Design, synthesis, biological evaluation and in silico studies of few novel 2-substituted benzothiazole derivatives as potential EGFR inhibitors

Background: There is a great unmet medical need for new anticancer small molecule therapeutics. Exhaustive literature review suggests that benzothiazole derivatives have good potential to exhibit anticancer activity. Compounds that inhibit the kinase activity of EGFR are of potential interest as new antitumor agent. Objective: To design, synthesize and carry out in silico along with biological evaluation of 2- substituted benzothiazole compounds with EGFR inhibitory activity. Methods: Benzothiazole derivatives designed from molecular docking method for potential EGFR tyrosine kinase inhibition have been synthesized based on the docking results and characterized. Insilico studies were carried out to understand the mode of EGFR enzyme inhibition by our molecules. As a preliminary study, these compounds were first screened for antioxidant activity and then for anticancer activity against MCF-7 cell lines and A549 cell line. Results: Compound B5 showed potent anticancer activity on MCF-7 cell line with IC₅₀ value of 9.7µM and compound B8 showed significant anticancer activity on A549 cell line with IC₅₀ value of 49.7µM in comparison with the standard drug Doxorubicin (IC₅₀ = 1.4µM on MCF-7 and 1.0µM on A549 cell lines). In EGFR inhibitory activity B8 showed maximum activity on A549 cell line by inactivating 69.10% of EGFR phosphorylation and B7 showed maximum activity on MCF-7 cell line by inactivating 41.90% of EGFR phosphorylation in comparison with the reference drug Gefitinib. Molecular dynamics simulation studies suggest that benzothiazole derivative could also bind to allosteric site and inhibit the EGFR enzyme activity. Conclusion: Reported compounds have shown potent anticancer activity through EGFR inhibition by possibly binding at allosteric site.