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.

Synthesis and evaluation of N-analogs of 1,2-diarylethane as Helicobacter pylori urease inhibitors

“…Similar to what was observed for 3,4-disubstituted derivatives, the 4-substituted analog with 3-nitro group in aniline moiety (12) showed a moderate decrease in potency when compared to the compound with 4-nitro group (6). In para-meta series (11)(12)(13), conversion of the chlorine atom in compound 12 to a N,N-dimethylamino group enhanced potency, while to a nitro group reduced potency.…”

“…In comparison with compound 4, removal of 3-OH led to the compound 5 with a 13-fold decrease in potency. The activity further decreased when 4-OH of 5 was replaced by Cl (6) or NO 2 (7). These findings indicate that 3,4-dihydroxyl group of benzyl moiety and 4-nitro group of aniline moiety are very essential to urease inhibition, which were confirmed by a partial tolerance of 3,4-dihydroxyl group being protected as methyl ether or 1,3-dioxolane (8 vs 9 or 10), and by an intolerance of 4-nitro group being further replaced (4 vs 16 or 17).…”

“…4 In infections with these bacteria, urease is considered to be implicated in urolithiasis (stone formation) and be directly involved in the development of acute pyelonephritis and infection-induced reactive arthritis. [5][6][7] Thus urease inhibition is of very great therapeutic and pharmacological significances. 8 According to recent statistics, at least half of the world population is estimated to be infected by H. pylori, and potent inhibitors of H. pylori urease have increasingly attracted the interests of medicinal chemists.…”

Fluoride inhibition of Sporosarcina pasteurii urease: structure and thermodynamics

“…Hydroxamates, heavy metal ions, as well as amide and ester derivatives of phosphoric and thiophosphoric acids compose another group of competitive and slow-binding inhibitors, some of which have found applications in medicine and agriculture because of their high efficacy; however, they exhibit either toxicity or low stability and are therefore not optimal for these applications [4,17]. Most recently, the synthesis and study of a novel class of inhibitors based on phosphinic and thiophosphinic acid skeletons, which contain a hydrolytically stable C-P bond, have been reported and represent promising leads for further developments [18][19][20]. The structural basis for the inhibition properties of some of these classes of inhibitors has been established by a series of crystal structures of ureases from different sources bound to b-mercaptoethanol [21], acetohydroxamic acid [14,22,23], phosphate [15,24], boric acid [25], and diamidophosphate [13].…”

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.…”