Discovery of a novel highly potent broad-spectrum heterocyclic chemical series of arenavirus cell entry inhibitors

Michael B. Plewe, Vidyasagar Reddy Gantla, Nadezda V. Sokolova, Young Jun Shin, Shibani Naik, Eric R. Brown, Alexandra Fetsko, Lihong Zhang, Birte Kalveram, Alexander N. Freiberg, Greg Henkel, Ken McCormack

Research output: Contribution to journalArticlepeer-review

Abstract

We identified and explored the structure–activity relationship (SAR) of a novel heterocyclic chemical series of arenavirus cell entry inhibitors. Optimized lead compounds, including diphenyl-substituted imidazo[1,2-a]pyridines, benzimidazoles, and benzotriazoles exhibited low to sub-nanomolar potency against both pseudotyped and infectious Old and New World arenaviruses, attractive metabolic stability in human and most nonhuman liver microsomes as well as a lack of hERG K + channel or CYP enzyme inhibition. Moreover, the straightforward synthesis of several lead compounds (e.g., the simple high yield 3-step synthesis of imidazo[1,2-a]pyridine 37) could provide a cost-effective broad-spectrum arenavirus therapeutic that may help to minimize the cost-prohibitive burdens associated with treatments for emerging viruses in economically challenged geographical settings.

Original languageEnglish (US)
Article number127983
JournalBioorganic and Medicinal Chemistry Letters
Volume41
DOIs
StatePublished - Jun 1 2021
Externally publishedYes

Keywords

  • Arenavirus
  • Entry inhibitor
  • Junin
  • Lassa
  • Machupo

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Discovery of a novel highly potent broad-spectrum heterocyclic chemical series of arenavirus cell entry inhibitors'. Together they form a unique fingerprint.

Cite this