Design, synthesis, biological evaluation and in silico study of N-(Pyrimidin-2-yl)alkyl/arylamide derivatives as quorum sensing inhibitors against Pseudomonas aeruginosa

Abstract

The emergence of bacterial resistance to antimicrobial agents poses a serious threat to the effectiveness of treating bacterial illnesses. A major factor contributing to antimicrobial resistance is biofilm formation, driven by quorum sensing (QS). QS suppression inhibits the QS signaling pathway, obstructing cell-to-cell communication. This study focuses on N-(pyrimidin-2-yl)alkyl/arylamide derivatives, which were designed, synthesized, and characterized for their QS inhibitory effects. Among the synthesized compounds (3a–j), compounds 3b, 3d, and 3h exhibited the highest QS inhibitory activity, with inhibition zones of 17.66 ± 6.17, 14.00 ± 6.24, and 17.33 ± 0.66 mm, respectively. Further, molecular docking studies revealed binding affinities between − 8.4 and − 6.3 kcal/mol, indicating strong interactions with the target proteins. Moreover, molecular dynamic simulations confirmed the stability of the protein–ligand complexes for compounds 3b and 3 h. Additionally, in-silico methods were employed to predict the physicochemical properties of these molecules. Overall, these findings underscore the potential of N-(pyrimidin-2-yl)alkyl/arylamide derivatives as QS inhibitors, offering a new perspective for developing alternative antimicrobial therapies. Graphical abstract: (Figure presented.). © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.