Biological Evaluation and Docking Studies of New Carbamate, Thiocarbamate, and Hydrazide Analogues of Acyl Homoserine Lactones as Vibrio fischeri -Quorum Sensing Modulators

• Published in: Biomolecules (Basel, Switzerland) Vol. 10; no. 3; p. 455
• Main Authors: Zhang, Qiang, Queneau, Yves, Soulère, Laurent
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.03.2020; MDPI
• Subjects: Acyl-Butyrolactones - chemistry; Aliivibrio fischeri - chemistry; Aliivibrio fischeri - metabolism; Biological activity; carbamate analogues; Carbonyl compounds; Chemical Sciences; Chromatography; Conformation; docking; Homoserine lactones; Hydrogen; Lactones; modulators; Molecular Docking Simulation; NMR; Nuclear magnetic resonance; Organic chemistry; Quorum Sensing; Repressor Proteins - chemistry; Repressor Proteins - metabolism; Solvents; Thiocarbamates - chemistry; Trans-Activators - chemistry; Trans-Activators - metabolism; Vibrio fischeri; France; docking; carbamate analogues; quorum sensing; modulators; agrocinopine; agrocin 84; glucose-2-phosphate; phosphodiesters; Agrobacterium fabrum
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10030455

A series of carbamate, thiocarbamate, and hydrazide analogues of acylhomoserine lactones (AHLs) were synthesized and their ability to modulate -quorum sensing was evaluated. The compounds in the series exhibit variable side chain length and the possible presence of a diversely substituted phenyl substituent. Biological evaluation on the quorum sensing system revealed that the ethyl substituted carbamate ( ) display a weak agonistic activity whereas compounds with longer chain length or benzyl substituents display significant antagonistic activity. The most active compounds in the series were the 4-nitrobenzyl carbamate and thiocarbamate and which exhibited an IC value of about 20 µM. These activities are in the range of other reported of AHL-structurally related quorum sensing (QS) inhibitors. Docking experiments conducted on the LuxR model showed that, compared to the natural ligand OHHL, the additional heteroatom of the carbamate group induces a new hydrogen bond with Tyr70 leading to a different global hydrogen-bond network. Tyr70 is an important residue in the binding site and is strictly conserved in the LuxR family. For the 4-nitrobenzyl carbamate and thiocarbamate analogues, the docking results highlight an additional hydrogen bond between the nitro group and Lys178. For hydrazide analogues, which are deprived of any activity, docking shows that the orientation of the carbonyl group is opposite as compared with the natural ligand, leading to the absence of a H-bond between the C=O with Tyr62. This suggests that, either this later interaction, or the influence of the C=O orientation on the overall ligand conformation, are essential for the biological activity.