Discovery of Anti-Neuroinflammatory Compounds in Alzheimer's Disease: Current Trends and Future Perspectives

Chronic neuroinflammation in response to abnormal protein aggregates has been implicated as a critical mechanism in several neurodegenerative diseases, and the modulation of signaling pathways associated with inflammation is being explored as a potential strategy for new therapeutics. In Alzheimer's disease (AD), the neuroinflammation hypothesis also starts to influence the landscape of drug discovery in place of the previously regarded amyloid hypothesis. As such, the objective of this review is to compile recent advanced in the discovery of anti-neuroinflammatory compounds developed through chemical synthesis and structural modification, providing an overview of current trends in drug discovery strategies and scaffold redesign for the development of the next-generation of anti-neuroinflammatory therapeutics. It was found that the compounds described in the publications could be categorized into four groups: modification of natural compounds, rational drug design, drug screening approaches, and drug repurposing. While the categorization seems to be similar to drug discoveries in other fields, with the modification of natural compounds accounting for most publications, specific observations could still be made. Namely, the growing interest in the multitarget-directed ligand approach reflects the increasing recognition of AD as a multifactorial disease. Despite this, further research is required to identify additional effective activities or the appropriate combinations besides anti-neuroinflammatory activity. Lastly, this review also gives brief overview regarding physicochemical properties of central nervous system-active agents, of which anti-neuroinflammatory compounds are parts of, and suggests the adoption of in silico prediction models as screening tools before the use of in vitro or in vivo models.