Novel AP2238-clorgiline hybrids as multi-target agents for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation.
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| Abstract |
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.
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| Authors | Guohui Zhong, Jie Guo, Chengyun Pang, Di Su, Chunli Tang, Lin Jing, Fengling Zhang, Ping He, Yaqian Yan, Zongji Chen, Jing Liu, Neng Jiang |
| Journal | Bioorganic chemistry (Bioorg Chem) Vol. 130 Pg. 106224 (01 2023) ISSN: 1090-2120 [Electronic] United States |
| PMID | 36332315 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2022. Published by Elsevier Inc. |
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