Mezeiova Eva, Korabecny Jan, Sepsova Vendula, Hrabinova Martina, Jost Petr, Muckova Lubica, Kucera Tomas, Dolezal Rafael, Misik Jan, Spilovska Katarina, Pham Ngoc Lam, Pokrievkova Lucia, Roh Jaroslav, Jun Daniel, Soukup Ondrej, Kaping Daniel, Kuca Kamil
Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic.
Molecules. 2017 Jul 28;22(8):1265. doi: 10.3390/molecules22081265.
Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer's disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors-THA and (-)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.
他克林（THA）是首个具有临床疗效的乙酰胆碱酯酶（AChE）抑制剂，也是首个获批用于治疗阿尔茨海默病（AD）的药物，但因其副作用，尤其是肝毒性而退出市场。如今，THA是设计可能适用于AD治疗的新型药物的重要骨架。其中一种化合物，即7-甲氧基他克林（7-MEOTA），展现出有趣的特性，具有降低的肝毒性并同时保留AChE抑制特性。另一类有趣的AChE抑制剂是百奈子，它是通过将已知的AChE抑制剂——THA和（-）-石杉碱甲的两个片段合并而设计的。该化合物家族的几个成员是比母体化合物更有效的人AChE抑制剂。最有前景的是所谓的百奈子X和Y。在此，我们报告了2-甲氧基百奈子的设计、合成、生物学评价及计算机模拟研究，该化合物在一个分子中融合了7-MEOTA和百奈子Y的结构特征。
