Discovery of dipiperidines as new antitubercular agents

Elena Bogatcheva, Colleen Hanrahan, Ping Chen, Jacqueline Gearhart, Katherine Sacksteder, Leo Einck, Carol Nacy, Marina Protopopova

Research output: Contribution to journalArticlepeer-review

Abstract

As part of our ongoing research effort to develop new therapeutics for treatment of tuberculosis (TB), we synthesized a combinatorial library of 10,358 compounds on solid support using a pool-and-split technique and tested the resulting compounds for activity against Mycobacterium tuberculosis. Structure-activity relationship (SAR) evaluation identified new compounds with antitubercular activity, including a novel hit series that is structurally unrelated to any existing antitubercular drugs, dipiperidines. Dipiperidine representatives exhibited MIC values as low as 7.8 μM, the ability to induce promoter Rv0341 activated in response to cell wall biosynthesis inhibition, relatively low nonspecific cellular toxicity in the range of 30-162 μM, and log P values less than 4.

Original languageEnglish (US)
Pages (from-to)201-205
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

Keywords

  • Antitubercular drugs
  • Dipiperidines
  • Tuberculosis

ASJC Scopus subject areas

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

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