Design, Synthesis and Evaluation of Indole‐Based 1,2,3‐Triazoles as Potential Quorum Sensing and Biofilm Inhibitors Against <i>Pseudomonas aeruginosa</i>

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 ¹H and ¹³C 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.