Synthesis and anticholinesterase activity of (−)-physostigmine analogues with modifications at C3a and C5

Abstract

A new series of physostigmine analogues 3a—3j with modifications at the C3a and C5 positions was designed and synthesized. Bioassay of the synthetic analogues 3a—3j, along with the previous synthesized C3a-ethyl-C5-triazole physostigmine analogues 1a—1g and 2a—2j was performed, which indicates that the replacement of the carbamoyl moiety of C3a-ethyl-C5-triazole analogues 1 and 2 with a triazole moiety decreased acetylcholinesterase(AchE) inhibitory activity, whereas the introduction of heterocycles into the triazole ring increased both AChE and butyrylcholinesterase(BchE) inhibitory activities. Structure-activity relationship(SAR) studies of C3a-methyl-C5-triazole analogues 3 reveal the C3a-methyl substituent is important for AChE and BChE inhibition and the introduction of a second ionizable N center improved the binding of the synthetic analogues to both AChE and BChE.

Keywords

C3a-ethyl-C5-triazole physostigmine analogue / C3a-methyl-C5-triazole physostigmine analogue / Anticholinesterase activity / Alzheimer’s disease

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