Rational Design, Green Synthesis, and Biological Evaluation of Novel Imidazole Derivatives as Potent EGFR Inhibitors...

This study reports a green, efficient, and high-yielding synthesis of novel imidazole derivatives 5a-i via a one-pot, four-component reaction under microwave irradiation. The optimized protocol demonstrates satisfactory yields (86%-92%), short reaction times (9-14 min), easy workup, and avoidance of toxic solvents, in accordance with sustainable chemistry principles. The antiproliferative efficacy of derivatives 5a-i was evaluated against H1975, A549, and A431 cells, using the MTT assay. The results indicated that derivatives 5b and 5g exhibited the greatest antiproliferative activity, with IC₅₀ values of 5.22 and 6.34 µM. The values obtained were markedly inferior to those of recognized EGFR inhibitors, such as osimertinib, gefitinib, and erlotinib. Compound 5b was exhibited as the most potent inhibitor of both EGFR^WT and EGFR^T790M kinases, with IC₅₀ values of 30.1 and 12.8 nM, respectively. The findings exceeded those of osimertinib and gefitinib, which demonstrated IC₅₀ values of 54.3, 19.1, 9.1, and 356.8 nM, respectively, which may explain its notable antiproliferative effect against the H1975 cell line. Molecular docking and dynamics simulations confirmed the stable binding of derivatives 5b and 5g within the EGFR active sites, aligning with experimental findings. Furthermore, in silico ADME properties for the promising EGFR inhibitors 5b and 5g, conducted using the egg-boiled technique, demonstrated favorable lipophilicity, G.I.T. absorption, and BBB permeability. As a result, imidazoles 5a-i, particularly 5b and 5g, exhibited promising antiproliferative properties, targeting EGFR^WT and EGFR^T790M kinase inhibitors.