Structural characteristics of phosphoramide derivatives as urease inhibitors. Requirements for activity.
Taking as a reference the structural characteristics of a set of compounds that act as jack bean ( Canavalia ensiformis) urease inhibitors, namely, phenylphosphorodiamidate (PPD), N- n-butylthiophosphorictriamide (NBPT), and N- n-butylphosphorictriamide (NBPTO), we have studied the structure-activity relationships of a series of phosphoramide derivatives for which the activity as urease inhibitors in both in vitro and in vivo assays is known. Molecular modeling studies were carried out, and the results highlighted the relevance of characteristics such as the presence of intramolecular hydrogen bonds, the volume of the fragment involved in the enzyme interaction, and the degree of conformational freedom as well as the HOMO orbital and atomic orbital contributions to the HOMO orbital, electron density, and PEM distributions on the activity of these compounds as urease inhibitors. These data, along with the preliminary docking study carried out, allow us to propose a union mode to the active site of the enzyme for these compounds.
Font
María
M
Molecular Modeling Section, Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain. mfont@unav.es
Domínguez
María-José
MJ
Sanmartín
Carmen
C
Palop
Juan A
JA
San-Francisco
Sara
S
Urrutia
Oscar
O
Houdusse
Fabrice
F
García-Mina
José M
JM
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D063088:Phosphoramides; D010756:Phosphoric Acids / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014510:Urease / Q000037:antagonists & inhibitors*
D000577:Amides; D004791:Enzyme Inhibitors; D063088:Phosphoramides; D010756:Phosphoric Acids; C005438:phosphoramide; D014510:Urease