Comprehensive Review and Outlook of the Synthetic Urease Inhibitors for Agricultural Applications

The development of efficient urease inhibitors represents a promising strategy for agricultural applications. This review examines the status of commercial urease inhibitors and the challenges encountered while systematically summarizing the urease inhibitory activities and structure-activity relationships (SARs) of 339 synthetic compounds belonging to 12 structural types reported from 2001 to 2025. It emphasizes phosphoramidate, thiourea, coumarin, azine, and amine derivatives that exhibit potent urease inhibitory activity. Furthermore, SAR analysis indicates that derivatives containing electron-withdrawing substituents, such as halogens and nitro groups, demonstrate significantly higher urease inhibitory potency compared with those with electron-donating substituents, such as methyl groups. The review also compares the binding modes and key active sites of representative inhibitors from each subtype with those of plant urease (4H9M) and soil microbial urease (4CEU) through molecular docking analysis. Finally, it outlines the challenges and future research priorities for soil urease inhibitors. This review enhances our understanding of urease inhibitors and guides the development of highly effective soil urease inhibitors to address critical global environmental sustainability challenges.