Synthesis of novel N4-substituted and C2-disubstituted 1,4-benzothiazine-1,1-dioxide derivatives: Integrative computational strategies for breast cancer therapy

This study presents a straightforward and efficient synthetic method for the preparation of 1,4-benzothiazine-3-one-1,1-dioxide derivatives, specifically N₄-substituted compounds 3a-c and C₂-disubstituted compounds 4–12, which were obtained via alkylation reactions with monobrominated agents following activation of the methylinic protons at the C₂ position through the transformation of sulfur into a sulfone group. All synthesized compounds were characterized by their ¹H- and ¹³C-NMR spectral data and HRMS analysis. Furthermore, compounds 3c, 4, 5, 9, and 11 additionally confirmed by single-crystal X-ray diffraction analysis. The synthesized compounds were evaluated through in silico studies, including network pharmacology for bioactivity, toxicity prediction, physicochemical properties, molecular docking, and molecular dynamics simulations. All designed compounds (3c, 4–12) exhibited favorable physicochemical properties. Molecular docking studies revealed favorable interactions between compounds 7 and 10 with the target protein AKT1. Compounds 7 and 10 showed the most favorable docking scores with low-energy conformations (-8.02 kcal/mol and -8.29 kcal/mol, respectively), compared to the standard drug Capivasertib (-8.40 kcal/mol). Molecular dynamics analysis showed that compound 7 demonstrated the most stable ligand RMSD and a compact molecular conformation, highlighting its potential as a lead candidate for targeting AKT1.