Design, Synthesis, and Evaluation of Orally Available Clioquinol-Moracin M Hybrids as Multitarget-Directed Ligands for Cognitive Improvement in a Rat Model of Neurodegeneration in Alzheimer's Disease

作者：Wang, Zhiren; Wang, Yali; Wang, Bo; Li, Wenrui; Huang, Ling^*; Li, Xingshu

来源：Journal of Medicinal Chemistry, 2015, 58(21): 8616-8637.

DOI：10.1021/acs.jmedchem.5b01222

A novel series of clioquinol-moracin hybrids were designed and synthesized by fusing the pharmacophores of clioquinol and moracin M, and their activities as multitarget-directed ligands against Alzheimer's disease were evaluated. Biological activity results demonstrated that these hybrids possessed significant inhibitory activities against phosphodiesterase 4D (PDE4D) and A beta aggregation as well as remarkable antioxidant effects and excellent blood brain barrier permeability. The optimal compound, 18d (WBQ5187), exhibited excellent PDE4D inhibitory potency (IC50 = 0.32 mu M), significant antioxidant effects, appropriate biometal chelating functions, and interesting properties that modulated self- and metal-induced A beta aggregation. Two-dimensional NMR studies revealed that 18d had significant interactions with A beta(1-42) at the R5, H6, H14, Q15, and F20 residues. Furthermore, this typical hybrid possessed preeminent neuroprotective effects against inflammation in microglial cells. Most importantly, oral administration of 18d center dot HCl demonstrated marked improvements in cognitive and spatial memory in a rat model of Alzheimer's disease and protected hippocampal neurons from necrosis.

• 出版日期2015-11-12
• 单位中山大学