Design and synthesis of benzofuran–pyrazole–triazole hybrids via click chemistry: Antimicrobial, anticancer, ADMET, docking, and DFT studies

Ten novel benzofuran–pyrazole–triazole hybrid compounds (10a–j) were synthesized via multistep methodology and characterized by 1H NMR,13 CMR, IR, and mass spectrometry. Molecular docking studies against epidermal growth factor receptor (EGFR) (1M17) and the fibrinogen-binding domain (4NYT) revealed compounds 10i and 10j as promising EGFR inhibitors, with binding scores of −6.22 and −6.21 kcal/mol, respectively, which are superior to that of combretastatin-A4 (−6.15 kcal/mol). Against the fibrinogen-binding domain, compounds 10d and 10h showed excellent binding (−8.65 kcal/mol each) compared to ciprofloxacin (−7.49 kcal/mol). Anticancer evaluation demonstrated compound 10c as the most potent with IC50 values of 2.18–2.50 µM against HT-29, MCF-7, and A549 cell lines. Compound 10j also exhibited significant activity (IC50: 2.61–3.82 µM) across multiple cancer cell lines. Antimicrobial screening revealed that compound 10h exhibited broad-spectrum activity (minimum inhibitory concentration [MIC]: 0.0157–0.0628 mg ml−1), while compounds 10i and 10j showed efficacy comparable to that of ciprofloxacin. Density functional theory (DFT) calculations (B3LYP/6–311++G(d,p)) indicated superior thermodynamic stability for compound 10h over 10j, absorption, distribution, metabolism, and excretion (ADMET) analysis confirmed acceptable drug-like properties with minimal Lipinski violations. These benzofuran–pyrazole–triazole hybrids represent promising scaffolds for the development of anticancer and antimicrobial drugs.