Synthesis, Structure–Activity Relationships, and Pharmacological Profile of Bioactive Urea‐Based Therapeutics

ABSTRACT This review summarizes the synthesis and biological activities of urea derivatives in medical chemistry. This work is dedicated to the 200th anniversary of the discovery of urea as a useful starting material for organic and medicinal chemistry. The review is focused on the role of urea as a versatile scaffold in organic and medicinal chemistry; predominant emphasis is given to the chemistry of bioactive compounds and especially to the synthesis of drugs of various pharmacologically relevant categories. Urea and its analogues are one of the core skeletons discovered in medicinal chemistry and are well‐known for their extensive use in various clinically active therapeutic agents. Its unusual structural and electronic properties, including its capacity as a planar hydrogen bond donor–acceptor functionality, allow its potent and specific interaction with a range of biological targets. This has placed the urea scaffold as a privileged structure for drug development. This exhaustive review assimilates all the research made on urea derivatives and is put across in two distinct ways, that is, synthesis and various bioactivities of urea derivatives. In the first part of the review, the synthetic approaches adopted for the assembly of urea‐motifs containing molecules is critically discussed. It describes both traditional mechanisms using phosgene and isocyanates as well as more contemporary and safer methods with significantly increased safety profiles and efficiency. The latter section is dedicated to an exhaustive analysis of the extended pharmacological profile of these compounds. We emphasize the importance of the urea derivatives as useful molecules with a great potential as drugs in many areas such as oncology (inhibitors of kinases), infectious diseases (antiviral, antibacterials, and antifungal), and central nervous system disorders (anticonvulsant). Their utilization as enzyme deactivates, antagonist to receptors, and blockers of ion channels is also addressed, with examples from both approved drugs and prospective clinical trial substances. This review intends to be an important resource for medicinal chemists by systematically summarizing the synthetic methods and the structure–activity relationship (SAR) of bioactive urea derivatives. It highlights the utility and continued significance of the urea pharmacophore and the hope that such studies will lead to new and better therapeutic agents.