Design and Evaluation of Piperidine-Based Inhibitors targeting Alzheimer’s Disease

Introduction

Alzheimer's Disease (AD) is a neurodegenerative illness causing severe cognitive decline, personality changes, and psychological issues, with over 10 million new cases per year which are expected to double by 2036. The most widely prescribed drug to treat symptoms of AD is the cholinesterase inhibitor donepezil, first approved in the US in 1996. Donepezil's activity comes largely from its nitrogen-containing heterocyclic piperidine structure. The piperidine ring appears frequently in other compounds targeting AD and has prompted AD research into piperidine containing derivatives.

Method

In this work, computer-aided drug design (CADD) was used to virtually screen a library of 32 piperidine-containing molecules derived from a lead against co-crystallized human acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE). Based on docking scores and detailed 2D and 3D interactions with the target, the top eight derivatives were synthesized via N-alkylation reaction, and confirmed with 1H-NMR and EI-MS. Their action on AChE and BuChE was determined via enzyme inhibition assay using Ellman’s method.

Result

The IC50 values of four derivatives showed significant action against both enzymes (MA13 [AChE IC50=69.2 µM; BuChE IC50=19.5 µM], MA29 [21.4; 13.2 µM], MA31 [20.4; 18.5 µM], MA32 [29.6; 23.5 µM]), while 2 within this group showed particularly strong inhibitory action against BuChE when compared with donepezil (MA29, MA31).

Conclusion

Overall, these results reveal new scaffolds with promising anti-Alzheimer’s potential, including two candidates that show particularly strong activity against BuChE. Further development of these molecules may yield viable candidates for next-generation therapeutics, providing new opportunities to slow or lessen the progression of AD.