Synthesis and in silico evaluation of novel hybrid 1,4-benzothiazine-1,1-dioxide-bis(1,2,3-triazole) derivatives as potential SRC kinase inhibitors via 1,3-dipolar cycloaddition.
Herein, we report the synthesis of new 1,4-benzothiazine-1,1-dioxide derivatives bearing bis(1,2,3-triazole) moieties via click chemistry in good to high yields and fully characterized by 1H NMR, 13C NMR and HRMS. The compounds were evaluated using a combined in silico approach, including physicochemical, pharmacokinetic and toxicity analysis, molecular docking and molecular dynamics studies. Drug-like properties of all compounds were favourable. Molecular docking against SRC kinase suggested binding affinities ranging from -7.14 to -8.13 kcal/mol. Compound 11 displayed the most favorable docking score (-8.13 kcal/mol), comparable to that of bosutinib (-8.54 kcal/mol), and formed key interactions within the active site. This finding was consistent with the 100 ns molecular dynamics simulations, which indicated that the SRC-compound 11 complex remained structurally stable and maintained key interactions with residues such as Met341, Tyr340 and Lys295. Despite showing conformational flexibility than bosutinib, compound 11 maintained stable binding throughout the simulation. Overall, compound 11 showed favorable predicted binding toward SRC kinase, suggesting that these bis-triazole derivatives may represent potential leads for future anticancer investigation.