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

Abstract

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 IC 50 values of 0.14 and 0.18 µM, respectively, in comparison with Gefitinib as a reference with an IC 50 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.

The Fundamental Role of Oxime and Oxime Ether Moieties in Improving the Physicochemical and Anticancer Properties of Structurally Diverse Scaffolds

“…A series of 5-(4-pyridyl)-1,2,4-triazole hybrids bearing acetophenone-oxime moieties rationally designed and synthesized were evaluated for their properties as epidermal growth factor receptor (EGFR) kinase inhibitor [126]. Some of these compounds moderately inhibited the growth of the NCI-60 human cancer cell lines when screened in vitro.…”

“…This compound exhibited an IC 50 value of 0.18 µM, in comparison with Gefitinib (IC 50 0.06 µM) used as a reference. Docking and molecular dynamic simulations indicated that this compound tightly binds to the EGFR tyrosine kinase binding site [126].…”

Why are heterocycles so special in medicinal chemistry?

“…Tahghighi et al reported the design of novel triazole/quinoline hybrids, some of which exhibited potential for treating invasive fungal infections caused by Saccharomyces cerevisiae (Jamshidi et al, 2022). Qayed et al reported the design of acetophenones-tethered 1,2,4-triazoles and their oximes as EGFR inhibitors with the IC 50 values as low as 0.18 μM (El-Wahab et al, 2021). Popova et al reported new coumarin[1,3]oxazine derivatives of 7-hydr oxy-6-isobornyl-4-methylcoumarin that inhibited Fe 2+ / ascorbate-initiated peroxidation of animal lipids in a heterogeneous environment (Popova et al, 2021).…”