Kynurenic acid derivatives in treatment for Alzheimer's disease

This review provides a comprehensive overview of kynurenic acid (KYNA) derivatives with specific focus on KYNA amides as an emerging class of multi-target directing drugs (MTDDs) for the treatment of Alzheimer's disease (AD). It highlights the urgent need for novel AD therapies, discusses the key structural and pharmacological attributes that position KYNA as a promising candidate for this role, outlines laboratory synthesis for KYNA scaffold. Furthermore, the review summarizes the most promising KYNA derivatives reported in the literature, critically evaluates the results from conducted bioassays, and establishes future prospectives for KYNA MTDDs. Overall, eleven leading structures (compounds 1-11) were identified whose MTDD profiles usually combine the neuroprotective and anti-inflammatory features of KYNA with neurotransmitter modulation, anti-amyloid-beta (Aβ) aggregation activity, and, less frequently, antioxidant properties and the maintenance of ion homeostasis. Comparative analysis of the bioassay data identifies compounds 2 and 6 as MTDDs with superior translational validity, evidenced by their demonstrated efficacy in vivo models (Caenorhabditis elegans). Conversely, compounds 7 and 8 emerged as the candidates with the highest potency and broadest pharmacological scope. These derivatives effectively modulated five distinct pathological hallmarks of AD: Aβ accumulation, oxidative stress, neurotransmitter imbalance, and neuroinflammation. Notably, they exhibit disease-modifying potential by functioning not only as neuroprotective agents but also as promoters of neurogenesis. Synthetically, amidation represents the predominant strategy for achieving an MTDD profile, facilitating the efficient modification of pharmacological activity in a single step via the incorporation of bioactive amines.