Computer-aided optimization of phosphinic inhibitors of bacterial ureases.
Urease inhibitors can be considered as a tool to control the damaging effect of ureolytic bacteria infections in humans which occur commonly in the developed countries. Computer-aided optimization of the aminomethylphosphinate structures by modifying both their N- and P-termini led to the invention of a novel group of inhibitors of bacterial ureases. Introduction of P-hydroxymethyl group into the molecule resulted in considerable increase of the inhibitory activity against enzymes purified from Bacillus pasteurii and Proteus vulgaris as compared with their P-methyl counterparts described previously. The designed compounds represent a competitive reversible class of urease inhibitors. The most potent, N-methyl-aminomethyl-P-hydroxymethylphosphinic acid, displayed K(i) = 360 nM against P. vulgaris enzyme.
Vassiliou
Stamatia
S
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wrocław, Poland.
Kosikowska
Paulina
P
Grabowiecka
Agnieszka
A
Yiotakis
Athanasios
A
Kafarski
Paweł
P
Berlicki
Lukasz
L
D001407:Bacillus / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003198:Computer Simulation; D004355:Drug Stability; D006868:Hydrolysis; D008958:Models, Molecular; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D011514:Proteus vulgaris / Q000201:enzymology; D013329:Structure-Activity Relationship; D014510:Urease / Q000037:antagonists & inhibitors* / Q000737:chemistry
D001426:Bacterial Proteins; C551945:N-methyl-aminomethyl-P-hydroxymethylphosphinic acid; D010721:Phosphinic Acids; D014510:Urease