Urease inhibitors

From Bioorganic
Jump to: navigation, search
  • Macegoniuk, K.; Kowalczyk, R.; Rudzińska, A.; Psurski, M.; Wietrzyk, J.; Berlicki, Ł., Potent covalent inhibitors of bacterial urease identified by activity-reactivity profiling Bioorg. Med. Chem. Lett. 2017, 27, 1346. View at Publisher
    Abstract

    Covalent enzyme inhibitors constitute a highly important group of biologically active compounds, with numerous drugs available on the market. Although the discovery of inhibitors of urease, a urea hydrolyzing enzyme crucial for the survival of some human pathogens, is a field of medicinal chemistry that has grown in recent years, covalent urease inhibitors have been rarely investigated until now. Forty Michael acceptor-type compounds were screened for their inhibitory activities against bacterial urease, and several structures exhibited high potency in the nanomolar range. The correlation between chemical reactivity towards thiols and inhibitory potency indicated the most valuable compound — acetylenedicarboxylic acid, with View the MathML source = 42.5 nM and logkGSH = –2.14. Molecular modelling studies revealed that acetylenedicarboxylic acid is the first example of highly effective mode of binding based on simultaneous bonding to a cysteine residue and interaction with nickel ions present in the active site. Activity-reactivity profiling of reversible covalent enzyme inhibitors is a general method for the identification of valuable drug candidates..
  • Ntatsopoulos, V.; Vassiliou, S.; Macegoniuk, K.; Berlicki, Ł.; Mucha, A., Novel organophosphorus scaffolds of urease inhibitors obtained by substitution of Morita-Baylis-Hillman adducts with phosphorus nucleophiles Eur. J. Med. Chem. 2017, 133, 107. View at Publisher
    Abstract

    The reactivity of Morita-Baylis-Hillman allyl acetates was employed to introduce phosphorus-containing functionalities to the side chain of the cinnamic acid conjugated system by nucleophilic displacement. The proximity of two acidic groups, the carboxylate and phosphonate/phosphinate groups, was necessary to form interactions in the active site of urease by recently described inhibitor frameworks. Several organophosphorus scaffolds were obtained and screened for inhibition of the bacterial urease, an enzyme that is essential for survival of urinary and gastrointestinal tract pathogens. α-Substituted phosphonomethyl- and 2-phosphonoethyl-cinnamate appeared to be the most potent and were further optimized. As a result, one of the most potent organophosphorus inhibitors of urease, α-phosphonomethyl-p-methylcinnamic acid, was identified, with Ki = 0.6 μM for Sporosarcina pasteurii urease. High complementarity to the enzyme active site was achieved with this structure, as any further modifications significantly decreased its affinity. Finally, this work describes the challenges faced in developing ligands for urease..
  • Macegoniuk, K.; Grela, E.; Palus, J.; Rudzińska-Szostak, E.; Grabowiecka, A.; Biernat, M.; Berlicki, Ł., 1,2-Benzisoselenazol-3(2H)-one Derivatives As a New Class of Bacterial Urease Inhibitors. J. Med. Chem. 2016, 59, 8125. View at Publisher
    Abstract

    Urease inhibitors are considered promising compounds for the treatment of ureolytic bacterial infections, particularly infections resulting from Helicobacter pylori in the gastric tract. Herein, we present the synthesis and the inhibitory activity of novel and highly effective organoselenium compounds as inhibitors of Sporosarcina pasteurii and Helicobacter pylori ureases. These studied compounds represent a class of competitive reversible urease inhibitors. The most active compound, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen), displayed Ki values equal to 2.11 and 226 nM against S. pasteurii and H. pylori enzymes, respectively, indicating ebselen as one of the most potent low-molecular-weight inhibitors of bacterial ureases reported to date. Most of these molecules penetrated through the cell membrane of the Gram-negative bacteria Escherichia coli (pGEM::ureOP) in vitro. Furthermore, whole-cell studies on the H. pylori J99 reference strain confirmed the high efficiency of the examined organoselenium compounds as urease inhibitors against pathogenic bacteria..
  • Macegoniuk, K.; Dziełak, A.; Mucha, A.; Berlicki, Ł., Bis(aminomethyl)phosphinic acid, a highly promising scaffold for the development of bacterial urease inhibitors. ACS Med. Chem. Lett. 2015, 6, 146. View at Publisher
    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 analogs 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 Ki = 108 nM against the S. pasteurii enzyme. .
  • Benini, S.; Kosikowska, P.; Cianci, M.; Mazzei, L.; Vara, A. G.; Berlicki, Ł.; Ciurli, S., The crystal structure of Sporosarcina pasteurii urease in a complex with citrate provides new hints for inhibitor design. J. Biol. Inorg. Chem. 2013, 18, 391. View at Publisher
    Abstract
    Urease, the enzyme that catalyses the hydrolysis of urea, is a virulence factor for ureolytic bacterial pathogens such as Mycobacterium tuberculosis, the etiological agent of tuberculosis, Helicobacter pylori, a class-I gastric carcinogen, and Proteus mirabilis, which is responsible for urinary tract infections. The increasing resistance of these pathogens to common antibiotics, as well as the need to control urease activity to improve the yield of soil nitrogen fertilisation in agricultural applications, has stimulated the development of novel classes of molecules that target urease as enzyme inhibitors. We report on the crystal structure of a complex formed between citrate and urease from Sporosarcina pasteurii, a widespread and highly ureolytic soil bacterium, with 1.50 Å resolution. The perfect fit of the ligand to the active site involves stabilising interactions, such as a carboxylate group that binds the nickel ions at the active site and several hydrogen bonds with the surrounding residues. The citrate ligand has a significantly extended structure compared with previously reported ligands co-crystallised with urease and thus represents a unique and promising scaffold for the design of new, highly active, stable, selective inhibitors..
  • Berlicki, Ł.; Bochno, M.; Grabowiecka, A.; Białas, A.; Kosikowska, P.; Kafarski, P., N-Substituted aminomethanephosphonic and aminomethane-P-methylphosphinic acids as inhibitors of ureases. Amino Acids 2012, 42, 1937. View at Publisher
    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 uM and 0.62±0.09 uM, 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. .
  • Vassiliou, S.; Grabowiecka, A.; Kosikowska, P.; Berlicki, Ł., Three component Kabachnik-Fields condensation leading to substituted aminomethane-P-hydroxymethylphosphonic acids as a tool for screening of bacterial urease inhibitors ARKIVOC 2012, 2012, 33
    Abstract
    Condensation of hydroxyalkane-H-phosphinic acids, formaldehyde and secondary amines has given entry to the synthesis of variously substituted aminomethane-P-hydroxymethylphosphinic acids. The proposed strategy allowed to perform a feasible synthesis of several molecules with designed biological activity towards bacterial urease – an enzyme which is a medicinally relevant molecular target. The inhibitory potency of compounds was validated using enzyme purified from Bacillus pasteurii. .
  • Kosikowska, P.; Berlicki, Ł., Urease inhibitors as potential drugs for gastric and urinary tract infections: A patent review. Expert Opin. Ther. Pat. 2011, 21, 945. View at Publisher
    Abstract
    Introduction: Urease is the enzyme that catalyzes the hydrolysis of urea, which is involved in serious infections caused by Helicobacter pylori in the gastric tract as well as Proteus and related species in the urinary tract. The necessity to treat such infections has stimulated intensive studies on various groups of urease inhibitors. \r\nAreas covered: Patent literature on urease inhibitors with possible applications in medicine is reviewed in this paper. Hydroxamic acids, phosphoramidates, urea derivatives, quinones and heterocyclic compounds constitute a major classes of structures with such activity.\r\nExpert opinion: Until now, only one compound, acetohydroxamic acid, has been clinically used for the treatment of urinary tract infections by urease inhibition. Unfortunately, it exhibits severe side effects. Thus, it seems that a high potential of urease inhibitors has not been fully explored.\r\n.
  • Vassiliou, S.; Kosikowska, P.; Grabowiecka, A.; Yiotakis, A.; Kafarski, P.; Berlicki, Ł., Computer-aided optimization of phosphinic inhibitors of bacterial ureases. J. Med. Chem. 2010, 53, 5597. View at Publisher
    Abstract

    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-methylaminomethyl-P-hydroxymethylphosphinic acid displayed Ki =360 nM against P. vulgaris enzyme..
  • Vassiliou, S.; Grabowiecka, A.; Kosikowska, P.; Yiotakis, A.; Kafarski, P.; Berlicki, Ł., Design, synthesis and evaluation of novel organophosphorus inhibitors of bacterial ureases. J. Med. Chem. 2008, 51, 5736. View at Publisher
    Abstract

    A new group of organophosphorus inhibitors of urease — P-methyl phosphinic acids was discovered 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..