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

Abstract

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.

The Role of the Phosphorus Atom in Drug Design

“…[195] Inhibitors of bacterialu reases can be considered as putative drugs for the treatment of infections caused by Helicobacter pylori,abacterium that provokes chronic inflammationi nt he stomach and duodenum. [196] Urease catalyzes the hydrolysis of urea present in an umber of organisms including fungi,b acteria, and algae, and from ap harmacological perspective,i nt he human gut and kidney.T he structures and biological action of representative compounds 199 and 200 are showni nF igure 30. Figure 28.…”

A review on the development of urease inhibitors as antimicrobial agents against pathogenic bacteria

“…The application of phosphordiamidates as urease inhibitors is restricted due to their susceptibility to hydrolysis. In an attempt to mitigate this problem, Berlicki and co-workers [165] , [166] , [167] , [168] adopted a structurally related analogue to phosphorodiamidic acid as a scaffold to design and synthesize phosphonic and phosphinic acid derivatives and evaluate their functions as urease inhibitors ( Scheme 54 ). These classes of compounds are potent inhibitors of enzymatic hydrolysis of the amide bond [169] , [170] .…”

Aminophosphinates against Helicobacter pylori ureolysis—Biochemical and whole-cell inhibition characteristics

“…Optimization of the lead structure yielded efficient inhibitors of Sporosarcina pasteurii and Proteus mirabilis ureases; these inhibitors comprise three classes of compounds, namely, aminomethyl- P -methylphosphinates, aminomethyl- P -hydroxymethylphosphinates, and bis(aminomethyl)phosphinates [23–27]. …”