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

• Published in: Journal of medicinal chemistry Vol. 58; no. 21; pp. 8616 - 8637
• Main Authors: Wang, Zhiren, Wang, Yali, Wang, Bo, Li, Wenrui, Huang, Ling, Li, Xingshu
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.11.2015; Amer Chemical Soc
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; Antioxidants - chemistry; Antioxidants - therapeutic use; Benzofurans - chemistry; Benzofurans - therapeutic use; Chemistry, Medicinal; Clioquinol - analogs & derivatives; Clioquinol - therapeutic use; Cognition - drug effects; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - physiopathology; Life Sciences & Biomedicine; Ligands; Male; Memory - drug effects; Models, Molecular; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - chemistry; Neuroprotective Agents - therapeutic use; Pharmacology & Pharmacy; Phosphodiesterase 4 Inhibitors - chemistry; Phosphodiesterase 4 Inhibitors - therapeutic use; Protein Aggregates - drug effects; Rats; Rats, Wistar; Resorcinols - chemistry; Resorcinols - therapeutic use; Science & Technology; TARGET; AMYLOID-BETA PEPTIDE; PHOSPHODIESTERASE-4 INHIBITORS; SMALL MOLECULES; ACETYLCHOLINESTERASE; ANTIOXIDANT; BIOLOGICAL EVALUATION; HIGHLY POTENT; DERIVATIVES; AGGREGATION
• DOI: 10.1021/acs.jmedchem.5b01222
• ISSN: 0022-2623; 1520-4804

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 Aβ 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 μM), significant antioxidant effects, appropriate biometal chelating functions, and interesting properties that modulated self- and metal-induced Aβ aggregation. Two-dimensional NMR studies revealed that 18d had significant interactions with Aβ1–42 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·HCl demonstrated marked improvements in cognitive and spatial memory in a rat model of Alzheimer’s disease and protected hippocampal neurons from necrosis.