Novel harmine derivatives as potent acetylcholinesterase and amyloid beta aggregation dual inhibitors for management of Alzheimer’s disease

Abstract

In this study, a series of potential ligands for the treatment of AD were synthesised and characterised as novel harmine derivatives modified at position 9 with benzyl piperazinyl. In vitro studies revealed that the majority of the derivatives exhibited moderate to potent inhibition against hAChE and Aβ_1 − 42 aggregation. Notably, compounds 13 and 17d displayed potent drug − likeness and ADMET properties, demonstrating remarkable inhibitory activities towards AChE (IC₅₀ = 58.76 nM and 89.38 nM, respectively) as well as Aβ aggregation (IC₅₀ = 9.31 μM and 13.82 μM, respectively). More importantly, compounds 13 and 17d showed exceptional neuroprotective effects against Aβ_1 − 42−induced SH − SY5Y damage, while maintaining low toxicity in SH − SY5Y cells. Further exploration of the mechanism through kinetic studies and molecular modelling confirmed that compound 13 could interact with both the CAS and the PAS of AChE. These findings suggested that harmine derivatives hold great potential as dual − targeted candidates for treating AD.

Keywords:

• Alzheimer’s disease
• harmine
• acetylcholinesterase
• β−amyloid peptide

Acknowledgement

The authors express our gratitude to Dr. Qiuju Zhou (Analysis and Testing Center, Xinyang Normal University) for her invaluable assistance in conducting compound structure analyses.

Author contribution

H.D. and Y.Y. were responsible for overseeing the research project. F. M. and J. S. synthesised the compounds under investigation. X. H. helped in conducting the structural analysis of the compounds. X.Z., H.G. and R.M. conducted biological activity tests to evaluate their effectiveness. The manuscript was written by H.D. and Y.Y., with contributions from all authors who have given their approval to the final version of the manuscript.

Disclosure statement

The authors report there are no competing interests to declare.

Additional information

Funding

This work was supported by the Program for Natural Science Foundation of China] under Grant [No. 21602178]; [Qin Chuan Yuan cited the high-level innovation and entrepreneurship talent program of Shaanxi] under Grant [No. QCYRCXM-2022–172, QCYRCXM-2022–196]; and [Doctoral Research Initiation Project of Yan’an University] under Grant [No. 205040406, 205040422].