Design, Synthesis, and Biological Evaluation of Phosphoramide Derivatives as Urease Inhibitors

Abstract

The design, synthesis, and biological evaluation of phosphoramide derivatives as urease inhibitors to reduce the loss of ammonia has been carried out. Forty phosphorus derivatives were synthesized and their inhibitory activities evaluated against that of jack bean urease. In addition, in vivo assays have been carried out. All of the compounds were characterized by IR, (1)H NMR, MS, and elemental microanalysis. In some cases, detailed molecular modeling studies were carried out, and these highlighted the interaction between the enzyme active center and the compounds and also the characteristics related to their activity as urease inhibitors. According to the IC(50) values for in vitro inhibitory activity, 12 compounds showed values below 1 microM and 8 of them represent improvements of activity in comparison to the commercial urease inhibitor N-n-butylthiophosphorictriamide (NBPT) (100 nM) (AGROTAIN). On the basis of the activity results and the conclusions of the molecular modeling study, a structural model for new potential inhibitors has been defined.

Ammonia and carbon dioxide emissions by stabilized conventional nitrogen fertilizers and controlled release in corn crop

“…The chemical basis proposed (Manuza et al, 1999;Dominguez et al, 2008;Font et al, 2008) for the mechanism of inhibition of urease activity by the NBPT (O) is based on the following chemical principles: 1) the NBPT molecule (O) coordinates with nickel atoms (Ni) of the urease (active site of the enzyme) in a bidentate geometry (each Ni atom is bonded in two points on NBPT molecule); 2) The oxygen and the amide of the NBPT are present in the bonds formed between the Ni atoms; 3) The other amino group of the NBPT molecule forms a hydrogen bond with the oxygen of the carbamate; These are the chemistry explanation for the reason why it is necessary to convert NBPT (S) to its analog NBPT (O): the urease inhibition efficiency is related to the presence of the oxygen atom instead of the sulfur in the NBPT molecule; 4) The stability of the bidentate complex bond is stronger than the hydrogen bond; 5) Thus, the molecule inhibitor binds to the active site of the urease enzyme in three points (tridentate bond); 6) Consequently, the possibility of urea to react with Ni atoms of the enzyme urease is reduced when the active site is blocked by the NBPT (O).…”

Benzamide Derivatives as Potential Candidates for Anti-Alzheimer, Anti-Fatigue, Anti-Urease and Anti-Oxidant Activity

“…Several classes of compounds have been reported as the agents having anti-urease activity; among them hydroxamicacids are the best recognized urease inhibitors (8)(9)(10). However, the teratogenicity of hydroxamicacid in rats and degradation of phosphoramidates at low pH (8,11,12) restrict their use as a drug in vivo.…”

Urease Inhibitors of Agricultural Interest Inspired by Structures of Plant Phenolic Aldehydes

“…8, 2016 are recognized as the most efficient urease inhibitors for crop production purposes. [13][14][15] Indeed, the N-(butyl)thiophosphoric triamide (NBPT) was found to become a very effective inhibitor when transformed to its corresponding oxo-derivative (oxo-NBPT) by soil microorganisms. 16 The NBPT effectiveness is directly related to soil properties in which low concentration of this urease proinhibitor is needed to achieve the desired result in temperate soils while greater concentrations are required for tropical soils.…”