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. 2013 Nov 1;23(21):5840-3.
doi: 10.1016/j.bmcl.2013.08.103. Epub 2013 Sep 5.

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

James R Burgeson  1 , Dima N Gharaibeh, Amy L Moore, Ryan A Larson, Sean M Amberg, Tove' C Bolken, Dennis E Hruby, Dongcheng Dai
Affiliations

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

James R Burgeson et al. Bioorg Med Chem Lett. .

Abstract

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.

Keywords: Antiviral; Arenavirus; Lassa fever; Lassa virus; SAR.

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Figures

Figure 1
Figure 1
Cyclopropyl N-acylhydrazone-linked scaffold
Figure 2
Figure 2
HTS hit
Scheme 1
Scheme 1
Reagents and conditions: (a) EtOH, rt, 18 h, reflux, 4 h (78%).
See this image and copyright information in PMC

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