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

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.