Revisiting multicomponent Doebner and Povarov quinoline synthesis for modern-day drug-discovery

Quinoline- and tetrahydroquinoline-containing heterocyclic compounds display potent and varied biological activity against several clinically relevant targets. Many strategies to construct the quinoline core have been described over several decades, but the Povarov and Doebner reactions stand out for operational simplicity and use of readily available starting materials. Hence, these two multicomponent reactions have been utilized as powerful tools in industrial and academic labs to quickly and efficiently synthesize chemically diverse drug-like molecules. In drug discovery, these reactions have been applied to rapidly synthesize extensive libraries of pharmaceutically relevant compounds. This review highlights the synthetic method advancements of the Povarov and Doebner reactions and their applications in drug development. Synthetic methods, both traditional and cutting-edge, are discussed with a focus on recent advances in photochemistry, asymmetric synthesis, intramolecular, electrochemistry, and metal-catalyzed atom-economical multicomponent chemistry. Further, we describe many compounds that are synthesized via these chemistries, which have shown potent anticancer, anti-inflammatory, antioxidant, antiviral, and antiparasitic bioactivity, in addition to being efficacious against neurodegenerative disease.