Novel Benzofuran-3-yl-methyl and Aliphatic Azacyclics: Design, Synthesis, and In Vitro and In Silico anti-Alzheimer Disease Activity Studies

Neurological disorders represent a significant burden on human health, particularly as global life expectancy continues to rise. Among these conditions, Alzheimer's disease is notably prevalent. Of greater concern, if left untreated or unaddressed, Alzheimer's disease can progress to dementia, leading to severe cognitive decline and a substantial reduction in quality of life. In this study, 15 novel benzofuran-azacyclic hybrids were designed and synthesized. The final compounds were evaluated for their inhibitory potency on AChE and BACE-1 Enzymes, and in silico studies were performed to clarify their binding modes. Finally, structure-activity relationships (SARs) were proposed for future studies. The results indicated that the most promising compound is 4m, which contains N-(2-hydroxyethyl)-piperazine and benzofuran moieties. These moieties effectively occupied the substrate channel of the AChE enzyme and the catalytic cleft of the BACE-1 enzyme. Additionally, compounds 4e (benzyl piperidine) and 4h (2-furoyl piperazine) showed dual inhibitory activity on both Enzymes. In conclusion, the tubular form with a stopper group shows great potential for the treatment of Alzheimer's disease, as it blocks the entrance cavity of the AChE active pocket for the substrate and increases the stability of the inactive BACE-1 enzyme. Moreover, electrolytes, specifically sodium ions in this case, play a crucial role in stabilizing the 4m-BACE-1 protein complex. For further studies, we suggest that the tubular form with a stopper can serve as a potential pharmacophore and an appropriate starting point for drug development.