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

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.