Structure‐Guided Design of Thiazolidine Derivatives as Mycobacterium tuberculosis Pantothenate Synthetase Inhibitors |
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| Authors: | Parthiban Brindha Devi Ganesh Samala Jonnalagadda Padma Sridevi Shalini Saxena Mallika Alvala Elena G Salina Prof Dharmarajan Sriram Prof Perumal Yogeeswari |
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| Affiliation: | 1. Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science‐Pilani, Hyderabad Campus, Hyderabad‐500078 (India);2. Institution of the Russian Academy of Sciences, A.N. Bach Institute of Biochemistry RAS, Moscow (Russia) |
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| 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 (IC50) value of (1.12±0.12) μM . 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 IC50 value of 350 nM and an Mtb minimum inhibitory concentration (MIC) of 1.55 μM . Some of these compounds also showed good activity against dormant Mtb cells. |
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| Keywords: | drug design enzymes inhibitors thiazolidines tuberculosis |
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