The Multifaceted Legacy of Thalidomide: Chemistry and Biology Driving Modern Drug Design.

Thalidomide represents one of the most instructive case studies in modern medicinal chemistry, embodying both a historic pharmaceutical tragedy and a remarkable example of drug repurposing and molecular reinvention. Initially introduced as a sedative and antiemetic, its catastrophic teratogenic effects reshaped global drug regulatory frameworks. Decades later, renewed investigation uncovered potent immunomodulatory, anti-inflammatory and antiangiogenic activities, leading to its controlled clinical use in erythema nodosum leprosum, multiple myeloma and related disorders. Central to this renaissance was the identification of cereblon as a key molecular target, transforming thalidomide and its analogs into versatile chemical tools for targeted protein degradation. This review provides a comprehensive overview of thalidomide from a synthetic and medicinal chemistry perspective, covering classical and modern synthetic strategies, access to analogs, stereochemical considerations and asymmetric approaches. Particular emphasis is placed on thalidomide-derived cereblon binders in PROTACs and molecular glue technologies. Beyond protein degradation, the diverse biological activities of thalidomide are discussed, including modulation of cytokines, angiogenesis, and immune signaling pathways. Collectively, thalidomide exemplifies how mechanistic insight, synthetic innovation and careful risk-benefit evaluation can transform a once-discarded molecule into a cornerstone of contemporary drug design.