Bis(7)-harmine derivatives as potential multi-target anti-Alzheimer agents

作者：Hongtao Du, Fang Ma, Yuanyuan Cao, Miaoyan Bai, Xinyi Gao, Ziyi Yang, Xinjian Yang, Yan Yan · 发表于：Frontiers in Chemistry · 年份：2025 · DOI：10.3389/fchem.2025.1545908 · 被引用次数：3 · 研究领域：Synthesis and bioactivity of alkaloids、Psychedelics and Drug Studies、Cholinesterase and Neurodegenerative Diseases

Introduction 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. Methods The derivatives were synthesized by chemical methods and their structure was confirmed by nuclear magnetic resonance (NMR). The Ellman’s assay was utilized to assess the inhibitory potential of derivatives against h AChE and h BuChE. The inhibitory activity of these derivatives on both h MAO-A and h MAO-B was assessed using a fluorescence-based method. The thioflavin T (Th-T) fluorescence assay was used to assess the inhibition of A β 1−42 self-aggregation. The cytotoxicity was evaluated using the MTT assay. The Surflex-Dock program in Sybyl-X2.0 Software was employed for molecular docking. Results In vitro studies revealed that numerous synthesized compounds exhibited potent inhibitory activity against h AChE, and h MAO-B (IC 50 < 1 μM), as well as A β 1−42 aggregation (IC 50 < 20 μM). Importantly, the multitarget compounds 6d , 8c , and 8d exhibited remarkable efficacy in simultaneously mitigating A β -induced toxicity in SH−SY5Y cells while demonstrating minimal cytotoxicity. Furthermore, predicted ADMET results suggested that 6d , 8c , and 8d possessed favorable pharmacokinetic prop...