Substituted 1,3,4‐oxadiazole coupled 1,2,3‐triazole derivatives as antiproliferative agents: Design, synthesis, biological evaluation and <i>in silico</i> studies

Abstract A novel class of substituted 1,3,4‐oxadiazole coupled 1,2,3‐triazole analogues were prepared and evaluated for their epidermal growth factor receptor (EGFR) inhibitory profiles and antiproliferative activities. The confirmation of the structures of the synthesized compounds was done using spectroscopic techniques. Using the MTT assay, the in vitro cytotoxicity was investigated against three human cancer cell lines, MDA‐MB‐468, HepG‐2, and A549. Compound 8a had the highest anticancer activity against all cancer cell lines, with an IC 50 range of 1.02 ± 0.56–3.67 ± 0.07 μM. The EGFR inhibition of the most active compounds, 8a , 8b , 8d , 8f , and 8h was further assessed. In contrast to Erlotinib (IC 50 = 0.19 ± 0.07 μM), compounds 8b and 8h , demonstrated IC 50 values of 0.54 ± 0.18 and 0.33 ± 0.06 μM, respectively. Binding interactions showed that the synthesized compounds were involved in inhibiting the growth of cancer by blocking the EGFR enzyme (PDB:3W2Q). The DFT/B3LYP method functionalized with a 6–31 g(d, p) basis set was employed to calculate quantum parameters, MEP analysis, HOMO, and LUMO. Compounds 8b , 8g , and 8h have displayed good in silico ADMET properties. Compounds 8b , 8g , 8h , and 8j displayed good drug‐likeness scores (1.02, 1.09, 0.60, and 0.75) and none of the compounds can cross the blood–brain barrier because they are all outside the boiled egg yolk.