title: 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.
authors.affiliation: Synthesis Section and Molecular Modeling Section, Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Domínguez
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanmartín
authors.forename: María
authors.initials: M
authors.lastname: Font
authors.forename: Juan A
authors.initials: JA
authors.lastname: Palop
authors.forename: Sara
authors.initials: S
authors.lastname: San Francisco
authors.forename: Oscar
authors.initials: O
authors.lastname: Urrutia
authors.forename: Fabrice
authors.initials: F
authors.lastname: Houdusse
authors.forename: José
authors.initials: J
authors.lastname: García-Mina
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015394:Molecular Structure; D063088:Phosphoramides; D010756:Phosphoric Acids / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014510:Urease / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D063088:Phosphoramides; D010756:Phosphoric Acids; C005438:phosphoramide; D014510:Urease