School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 211189, PR China.
Department of Medicinal Chemistry and the Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA.
Bioorg Chem. 2019 Jun;87:720-727. doi: 10.1016/j.bioorg.2019.03.064. Epub 2019 Mar 28.
A series of compounds following the lead compounds including deferasirox and tacrine were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease (AD). In vitro studies showed that most synthesized compounds exhibited good multifunctional activities in inhibiting acetylcholinesterase (bAChE), and chelating metal ions. Especially, compound TD demonstrated significant metal chelating property, a moderate acetylcholinesterase (AChE) inhibitory activity and an antioxidant activity. Results from the molecular modeling indicated that TD compounds were mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of TcAChE. Moreover, TD showed a low cytotoxicity but a good protective activity against the injury caused by HO. These results suggest that TD compounds might be considered as attractive multi-target cholinesterase inhibitor and will play important roles in the treatment of AD.
一系列以先导化合物地拉罗司和他克林为基础的化合物被设计、合成并评估为治疗阿尔茨海默病（AD）的多功能药物。体外研究表明，大多数合成的化合物在抑制乙酰胆碱酯酶（bAChE）和螯合金属离子方面表现出良好的多功能活性。特别是，化合物 TD 表现出显著的金属螯合特性、适度的乙酰胆碱酯酶（AChE）抑制活性和抗氧化活性。分子建模的结果表明，TD 化合物是混合类型抑制剂，同时与 TcAChE 的催化阴离子部位（CAS）和外周阴离子部位（PAS）结合。此外，TD 表现出低细胞毒性和对 HO 引起的损伤的良好保护活性。这些结果表明，TD 化合物可能被认为是有吸引力的多靶点胆碱酯酶抑制剂，并将在 AD 的治疗中发挥重要作用。
