Novel AP2238-clorgiline hybrids as multi-target agents for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation

[Display omitted] •A novel series of AP2238-clorgiline hybrids as anti-Alzheimer agents has been designed and synthesized.•5l showed the balanced and good inhibitory activity against AChE, BuChE and MAO-B.•5l exhibited no toxicity to PC12 and BV-2 cells at 12.5 μM and no acute toxicity at a dosage o...

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Published in:Bioorganic chemistry 2023-01, Vol.130, p.106224, Article 106224
Main Authors: Zhong, Guohui, Guo, Jie, Pang, Chengyun, Su, Di, Tang, Chunli, Jing, Lin, Zhang, Fengling, He, Ping, Yan, Yaqian, Chen, Zongji, Liu, Jing, Jiang, Neng
Format: Article
Language:English
Subjects:
Alzheimer’s disease
Cholinesterase inhibitors
Clorgiline
Monoamine oxidase inhibitors
Multi-target agents
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Summary:[Display omitted] •A novel series of AP2238-clorgiline hybrids as anti-Alzheimer agents has been designed and synthesized.•5l showed the balanced and good inhibitory activity against AChE, BuChE and MAO-B.•5l exhibited no toxicity to PC12 and BV-2 cells at 12.5 μM and no acute toxicity at a dosage of 2500 mg/kg.•5l could significantly reverse scopolamine-induced memory deficit in mice and penetrate the BBB. Cholinesterase and monoamine oxidase are potential targets for the therapy of Alzheimer's disease. A series of novel AP2238-clorgiline hybrids as multi-target agents were designed, synthesized and investigated in vitro for their inhibition of cholinesterases and monoamine oxidases. Many compounds displayed balanced and good inhibitory activity against AChE, BuChE and MAO-B with an obvious selective inhibitory effect on MAO-B. Among them, Compound 5l showed the most balanced potency to inhibit ChEs (eeAChE: IC50 = 4.03 ± 0.03 μM, eqBuChE: IC50 = 5.64 ± 0.53 μM; hAChE: IC50 = 8.30 ± 0.04 μM, hBuChE: IC50 = 1.91 ± 0.06 μM) and hMAO-B (IC50 = 3.29 ± 0.09 μM). Molecular modeling and kinetic studies showed that 5l was a mixed inhibitor for both AChE and BuChE, and a competitive MAO-B inhibitor. Compound 5l exhibited no toxicity to PC12 and BV-2 cells at 12.5 μM and no acute toxicity at a dosage of 2500 mg/kg. Moreover, 5l can improve the memory function of mice with scopolamine-induced memory impairment and have an excellent ability to cross the blood–brain barrier. Overall, these findings suggested that compound 5l could be deemed as a promising, balanced multi-target drug candidate against Alzheimer's disease.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2022.106224