Synthesis, in vitro assay, and molecular modeling of new piperidine derivatives having dual inhibitory potency against acetylcholinesterase and Aβ1–42 aggregation for Alzheimer’s disease therapeutics

With the goal of developing Alzheimer’s disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Aβ) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Aβ1–42 peptide aggregation, AChE-induced Aβ1–42 aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Aβ1–42 aggregation and AChE-induced Aβ aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel π–π stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Aβ1–42 peptide aggregation.

We designed and synthesized new piperidine derivatives having dual inhibitory potency of AChE and Aβ1–42 peptide aggregation. Compound 12 (X = none, R = benzhydryl, R1 = 4-Cl) displayed the most inhibitory potency against AChE (IC50 = 0.32 μM) and selectivity (AChE relative to BChE) of 120 times. Compounds 12 and 15 (X = none, R = benzhydryl, R1 = 4-tert-butyl) showed good inhibition effects on Aβ1–42 peptide oligomerization and the AChE-induced aggregation.Figure optionsDownload as PowerPoint slide