Targeting quorum sensing by designing azoline derivatives to inhibit the N-hexanoyl homoserine lactone-receptor CviR: Synthesis as well as biological and theoretical evaluations

Abstract

To counteract bacterial resistance, we investigated the interruption of quorum sensing mediated by non-classical bioisosteres of the N-hexanoyl homoserine lactone with an azoline core. For this purpose, a set of selected 2-substituted azolines was synthesized, establishing the basis for a new protocol to synthesize 2-amino imidazolines. The synthesized compounds were evaluated as inhibitors of violacein production in Chromobacterium violaceum. Theoretical studies on bioisostere-protein interactions were performed using CviR. The results show that some azolines decreased violacein production, suggesting an antiquorum sensing profile against Gram-negative bacteria. Docking and molecular dynamic simulations together with binding free energy calculations revealed the exact binding and inhibitory profiles. These theoretical results show relationship with the in vitro activity of the azoline series.

Effect of New Analogs of Hexyloxy Phenyl Imidazoline on Quorum Sensing in Chromobacterium violaceum and In Silico Analysis of Ligand-Receptor Interactions

“…is value can be compared to those reported by Bucio-Cano et al for 9, 19-23 [12,14], 24, and the other synthesized inhibitors [19] (Figure 4). [14] and is comparable to 2-(4′-chlorophenoxy)-N-butanoyl homoserine lactone 24 [19]. e latter is proposed as the most active analog of AHL known so far, giving 100% inhibition of violacein at 10 − 4 M.…”

“…All compounds were characterized by spectroscopic methods (IR, NMR, and HRMS), identifying 8-pentyloxyphenyl-2-imidazoline (13), 8-octyloxyphenyl-2-imidazoline (14), 8-decyloxyphenyl-2-imidazoline (15), 9pentyloxyphenyl-2-oxazoline (16), 9-octyloxyphenyl-2oxazoline (17), and 9-decyloxyphenyl-2-oxazoline (18). as Quorum-Sensing Inhibitors in Chromobacterium violaceum CV026.…”

“…Bacterial enzymes of some Gram-positive bacteria like the Bacillus species interfere with QS via an AHL-lactonase [13], Figure 1. Various analogs and bioisosteres of AHLs have been synthesized as inhibitors of Gram-negative bacteria [12], and some of them designed to interfere with QS in Chromobacterium violaceum [14].…”

Synthesis of imidazolidine‐2,4‐dione and 2‐thioxoimidazolidin‐4‐one derivatives as inhibitors of virulence factors production in Pseudomonas aeruginosa

“…For example, imidazole derivatives V–VII (Figure 2) displayed effective LuxR inhibition activity of P. aeruginosa . [ 23–25 ] Moreover, the scaffold of brominated furanone (compounds VIII [ 26 ] and IX [ 27 ] ) were reported to exhibit strong decrease in the production of bacterial virulence factors, in addition to reduced toxicity to mammalian cells due to the presence of conjugated exocyclic vinyl bromide.…”

Design and Synthesis of Imidazo[1,2‐a]pyridines with Carboxamide Group Substitution andIn silicoEvaluation of their Interaction with a LuxR‐type Quorum Sensing Receptor

“…The rational design of AHL‐based QS compounds is hindered by the fact that most LuxR‐type receptors show a very high specificity for their cognate autoinducers. For all of these reasons, the development of small molecule and macromolecular QS inhibitors as anti‐virulence agents has attracted considerable attention .…”