Urease is an important virulence factor for Helicobacter pylori and Proteus mirabilis as well as in environmental transformations of certain nitrogenous compounds. Urea hydrolysis caused by these microorganisms leads to increased pH and ammonia toxicity and enables bacterial colonization of the human gastric mucosa and urinary tract formation of struvite and carbonate-apatite stones. Due to the possibility of medical applications the development of novel, selective and efficient classes of urease inhibitors which satisfy the low toxicity requirement for human health and have low environmental impact is necessary. In this article are described the various urease inhibitors used so far by researchers, especially in the last few years.
urea, urease, inhibitor, ulcer disease, kidney stones
Amtul, Z., Rahman, A., Siddiqui, R.A. & Choudhary, M.I. 2002. Chemistry and Mechanism of Urease Inhibition. Current Medicinal Chemistry, 9: 1323–1348.
Aslam, M.A.S., Mahmood, S., Shahid, M., Saeed, A. & Iqbal, J. 2011. Synthesis, biological assay in vitro and molecular docking studies of new Schiff base derivatives as potential urease inhibitors. European Journal of Medicinal Chemistry, 46: 5473–5479.
Bacanamwo, M., Witte, C.P., Lubbers, M.W., Polacco, J.C. 2002. Activation of the urease of Schizosaccharomycespombe by the UreF accessory protein from soybean,Molecular Genetics and Genomics, 268: 525–534.
Balasubramanian, A. & Ponnuraj, K. 2010. Crystal structure of the first plant urease from jack bean: 83 years of journey froms its first crystal to molecular structure. Journal of Molecular Biology, 400: 274–283.
Beaton, J.D. 1978. Urea: its popularity grows as a dry source of nitrogen. Crops Soils, 30: 11–14.
Benini, S., Ciurli, S., Nolting, H.F. & Mangani S. 1996. X-ray Absorption Spectroscopy Study of Native and Phenylphosphorodiamidate-Inhibited Bacillus pasteurii Urease. European Journal of Biochemistry, 239: 61–66.
Benini, S., Rypniewski, W.R., Wilson, K.S., Miletti, S., Ciurli, S. & Mangani S. 1999. A new proposal for urease mechanism based on the crystal structures of the native and inhibited enzyme from Bacillus pasteurii: why urea hydrolysis costs two nickels. Structure, 7: 205–216.
Benini, S., Kosikowska, P., Cianci, M., Mazzei, L., Vara, A.G., Berlicki, Ł. & Ciurli S. 2013. The crystal structure of Sporosarcina pasteurii urease in a complex with citrate provides new hints for inhibitor design. Journal of Biological Inorganic Chemistry, 18: 391–399.
Breitenbach, J.M. & Hausinger, R.P. 1988. Proteus mirabilis urease: Partial purification and inhibition by boric acid and boronic acids. Biochemical Journal, 250: 917.
Bremner, J.M. 1995. Recent research on problems in the use of urea as anitrogen fertilizer. Fertilizer Research, 42: 321–329.
Burns, R.G. 1978. Soil enzymes. Academic Press, 149–196.
Domínguez, M.J., Sanmartín, C., Font, M., Palop, J.A., Francisco, S.S., Urrutia, O., Houdusse, F. & Garcia-Mina, J. 2008. Design, synthesis, and biological evaluation of phosphoramide derivatives as urease inhibitors. Journal of Agricultural and Food Chemistry, 56: 3721–3731.
Firdous, S., Ansari, N.H., Fatima, I. , Malik, A., Afza, N., Iqbal, L. & Lateef, M. 2012. Ophiamides A-B, new potent urease inhibitory sphingolipids from Heliotropiumophioglossum. Archives of Pharmacal Research, 35: 1133–1137.
Giovannini, C., Garcia-Mina, J.M., Ciavatta, C. & Marzadori, C.J. 2009. Ureic nitrogen transformation in multi-layer soil columns treated with urease and nitrification inhibitors. Journal of Agricultural and Food Chemistry, 57: 4883–4887.
Haq, M.A.Z., Lodhi, S.A., Nawaz, S., Iqbal, K.M., Khan, B.M., Rahman, A. & Choudhary, M.I. 2008. 3D-QSAR CoMFA studies on bis-coumarine analogues asurease inhibitors: A strategic design in anti-urease agents. Bioorganic & Medicinal Chemistry, 16: 3456–3461.
Holm, L. & Sander, C. 1997. An evolutionary treasure: unification of a broad set of amidohydrolases related to urease. Proteins, 28: 72–82.
Jabri, E., Carr, M.B., Hausinger, R.P. & Karplus, P.A. 1995. The crystal structure of urease from Klebsiella aerogenes. Protein Science, 268: 998–1004.
Janser, I., Vortolomei, C.M., Meka, R.K., Walsh, C.A. & Janser F.J. 2013. Ethacrynic acid as a lead structure for the development of potent urease inhibitors. C. R. Chimie, accepted for publication.
Kobashi, K., Hase, J. & Uehare K. 1962. Specific inhibition of urease by hydroxamic acids. Biochimica et Biophysica Acta, 65: 380–383.
Kosikowska, P. & Berlicki Ł. 2012. N-substituted aminomethanephosphonic and aminomethane-Pmethylphosphinic acids as inhibitors of ureases. Amino Acids, 42: 1937–1945.
Kot, M., Zaborska, W. & Orlinska K. 2001. Inhibition of jack bean urease by N-(nbutyl) thiophosphorictriamide and N-(nbutyl) phosphorictriamide: determination of the inhibition mechanism. Journal of Enzyme Inhibition and Medicinal Chemistry, 16: 507–516.
Krajewska B. 1991. Urease immobilized on chitosan membrane. Inactivation by heavy metal ions. Journal of Chemical Technology and Biotechnology, 52: 157.
Krajewska B. 2008. Mono-(Ag, Hg) and di-(Cu, Hg) valent metal ions effects on the activity of jack bean urease. Probing the modes of metal binding to the enzyme. Journal of Enzyme Inhibition and Medicinal Chemistry, 23: 535–542.
Krajewska B. 2009. Ureases I. Functional, catalytic and kinetic properties: A review. Journal of Molecular Catalysis B: Enzymatic, 59: 9–21.
Kreybig, T., Preussmann, R. & Schmidt W.1968. Chemical constitution and teratogenic effect in rats. Carbonic acids amides, carbonic acid hydrazides and hydroxamic acids. ArzneimittelForschung, 18: 645–657.
Kumar, P., Narasimhan, B. & Sharma D. 2012. Substituted benzoic acid benzylidene/furan-2-ylmethylene hydrazides: synthesis, antimicrobial evaluation and QSAR analysis. Arkivoc, 159–178.
Leite, A.C.L., DE Lima, R.S., Moreira, D.R., Cardoso, M.V., De Brito, A.C.G., Dos Santos L.M.F., Hernandes, M.Z., Kipustok, A.C. & Soares, M.B.P. 2006. Synthesis, docking, and in vitro activity of thiosemicarbazones, aminoacyl-thiosemicarbazides and acyl-thiazolidones against Trypanosomacruzi. Bioorganic & Medicinal Chemistry, 14: 3749–3757.
Li, H.Q., Xiao, Z.P., Luo, Y., Yan, T., Lv, P.C. & Zhu, H.L. 2009. Amines and oximes derived from deoxybenzoins as Helicobacter pylori urease inhibitors. European Journal of Medicinal Chemistry, 44: 2246–2251.
Matsubara, S., Shibata, H., Ishikawa, F., Yokokura, T., Takahashi, M. & Sugimura, T. 2003. Suppresion of Helicobacter pylori-induced gastsritis by green tea extract in Mongolian gerbils. Biochemical and Biophysical Research Communications, 310: 715–719.
Mobley, H.L.T. & Hausinger R.P. 1989. Microbial ureases: significance, regulation, and molecular characterization. Microbiology Reviews, 53: 85–108.
Mobley, H.L.T., Island, M.D. & Hausinger, R.P. 1995. Molecular biology of microbial ureases. Microbiology Reviews, 59: 451–480.
Muri, E.M.F., Mishra, H., Avery, M.A. & Williamson, J.S. 2003. Design and synthesis of heterocyclic hydroxamic acid derivatives as inhibitors of Helicobacter pylori urease. Synthetic Communications, 33: 1977–1995.
Nussbaum, F, Brands, M., Hinzen, B., Weigand S. & Häbich D. 2006. Antibacterial Natural Products in Medicinal Chemistry—Exodus or Revival? AngewandteChemie International Edition, 45: 5072–5129.
Ramsay, K.S.T., Wafo, P., Ali, Z., Khan, A., Oluyemisi, O.O., Marasini, B.P., Khan, I.A., Bonaventure, N.T. & Choudhary, M.I. 2012. Attaur-Rahman, Chemical constituents of Stereospermumacuminatissimum and their urease and α-chymotrypsin inhibitions. Fitoterapia, 83: 204–208.
San Francisco, S., Urrutia, O., Martin, V., Peristeropoulos, A. & Garcia-Minaj, M.A. 2011. Efficiency of urease and nitrification inhibitors in reducing ammonia volatilization from diverse nitrogen fertilizers applied to different soil types and wheat straw mulching. Journal of the Science of Food and Agriculture, 91: 1569–1575.
Schwedt, G., Waldheim, D.O., Neumann, K.D. & Stein, K. J. 1993. Trace analysis and speciation of copper by application of an urease reactor. Analytical Chemistry, 346: 659–662.
Shi, D.H., You, Z.L., Xu, C., Zhang, Q. & Zhu, H.L. 2007.Synthesis, crystal structure and urease inhibitory activities of Schiff base metal complexes. Inorganic Chemistry Communications, 10: 404–406.
Shin, J.E., Kim, J.M., Bae, E.A., Hyun, Y.J. & Kim, D.H. 2005.In vitro inhibitory effect of flavonoids on growth, infection and vacuolation of Helicobacter pylori. PlantaMedica, 71: 197–201.
Smalley, T.L., Peat, A.J., Boucheron, J.A., Dickerson, S., Garrido, D., Preugschat, F., Schweiker, S.L., Thomson, S.A. & Wang, T.Y. 2006. Synthesis and evaluation of novel heterocyclic inhibitors of GSK-3. Bioorganic & Medicinal Chemistry Letters, 16: 2091–2094.
Sztanke, K., Pasterhak, K., Rzymowska, J., Sztanke, M. & Kandefer-Szerszen, M. 2007. Synthesis, determination of the lipophilicity, anticancer and antimicrobial properties of some fused 1,2,4-triazole derivatives. European Journal of Medicinal Chemistry, 43: 404–419.
Tanaka, T., Kawase, M. & Tani, S. 2003.Urease inhibitory activity of simple alpha,beta-unsaturated ketones. Life Sciences, 73: 2985.
Todd, M.J. & Hausinger R.P. 1989. Competitive inhibitors of Klebsiella aerogenes urease. Mechanisms of interaction with the nickel active site. The Journal of Biological Chemistry, 264: 15835–15842.
Vassiliou, S., Grabowiecka, A., Kosikowska, P., Yiotakis, A., Kafarski, P. & Berlicki Ł. 2008. Design, Synthesis, and Evaluation of Novel Organophosphorus Inhibitors of Bacterial Ureases. Journal of Medicinal Chemistry, 51: 5736–5744.
Vassiliou, S., Kosikowska, P., Grabowiecka, A., Yiotakis, A., Kafarski, P. & Berlicki, Ł. 2010. Computer-Aided Optimization of Phosphinic Inhibitors of Bacterial Ureases. Journal of Medicinal Chemistry, 53: 5597–5606.
Vittorio, F., Ronsisvalle, G., Marrazzo, A. & Blandini, G. 1995. Synthesis and antimicrobial evaluation of 4-phenyl-3-isoquinolinoyl-hydrazones. Farmaco, 50: 265–272.
Xiao, Z. P., Peng, Z. Y., Peng, M.J., Yan, W. B., Ouyang, Y. Z. & Zhu, H. L. 2011. Flavonoids health benefits and their molecular mechanism. Mini Reviews in Medicinal Chemistry, 11: 69–177.
Zhang, L., Mulrooney, S.B., Leung, A.F.K., Zeng, Y., Ko, B.B.C., Hausinger, R.P. & Sun, H. 2006. Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs. Biometals, 19: 503–511.
Zhu-Ping, X., Zhi-Yun, P., Jing-Jun, D., Juan, H., Hui, O., Yu-Ting, F., Chun-Lei, L., Wan-Qiang, L., Jin-Xiang, W., Yin-Ping, X. & Hai-Liang, Z. 2013. Synthesis, structure activity relationship analysis and kinetics study of reductive derivatives of flavonoids as Helicobacter pylori urease inhibitors. European Journal of Medicinal Chemistry, 63: 685–689.
Zonia, L.E., Stebbins, N.E. & Polacco, J.C. 1995. Essential role of urease in germination of nitrogenlimited Arabidopsis thaliana seeds. Plant physiology, 107: 1097–1103.