Synthesis, biological evaluation, and molecular modeling studies of acetophenones-tethered 1,2,4-triazoles and their oximes as epidermal growth factor receptor inhibitors.

A series of 5-(4-pyridyl)-1,2,4-triazoles hybrids with acetophenones and their oxime derivatives was rationally designed and synthesized as epidermal growth factor receptor (EGFR) kinase inhibitors. Initially, drug Likeness and pharmacokinetics properties of the prepared compounds were evaluated. Afterward, the prepared compounds were in vitro screened for their ability to inhibit the growth of the NCI-60 human cancer cell lines where certain compounds showed moderate activity. Compounds 4e and 5b emerged as the most potent compounds in this series were further tested for their EGFR enzyme inhibition activity. They showed IC50 values of 0.14 and 0.18 µM, respectively, in comparison with Gefitinib as a reference with an IC50 value of 0.06 µM. Docking of compounds 4e and 5b into the binding site of EGFR tyrosine kinase was performed to explains their possible binding mode and to compare it with known inhibitors. Moreover, molecular dynamic simulations were estimated for deeper understanding of the binding mode of compounds 4e and 5b at the binding site of EGFR tyrosine kinase. The findings indicated that the novel ligands 4e and 5b were stable in the EGFR tyrosine kinase active site.