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.