Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Jagiellonian University Medical College, Medyczna 9 St. 30-688 Kraków, Poland.
Eur J Med Chem. 2010 Dec;45(12):5602-11. doi: 10.1016/j.ejmech.2010.09.010. Epub 2010 Sep 17.
The study presents synthesis and biological activity of novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties designed as cholinesterases inhibitors. These fragments turned out to determine compounds' selectivity between AChE and BuChE. Derivatives of N-benzylpiperazine (16-25) were selective BuChE inhibitors with 3-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-phenyl butylcarbamate (22) being the most potent compound (pIC50=5.00) while a series of carbamate derivatives of N-benzylpiperidine (5-14) displayed non-selective BuChE/AChE inhibitory activity. Molecular modelling studies point out significant differences between orientations of these two groups of compounds in the active site of AChE, which can be an explanation of their different biological activity.
本研究合成了一系列具有 N-苄基哌啶和 N-苄基哌嗪结构的新型烷基和芳基氨基甲酸酯衍生物，并将其作为胆碱酯酶抑制剂进行了生物学活性评价。这些片段可确定化合物对 AChE 和 BuChE 的选择性。N-苄基哌嗪衍生物（16-25）为选择性 BuChE 抑制剂，其中 3-（2-（4-苄基哌嗪-1-基）-2-氧代乙基）-苯基丁基氨基甲酸酯（22）是最有效的化合物（pIC50=5.00），而一系列 N-苄基哌啶的氨基甲酸酯衍生物（5-14）则表现出非选择性 BuChE/AChE 抑制活性。分子模拟研究指出，这两组化合物在 AChE 活性部位的取向存在显著差异，这可以解释它们不同的生物学活性。
