Multitargeted Imidazoles: Potential Therapeutic Leads for Alzheimer's and Other Neurodegenerative Diseases

Abstract

Alzheimer's disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aβ species as well as neuroinflammation. In this context, the development of single multitargeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure-activity relationship studies that led to the identification of multitargeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several examples are brain-penetrant and exhibit balanced multitargeted in vitro activity in the low μM range. As brain-penetrant MT-stabilizing agents have proven effective against tau-mediated neurodegeneration in animal models, and because COX- and 5-LOX-derived eicosanoids are thought to contribute to Aβ plaque deposition, these 1,5-diarylimidazoles provide tools to explore novel multitargeted strategies for AD and other neurodegenerative diseases.

Figure 1

(A) Comparison of representative examples of fungicidal diaryl-pyrazoles (1) and -imidazoles (2) with reported MT-stabilizing activity, with known COX- (3) and dual COX/5-LOX (4) inhibitors; molecular docking of 2 (B) and 3 (C) within the arachidonic acid binding site of COX-1.

Scheme 1

Reagents and reaction conditions: (a) Dean–Stark apparatus, toluene, 110 °C, 4 days, 99%; (b) 4 Å molecular sieves, Et₂O, 30 °C, 48 h, 99%; (c) appropriate TosMIC reagent, K₂CO₃, DMF/1,2-dimethoxyethane, 100 °C, 16 h, 7–90%; (d) N-chlorosuccinimide, CHCl₃, 60 °C, 16 h, 43–71%; (e) LDA, methyliodide, THF, −20 °C to rt, 1.5 h, 29–56%.

Scheme 2

Reagents and reaction conditions: (a) N-chlorosuccinimide, CHCl₃, 60 °C, 16 h, 9–77% for monohalogenation at C4, 3–18% for monohalogenation at C2, and 2–20% for dihalogenation at C2/C4; (b) LDA, methyliodide, THF, −20 °C to rt, 1.5 h, 2–48%; (c) NaOMe, MeOH, THF, rt, 19 h, 33–97%; (d) LDA, ethyliodide, THF, −20 °C to rt, 1.5 h, 35%.

Figure 2

Summary of SARs (top) and representative structures exemplifying the different activity profiles exhibited by the 1,5-diarylimidazoles (bottom).

Figure 3

Representative dose–response curves in the RBL-1 cell assays. Samples were run in triplicate at each concentration, with the error bars representing standard error of the mean.