Synthesis and Anticancer Activities of Pyrazole-Thiadiazole-Based EGFR Inhibitors

Lung cancer is one of the most common cancer types ofcancer withthe highest mortality rates. However, while epidermal growth factorreceptor (EGFR) is an important parameter for lung cancer, EGFR inhibitorsalso show great promise in the treatment of the disease. Therefore,a series of new EGFR inhibitor candidates containing thiadiazole andpyrazole rings have been developed. The activities of the synthesizedcompounds were elucidated by in vitro MTT, (which is chemically 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide), cytotoxicity assay, analysis of mitochondrial membrane potential(MMP) by flow cytometry, and EGFR inhibition experiments. Moleculardocking and molecular dynamics simulations were performed as in silicostudies. Compounds 6d, 6g, and 6j showed inhibitor activity against the A549 cell line with IC50 = 5.176 & PLUSMN; 0.164; 1.537 & PLUSMN; 0.097; and 8.493 & PLUSMN;0.667 & mu;M values, respectively. As a result of MMP by flow cytometry,compound 6g showed 80.93% mitochondrial membrane potential.According to the results of the obtained EGFR inhibitory assay, compound 6g shows inhibitory activity on the EGFR enzyme with a valueof IC50 = 0.024 & PLUSMN; 0.002 & mu;M.