Pd-Catalyzed Direct Diversification of Natural Anti-Alzheimer’s Disease Drug: Synthesis and Biological Evaluation of N-Aryl Huperzine A Analogues
| Autor: | Feng Gao, Shi-Xing Miao, Lin-Xi Wan, Zhen-Xiang He, Xiaohuan Li, Xian-Li Zhou |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Natural product Stereochemistry Aryl Organic Chemistry Pharmaceutical Science Acetylcholinesterase Neuroprotection In vitro Analytical Chemistry chemistry.chemical_compound Complementary and alternative medicine chemistry Drug Discovery medicine Molecular Medicine Lead compound IC50 Huperzine A medicine.drug |
| Zdroj: | Journal of Natural Products. 84:2374-2379 |
| ISSN: | 1520-6025 0163-3864 |
| DOI: | 10.1021/acs.jnatprod.1c00600 |
| Popis: | The first systematic direct diversification of a complex natural product by metal-catalyzed N-H functionalization was carried out. A new series of N-(hetero)aryl analogues (1-32) of the natural anti-Alzheimer's disease drug huperzine A (HPA) was prepared via palladium-catalyzed Buchwald-Hartwig cross-coupling reactions of HPA with various aryl bromides in good yields. Most of the N-aryl-huperzine A (N-aryl-HPA) analogues showed good acetylcholinesterase (AChE) inhibitory activity in in vitro experiments. Three arylated huperzine A analogues (14, 19, and 30) exhibited stronger anti-AChE activity than HPA. The 5-methoxy-2-pyridyl analogue (30) displayed the most potent AChE inhibition activity, with an IC50 value of 1.5 μM, which was 7.6-fold more active than HPA. Compound 30 also exhibited better neuroprotective activity for H2O2-induced damage in SH-SY5Y cells than HPA. Structure-activity relationship analysis suggested that the electron density of the installed aromatic ring or heteroaromatic ring played a significant role in inducing the AChE inhibition activity. Overall, compound 30 showed the advantages of easy synthesis, high potency and selectivity, and improved neuroprotection, making it a potential huperzine-type lead compound for Alzheimer's disease drug development. |
| Databáze: | OpenAIRE |
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