DHPMs C5 Amide Bearing Benzothiazole Moiety Inhibit AChE: Design, Synthesis, In Vitro and In Silico Studies

Objective: The well-accepted hypothesis in Alzheimer’s disease (AD) emphasizes the role of the cholinergic system in the disease. Therefore, the design and development of selective AChE inhibitors have been considered a promising strategy for AD treatment. Dihydropyrimidin-2-one is a privileged heterocyclic scaffold with a wide range of biological activities. Methods: Our initial docking studies indicated that substitution at the para position of the C4 aryl in the DHPM ring could interact with the gorge of the active site. Accordingly, we designed and synthesized eight DHPM derivatives to test the hypothesis. Results and Discussion: The results indicated that the DHPM with a benzothiazolyl carbamyl moiety at C5 and an OCF₃ group at the para position of the C4 aryl ring was the most potent inhibitor. The propargyloxy group was less potent than the OCF₃ group but had the same ligand efficiency. Conclusions: Introducing electron-rich substitutions of proper size increased activity, but the ligand efficiency remained constant. In silico studies revealed that the para substitution of the aryl ring interacted with the gorge residues in the R-enantiomer.