Conjugates of anticholinesterase drugs ipidacrine and tacrine with thiouracils: synthesis and biological properties

IF 1.7 4区化学 Q3 CHEMISTRY, MULTIDISCIPLINARY

Russian Chemical Bulletin Pub Date : 2025-01-14 DOI:10.1007/s11172-024-4457-6

M. V. Grishchenko, O. G. Khudina, G. F. Makhaeva, Ya. V. Burgart, N. V. Kovaleva, E. V. Rudakova, N. P. Boltneva, M. V. Ulitko, V. I. Saloutin, V. N. Charushin

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Abstract

Chloroalkylene amide derivatives were obtained by acylation of known Cholinesterase inhibitors, ipidacrine and tacrine. The acylated derivatives were used in the alkylation of substituted 2-thiouracils (R = Me, CF₂H, CF₃, (CF₂)₂H)) for the synthesis of new hybrid compounds. Study of the esterase profile revealed a pronounced activity and selectivity of the obtained conjugates against butyrylcholinesterase (IC₅₀ up to 2.03 µmol L⁻¹), moderate displacement of propidium from the acetylcholinesterase peripheral anionic site, and moderate inhibition of the β-amyloid self-aggregation. It was found that conjugation of thiouracils with tacrine leads to a decrease in the hepatotoxicity of the hybrid compounds compared to that of tacrine, while in the case of ipidacrine derivatives, no hepatotoxicity was observed.

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抗胆碱酯酶药物ipidacrine和tacrine与硫脲嘧啶的偶联物：合成及其生物学特性

氯炔酰胺衍生物是由已知的胆碱酯酶抑制剂，伊匹克林和他克林酰化得到的。酰基化衍生物用于取代2-硫脲嘧啶（R = Me, CF2H, CF3, (CF2)2H）)的烷基化反应，以合成新的杂化化合物。酯酶谱的研究表明，获得的偶联物对丁基胆碱酯酶具有明显的活性和选择性（IC50高达2.03µmol L−1），适度地从乙酰胆碱酯酶外周阴离子位点置换丙啶，适度抑制β-淀粉样蛋白自聚集。结果发现，与他克林相比，硫脲嘧啶与他克林偶联导致杂化化合物的肝毒性降低，而对于伊匹克啶衍生物，没有观察到肝毒性。

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来源期刊

Russian Chemical Bulletin 化学-化学综合

CiteScore

2.70

自引率

47.10%

发文量

257

审稿时长

3-8 weeks

期刊介绍： Publishing nearly 500 original articles a year, by leading Scientists from Russia and throughout the world, Russian Chemical Bulletin is a prominent international journal. The coverage of the journal spans practically all areas of fundamental chemical research and is presented in five sections: General and Inorganic Chemistry; Physical Chemistry; Organic Chemistry; Organometallic Chemistry; Chemistry of Natural Compounds and Bioorganic Chemistry.