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.
Org Biomol Chem. 2014 Feb 7;12(5):801-14. doi: 10.1039/c3ob42010h. Epub 2013 Dec 6.
A series of tacrine-rhein hybrid compounds have been designed and synthesized as novel multifunctional potent ChE inhibitors. Most of the compounds inhibited ChEs in the nanomolar range in vitro effectively. Compound 10b was one of the most potent inhibitors and was 5-fold more active than tacrine toward AChE, and it also showed a moderate BuChE inhibition with an IC50 value of 200 nM. Kinetic and molecular modeling studies of 10b also indicated that it was a mixed-type inhibitor binding simultaneously to the active and peripheral sites of AChE. In inhibition of the AChE-induced Aβ aggregation assay, compound 10b (70.2% at 100 μM) showed the greatest inhibitory activity. In addition, 10b showed metal-chelating property and low hepatotoxicity. These results suggested that 10b might be an excellent multifunctional agent for AD treatment.
一系列的他克林-大黄素混合化合物被设计并合成，作为新型多功能强效 ChE 抑制剂。大多数化合物在体外以纳摩尔级有效地抑制了 ChE。化合物 10b 是最有效的抑制剂之一，对 AChE 的活性比他克林高 5 倍，对 BuChE 也有适度的抑制作用，IC50 值为 200 nM。10b 的动力学和分子建模研究也表明，它是一种同时结合 AChE 活性和外周部位的混合型抑制剂。在抑制 AChE 诱导的 Aβ 聚集试验中，化合物 10b（在 100 μM 时为 70.2%）表现出最大的抑制活性。此外，10b 还表现出金属螯合特性和低肝毒性。这些结果表明，10b 可能是一种治疗 AD 的优秀多功能药物。
