Synthesis and biological evaluation of thiazolidinedione derivatives with high ligand efficiency to P. aeruginosa PhzS

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 ¼ 18 mM and LE ¼ 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-2,4dione) with 10-fold improvement in affinity (Kd¼ 1.68 mM) and more than 100% increase in LE (0.45), which follows the same inhibition mode as the original hit compound (competitive to NADH).

Antifungal Thiazolidines: Synthesis and Biological Evaluation of Mycosidine Congeners

“…Most of the works on the synthesis of these compounds are devoted to the search for new hypoglycemic drugs—aldose reductase inhibitors [ 58 , 59 , 60 , 61 , 62 , 63 ]—or anticancer [ 64 ] and antimicrobial drugs [ 65 ]. Recently, an article was published showing that several TZD derivatives specifically inhibit the initiation of hyphal growth in C. albicans without affecting cell viability or budded growth [ 66 ].…”

Antibacterial and antibiofilm activities of thiazolidine-2,4-dione and 4-thioxo-thiazolidin-2-one derivatives against multidrug-resistant Staphylococcus aureus clinical isolates

“…The analogue series of thiazolidine‐2,4‐dione and 4‐thioxo‐thiazolidin‐2‐one were synthesized by Knoevenagel condensation (Figure 1), and their chemical characteristics are described in our previously published works (Froes et al, 2021; Gouveia et al, 2009; Leite et al, 2016; Silva et al, 2014).…”

Targeting the Holy Triangle of Quorum Sensing, Biofilm Formation, and Antibiotic Resistance in Pathogenic Bacteria

“…Additionally, these compounds exert anti-QS activity against Vibrio harveyi by decreasing the DNA-binding activity of LuxR [984]. Additionally, these compounds exerted anti-QS activities against Pseudomonas aeruginosa by targeting the LasI quorumsensing signal synthase [981] and PhsZ, a key enzyme in the biosynthesis of the virulent factor pyocyanin [1036].…”