Discovery and Structure Optimization of a Series of Isatin Derivatives as Mycobacterium tuberculosis Chorismate Mutase Inhibitors. (April 2014)

• Record Type: Journal Article
• Authors: Jeankumar, Variam U.; Alokam, Reshma; Sridevi, Jonnalagadda P.; Suryadevara, Priyanka; Matikonda, Siddharth S.; Peddi, Santosh; Sahithi, Seedarala; Alvala, Mallika; Yogeeswari, Perumal; Sriram, Dharmarajan
• Is Part Of: Chemical biology & drug design. Volume 83:Number 4(2014:Apr.)
• Page Start: 498
• Page End: 506
• Publication Date: 2014-04
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12265
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12265-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>In this study, the crystal structure of the <italic>Mycobacterium tuberculosis</italic> (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 <italic>in vitro</italic> for their ability to inhibit MTB CM, and activity against <italic>M. tuberculosis</italic> as steps towards the derivation of structure–activity relationships (SAR) and lead optimization. Compound 3‐(4‐nitrobenzylidene)indolin‐2‐one, <bold>24</bold> emerged as the most promising lead with an IC₅₀ of 1.01 ± 0.22 <italic>μ</italic><sc>m</sc> for purified CM and MIC of 23.5 <italic>μ</italic><sc>m</sc> for <italic>M. tuberculosis</italic>, with little or no cytotoxicity.</p> </abstract>