Synthesis of derivatives of cleistopholine and their anti-acetylcholinesterase and anti-β-amyloid aggregation activity

A series of 6- and 9-substituted cleistopholine derivatives have been synthesized and tested for their ability to inhibit cholinesterase and β-amyloid aggregation in vitro. Their blood-brain barrier permeability was also assessed. [Display omitted] •The new cleistopholine derivatives exhibited high AChE inhibitory activity in intro.•The derivatives exhibited a significant in vitro inhibitory potency toward Aβ secretion levels.•Most of the synthetic derivatives were predicted to be able to cross the blood-brain barrier. A series of 6- and 9-substituted cleistopholine derivatives has been designed, synthesized and investigated to inhibit the aggregation of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-myloid (A β). Results showed that these synthetic compounds had excellent AChE inhibitory activity and a significant in vitro inhibitory potency toward the self-induced A β aggregation. When SH-SY5Y cells were treated with these substituted cleistopholine derivatives during they overexpressed the Swedish mutant form of human β -amyloid precursor protein (APPsw), A β 42 secretion levels were significantly reduced. According to a parallel artificial membrane permeation assay for BBB, seven out of these sixteen synthetic compounds probably could cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS).