Decoding Urease Inhibition: A Comprehensive Review of Inhibitor Scaffolds

Urease is a metalloenzyme produced by a wide range of organisms and plays a critical role in nitrogen microbial metabolism by catalyzing the hydrolysis of urea into ammonia and carbamic acid. High urease activity can lead to excessive ammonia levels, causing nitrogen loss from the soil, and also contributes as a virulent factor in some human pathogenic infections. Given its impact, urease inhibition has garnered significant attention in agriculture, environmental sciences, and medicine. Despite efforts to develop potent and selective inhibitors, discovering new agrochemicals and drugs faces significant challenges due to chemical and metabolic stability, lack of selectivity and toxicity, typically seen in urease inhibitors. As a result, extensive chemical diversity has been reported for urease inhibition and can lay the foundation for designing new inhibitors. Previous structure-activity relationship analyses have mainly focused on small subsets of compounds, leaving a broader comprehensive understanding across all known classes yet to be described. In an effort to support new exploratory strategies, this review provides a complete overview of the chemical landscape in urease inhibitors, covering more than 8000 compounds. We discuss current challenges, the biological and practical implications of urease inhibition and highlight potential scaffolds associated with activity. By exploring the diversity of reported inhibitors, we aim to identify broad activity patterns and gain deeper insights into activity relationships that govern inhibitory efficacy, paving the way for the future directions of finding new classes of urease inhibitors.