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Design, synthesis and biological evaluation of novel carbamates as potential inhibitors of acetylcholinesterase and butyrylcholinesterase.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-18 , DOI: 10.1016/j.bmc.2020.115324
Jie Wu 1 , Marco Pistolozzi 2 , Siyu Liu 3 , Wen Tan 4
Affiliation  

Rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), has been approved by U.S. Food and Drug Administration to treat Alzheimer's disease (AD) and Parkinson's disease (PD) dementia. In the current work, a bambuterol derivative lacking one of the carbamoyloxy groups on the benzene ring (BMC-1) and its analogues were synthesized using 1-(3-hydroxyphenyl) ethan-1-one and 1-(4-hydroxyphenyl) ethan-1-one as starting materials. In-vitro cholinesterase assay established that nine compounds were more potent to inhibit both electric eel AChE and equine serum BChE than rivastigmine under the same experimental conditions. Further study confirmed that among the nine carbamates, BMC-3 (IC50(AChE) = 792 nM, IC50(BChE) = 2.2 nM) and BMC-16 (IC50(AChE) = 266 nM, IC50(BChE) = 10.6 nM) were excellent cholinesterase inhibitors with potential of permeating through the blood-brain barrier. These carbamates could be used as potential dual inhibitors of AChE and BChE and to discover novel drugs for the treatment of AD and PD dementia.

中文翻译:

设计,合成和生物学评估新型氨基甲酸酯作为乙酰胆碱酯酶和丁酰胆碱酯酶的潜在抑制剂。

Rivastigmine是乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)的双重抑制剂,已被美国食品和药物管理局批准用于治疗阿尔茨海默氏病(AD)和帕金森氏病(PD)痴呆。在目前的工作中,使用1-(3-羟苯基)乙烷-1-酮和1-(4-羟苯基)乙烷合成了在苯环(BMC-1)上缺少氨基甲酰氧基基团的班布特罗衍生物及其类似物-1作为起始原料。体外胆碱酯酶测定法确定,在相同的实验条件下,九种化合物比rivastigmine抑制电鳗AChE和马血清BChE的效力更高。进一步的研究证实,在9种氨基甲酸酯中,BMC-3(IC50(AChE)= 792 nM,IC50(BChE)= 2.2 nM)和BMC-16(IC50(AChE)= 266 nM,IC50(BChE)= 10。6 nM)是极好的胆碱酯酶抑制剂,具有渗透血脑屏障的潜力。这些氨基甲酸酯可用作潜在的AChE和BChE双重抑制剂,并发现用于治疗AD和PD痴呆的新药。
更新日期:2020-01-21
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