Exploring the synthetic approaches and clinical prowess of established macrocyclic pharmaceuticals.

Macrocyclic compounds, characterized by cyclic structures, often originate from either modified forms of unicyclic canonical molecules or natural products. Within the field of medicinal chemistry, there has been a growing fascination with drug-like macrocycles in recent years, primarily due to compelling evidence indicating that macrocyclization can significantly influence both the biological and physiochemical properties, as well as the selectivity, when compared to their acyclic counterparts. The approval of contemporary pharmaceutical agents like Lorlatinib underscore the notable clinical relevance of drug-like macrocycles. Nonetheless, the synthesis of these drug-like macrocycles poses substantial challenges, primarily stemming from the complexity of ring-closing reactions, which are inherently dependent on the size and geometry of the bridging linker, impacting overall yields. Nevertheless, macrocycles offer a promising avenue for expanding the synthetic toolkit in medicinal chemistry, enabling the creation of bioactive compounds. To shed light on the subject, we delve into the clinical prowess of established macrocyclic drugs, spanning various therapeutic areas, including oncology, and infectious diseases. Case studies of clinically approved macrocyclic agents illustrate their profound impact on patient care and disease management. As we embark on this journey through the world of macrocyclic pharmaceuticals, we aim to provide a comprehensive overview of their synthesis and clinical applications, shedding light on the pivotal role they play in modern medicine. [Display omitted] • A summary of FDA-approved macrocyclic pharmaceuticals is systematically provided. • The clinical applications and synthetic routes of representative macrocycles are emphasized. • Challenges and prospects are briefly discussed to guide future design of macrocyclic drugs. [ABSTRACT FROM AUTHOR]