Synthesis and Anticholinesterase Activity of (-)-Physostigmine Analogues with Modifications at C3a and C5 |
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Authors: | WANG Hui-jing ZHANG Dan WANG Fu-sheng WU Yi SONG Hao |
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Institution: | 1. Innovative Drug Research Center, Chongqing University, Chongqing 401331, P. R. China;
2. Key Laboratory of Drug Targeting and Novel Delivery System of the Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China |
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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. |
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Keywords: | C3a-ethyl-C5-triazole physostigmine analogue C3a-methyl-C5-triazole physostigmine analogue Anticholinesterase activity Alzheimer's disease |
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