Synthesis and Anticholinesterase Activity of （-）-Physostigmine Analogues with Modifications at C3a and C5

• Published in: Chemical research in Chinese universities Vol. 29; no. 5; pp. 888 - 893
• Main Authors: Wang, Hui-jing, Zhang, Dan, Wang, Fu-sheng, Wu, Yi, Song, Hao
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2013; Innovative Drug Research Center, Chongqing University, Chongqing 401331, P.R.China%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
• Subjects: Analytical Chemistry; C3a; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Inorganic Chemistry; Organic Chemistry; Physical Chemistry; 丁酰胆碱酯酶; 乙酰胆碱酯酶; 修饰; 合成类似物; 毒扁豆碱; 酯酶活性; C3; ethyl-C5-triazole physostigmine analogue; methyl-C5-triazole physostigmine analogue; Alzheimer’s disease; Anticholinesterase activity; C3a-methyl-C5-triazole physostigmine analogue; C3a-ethyl-C5-triazole physostigmine analogue; Alzheimer's disease
• ISSN: 1005-9040; 2210-3171
• DOI: 10.1007/s40242-013-3066-y

A new series of physostigmine analogues 3a--3j with modifications at the C3a and C5 positions was de- signed and synthesized. Bioassay of the synthetic analogues 3a--3j, along with the previous synthesized C3a-ethyl-C5-triazole physostigmine analogues laJlg and 2a--2j was performed, which indicates that the replace- ment of the carbamoyl moiety of C3a-ethyl-C5-triazole analogues 1 and 2 with a triazole moiety decreased acetyl- cholinesterase（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.