Novel benzothiazole sulfonamides as potent α-glucosidase and cholinesterase inhibitors: Design, synthesis, structural properties, biological evaluation and docking studies

Abstract

A simplified synthetic method yielded diverse 2-aminobenzothiazole variants through sulfonylation and amino group alkylation. Extensive characterization via X-ray diffraction, UV/vis, infrared, 1H, and 13CNMR spectroscopies was performed. Compounds 19, 25, 29, 33, and 37 displayed dose-dependent α-glucosidase inhibition, with IC50 values, compared to acarbose, of 79.35 ± 1.13 µM, 139.53 ± 1.12 µM, 172.16 ± 1.23 µM, 179.35 ± 1.13 µM, and 97.36 ± 1.15 µM, respectively. For BChE (Butyrylcholinesterase) inhibition, compounds 25, 31, 32, 36, 37, 38, and 39 exhibited IC50 values, compared to Eserine, of 153.73 ± 1.17 µM, 175.64 ± 1.13 µM, 252.98 ± 1.19 µM, 124.92 ± 1.17 µM, 286.38 ± 1.16 µM, 128.62 ± 1.18 µM, and 97.28 ± 1.15 µM. Molecular docking validated these results, linking structure to activity and assessing α-glucosidase inhibition. Detailed ligand-protein interactions were explored, illuminating bond types and atomic distances within the active site, particularly for acarbose. Compound 29, indicated by its small Eg value, exhibited high reactivity due to specific electron density and structural features. Drug-likeness was evaluated using multiple criteria and compared favorably to existing drugs like penfluridol and amiodarone. NAMD (Nanoscale Molecular Dynamics) simulated ligand-protein complex behavior in a cell-like context and used Root Mean Square Deviation (RMSD) to assess stability and conformational changes. Computationally determined SASA values evaluated water molecule accessibility and stability. Compound stability and solvent interactions in ligand-protein complexes highlighted compound 33 as most stable, while compounds 19 and 37 resembled acarbose, and compound 25 achieved stability over time. These findings enhance comprehension of solid-state arrangements of novel aminobenzothiazole sulfonamide derivatives, potentially stimulating further research for drug discovery within the scientific community.