Design, regioselective, time gated synthesis of novel benzo[d]imidazole analogues as potential quorum sensing inhibitors targeting LasR in Pseudomonas aeruginosa.

The rapid emergence of antibiotic-resistant pathogens highlights the crucial need for alternate anti-infective strategies. Quorum sensing inhibition (QSI) offers compelling approaches to attenuate bacterial virulence while limiting the resistance. In this study, fourteen Benzo[d]imidazole derivatives were synthesized and proposed as potential LasR antagonists exhibiting quorum-sensing inhibitory activity. Among these, compounds 7f, 7 h, 11b, 11c, and 11f demonstrated a marked ability to suppress biofilm formation in P. aeruginosa by (83%, 87%, 84%, 87%, 86%), pyocyanin production (76%, 84%, 86%, 82%, 81%), and motility activity; swimming (90%, 86%, 91%, 88%, 90%), twitching (90%, 94%, 93%, 86%, 92%), respectively. Additionally, compounds 7f and 11c effectively inhibited LasR, with IC50 values equal to 0.74 ± 0.005, 0.79 ± 0.001 μM, respectively. Moreover, a 200-ns molecular dynamics simulation (MDS) of the 7f analogue indicated its potential to disrupt the dimeric structure of the LasR protein, thereby confirming its inhibitory activity toward LasR. Collectively, these results establish benzo[d]imidazole scaffolds as promising leads for the development of next-generation quorum sensing modulators aimed at disarming bacterial pathogenicity and countering antimicrobial resistance.