Molecular Docking, ADMET Study, Synthesis, Characterization, and Anti-proliferative Activity Study of Novel Schiff Base Derivatives of N'-benzylidene-4H-benzo[b][1,4]thiazine-3-carbohydrazide Against Lung Cancer Cell Line.

Abstract

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is a vastly fascinating epigenetic target for medicine treatment. EGFR-TK is overexpressed in several diseases, including cancers. In this study, we designed new EGFR-TK inhibitors with the same consists of erlotinib (approved anticancer drug) with longer linker and substituted hydrophobic moiety using Ligand Designer from Glide (Schrodinger LLC). By experimenting with different amide and Schiff base residues, the linker was optimized. Using licensed Schrodinger modeling software, the probable inhibition over EGFR-TK for the best-designed items was virtually assessed. The findings demonstrated that there is a possibility of an acceptable level of fitness interaction between the hydroxylated substitution hydrophobic moiety and the EGFR-TK active site. To forecast the final drugs' pharmacokinetic characteristics, an ADMET analysis was conducted. Good predicted drug-like characteristics were displayed by the final compounds. Recrystallization was used to successfully manufacture and purify the intermediates and final chemicals. FTIR, ¹HNMR, and ¹³CNMR spectroscopy were used to characterize the chemical structure of the intermediates and final products. Using MTT technique; all synthesized compounds (SH1-SH6) exposed a reassuring antiproliferative activity in A504 lung tumor cells lines with IC50 of 10.24 μM, 5.47 μM, 19.98 μM, 4.18 μM, 13.13 μM, and 3.88 μM respectively, and inhibition percentage of 82.3%, 88.2%, 70.5%, 82.3%, 82.3%, and 94.1% respectively, which is comparable to erlotinib IC50 of 3.86 μM and inhibition percentage of 94.7%. The compound SH6 was the most promising one (IC50=3.88µM and a percentage of inhibition=94.1%), compared with erlotinib, a reference authorized anticancer drug.