Discovery of novel β-carboline derivatives as selective AChE inhibitors with GSK-3β inhibitory property for the treatment of Alzheimer's disease

The natural product harmine, a representative beta-carboline alkaloid from the seeds of Peganum harmala L. (Zygophyllaceae), possesses a broad spectrum of biological activities. In this study, a novel series of harmine derivatives containing N-benzylpiperidine moiety were identified for the treatment of Alzheimer's disease (AD). The results showed that all the derivatives possessed significant anti-acetylcholinesterase (AChE) activity and good selectivity over butyrylcholinesterase (BChE). In particular, compound ZLWH-23 exhibited potent anti-AChE activity (IC50 = 0.27 mu M) and selective BChE inhibition (IC50 = 20.82 mu M), as well as acceptable glycogen synthase kinase-3 (GSK-3 beta) inhibition (IC50 = 6.78 mu M). Molecular docking studies and molecular dynamics simulations indicated that ZLWH-23 could form stable interaction with AChE and GSK-3 beta. Gratifyingly, ZLWH-23 exhibited good selectivity for GSK-3 beta over multi-kinases and very low cytotoxicity towards SH-SY5Y, HEK-293T, HL-7702, and HepG2 cell lines. Importantly, ZLWH-23 displayed efficient reduction against tau hyperphosphorylation on Ser-396 site in Tau (P301L) 293T cell model. Collectively, harmine-based derivatives could be considered as possible drug leads for the development of AD therapies.& nbsp;(c) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

This study identifies a novel series of harmine derivatives with potential value for the treatment of Alzheimer's disease (AD). Compound ZLWH-23 shows significant anti-acetylcholinesterase activity, selective inhibition of butyrylcholinesterase, and acceptable inhibition of glycogen synthase kinase-3 beta. Furthermore, ZLWH-23 exhibits good selectivity for GSK-3 beta over other kinases and reduces tau hyperphosphorylation in a cell model. Harmine-based derivatives could be considered as drug leads for AD therapies.