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Synthesis and biological evaluation of thiazolidinedione derivatives with high ligand efficiency to P. aeruginosa PhzS
- Source :
- Journal of Enzyme Inhibition and Medicinal Chemistry, article-version (VoR) Version of Record, Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 1217-1229 (2021)
- Publication Year :
- 2021
- Publisher :
- Taylor & Francis, 2021.
-
Abstract
- The thiazolidinone ring is found in compounds that have widespan biology activity and there is mechanism-based evidence that compounds bearing this moiety inhibit P. aeruginosa PhzS (PaPzhS), a key enzyme in the biosynthesis of the virulence factor named pyocyanin. Ten novel thiazolidinone derivatives were synthesised and screened against PaPhzS, using two orthogonal assays. The biological results provided by these and 28 other compounds, whose synthesis had been described, suggest that the dihydroquinazoline ring, found in the previous hit (A- Kd = 18 µM and LE = 0.20), is not required for PaPzhS inhibition, but unsubstituted nitrogen at the thiazolidinone ring is. The molecular simplification approach, pursued in this work, afforded an optimised lead compound (13- 5-(2,4-dimethoxyphenyl)thiazolidine-2,4-dione) with 10-fold improvement in affinity (Kd= 1.68 µM) and more than 100% increase in LE (0.45), which follows the same inhibition mode as the original hit compound (competitive to NADH).Executive summaryPhzS is a key enzyme in the pyocyanin biosynthesis pathway in P. aeruginosa.Orthogonal assays (TSA and FITC) show that fragment-like thiazolidinedione derivatives bind to PaPhzS with one-digit micromolar affinity.Fragment-like thiazolidinedione derivatives bind to the cofactor (NADH) binding site in PaPhzS.The molecular simplification optimised the ligand efficiency and affinity of the lead compound.
- Subjects :
- medicine.drug_class
Stereochemistry
RM1-950
Ring (chemistry)
Ligands
01 natural sciences
Drug Discovery
medicine
Moiety
Humans
antimicrobial resistance
Thiazolidinedione
Biological evaluation
Pharmacology
Ligand efficiency
010405 organic chemistry
pyocyanin biosynthesis inhibition
General Medicine
0104 chemical sciences
Anti-Bacterial Agents
010404 medicinal & biomolecular chemistry
P. aeruginosa
Thiazolidinone
Pseudomonas aeruginosa
Thiazolidinediones
Therapeutics. Pharmacology
Research Article
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 14756374 and 14756366
- Volume :
- 36
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....dabb69e68f8a08e7aefcd2eb5997826a