| Summary: | <p>Abstract</p> <p>Background</p> <p>Alzheimer’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.</p> <p>Findings</p> <p>A series of lycorine derivatives (<b>1</b>–<b>10</b>) were synthesized and evaluated for anti-cholinesterase activity. Result showed that the novel compound 2-<it>O</it>-<it>tert</it>-butyldimethylsilyl-1-<it>O</it>-(methylthio)methyllycorine (<b>7</b>) was a dual inhibitor of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) with IC<sub>50</sub> values of 11.40 ± 0.66 μM and 4.17 ± 0.29 μM, respectively. The structure-activity relationships indicated that (i) the 1-<it>O</it>-(methylthio)methyl substituent in lycorine was better than the 1-<it>O</it>-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.</p> <p>Conclusion</p> <p>Acylated 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.</p>
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