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

Area of Science:

• Agricultural Chemistry
• Enzyme Inhibition
• Medicinal Chemistry

Background:

• Urease inhibitors are crucial for agricultural applications, particularly in managing nitrogen loss.
• Developing efficient urease inhibitors is a key strategy to improve fertilizer efficiency and reduce environmental impact.
• This review focuses on synthetic compounds, evaluating their potential as agricultural urease inhibitors.

Purpose of the Study:

• To systematically review urease inhibitory activities and structure-activity relationships (SARs) of synthetic compounds.
• To identify potent urease inhibitors and analyze structural features influencing their activity.
• To compare binding modes with plant and microbial ureases and outline future research directions.

Main Methods:

• Comprehensive literature review of 339 synthetic compounds reported between 2001 and 2025.
• Analysis of structure-activity relationships (SARs) for 12 distinct structural types.
• Molecular docking analysis to compare inhibitor binding modes with plant (4H9M) and soil microbial urease (4CEU).

Main Results:

• Phosphoramidate, thiourea, coumarin, azine, and amine derivatives show potent urease inhibitory activity.
• Electron-withdrawing substituents (e.g., halogens, nitro groups) significantly enhance inhibitory potency compared to electron-donating groups (e.g., methyl groups).
• Molecular docking revealed key interactions within the active sites of plant and microbial ureases.

Conclusions:

• Highly effective soil urease inhibitors can be developed by understanding SARs and binding interactions.
• Future research should prioritize addressing challenges in developing potent and environmentally sustainable soil urease inhibitors.
• This work provides a foundation for designing novel urease inhibitors to meet global environmental sustainability goals.