title: 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.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad, Andhra Pradesh, 500078, India.
authors.forename: Variam U
authors.initials: VU
authors.lastname: Jeankumar
authors.forename: Reshma
authors.initials: R
authors.lastname: Alokam
authors.forename: Jonnalagadda P
authors.initials: JP
authors.lastname: Sridevi
authors.forename: Priyanka
authors.initials: P
authors.lastname: Suryadevara
authors.forename: Siddharth S
authors.initials: SS
authors.lastname: Matikonda
authors.forename: Santosh
authors.initials: S
authors.lastname: Peddi
authors.forename: Seedarala
authors.initials: S
authors.lastname: Sahithi
authors.forename: Mallika
authors.initials: M
authors.lastname: Alvala
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D002826:Chorismate Mutase / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007510:Isatin / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007510:Isatin; D002826:Chorismate Mutase
keywords: Mycobacterium tuberculosis; chorismate mutase; isatin; tuberculosis