Design, Synthesis, Biological Evaluation, and Docking Study of Novel 4-Anilinoquinazolines Derivatives as Anticancer Agents

Document Type : Research Article


1 Department of Chemistry, Rasht Branch, Islamic Azad University, Rasht, I.R. IRAN

2 Department of Pharmaceutical Biotechnology, School of Pharmacy, Guilan University of Medical Sciences, Rasht, I.R. IRAN


Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR) as appropriate targets for cancer therapy have recently made a noteworthy field since the introduction of vandetanib as a dual inhibitor of VEGFR and EGFR tyrosine kinases (TKIs). In this study, twelve quinazoline derivatives were designed, synthesized, and evaluated for their cytotoxicity on A431 (human carcinoma cell) as well as HU02 (Foreskin fibroblast) cell lines by MTT assay. The binding mode of the most potent compound (8a) with EGFR and VEGFR2 was studied using molecular docking. Most of the compounds showed significant inhibition on the growth of A431 cells at the concentration lower than 100 µM. The compound 8a bearing diethylamine along with 4-bromo-2-fluoroaniline exhibited the best cytotoxic activity (IC50=2.62 μM) compared to erlotinib and vandetanib as positive controls. Synthesized compounds did not indicate significant cytotoxicity against HU02 cell line. The compound 8a indicated binding energies of -6.39 and -8.24 kcal/mol as well as inhibition constants of 20.67µM and 0.9µM with EGFR and VEGFR-2, respectively, which showed the effective binding with VEGFR-2.  The higher potency of 8a may be put down to the flexibility of diethylamine and its higher lipophilicity as well as lower steric hindrance of this substituent.


Main Subjects

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