Analysis of skeletal diversity of multi-target directed ligands (MTDLs) targeting Alzheimer’s disease

Alzheimer's disease (AD) remains a significant healthcare challenge, necessitating innovative therapeutic approaches to address its complex and multifactorial nature. Traditional drug discovery strategies targeting single molecular targets are not sufficient for the effective treatment of AD. In recent years, MTDLs have emerged as promising candidates for AD therapy, aiming to simultaneously modulate multiple pathological targets. Among the various strategies employed in MTDL design, pharmacophore hybridization offers a versatile approach to integrate diverse pharmacophoric features within a single molecular scaffold. This strategy provides access to a wide array of chemical space for the design and development of novel therapeutic agents. This review, therefore, provides a comprehensive overview of skeletal diversity exhibited by MTDLs designed recently for AD therapy based on pharmacophore hybridization approach. A diverse range of pharmacophoric elements and core scaffolds hybridized to construct MTDLs that has the potential to target multiple pathological features of AD including amyloid-beta aggregation, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, and neuroinflammation are discussed. Through the comprehensive analysis and integration of structural insights of key biomolecular targets, this review aims to enhance optimization efforts in MTDL design, ultimately striving towards a comprehensive cure for the multifaceted pathophysiology of the disease.