Abstract
BackgroundAlzheimer’s disease (AD) is a neurologically degenerative disorder that affects more than 20 million people worldwide. The selective butyrylcholinesterase (BChE) inhibitors and bivalent cholinesterase (ChE) inhibitors represent new treatments for AD.FindingsA series of lycorine derivatives (1–10) were synthesized and evaluated for anti-cholinesterase activity. Result showed that the novel compound 2-O-tert-butyldimethylsilyl-1-O-(methylthio)methyllycorine (7) was a dual inhibitor of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) with IC50 values of 11.40 ± 0.66 μM and 4.17 ± 0.29 μM, respectively. The structure-activity relationships indicated that (i) the 1-O-(methylthio)methyl substituent in lycorine was better than the 1-O-acetyl group for the inhibition of cholinesterase; (ii) the acylated or etherified derivatives of lycorine and lycorin-2-one were more potent against hBChE than hAChE; and (iii) the oxidation of lycorine at C-2 decreases the activity.ConclusionAcylated or etherified derivatives of lycorine are potential dual inhibitors of hBChE and hAChE. Hence, further study on the modification of lycorine for ChE inhibition is necessary.
Highlights
Alzheimer’s disease (AD) is a neurologically degenerative disorder that affects more than 20 million people worldwide [1], and is the third-most costly disease after cardiovascular disease and cancer [2]
Based on the cholinergic hypothesis, the symptoms of AD are the result of the reduction in brain acetylcholine (ACh) activity due to the catabolism of ACh by its principal hydrolytic enzyme acetylcholinesterase (AChE)
Selective BChE inhibitors or bivalent ChE inhibitors represent a new treatment for AD
Summary
Alzheimer’s disease (AD) is a neurologically degenerative disorder that affects more than 20 million people worldwide.
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