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

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.