Palladium-catalyzed synthesis and acetylcholinesterase inhibitory activity evaluation of 1-arylhuperzine A derivatives

Abstract

A series of arylated huperzine A (HPA) derivatives (1–24) were efficiently synthesized in good yields (45–88% yields) through the late-stage modification of structurally complex natural anti-Alzheimer’s disease (AD) drug huperzine A (HPA), using the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The acetylcholinesterase (AChE) inhibitory activity of all synthesized compounds was evaluated to screen the potential anti-AD bioactive molecules. The results showed that introducing the aryl groups to C-1 position of HPA resulted in the unsatisfactory AChE inhibitory activity. The present study demonstrably verifies pyridone carbonyl group could be the necessary and unchangeable pharmacophore for maintaining HPA's anti-AChE potency, and provides the helpful information on the further research for developing anti-AD HPA analogues.

Keywords:

• Huperzine A
• Alzheimer’s disease
• acetylcholinesterase inhibitors
• metal-catalysis
• Suzuki-Miyaura reaction

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was financially supported by grants from the National Natural Science Foundation of China [82204244] and the Natural Science Foundation of Sichuan Province [23NSFSC2370].