Hongtao Du
*
Fang Ma
The final, formatted version of the article will be published soon.
ORIGINAL RESEARCH article
Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 13 - 2025 |
doi: 10.3389/fchem.2025.1545908
Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents
Provisionally accepted- Yan'an University, Yan'an, China
The multi-targeted ligands (MTDL) strategy has been recognized as a promising approach for the development of effective treatments against Alzheimer's disease (AD), due to the presence of multiple pathological mechanisms in AD. In this study, a series of bis(7)-harmine derivatives were designed and synthesized as multifunctional drugs for the treatment of AD. In vitro studies revealed that numerous synthesized compounds exhibited potent inhibitory activity against hAChE, and hMAO-B (IC50 < 1 μM), as well as Aβ1-42 aggregation (IC50 < 20 μM). Importantly, the multitarget compounds 6d, 8c, and 8d exhibited remarkable efficacy in simultaneously mitigating Aβ-induced toxicity in SH-SY5Y cells while demonstrating minimal cytotoxicity. Furthermore, predicted ADMET results suggested that 6d, 8c, and 8d possessed favorable pharmacokinetic properties and demonstrated low toxicity levels. Additionally, molecular docking studies of 6d within the active sites of hAChE, hMAO-B, and Aβ1-42 elucidated the inhibition mechanism. Based on these findings, it is evident that 6d, 8c, and 8d hold potential as promising multi-functional drugs for AD treatment.
Keywords: Alzheimer's disease, Harmine, Acetylcholinesterase, Monoamine Oxidase, amyloid peptide (Aβ)
Received: 16 Dec 2024; Accepted: 02 Jan 2025.
Copyright: © 2025 Du, Ma, Cao, Bai, Gao, Yang, Xu and Yan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Hongtao Du, Yan'an University, Yan'an, China
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