Synthesis, X-ray, spectroscopic characterizations, DFT calculations, Hirschfeld surface analyses, molecular docking, and molecular dynamic simulations of some 1,4-benzothiazine-1,1-dioxide derivatives as human kinase CK2 inhibitors

Abstract

Several derivatives (4a-d - 5a-d) based on 1,4-benzothiazine-1,1-dioxide were synthesized in this study. The process began by preparing 1,4-benzothiazin-3-one 2 from 2-aminothiophenol 1 and 2-chloroacetic acid under alkaline conditions in water. Compound 2 was then oxidized using potassium permanganate to yield 1,4-benzothiazin-3-one-1,1-dioxide 3, which was used to undergo Knoevenagel condensation with various aromatic aldehydes in dimethylformamide with sodium methoxide under different conditions. Bis 3-oxo-1,4-benzothiazine-1,1-dioxide derivatives 4a-d were obtained at room temperature while heating the reaction mixture produced 2-benzyl-1,4-benzothiazine dioxide compounds 5a-d. The structural characterization was performed using spectroscopic techniques, and 4c and 5a-5d were further confirmed by single-crystal X-ray diffraction (XRD) analysis. Moreover, theoretical calculations using the DFT method and Hirshfeld surface analysis showed good agreement with experimental data. Lastly, molecular docking studies revealed that 4c, 5a-5d have a binding affinity with Human Kinase CK2, with 4c exhibiting the highest binding affinity. Molecular dynamics simulation of the CK2-4c complex indicated stable interaction, suggesting potential therapeutic use against various diseases.