Synthesis, Cytotoxic Activity, Antiquorum Sensing Effect, Docking and Md Simulation of Novel 1,3-Disubstituted 2-Mercapto-1H-Benzo[D]Imidazolium Chlorides

Abstract

A series of benzimidazolium chlorides (2a-c) and their corresponding 2-mercapto derivatives (3a-c) were proficiently synthesized and analyzed by NMR and LC-MS spectra. The in vitro cytotoxic assay demonstrated that some synthesized compounds were active on the cancer cell lines. The binding potential of the most active three compounds to topoisomerase II alpha (topo2α) was explored to unveil the possible mode of action for the cytotoxic activity. The binding potential was examined through molecular docking. The stability of compound-enzyme complexes from docking was investigated through molecular dynamics (MD) simulation. The docking study revealed that the three compounds (3a-c) showed the ability to bind to the enzyme. However, the binding strength of compounds was weaker than that of the standard drug, doxorubicin. The MD simulation analysis demonstrated that compounds 3a and 3b gave relatively stable complexes with the enzyme and thus they would remain inside the binding pocket during the simulation period. Furthermore, the pharmacokinetic properties of the relatively active compounds were computed in silico. The computation disclosed that all of compounds exhibited drug-like properties. It is worth mentioning that all of them were found to be nontoxic. In furtherance, the inhibitory effect of compounds (3a-c) on the quorum sensing system was inspected using the biomonitor strains Chromobacterium violaceum 026, Chromobacterium. violaceum VIR07 and Pseudomonas aeruginosa PAO1. In this regard, we focused on the appraisal of the virulence factors, including pyocyanin, elastase, and biofilm formation that are created by P. aeruginosa PAO1 as the source of infectious diseases. As a result, it was determined that all examined compounds displayed statistically significant inhibition effects, and the highest activity was observed on elastase production with an inhibition rate of 84–86%. © 2025 Elsevier B.V., All rights reserved.