N-Cyclohexylimidazo[1,2-a]pyridine derivatives as multi-target-directed ligands for treatment of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia. While drugs that target several pathways underlying AD have been proposed, effective treatments remain to be discovered. BACE1, an Enzyme associated with AD progression, is a promising target for developing anti-Alzheimer drugs. To find novel multifunctional anti-Alzheimer agents, we designed and synthesized a series of new substituted benzyl-1H-1,2,3-triazol-4-yl-N-cyclohexylimidazo[1,2-a]pyridin-3-amine. The in vitro screening results revealed that most of the compounds exhibited moderate to potent BACE1 and BuChE inhibitory and antioxidant activities. Compounds 7f and 7g, bearing dichloro (2,3-Cl₂ and 3,4-Cl₂) moieties on the benzyl pendant were selected as the most active compounds in our BACE1 inhibitory assay with respective IC₅₀ values of about 12 and 8.9 μM. In addition, compounds 7g and 7h (4-bromo derivative) showed the highest BuChE inhibitory activity with IC₅₀ of 3.2 and 2.5 µM, respectively. Compound 7g also possessed antioxidant activity with an IC₅₀ value of 10.2 μM and metal chelation potential. Moreover, docking studies were performed to investigate the possible mechanism of inhibition. Taken together, we demonstrate that N-cyclohexylimidazo[1,2-a]pyridine containing triazole motif derivatives deserve further investigation for anti-Alzheimer drug development.