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

Abstract

A series of carbamate, thiocarbamate, and hydrazide analogues of acylhomoserine lactones (AHLs) were synthesized and their ability to modulate Vibrio fischeri-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 Vibrio fischeri quorum sensing system revealed that the ethyl substituted carbamate (1) 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 7 and 11 which exhibited an IC₅₀ 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.

Keywords: carbamate analogues; docking; modulators; quorum sensing.

Figure 1

Design of analogues of OHHL modified on the amide functional group.

Scheme 1

Synthesis of carbamate, thiocarbamate, and hydrazide analogues of acylhomoserine lactone.

Figure 2

Antagonistic activity of carbamate and thiocarbamate analogues 1–11: residual bioluminescence observed for all compounds at 100 µM. The luminescence was induced by OHHL at a concentration of 200 nM.

Figure 3

Proposed binding modes of compounds 2 (A) and 7 (B) within the binding site of the LuxR model obtained as a result of docking experiments. (C) Proposed binding modes of compound 12 (magenta) and OHHL (cyan) [30] obtained as a result of docking experiments. Hydrogen bonds are indicated in red dashes. Design of analogues of OHHL modified on the amide functional group.