具有胆碱能、抗氧化、神经保护和肝保护作用的多功能他克林-trolox 杂合体，用于治疗阿尔茨海默病。
Multifunctional tacrine-trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties.
机构信息
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
出版信息
Eur J Med Chem. 2015 Mar 26;93:42-50. doi: 10.1016/j.ejmech.2015.01.058. Epub 2015 Jan 28.
Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional agent for AD treatment.
将他克林与 Trolox 结合在一个单一的分子中，设计并合成了新型多功能杂合体。所有这些杂种在纳摩尔范围内表现出 ChE 抑制活性，并且具有接近母体化合物 Trolox 的强抗氧化活性。其中，化合物 6d 是对 AChE（eeAChE 的 IC50 值为 9.8 nM，hAChE 的 IC50 值为 23.5 nM）最有效的抑制剂，也是 BuChE 的强抑制剂（eqBuChE 的 IC50 值为 22.2 nM，hBuChE 的 IC50 值为 20.5 nM）。分子建模和动力学研究表明，6d 是一种混合类型抑制剂，同时与 AChE 的 CAS 和 PAS 结合。体内肝毒性试验表明，6d 比他克林的毒性小得多。此外，它还表现出神经保护作用和良好的穿透 BBB 的能力。总的来说，所有这些结果都突出了 6d 作为治疗 AD 的一种很有前途的多功能药物。
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