Synthesis, computational analysis, and exploring antiproliferative activity of triazolo- and thiazolo-pyrimidine derivatives as potential EGFR inhibitors

Abstract

Anticancer drug acquiring usually discloses with an in vitro testing in cell panels to certainly detect the lead compounds. EGFR is a tyrosine kinase cell surface receptor that plays a key function in signal transduction processes and is observed on most cell surfaces. One of the promising frameworks in drug detection is pyrimidine and its fused heteroannulated bicyclic derivatives which exhibited promising anticancer activity. The prepared triazolopyrimidine and thiazolopyrimidine derivatives were proposed to fit into the ATP binding site of EGFR protein. The in vitro antiproliferative screening against MCF7 and HCT116 cancer cell panels disclosed the most influence of triazolopyrimidine 3, thiazolopyrimidine 9, and pyrimidinethione 1 compared to the reference drug, roscovitine (imidazopyrimidine hybrid). The inhibitory action of the most promising compounds was explored versus EGFR enzyme, which displayed the highest efficacy of triazolopyrimidine 3 compared to the standard drug (erlotinib). The structure-activity relationship (SAR) probe demonstrated that specific structural modifications had a significant impact on the antiproliferative action. In silico molecular docking was performed on these promising compounds versus EGFR enzyme (breast cancer protease, PDB ID: 3W32) to show the enzyme-inhibitor interactions, which uncovered the superlative binding interactions of triazolopyrimidine 3 with key nucleobases and amino acids of EGFR kinase. Among DFT calculations, E_LUMO of compounds 3 < 1 < 9, which enriched its binding affinity of with nucleophilic receptor's active pockets. Regarding ADME simulation, they had gastrointestinal tract (GIT) absorption, good bioavailability score, and worthy lead-likeness. This work may contribute to developing new effective EGFR inhibitor.