ABSTRACT Targeting quorum‐sensing inhibitors (QSIs) is a promising strategy to combat antibiotic‐resistant bacteria by disrupting biofilm formation without imposing direct lethal pressure. In this study, we designed and synthesized a library of 30 2‐phenylindole‐based 1,2,3‐triazole derivatives ( 11a–g, 12a–i, 13a–h , and 14a–f), which were structurally characterized using HRMS, IR, and 1 H and 13 C NMR spectroscopy. These compounds were evaluated for their in vitro QS inhibitory activity against the Pseudomonas aeruginosa MH602 reporter strain at concentrations ranging from 250 to 8 μM. All compounds demonstrated good to excellent QS inhibition (> 60%) at 250 μM and moderate inhibition (> 30%) at 8 μM. Structure–activity relationship (SAR) analysis indicated that halogen substitution had a positive influence on QS inhibitory potency. Among the series, compound 12a showed the most potent activity, with 82.6% and 38.9% inhibition at 250 and 8 μM, respectively. Further studies, including in silico ADME prediction, molecular docking, molecular dynamics simulations, and binding free energy analysis, were performed for 12a . The most active compounds from each series were also assessed for cytotoxicity against the HEK 293 T cell line, showing IC₅₀ values in the range of 83.7–168.7 μM. Antimicrobial evaluation revealed that the top seven compounds exhibited minimal or no antibacterial activity at 125 μM; however, compounds 12h, 13a , and 14c showed significant biofilm inhibition addition to pyocyanin and QS suppression, highlighting their potential as promising leads to combat antimicrobial resistance.
Chaitanya et al. (Sun,) studied this question.