Pharmacological landscape of carbolines: a holistic view

Natural resources have served as a cornerstone for the discovery of innovative pharmaceutical compounds for millennia. Among the diverse natural compounds demonstrating significant pharmacological activities, carbolines cannot be overlooked. Carbolines are a class of heterocyclic indole alkaloids that exhibit diverse biological activities, with several compounds approved by the US Food and Drug Administration or currently under preclinical evaluation. Carbolines exist in four distinct isomers including α-, β-, γ-, and δ-carbolines, and each exhibits unique biological properties owing to the variation in the position of the pyridine N within their tricyclic frameworks. Meanwhile, extensive research has been conducted on carbolines over the past two decades, solidifying their role as a vital component in the modern drug discovery landscape. This review comprehensively explores the design, synthesis, and pharmacological activities of carboline isomers reported between 2000 and 2025, with a particular emphasis on their key bioactivities, encompassing anticancer, neuroprotective, antiparasitic, and antimicrobial. Additionally, it delves into the mechanisms of action and structure-activity relationship analysis of many key carboline derivatives, offering an invaluable perspective on this class of heterocyclic compounds. Moreover, it highlights the emerging trends and forward-looking strategies in design of carboline derivatives, aiming to inspire researchers interested in heterocycle-driven drug discovery. Furthermore, by uncovering the critical research gaps and proposing novel approaches such as heterodimerization and dual/multi-targeting strategies, this review underscores the enduring and evolving significance of carbolines in next-generation pharmaceutical development.