Synthesis and evaluation of the complex-forming ability of hydroxypyranones and hydroxypyridinones with Ni (II) as possible inhibitors for urease enzyme in Helicobacter pylori

Abbasali Palizban, Lotfollah Saghaie


The complex-forming ability of 2-methyl-3-hydroxypyran-4-one (1a), 2-ethyl-3-hydroxypyran-4-one (1b), 1,2-dimethyl-3-hydroxypyridin-4-one (4a) and 1-ethyl-2-methyl-3-hydroxypyridin-4-one (4b) with nickel(Ni(II)) were characterized by infrared, ultraviolet, proton nuclear magnetic resonance spectroscopy and melting point. The mole-ratio of nickel:ligands was analyzed by atomic-absorption-spectrometry. The partition-coefficients (KOW) of the compounds were also determined. The binding of ligands with Ni(II) are through deprotonated hydroxyl group (-O-, disapeared at 3259 cm-1) and ioan-pairs of carbonyl group (=CO., shifted from 1650 to 1510-1515 cm-1). The characterization of complex geometry for bis-(2-methyl-3-hydroxypyranonato)Ni(II) (5a) and bis-(2-ethyl-3-hydroxypyranonato)Ni(II) (5b) predicted to be square-planer while for bis-(1,2-dimethyl-3-hydroxypyridinonato)Ni(II) (5c) and bis-(1-ethyl-2-methyl-3-hydroxypyridinonato)Ni(II) (5d) distorted to tetrahedral-geometry. Inhibitors of Helicobacter pylori urease are nickel chelators. The compounds 1a, 4a and 4b are likely suitable ligands with complex forming-ability to make complexes of 5a, 5c and 5d with nickel. The KOW values show the compound 5c with low partition-coefficient is more suitable ligand with lower penetration from GI lumen. Future studies demand to find out the biological activity of developed compounds on H. pylori.


3-Hydroxypyran-4-one; 3-Hydroxypyridin-4-one; Nickel(II) complexes; Helicobacter pylori.

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Sunderman FW Jr, Decsy MI, McNeely MD. Nickel metabolism in health and disease. Ann NY Acad Sci. 1972;28:300-312.

Angelova MG, Petkova-Marinova TV, Pogorielov MV, Loboda AN, Nedkova-Kolarova VN, Bozhinova AN. Trace element status (iron, zinc, copper, chromium, cobalt, and nickel) in iron-deficiency anaemia of children under 3 years. Anemia. 2014;2014:ID718089,1-8.

Nielsen FH, Shuler TR, McLeod TG, Zimmerman TJ. Nickel influences iron metabolism through physiologic, pharmacologic and toxicologic mechanisms in the rat. J Nutr. 1984;114:1280-1288.

Zhang Y, Rodionov DA, Gelfand MS, Gladyshev VN. Comparative genomic analyses of nickel, cobalt and vitamin B12 utilization. BMC Genomics. 2009;10:78.

Denkhaus E, Salnikow K. Nickel essentiality, toxicity, and carcinogenicity. Crit Rev Oncol Hematol. 2002;42:35-56.

Wattt RK, Ludden PW. Nickel-binding proteins. Cell Mol Life Sci. 1999;56(7-8):604-625.

Christensen JM, Kristiansen J, Nielsen NH, Menné T, Byrialsen K. Nickel concentrations in serum and urine of patients with nickel eczema. Toxicol Lett. 1999;108:185-189.

Sunderman FW Jr. Biological monitoring of nickel in humans. Scand J Work Environ Health. 1993;19 Suppl 1:34-38.

McNeely MD, Nechay MW, Sunderman FW Jr. Measurements of nickel in serum and urine as indices of environmental exposure to nickel. Clin Chem. 1972;18:992-995.

Menne T. Quantitative aspects of nickel dermatitis. Sensitization and eliciting threshold concentrations. Sci Total Environ. 1994;148:275-281.

Patriarca M, Lyon TD, Fell GS. Nickel metabolism in humans investigated with an oral stable isotope. Am J Clin Nutr. 1997;66:616-621.

Salnikow K, Li X, Lippmann M. Effect of nickel and iron co-exposure on human lung cells. Toxicol Appl Pharmacol. 2004;196:258-265.

Danadevi K, Rozati R, Banu BS, Grover P. Genotoxic evaluation of welders occupationally exposed to chromium and nickel using the Comet and micronucleus assays. Mutagenesis. 2004;19:35-41.

Costa M, Yan Y, Zhao D, Salnikow K. Molecular mechanisms of nickel carcinogenesis: gene silencing by nickel delivery to the nucleus and gene activation/inactivation by nickel-induced cell signaling. J Environ Monit. 2003;5:222-223.

Cavani A, Nasorri F, Ottaviani C, Sebastiani S, De Pità O, Girolomoni G. Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals. J Immunol. 2003;171:5760-5768.

Blaser MJ, Atherton JC. Helicobacter pylori persistence: biology and disease. J Clin Invest. 2004;113:321-333.

Salama NR, Hartung ML, Müller A. Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Microbiol. 2013;11:385-399.

Beckwith CS, McGee DJ, Mobley HL, Riley LK. Cloning, expression, and catalytic activity of Helicobacter hepaticus urease. Infect Immun. 2001;69:5914-5920.

Perez-Perez GI, Gower CB, Blaser MJ. Effects of cations on Helicobacter pylori urease activity, release, and stability. Infect Immun. 1994;62:299-302.

Hendricks JK, Mobley HL. Helicobacter pylori ABC transporter: effect of allelic exchange mutagenesis on urease activity. J Bacteriol. 1997;179:5892-5902.

Mulrooney SB, Hausinger RP. Nickel uptake and utilization by microorganisms. FEMS Microbiol Rev. 2003;27:239-261.

Bauerfeind P, Garner RM, Mobley LT. Allelic exchange mutagenesis of nixA in Helicobacter pylori results in reduced nickel transport and urease activity. Infect Immun. 1996;64:2877-2880.

Benini S, Rypniewski WR, Wilson KS, Miletti S, Ciurli S, Mangani S. 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. 1999;7:205-216.

Jabri E, Lee MH, Hausinger RP, Karplus PA. Preliminary crystallographic studies of urease from jack bean and from Klebsiella aerogenes. J Mol Biol. 1992;227:934-937.

Jabri E, Carr MB, Hausinger RP, Karplus PA. The crystal structure of urease from Klebsiella aerogenes. Science. 1995;268:998-1004.

Mobley HL, Island MD, Hausinger RP. Molecular biology of microbial ureases. Microbiol Rev. 1995;59:451-480.

Harris RLN. Potential wool growth inhibitors. Improved syntheses of mimosine and related 4(1H)-pyridones. Aust J Chem. 1976;29:1320-1334.

Saghaie L, Houshfar G, Neishabor M. Synthesis and determination of partition coefficients of zinc complexes with clinical potential application. Iran J Pharm Res. 2006;3:179-189.

Saghaie L, Sadeghi-Aliabadi H, Kafiri M. Synthesis and biological evaluation of bidentate 3-hydroxypyridin-4-ones iron chelating agents. Res Pharm Sci. 2011;6:117-122.

Gaona MA, Montilla F, Alvarez E, Galindo A. Synthesis, characterization and structure of nickel and copper compounds containing ligands derived from keto-enehydrazines and their catalytic application for aerobic oxidation of alcohols. Dalton Trans. 2015;44:6516-6525.

Sangster J. Octanol-water partition coefficients of simple organic compounds. J. Phys Chem Ref Data. 1989; 18: 1111-11129.

Ragsdale SW. Nickel biochemistry. Curr Opin Chem Biol. 1998;2:208-215.

Ellis JE. Metal carbonyl anions: from [Fe(CO)4]2− to [Hf(CO)6]2− and beyond. Organometallics. 2003;22(17):3322–3338.

Haley KP, Gaddy JA. Metalloregulation of Helicobacter pylori physiology and pathogenesis. Front Microbiol. 2015;6:911. Doi: 10.3389.


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