Novel Benzimidazole‐1,2,3‐Triazole Hybrids: Synthesis, Dual Antimicrobial, Anticancer Activity, Mechanistic Insights, and Computational Studies

Abstract This study reports the synthesis and biological evaluation of two series of novel hybrid heterocyclic scaffolds tethering 1,2,3‐triazole and benzimidazole moieties using the click chemistry approach. Aromatic azides were synthesized from aniline derivatives followed by the preparation of S‐propargylated benzimidazole intermediates. These intermediates were then reacted with azides through 1,3‐dipolar cycloaddition to yield the benzimidazole‐1,2,3‐triazole hybrids. The compounds were fully characterized by NMR spectroscopy. Biological testing revealed significant antibacterial, antifungal, and cytotoxic activities. Notably, the acetamide‐linked 1,2,3‐triazole‐benzimidazole hybrids exhibited potent activity against Gram‐negative bacteria and fungal strains with MIC values of 0.156–0.312 mg/mL and several compounds demonstrating selectivity against cancer cell lines, particularly HepG‐2 and A‐549 with IC 50 7–30 µg/mL. EGFR‐TK enzyme inhibition assays further highlighted the potential of these compounds as anticancer agents. Docking simulation was done for the most active 5d and 9f as promising triazole hits with different linker structures to study the interaction of these analogs to both valuable targets contributing to cancer growth such as; EGFRWT and EGFRT790 in cancer disease; revealed the fragments contributions are able to stabilize molecular targets by different interactions. The promising bioactivity of the synthesized hybrids positions them as candidates for further optimization and development as broad‐spectrum antimicrobial and anticancer agents.