Design And Synthesis of Novel Quinazoline Derivatives as Potent EGFR Inhibitors for Cancer Therapy

Abstract

Quinazoline-based compounds have been shown to be important scaffolds in the tyrosine kinase inhibitors particularly in the treatment of the epidermal growth factor receptor (EGFR) in cancer chemotherapy. The present study is focused on the synthesis, design, and testing of a series of new quinazoline-related structures due to their possible inhibitory effects to the EGFR. A series of twelve quinazoline derivatives were designed based on structure of a drug and synthesised via a multi-step synthetic procedure along the path of nucleophilic substitution and formation of amide bonds. FTIR, NMR and mass spectrometry were used to determine the nature of the compounds. Cytotoxicity of compounds was measured in vitro by examination of inhibited cell growth in A549 (lung carcinoma) and MCF-7 (breast cancer) cell lines through MTT assay. Auto Dock Vina molecular docking results indicated high binding affinity scores of QZ-3, QZ-5 and QZ-9 in the ATP-binding site of EGFR starting at -9.8 kcal/mol to -11.2 kcal/mol. QZ-5 was the most cytotoxic (IC 50 = 1.6 um) as well as selective EGFR inhibitor (IC 50 = 0.8 um). The findings validate the possibility of these derivatives as the lead of the cancer therapy against EGFR.