Synthesis and evaluation of α-aminoacyl amides as antitubercular agents effective on drug resistant tuberculosis

Eur J Med Chem. 2019 Feb 15:164:665-677. doi: 10.1016/j.ejmech.2019.01.002. Epub 2019 Jan 3.

Abstract

The development of an effective antitubercular agent is a challenge due to the complex nature of tuberculosis. Herein, we report the synthesis and evaluation of α-aminoacyl amides as antitubercular agents. The systematic medicinal chemistry approach led to identification of optimal substitutions required for the activity. Compound 11l was identified as antitubercular lead with drug like properties. Further, 11l selectively inhibited M. tuberculosis H37Rv with MIC value of 0.78 μM and was found to be non-toxic to CHOK1 cells. The lead compound inhibited multidrug resistant and Pre-Extensively drug resistant strains of Mycobacterium at 2 μg/mL and 8 μg/mL respectively.

Keywords: Antitubercular agents; Drug-resistant tuberculosis; Heterocyclic compounds; Ugi reaction.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology
  • Cell Line
  • Chemistry, Pharmaceutical / methods*
  • Humans
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects
  • Tuberculosis, Multidrug-Resistant / drug therapy*

Substances

  • Amides
  • Antitubercular Agents