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Structure‐Guided Design of Thiazolidine Derivatives as Mycobacterium tuberculosis Pantothenate Synthetase Inhibitors
Author(s) -
Devi Parthiban Brindha,
Samala Ganesh,
Sridevi Jonnalagadda Padma,
Saxena Shalini,
Alvala Mallika,
Salina Elena G.,
Sriram Dharmarajan,
Yogeeswari Perumal
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402171
Subject(s) - pharmacophore , thiazolidine , mycobacterium tuberculosis , enzyme , chemistry , stereochemistry , in vitro , biochemistry , tuberculosis , minimum inhibitory concentration , lead compound , ic50 , combinatorial chemistry , medicine , pathology
Abstract The pantothenate biosynthetic pathway is essential for the persistent growth and virulence of Mycobacterium tuberculosis ( Mtb ) and one of the enzymes in the pathway, pantothenate synthetase (PS, EC: 6.3.2.1), encoded by the panC gene, has become an appropriate target for new therapeutics to treat tuberculosis. Herein, we report nanomolar thiazolidine inhibitors of Mtb PS developed by a rational inhibitor design approach. The thiazolidine compounds were discovered by using energy‐based pharmacophore modelling and subsequent in vitro screening, which resulted in compounds with a half maximal inhibitory concentration (IC 50 ) value of (1.12±0.12) μ M . These compounds were subsequently optimised by a combination of modelling and synthetic chemistry. Hit expansion of the lead by chemical synthesis led to an improved inhibitor with an IC 50 value of 350 n M and an Mtb minimum inhibitory concentration (MIC) of 1.55 μ M . Some of these compounds also showed good activity against dormant Mtb cells.