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Pd-Catalyzed Direct Diversification of Natural Anti-Alzheimer’s Disease Drug: Synthesis and Biological Evaluation of N-Aryl Huperzine A Analogues
- Source :
- Journal of Natural Products. 84:2374-2379
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15206025 and 01633864
- Volume :
- 84
- Database :
- OpenAIRE
- Journal :
- Journal of Natural Products
- Accession number :
- edsair.doi...........d978ea0896c9504ec392ce4468fb9253