Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease involve progressive neuronal dysfunction driven by mechanisms including protein aggregation, oxidative stress, mitochondrial impairment, and neuroinflammation. Current treatments are largely symptomatic, with limited disease-modifying options. Advances in medicinal chemistry have led to the development of small-molecule derivatives targeting specific pathological pathways, offering new therapeutic opportunities. This review summarizes recent progress in designing and optimizing such molecules to modulate amyloid-β metabolism, tau acetylation, α-synuclein aggregation, RNA-binding protein interactions, and NLRP3 inflammasome activation. Compounds acting on key signaling cascades, including PI3K/Akt, MAPK/ERK, Nrf2/ARE, and Wnt/β-catenin, are discussed, alongside drug repurposing strategies and preclinical-to-clinical translation. Special focus is given to microglial modulation, challenges in crossing the blood–brain barrier, and integration of precision medicine, metabolomics, and artificial intelligence into drug discovery. The review also highlights novel therapeutic concepts such as multi- target ligands, metal-chelation approaches, and modulation of neuroinflammatory pathways. Despite promising leads, significant challenges remain in optimizing pharmacokinetics, target selectivity, and delivery. Future directions include the identification of robust biomarkers, advanced imaging techniques, and computational tools to accelerate candidate validation. Collectively, smallmolecule therapeutics hold considerable promise in addressing unmet needs in neurodegenerative disease management, but their successful translation will require multidisciplinary approaches bridging molecular insights and clinical application.
Singh et al. (2026) studied this question.