title: N-substituted aminomethanephosphonic and aminomethane-P-methylphosphinic acids as inhibitors of ureases.
abstract: Small unextended molecules based on the diamidophosphate structure with a covalent carbon-to-phosphorus bond to improve hydrolytic stability were developed as a novel group of inhibitors to control microbial urea decomposition. Applying a structure-based inhibitor design approach using available crystal structures of bacterial urease, N-substituted derivatives of aminomethylphosphonic and P-methyl-aminomethylphosphinic acids were designed and synthesized. In inhibition studies using urease from Bacillus pasteurii and Canavalia ensiformis, the N,N-dimethyl derivatives of both lead structures were most effective with dissociation constants in the low micromolar range (Ki=13±0.8 and 0.62±0.09 μM, respectively). Whole-cell studies on a ureolytic strain of Proteus mirabilis showed the high efficiency of N,N-dimethyl and N-methyl derivatives of aminomethane-P-methylphosphinic acids for urease inhibition in pathogenic bacteria. The high hydrolytic stability of selected inhibitors was confirmed over a period of 30 days using NMR technique.
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370, Wrocław, Poland. lukasz.berlicki@pwr.wroc.pl
authors.forename: Lukasz
authors.initials: L
authors.lastname: Berlicki
authors.forename: Marta
authors.initials: M
authors.lastname: Bochno
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Grabowiecka
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Białas
authors.forename: Paulina
authors.initials: P
authors.lastname: Kosikowska
authors.forename: Paweł
authors.initials: P
authors.lastname: Kafarski
mesh_terms: D001407:Bacillus / Q000187:drug effects; D032449:Canavalia / Q000187:drug effects; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D007700:Kinetics; D008958:Models, Molecular; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017553:Phosphorus Compounds / Q000737:chemistry; D011487:Protein Conformation; D011513:Proteus mirabilis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014510:Urease / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000302:isolation & purification
chemical_list: D004791:Enzyme Inhibitors; D010721:Phosphinic Acids; D017553:Phosphorus Compounds; C527238:methylphosphinic acid; C436301:phosphorodiamidic acid; D014510:Urease