Lead optimization of an acylhydrazone scaffold possessing antiviral activity against Lassa virus.
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.
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James R
JR
Burgeson
Dima N
DN
Gharaibeh
Amy L
AL
Moore
Ryan A
RA
Larson
Sean M
SM
Amberg
Tove' C
TC
Bolken
Dennis E
DE
Hruby
Dongcheng
D
Dai
D000215:Acylation; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology*; D007835:Lassa Fever / Q000188:drug therapy; D007836:Lassa virus / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D006835:Hydrazones; D054852:Small Molecule Libraries
Antiviral; Arenavirus; Lassa fever; Lassa virus; SAR