Synthesis, Formation Mechanisms, and Molecular Dynamics Simulation of Novel Benzothiazole and Benzo[1,4]oxazin-3(4)-one as Potential Acetylcholinesterase Inhibitors.

A novel series of benzothiazole derivatives was synthesized using straightforward and easily implementable procedures, achieving a high yield. Among these synthesized compounds, amino acids containing the benzothiazole moiety were successfully produced through an 8-step process, with yields reaching as high as 95%. Notably, a serendipitous compound containing both benzothiazole and benzo[1,4]oxazin-3(4)-one moieties was also synthesized using the same protocol, bypassing purification at step 7 and proceeding directly to hydrolysis. This highlights the unique role of the coupling reagent HATU (hexafluorophosphate azabenzotriazole tetramethyluronium) in the reaction, as it facilitated high yields, reaching up to 90%. The structures of the newly synthesized compounds were confirmed through spectral analysis. Density functional theory calculations suggested that energy barriers can be overcome by utilizing the energy from an exothermic reaction, enabling the thermodynamically favorable formation of this novel structure. Compounds and demonstrated significant inhibitory activity against the enzyme acetylcholinesterase, with IC values of 32.00 and 25.33 μg/mL, respectively. Molecular docking and molecular dynamics analyses indicate that compounds and hold potential for combating Alzheimer's disease, due to their interactions with critical amino acid residues and structural stability.