Structure-activity relationship studies on 2,5,6-trisubstituted benzimidazoles targetingMtb-FtsZ as antitubercular agents

Krupanandan Haranahalli, Simon Tong, Saerom Kim, Monaf Awwa, Lei Chen, Susan E. Knudson, Richard A. Slayden, Eric Singleton, Riccardo Russo, Nancy Connell, Iwao Ojima

Research output: Contribution to journalArticlepeer-review

Abstract

Filamenting temperature sensitive protein Z (FtsZ) is an essential bacterial cell division protein and a promising target for the development of new antibacterial therapeutics. As a part of our ongoing SAR studies on 2,5,6-trisubstituted benzimidazoles as antitubercular agents targetingMtb-FtsZ, a new library of compounds with modifications at the 2 position was designed, synthesized and evaluated for their activity againstMtb-H37Rv. This new library of trisubstituted benzimidazoles exhibited MIC values in the range of 0.004-50 μg mL−1. Compounds6b,6c,20fand20gshowed excellent growth inhibitory activities ranging from 0.004-0.08 μg mL−1. This SAR study has led to the discovery of a remarkably potent compound20g(MIC 0.0039 μg mL−1; normalized MIC 0.015 μg mL−1). Our 3DQSAR model predicted20gas the most potent compound in the library.

Original languageEnglish (US)
Pages (from-to)78-94
Number of pages17
JournalRSC Medicinal Chemistry
Volume12
Issue number1
DOIs
StatePublished - Jan 2021

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Pharmacology

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