arenavirus / Q000187:drug effects*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004195:Disease Models, Animal; D055808:Drug Discovery; D006168:Guinea Pigs; D054852:Small Molecule Libraries
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; C581846:ST-193; D054852:Small Molecule Libraries