Discovery and structure optimization of a series of isatin derivatives as Mycobacterium tuberculosis chorismate mutase inhibitors

Chem Biol Drug Des. 2014 Apr;83(4):498-506. doi: 10.1111/cbdd.12265.

Abstract

In this study, the crystal structure of the Mycobacterium tuberculosis (MTB) enzyme chorismate mutase (CM) bound to transition state analogue (PDB: 2FP2) was used as a framework for virtual screening of the BITS-Pilani in-house database (2500 compounds) to identify new scaffold. We identified isatin as novel small molecule MTB CM inhibitors; further twenty-four isatin derivatives were synthesized and evaluated in vitro for their ability to inhibit MTB CM, and activity against M. tuberculosis as steps towards the derivation of structure-activity relationships (SAR) and lead optimization. Compound 3-(4-nitrobenzylidene)indolin-2-one, 24 emerged as the most promising lead with an IC50 of 1.01 ± 0.22 μm for purified CM and MIC of 23.5 μm for M. tuberculosis, with little or no cytotoxicity.

Keywords: Mycobacterium tuberculosis; chorismate mutase; isatin; tuberculosis.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chorismate Mutase / antagonists & inhibitors*
  • Crystallography, X-Ray
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Isatin / chemistry*
  • Isatin / pharmacology*
  • Molecular Structure
  • Mycobacterium tuberculosis* / enzymology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Isatin
  • Chorismate Mutase