Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str. 8, 420088 Kazan, Russia.
Institute of Neuroscience, Kazan State Medical University, 420012 Kazan, Russia.
Molecules. 2020 Sep 12;25(18):4191. doi: 10.3390/molecules25184191.
In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.
在这项研究中，我们合成了基于 6-甲基尿嘧啶和稠合尿嘧啶的新型衍生物，即嘧啶环 N 原子上带有ω-（-氰基苯乙基氨基）烷基链的 2,4-喹唑啉-2,4-二酮。在这一系列合成的化合物中，聚亚甲基链的长度从四亚甲基到六亚甲基不等，并且在链中引入了仲 NH、叔乙氨基和季铵基团。化合物的分子建模表明，它们可以作为双结合位点乙酰胆碱酯酶抑制剂，与外周阴离子结合位点和活性位点结合。体外实验数据表明，最活跃的化合物对乙酰胆碱酯酶的亲和力在纳摩尔范围内，对乙酰胆碱酯酶的选择性比对丁酰胆碱酯酶的选择性高出四个数量级。体内生物学实验证明了这些化合物在使用阿尔茨海默病动物模型治疗记忆障碍方面的功效。
