Structure-guided design of thiazolidine derivatives as Mycobacterium tuberculosis pantothenate synthetase inhibitors.

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.

• Authors: Parthiban Brindha Devi, Ganesh Samala, Jonnalagadda Padma Sridevi, Shalini Saxena, Mallika Alvala, Elena G Salina, Dharmarajan Sriram, Perumal Yogeeswari
• Journal: ChemMedChem (ChemMedChem) Vol. 9 Issue 11 Pg. 2538-47 (Nov 2014) ISSN: 1860-7187 [Electronic] Germany
• PMID: 25155986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antitubercular Agents
• Enzyme Inhibitors
• Recombinant Proteins
• Thiazolidines
• Peptide Synthases
• pantothenate synthetase

Topics

• Animals
• Antitubercular Agents (chemistry, metabolism, toxicity)
• Binding Sites
• Cell Line
• Cell Survival (drug effects)
• Drug Design
• Enzyme Inhibitors (chemistry, metabolism, toxicity)
• Mice
• Microbial Sensitivity Tests
• Molecular Docking Simulation
• Mycobacterium tuberculosis (drug effects, enzymology)
• Peptide Synthases (antagonists & inhibitors, genetics, metabolism)
• Protein Structure, Tertiary
• Recombinant Proteins (biosynthesis, chemistry, metabolism)
• Structure-Activity Relationship
• Thiazolidines (chemistry, metabolism, toxicity)