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

• Published in: ACS medicinal chemistry letters Vol. 6; no. 2; pp. 146 - 150
• Main Authors: Macegoniuk, Katarzyna, Dziełak, Anna, Mucha, Artur, Berlicki, Łukasz
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-02-2015
• Subjects: Letter; Mannich-type reaction; inhibitor; ureases; urealytic bacteria
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml500380f

Inhibitors of bacterial ureases are considered to be promising compounds in the treatment of infections caused by Helicobacter pylori in the gastric tract and/or by urealytic bacteria (e.g., Proteus species) in the urinary tract. A new, extended transition state scaffold, bis(aminomethyl)phosphinic acid, was successfully explored for the construction of effective enzyme inhibitors. A reliable methodology for the synthesis of phosphinate analogues in a three-component Mannich-type reaction was elaborated. The obtained molecules were assayed against ureases purified from Sporosarcina pasteurii and Proteus mirabilis, and aminomethyl(N-n-hexylaminomethyl)phosphinic acid was found to be the most potent inhibitor, with a K i = 108 nM against the S. pasteurii enzyme.