Design, Synthesis, and Evaluation of Novel Organophosphorus Inhibitors of Bacterial Ureases

Abstract

A new group of organophosphorus inhibitors of urease, P-methyl phosphinic acids was discovered by using the structure based inhibitor design approach. Several derivatives of the lead compound, aminomethyl(P-methyl)phosphinic acid, were synthesized successfully. Their potency was evaluated in vitro against urease from Bacillus pasteurii and Proteus vulgaris. The studied compounds constitute a group of competitive, reversible inhibitors of bacterial ureases. Obtained thiophosphinic analogues of the most effective structures exhibited kinetic characteristics of potent, slow binding urease inhibitors, with Ki = 170 nM (against B. pasteurii enzyme) for the most active N-( N'-benzyloxycarbonylglycyl)aminomethyl(P-methyl)phosphinothioic acid.

Bis(aminomethyl)phosphinic Acid, a Highly Promising Scaffold for the Development of Bacterial Urease Inhibitors

“…33,34 In the previous studies, we successfully explored aminomethyl-(P-methyl)phosphinic acid (scaffold 2), 32 followed by aminomethyl(P-hydroxymethyl)phosphinic acids. 33 These studies resulted in a highly potent compound (5) with a K i = 0.36 μM against urease from Proteus vulgaris.…”

Cbz-aminomethylphosphonic acid and its structural variations: synthesis from a common precursor and a stability study

“…All compounds were prepared from Cbz-aminomethylphosphinic acid 1. 8 To date, this is the first report for the sulfur, selenium and borane analogs.…”

Inhibitors of bacterial and plants urease. A review

“…Several phosphorodiamidates and their thiophosphoric analogues were successfully introduced to agriculture to control hydrolysis of urea in soil and diminish nitrogen loss. Unfortunately, their possible therapeutical use is limited by low hydrolytic stability of P-N bond in acidic pH (Marzadori et al 2009;Garcia-Mina et al 2011;Berlicki et al 2008). Inhibitory properties of phosphinic and phosphonic acid derivatives towards urease for a long time are synthesized and analyzed in Wroclaw University of Technology in the Bioorganic Chemistry group (Figure 4).The idea of using this compound as urease inhibitor corresponds to its structural similarity to the transition state of urea hydrolysis as well as to phosphorodiamidate, which is one of the most potent urease inhibitor.…”