Synthesis of β-Ketosulfone Derivatives As New Non-Cytotoxic Urease Inhibitors In Vitro

Author(s): Sarosh Iqbal*, Ajmal Khan, Rashid Nazir, Shumaila Kiran, Shahnaz Perveen, Khalid M. Khan*, Muhammad I. Choudhary*.

Journal Name: Medicinal Chemistry

Volume 16 , Issue 2 , 2020

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Abstract:

Background: Peptic ulcer and urolithiasis are largely due to infection caused by ureaseproducing bacteria. Therefore, the discovery of urease inhibitors is an important area of medicinal chemistry research.

Objective: The main aim of the work was to identify novel urease inhibitors with no cytotoxicity.

Methods: During the current study, a series of β-ketosulfones 1-26 was synthesized in two steps and evaluated for their in vitro urease inhibition potential.

Results: Out of twenty-six compounds, seventeen have shown good to significant urease inhibitory activity with IC50 values ranging between 49.93-351.46 µM, in comparison to standard thiourea (IC50 = 21 ± 0.11 µM). Moreover, all compounds found to be non-cytotoxic against normal 3T3 cell line.

Conclusion: This study has identified β-ketosulfones as novel and non-cytotoxic urease inhibitors.

Keywords: Urease inhibitors, β-ketosulfones, peptic ulcer, urolithiasis, non-cytotoxic, H. pylori.

[1]
Cruchaga, S.; Artola, E.; Lasa, B.; Ariz, I.; Irigoyen, I.; Moran, J.F.; Aparicio-Tejo, P.M. Short term physiological implications of NBPT application on the N metabolism of Pisum sativum and Spinacea oleracea. J. Plant Physiol., 2011, 168, 329-336.
[2]
Khan, K.M.; Wadood, A.; Ali, M. Zia-Ullah, Ul-Haq, Z.; Khan, M.; Perveen, S.; Choudhary, M.I.; Lodhi, A.M. Identification of potent urease inhibitors via ligand and structure based virtual screening and in vitro assays. J. Mol. Graph. Model., 2010, 28, 792-798.
[3]
Xiao, Z.; Ma, T.; Fu, W.; Peng, X.; Zhang, A.; Zhu, H. The synthesis, structure and activity evaluation of pyrogallol and catechol derivatives as Helicobactor pylori urease inhibitors. Eur. J. Med. Chem., 2010, 45, 5064-5070.
[4]
You, Z.; Ni, L.; Shi, D.; Bai, S. Synthesis, structures and urease inhibitory activities of three copper (II) and zinc (II) complexes with 2-[2-(2-hydroxyethylamino)-ethylimino]methyl-4-nitrophenol. Eur. J. Med. Chem., 2010, 45, 3196-3199.
[5]
Mobley, H.L.T.; Hausinger, R.P. Microbial ureases: significance, regulation, and molecular characterization. Microbiol. Rev., 1989, 53, 85-108.
[6]
Mobley, H.L.T.; Island, M.D.; Hausinger, R.P. Molecular biology of microbial ureases. Microbiol. Rev., 1995, 59, 451-480.
[7]
Blakeley, R.L.; Zerner, B. Jack bean urease: the first nickel enzyme. J. Mol. Catal., 1984, 23, 283-292.
[8]
Smoot, D.T.; Mobley, H.L.; Chippendale, G.R.; Lewison, J.F. Helicobactor pylori urease activity is toxic to human gastric epithelial cells. Infect. Immun., 1990, 58, 1992-1994.
[9]
Bayerdörffer, E.; Ottenjhan, R. The role of antibiotics in Campylobacter pylori associated peptic ulcer disease. Scand. J. Gastroenterol. Suppl., 1988, 142, 93-100.
[10]
Shahzad, S.A.; Yar, M.; Khan, Z.A.; Khan, I.U.; Naqvi, S.A.R.; Mahmood, N.; Khan, K.M. Microwave-assisted solvent free efficient synthesis of 1,3,4-oxazole-2(3H)-thiones and their in vitro urease inhibitory activity. Eur. J. Chem., 2012, 3, 143-146.
[11]
Khan, K.M.; Ali, M.; Wadood, A. Zaheer-ul-Haq; Khan, M.; Lodhi, M.A.; Perveen, S.; Choudhary, M.I. Molecular modeling-based antioxidant arylidene barbiturates as urease inhibitors. J. Mol. Graph. Model., 2011, 30, 153-156.
[12]
Khan, K.M.; Naz, F.; Taha, M.; Khan, A.; Perveen, S.; Choudhary, M.I. Synthesis and in vitro urease inhibitory activity of N,N’-disubstituted thioureas. Eur. J. Med. Chem., 2014, 74, 314-323.
[13]
Dixon, N.E.; Riddles, P.W.; Blakeley, R.L.; Zerner, B. Jack Jack Bean Urease (EC3.5.1.5) V On the Mechanism of action of urease on urea, formamide, acetamide, N-methylurea, and related compounds. Can. J. Biochem., 1979, 58, 1335-1344.
[14]
Karplus, P.A.; Pearson, M.A.; Hausinger, R.P. 70 years of crystalline urease: What have we learned? Acc. Chem. Res., 1997, 30, 330-337.
[15]
Benini, S.; Rypniewski, W.R.; Wilson, K.S.; 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.
[16]
Zambelli, B.; Musiani, F.; Benini, S. Ciurli, S. Chemistry of Ni2+ in urease: Sensing, trafficking, and catalysis. Acc. Chem. Res., 2011, 44, 520-530.
[17]
Lai, C.; Xi, C.; Jiang, Y.; Hua, R. One pot approach for the regioselective synthesis of β-ketosulfones based on acid catalyzed reaction of sulfonyl chlorides with arylacetylenes and water. Tetrahedron Lett., 2005, 46, 513-515.
[18]
Suryakiran, N.; Prabhakar, P.; Rajesh, K.; Suresh, V.; Venkateswarlu, Y. Synthesis of β-ketosulfones using ionic liquid [TPA][Pro] as an efficient and reusable reaction medium. J. Mol. Catal., 2007, 270, 201-204.
[19]
Zhao, G.; Hu, J.; Qian, Z.; Yin, W. Enantioselective reduction of β-ketosulfones using the NaBH4/Me3SiCl system catalyzed by polymer supported chiral sulfonamide. Tetrahedron Asymmetry, 2002, 13, 2095-2098.
[20]
Cho, B.; Kim, D. Efficient synthesis of optically active β-hydroxy-p-tolylsulfones with very high enantiomeric excess via CBS-oxazaborolidine catalyzed borane reduction. Tetrahedron Asymmetry, 2001, 12, 2043-2047.
[21]
Kurth, M.J.; O’ Brien, M.J. Desulfurization/alpha-alkylation of β -ketosulfones. J. Org. Chem., 1985, 50, 3846-3848.
[22]
Sengupta, S.; Sarma, D.S.; Mondal, S. γ-Chiral β-ketosulfones in asymmetric synthesis: A unified synthetic strategy for enantiopure γ-amino and γ-hydroxy vinyl sulfones. Tetrahedron Asymmetry, 1998, 9, 2311-2316.
[23]
Marco, J.L. Michael reactions of β-ketosulfoxides and β-ketosulfones. J. Org. Chem., 1997, 62, 6575-6581.
[24]
Bartlett, P.A.; Green, F.R.; Rose, E.H. Synthesis of acetylenes from carboxylic acid derivatives via β-ketosulfones. J. Amm Chem. Soc., 100, , 4852-4858.
[25]
Wolf, W.M. The fungicidal activity of β-ketosulfones. Molecular conformation of α-phenylhydrazono- β-ketosulfones as determined by an X-ray analysis. J. Mol. Struct., 1999, 474, 113-124.
[26]
Fernandez, I.; Khira, N.; Fernandez, P.; Romero, A. Michael additions of α-sulfinyl and α-sulfonyl carbanions: The unprecedented reaction of β-ketosulfoxides and β-ketosulfones with highly stabilized Michael acceptors. J. Org. Chem., 1995, 60, 6678-6679.
[27]
Ihara, M.; Suzuki, S.; Taniguchi, T.; Tokunaga, Y.; Fukumoto, K. Preparation of olefins and acetylenes via reductive elimination with SmI2-HMPA. Tetrahedron, 1995, 51, 9873-9890.
[28]
Baldwin, J.E.; Adlington, R.M.; Crouch, N.P.; Hill, R.L.; Laffeg, T.G. An expedient synthesis of trisubstituted allenes. Tetrahedron Lett., 1995, 36, 7925-7928.
[29]
Looker, J.J. Cleavage of β-ketosulfones by pyrrolidine. J. Org. Chem., 1966, 31, 2714-2715.
[30]
Sengupta, S.; Sarma, D.S.; Mondal, S. γ-Amino-β-ketosulfones as chiral educts: A facile synthesis of enantiopure α-amino ketones. Tetrahedron, 1998, 54, 9791-9798.
[31]
Gotor, V.; Rebolledo, F.; Liz, R. Enantioselective bioreduction of β-ketosulfones with the fungus Curvularia lunata. Tetrahedron Asymmetry, 2001, 12, 513-515.
[32]
Antane, S.; Bernotas, R.; Li, Y.; David, M.R.; Yan, Y. Chloromethyl sulfones from sulfonyl chlorides via a one pot procedure. Synth. Commun., 2004, 34, 2443-2449.
[33]
Grossert, J.S.; Dubey, P.K.; Gill, G.H.; Cameron, T.S.; Gardner, P.A. The preparation, spectral properties, structures, and base induced cleavage reactions of some α-halo-β-ketosulfones. Can. J. Chem., 1984, 62, 798-807.
[34]
Bertu, P.; Phansavath, P.; Vidal, V.R.; Genet, J.P.; Touati, A.R.; Homri, T.; Hassine, B.B. Enantioselective hydrogenation of β-ketosulfones with chiral Ru(II)-catalysts: synthesis of enantiomerically pure butenolides and γ-butyrolactones. Tetrahedron Asymmetry, 1999, 10, 1369-1380.
[35]
(a)Khan, K.M.; Khan, M.; Khan, A.; Perveen, S.; Naz, F.; Choudhary, M.I. 5-Arylidene N, N-dimethylbarbiturates as urease inhibitors. J. Chem. Soc. Pak., 2014, 36, 524-527.
(b)Lodhi, M.A. Zaheer-ul-Haq, Iqbal, S.; Khan, K.M.; Atta-ur-Rahman, Choudhary, M.I. Three-dimentional quantitative structure-activity relationship (CoMSIA) analysis of bis-coumarin analogues as urease inhibitors. Med. Chem. Res., 2013, 22, 498-504.
(c)Hameed, A.; Anwar, A.; Khan, K.M.; Malik, R.; Shahab, F.; Siddiq, S.; Basha, F.Z.; Choudhary, M.I. Urease inhibition and anticancer activity of novel polyfuntional 5,6-dihydropyrimidine derivatives and their structure-activity relationship. Eur. J. Chem., 2013, 4, 49-52.
[36]
Curti, C.; Laget, M.; Carle, A.O.; Gellis, A. Rapid synthesis of sulfone derivatives as potential anti-infectious agents. Eur. J. Med. Chem., 2007, 42, 880-884.
[37]
Yousaf, S.; Iqbal, S.; Ambreen, N.; Khan, K.M. 1-(3-Methoxyphenyl)-2-(phenylsulfonyl)ethan-1-one. Acta Crystallographica Section E,, 2012, E68, o2562.
[38]
Weatherburn, M.W. Phenol-hypochlorite reaction for determination of ammonia. Anal. Chem., 1967, 39, 971-974.
[39]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65, 55-63.


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Article Details

VOLUME: 16
ISSUE: 2
Year: 2020
Page: [244 - 255]
Pages: 12
DOI: 10.2174/1573406415666190415163309
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