title: 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.affiliation: Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad-500078 (India).
authors.forename: Parthiban Brindha
authors.initials: PB
authors.lastname: Devi
authors.forename: Ganesh
authors.initials: G
authors.lastname: Samala
authors.forename: Jonnalagadda Padma
authors.initials: JP
authors.lastname: Sridevi
authors.forename: Shalini
authors.initials: S
authors.lastname: Saxena
authors.forename: Mallika
authors.initials: M
authors.lastname: Alvala
authors.forename: Elena G
authors.initials: EG
authors.lastname: Salina
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D053778:Thiazolidines; D010453:Peptide Synthases; C022318:pantothenate synthetase
keywords: drug design; enzymes; inhibitors; thiazolidines; tuberculosis