Kulkarni Akshay S, Ramana Sreenivasa Rao, Nuthakki Vijay K, Bhatt Shipra, Jamwal Ashiya, Nandawadekar Laxman D, Jotshi Anshika, Kumar Ajay, Nandi Utpal, Bharate Sandip B, Reddy D Srinivasa
Organic Chemistry Division, CSIR-National Chemical Laboratory Dr. Homi Bhabha Road Pune 411008 India.
Academy of Scientific and Innovative Research (AcSIR) Ghaziabad 201002 India.
RSC Med Chem. 2025 Mar 7. doi: 10.1039/d5md00019j.
Tacrine, an orally bioavailable cholinesterase inhibitor, was previously used to treat Alzheimer's disease but was withdrawn due to hepatotoxicity. The unique structural features of tacrine have once again captured the interest of medicinal chemists. However, the blood-brain barrier (BBB) permeability hampered the development of the majority of its new analogs. Herein, we employed a silicon switch approach for improving the BBB permeability of CNS drugs with tacrine as a tool compound. The replacement of C2 methylene of tacrine with dimethyl silicon yielded 'sila-tacrine' that inhibits acetylcholinesterase as well as butyrylcholinesterase with IC values of 3.18 and 6.09 μM, respectively. Sila-tacrine competitively inhibits acetylcholinesterase while it is a non-competitive inhibitor of butyrylcholinesterase. The molecular docking results corroborated with the cholinesterase inhibition activity of tacrine sila-tacrine. Sila-tacrine demonstrated metabolic stability in HLM and MLM and exhibited superior plasma exposure in an oral pharmacokinetic study in Swiss albino mice. However, tissue distribution studies revealed lower-than-expected brain levels due to efflux pump-mediated transport. This study offers a proof-of-concept for the silicon switch approach in improving the BBB permeability of CNS-active compounds.
他克林是一种口服生物可利用的胆碱酯酶抑制剂，曾被用于治疗阿尔茨海默病，但由于肝毒性而被撤市。他克林独特的结构特征再次引起了药物化学家的兴趣。然而，血脑屏障（BBB）通透性阻碍了其大多数新类似物的开发。在此，我们采用硅开关方法，以他克林作为工具化合物来提高中枢神经系统药物的血脑屏障通透性。用二甲基硅取代他克林的C2亚甲基得到“硅他克林”，其对乙酰胆碱酯酶和丁酰胆碱酯酶均有抑制作用，IC值分别为3.18和6.09 μM。硅他克林竞争性抑制乙酰胆碱酯酶，而对丁酰胆碱酯酶是非竞争性抑制剂。分子对接结果与他克林-硅他克林的胆碱酯酶抑制活性相符。硅他克林在人肝微粒体（HLM）和小鼠肝微粒体（MLM）中表现出代谢稳定性，并且在瑞士白化小鼠的口服药代动力学研究中表现出优异的血浆暴露。然而，组织分布研究显示，由于外排泵介导的转运，脑内水平低于预期。本研究为硅开关方法提高中枢神经系统活性化合物的血脑屏障通透性提供了概念验证。
