Mandelic acid-based spirothiazolidinones targeting M. tuberculosis: Synthesis, in vitro and in silico investigations

[Display omitted] •A small series of new mandelic acid-based spirothiazolidinones have been synthesized.•New compounds have been evaluated for their antimycobacterial activity against Mycobacterium tuberculosis strain H37Rv.•Compound 16 have the highest inhibition value 98%.•To study the molecular s...

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Published in:Bioorganic chemistry 2022-04, Vol.121, p.105688-105688, Article 105688
Main Authors: Trawally, Muhammed, Demir-Yazıcı, Kübra, Dingiş-Birgül, Serap İpek, Kaya, Kerem, Akdemir, Atilla, Güzel-Akdemir, Özlen
Format: Article
Language:English
Subjects:
4-Thiazolidinone
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Bacterial Proteins - metabolism
Enoyl-[acyl-carrier-protein]-reductase
Humans
Mandelic acid
Mandelic Acids
Microbial Sensitivity Tests
Molecular docking
Molecular Docking Simulation
Molecular dynamics
MtInhA
Mycobacterium tuberculosis
Mycobacterium tuberculosis - metabolism
Spirothiazolidinone
Structure-Activity Relationship
Tuberculosis
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Summary:[Display omitted] •A small series of new mandelic acid-based spirothiazolidinones have been synthesized.•New compounds have been evaluated for their antimycobacterial activity against Mycobacterium tuberculosis strain H37Rv.•Compound 16 have the highest inhibition value 98%.•To study the molecular structure and possible mechanism of action of compound 16, X-ray and molecular modelling studies were performed. A series of new spirothiazolidinone derivatives with a mandelic acid moiety were synthesized and subsequently tested in growth inhibition assays against Mycobacterium tuberculosis strain H37Rv. Compound 16 displayed the highest inhibition value of 98% at lower than 6.25 µg/mL concentration. A single crystal X-ray analysis was conducted on this compound to confirm the structure and determine its absolute configuration. Afterwards, reverse docking and molecular dynamics simulations of this specific stereoisomer were performed against a selection of 10 putative targets of M. tuberculosis to suggest possible mechanisms of action. Our results suggest HadAB, Pks13, DprE1, FadD32 and InhA as possible target proteins for the observed antimycobacterial activity of compound 16.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2022.105688