Apigenin-rivastigmine hybrids as multi-target-directed liagnds for the treatment of Alzheimer’s disease

• Published in: European journal of medicinal chemistry 2020-02, Vol.187, p.111958, Article 111958
• Main Authors: Sang, Zhipei, Wang, Keren, Shi, Jian, Cheng, Xinfeng, Zhu, Gaofeng, Wei, Rongrui, Ma, Qinge, Yu, Lintao, Zhao, Yiyang, Tan, Zhenghuai, Liu, Wenmin
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; Apigenin - chemistry; Apigenin - metabolism; Apigenin - pharmacology; Apigenin-rivastigmine hybrids; Butyrylcholinesterase - metabolism; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Humans; In vivo assay; Ligands; Metabolism in vitro; Microsomes, Liver - chemistry; Microsomes, Liver - metabolism; Molecular Docking Simulation; Molecular Structure; Multi-function agents; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Rats; Rivastigmine - chemistry; Rivastigmine - metabolism; Rivastigmine - pharmacology; Structure-Activity Relationship; Transcriptome sequencing; Zebrafish
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111958

Here we reported novel apigenin-rivastigmine hybrids were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, their activity in vitro results revealed that compound 3d showed significant antioxidant potency (ORAC = 1.3 eq), and it was a reversible huAChE (IC50 = 6.8 μM) and huBChE (IC50 = 16.1 μM) inhibitor. 3d also served as a selective metal chelator, and it significantly inhibited and disaggregated self-mediated and Cu2+-mediated Aβ1-42 aggregation, and also inhibited hAChE-mediated induced Aβ1-40 aggregation. Compound 3d exhibited remarkable neuroprotective effect and hepatoprotective activity. In addition, compound 3d presented favourable blood-brain barrier penetration in vitro and drug-like property. Further, the in vivo assay displayed that 3d indicated remarkable dyskinesia recovery rate and response efficiency on AD zebrafish, and exhibited surprising protective effect on Aβ1-40-mediated zebrafish vascular injury. More importantly, 3d did not indicate obvious acute toxicity at dose up to 2000 mg/kg, and could improve scopolamine-induced memory impairment. Subsequently, the regulation of multi-targets for 3d were further confirmed through transcriptome sequencing of brain hippocampi, which also offered novel potential targets and opened a new way to treat Alzheimer’s disease. More interestingly, the metabolism of 3din vitro indicated that 4 metabolites in rat liver microsome metabolism, 2 metabolites in human liver microsome metabolism, and 4 metabolites in intestinal flora metabolism, which offered supports for the preclinical study of 3d. Overall, this study exhibited that compound 3d was a promising advanced compound targeted multiple factors associated with AD. [Display omitted] •Novel apigenin-rivastigmine hybrids was rationally designed.•3d was a promising multi-function agent.•3d could improve AlCl3-induced zebrafish AD.•3d could protect Aβ1-40-mediated zebrafish vascular injury.•3d could improve scopolamine-induced memory impairment.