4-Aminocoumarin based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies

Author(s): Tanzeela A. Fattah, Aamer Saeed*, Zaman Ashraf*, Qamar Abbas, Pervaiz A. Channar, Fayaz A. Larik, Mubashir Hassan.

Journal Name: Medicinal Chemistry

Volume 16 , Issue 2 , 2020

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Graphical Abstract:


Background: Urease enzyme catalyzes the hydrolysis of urea into ammonia and CO2, excess ammonia causes global warming and crop reduction. Ureases are also responsible for certain human diseases such as stomach cancer, peptic ulceration, pyelonephritis, and kidney stones. New urease inhibitors are developed to get rid of such problems.

Objective: This article describes the synthesis of a series of novel 1-aroyl-3-(2-oxo-2H-chromen-4- yl)thiourea derivatives (5a-j) as Jack bean urease inhibitors.

Methods: Freshly prepared aryl isothiocyanates were reacted with 4-aminocoumarin in the same pot in an anhydrous medium of acetone. The structures of the title thioureas (5a-j) were ascertained by their spectroscopic data. The inhibitory effects against jack bean urease were determined.

Results: It was found that compounds 5i and 5j showed excellent activity with IC50 values 0.0065 and 0.0293, µM respectively. Compound 5i bearing 4-methyl substituted phenyl ring plays a vital role in enzyme inhibitory activity. The kinetic mechanism analyzed by Lineweavere-Burk plots revealed that compound 5i inhibits the enzyme non-competitively. The Michaelis-Menten constant Km and inhibition constants Ki calculated from Lineweavere-Burk plots for compound 5i are 4.155mM and 0.00032µM, respectively. The antioxidant activity results displayed that compound 5j showed excellent radical scavenging activity. The cytotoxic effects determined against brine shrimp assay showed that all of the synthesized compounds are non-toxic to shrimp larvae. Molecular docking studies were performed against target protein (PDBID 4H9M) and it was determined that most of the synthesized compounds exhibited good binding affinity with the target protein. Molecular dynamics simulation (MDS) results revealed that compound 5i forms a stable complex with target protein showing little fluctuation.

Conclusions: Based upon our investigations, it is proposed that 5i derivative may serve as a lead structure for devising more potent urease inhibitors.

Keywords: Ammonia, aroylthioureas, urease inhibitors, synthesis, enzyme inhibitory kinetics, docking studies.

Backhouse, C.N.; Delporte, C.L.; Negrete, R.E.; Erazo, S.; Zuñiga, A.; Pinto, A.; Cassels, B.K. Active constituents isolated from Psoralea glandulosa L. with antiinflammatory and antipyretic activities. J. Ethnopharmacol., 2001, 78(1), 27-31.
[http://dx.doi.org/10.1016/S0378-8741(01)00309-9] [PMID: 11585684]
Torres, R.; Faini, F.; Modak, B.; Urbina, F.; Labbé, C.; Guerrero, J. Antioxidant activity of coumarins and flavonols from the resinous exudate of Haplopappus multifolius. Phytochemistry, 2006, 67(10), 984-987.
[http://dx.doi.org/10.1016/j.phytochem.2006.03.016] [PMID: 16684545]
Ramanitrahasimbola, D.; Rakotondramanana, D.A.; Rasoanaivo, P.; Randriantsoa, A.; Ratsimamanga, S.; Palazzino, G.; Galeffi, C.; Nicoletti, M. Bronchodilator activity of Phymatodes scolopendria (Burm.) Ching and its bioactive constituent. J. Ethnopharmacol., 2005, 102(3), 400-407.
[http://dx.doi.org/10.1016/j.jep.2005.06.037] [PMID: 16084046]
(a)Ivanov, I.C.; Angelova, V.T.; Vassilev, N.; Tiritiris, I.; Iliev, B. Synthesis of 4-aminocoumarin derivatives with N-substitutents containing hydroxy or amino groups. Z. Naturforsch. B, 2013, 68, 1031-1040.
(b)Heide, L. The aminocoumarins: biosynthesis and biology. Nat. Prod. Rep., 2009, 26(10), 1241-1250.
[http://dx.doi.org/10.1039/b808333a] [PMID: 19779639]
(c)Anderle, C.; Li, S-M.; Kammerer, B.; Gust, B.; Heide, L. New aminocoumarin antibiotics derived from 4-hydroxycinnamic acid are formed after heterologous expression of a modified clorobiocin biosynthetic gene cluster. J. Antibiot. (Tokyo), 2007, 60(8), 504-510.
[http://dx.doi.org/10.1038/ja.2007.64] [PMID: 17827661]
a)Maddi, V.; Mamledesai, S.; Satyanarayana, D.; Swamy, S. Synthesis and antiinflammatory activity of substituted (2-oxochromen-3-yl) benzamides. Indian J. Pharm. Sci., 2007, 69, 847.
(b)Faisal, M.; Saeed, A.; Shahzad, D.; Fattah, T.A.; Lal, B.; Channar, P.A.; Mahar, J.; Saeed, S.; Mahesar, P.A.; Larik, F.A. Enzyme inhibitory activities an insight into the structure-Activity relationship of biscoumarin derivatives. Eur. J. Med. Chem., 2017, 141, 386-403.
[http://dx.doi.org/10.1016/j.ejmech.2017.10.009] [PMID: 29032032]
(a)Lewis, E.K.; Haaland, W.C.; Nguyen, F.; Heller, D.A.; Allen, M.J.; MacGregor, R.R.; Berger, C.S.; Willingham, B.; Burns, L.A.; Scott, G.B.; Kittrell, C.; Johnson, B.R.; Curl, R.F.; Metzker, M.L. Color-blind fluorescence detection for four-color DNA sequencing. Proc. Natl. Acad. Sci. USA, 2005, 102(15), 5346-5351.
[http://dx.doi.org/10.1073/pnas.0501606102] [PMID: 15800037]
(b)Fattah, T.A.; Saeed, A.; Channar, P.A.; Larik, F.A.; Hassan, M.; Raza, H.; Abbas, Q.; Seo, S-Y. Synthesis and molecular docking studies of (E)-4-(Substituted-benzylideneamino)-2H-Chromen-2-one derivatives: Entry to new carbonic anhydrase class of inhibitors. Drug Res. (Stuttg.), 2018, 68(7), 378-386.
[http://dx.doi.org/10.1055/s-0043-123998] [PMID: 29433141]
Stamboliyska, B.; Janevska, V.; Shivachev, B.; Nikolova, R.P.; Stojkovic, G.; Mikhova, B.; Popovski, E. Experimental and theoretical investigation of the structure and nucleophilic properties of 4-aminocoumarin. ARKIVOC, 2010, (x), 62-76.
Heide, L. New aminocoumarin antibiotics as gyrase inhibitors. Int. J. Med. Microbiol., 2014, 304(1), 31-36.
[http://dx.doi.org/10.1016/j.ijmm.2013.08.013] [PMID: 24079980]
Kym, P.R.; Iyengar, R.; Souers, A.J.; Lynch, J.K.; Judd, A.S.; Gao, J.; Freeman, J.; Mulhern, M.; Zhao, G.; Vasudevan, A.; Wodka, D.; Blackburn, C.; Brown, J.; Che, J.L.; Cullis, C.; Lai, S.J.; LaMarche, M.J.; Marsilje, T.; Roses, J.; Sells, T.; Geddes, B.; Govek, E.; Patane, M.; Fry, D.; Dayton, B.D.; Brodjian, S.; Falls, D.; Brune, M.; Bush, E.; Shapiro, R.; Knourek-Segel, V.; Fey, T.; McDowell, C.; Reinhart, G.A.; Preusser, L.C.; Marsh, K.; Hernandez, L.; Sham, H.L.; Collins, C.A. Discovery and characterization of aminopiperidinecoumarin melanin concentrating hormone receptor 1 antagonists. J. Med. Chem., 2005, 48(19), 5888-5891.
[http://dx.doi.org/10.1021/jm050598r] [PMID: 16161992]
Jacquot, Y.; Laïos, I.; Cleeren, A.; Nonclercq, D.; Bermont, L.; Refouvelet, B.; Boubekeur, K.; Xicluna, A.; Leclercq, G.; Laurent, G. Synthesis, structure, and estrogenic activity of 4-amino-3-(2-methylbenzyl)coumarins on human breast carcinoma cells. Bioorg. Med. Chem., 2007, 15(6), 2269-2282.
[http://dx.doi.org/10.1016/j.bmc.2007.01.025] [PMID: 17275315]
Saeed, A.; Qamar, R.; Fattah, T.A.; Flörke, U.; Erben, M.F. Recent developments in chemistry, coordination, structure and biological aspects of 1-(acyl/aroyl)-3-(substituted) thioureas. Res. Chem. Intermed., 2017, 43, 3053-3093.
Abbas, S.Y.; El-Sharief, M.A.S.; Basyouni, W.M.; Fakhr, I.M.; El-Gammal, E.W. Thiourea derivatives incorporating a hippuric acid moiety: synthesis and evaluation of antibacterial and antifungal activities. Eur. J. Med. Chem., 2013, 64, 111-120.
[http://dx.doi.org/10.1016/j.ejmech.2013.04.002] [PMID: 23644194]
Saeed, S.; Rashid, N.; Jones, P.G.; Ali, M.; Hussain, R. Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole moiety as potential antimicrobial and anticancer agents. Eur. J. Med. Chem., 2010, 45(4), 1323-1331.
[http://dx.doi.org/10.1016/j.ejmech.2009.12.016] [PMID: 20056520]
Saeed, A.; Khera, R.A.; Abbas, N.; Latif, M.; Sajid, I.; Floerke, U. Synthesis, characterization, crystal structures, and antibacterial activity of some new 1-(3, 4, 5-trimethoxybenzoyl)-3-aryl thioureasreas. Turk. J. Chem., 2010, 34, 335-346.
Eweis, M.; Elkholy, S.S.; Elsabee, M.Z. Antifungal efficacy of chitosan and its thiourea derivatives upon the growth of some sugar-beet pathogens. Int. J. Biol. Macromol., 2006, 38(1), 1-8.
[http://dx.doi.org/10.1016/j.ijbiomac.2005.12.009] [PMID: 16413607]
Ozgur, A.; Yenidunya, E.; Koca, I.; Tutar, Y. Acyl thiourea derivatives containing pyrazole ring selective targeting of human aurora kinases in breast and bone cancer. Lett. Drug Des. Discov., 2015, 12, 180-189.
Stefanska, J.; Nowicka, G.; Struga, M.; Szulczyk, D.; Koziol, A.E.; Augustynowicz-Kopec, E.; Napiorkowska, A.; Bielenica, A.; Filipowski, W.; Filipowska, A.; Drzewiecka, A.; Giliberti, G.; Madeddu, S.; Boi, S.; La Colla, P.; Sanna, G. Antimicrobial and anti-biofilm activity of thiourea derivatives incorporating a 2-aminothiazole scaffold. Chem. Pharm. Bull. (Tokyo), 2015, 63(3), 225-236.
[http://dx.doi.org/10.1248/cpb.c14-00837] [PMID: 25757494]
Taha, M.; Ismail, N.H.; Jamil, W.; Khan, K.M.; Salar, U.; Kashif, S.M.; Rahim, F.; Latif, Y. Synthesis and evaluation of unsymmetrical heterocyclic thioureas as potent β-glucuronidase inhibitors. Med. Chem. Res., 2015, 24, 3166-3173.
a)Zang, W.; Hao, Y.; Wang, Z.; Zheng, W. Novel thiourea-based sirtuin inhibitory warheads. Bioorg. Med. Chem. Lett., 2015, 25(16), 3319-3324.
[http://dx.doi.org/10.1016/j.bmcl.2015.05.058] [PMID: 26081291]
b)Daud, A.I.; Khairul, W.M.; Mohamed Zuki, H. KuBulat, K. Synthesis and characterization of N-(4-Aminophenylethynylbenzo-nitrile)-N′-(1-naphthoyl) thiourea as single molecular chemosensor for carbon monoxide sensing. J. Sulfur Chem., 2014, 35, 691-699.
Guang-Yi, L.; Hong, Z.; Liu-Yin, X.; Shuai, W.; Zheng-He, X. Improving copper flotation recovery from a refractory copper porphyry ore by using ethoxycarbonyl thiourea as a collector. Miner. Eng., 2011, 24, 817-824.
a)Sanz-Cobena, A.; Misselbrook, T.H.; Arce, A.; Mingot, J.I.; Diez, J.A.; Vallejo, A. An inhibitor of urease activity effectively reduces ammonia emissions from soil treated with urea under Mediterranean conditions. Agric. Ecosyst. Environ., 2008, 126, 243-249.
b )Kot, M.; Karcz, W.; Zaborska, W. 5-Hydroxy-1,4-naphthoquinone (juglone) and 2-hydroxy-1,4-naphthoquinone (lawsone) influence on jack bean urease activity: Elucidation of the difference in inhibition activity. Bioorg. Chem., 2010, 38(3), 132-137.
[http://dx.doi.org/10.1016/j.bioorg.2010.02.002] [PMID: 20202666]
c)Ito, Y.; Shibata, K.; Hongo, A.; Kinoshita, M. Ecabet sodium, a locally acting antiulcer drug, inhibits urease activity of Helicobacter pylori. Eur. J. Pharmacol., 1998, 345(2), 193-198.
[http://dx.doi.org/10.1016/S0014-2999(97)01622-1] [PMID: 9600637]
d)Weatherburn, M. Phenol-hypochlorite reaction for determination of ammonia. Anal. Chem., 1967, 39, 971-974.
Reddy, C.V.K.; Sreeramulu, D.; Raghunath, M. Antioxidant activity of fresh and dry fruits commonly consumed in India. Food Res. Int., 2010, 43, 285-288.
Saeed, A.; Mahmood, S.U.; Rafiq, M.; Ashraf, Z.; Jabeen, F.; Seo, S.Y. Iminothiazoline-Sulfonamide Hybrids as Jack Bean Urease Inhibitors; Synthesis, Kinetic Mechanism and Computational Molecular Modeling. Chem. Biol. Drug Des., 2016, 87(3), 434-443.
[http://dx.doi.org/10.1111/cbdd.12675] [PMID: 26496515]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
Chen, V.B.; Arendall, W.B., III; Headd, J.J.; Keedy, D.A.; Immormino, R.M.; Kapral, G.J.; Murray, L.W.; Richardson, J.S.; Richardson, D.C. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr., 2010, 66(Pt 1), 12-21.
[http://dx.doi.org/10.1107/S0907444909042073] [PMID: 20057044]
Gasteiger, E.; Hoogland, C.; Gattiker, A.; Duvaud, S.; Wilkins, M.R.; Appel, R.D.; Bairoch, A. The Proteomics Protocols Handbook; Walker, J.M., Ed.; Humana Press, 2005, pp. 571-607.
Studio, D. Discovery. version 2.1; In: Accelrys: San Diego, CA, 2008.
Willard, L.; Ranjan, A.; Zhang, H.; Monzavi, H.; Boyko, R.F.; Sykes, B.D.; Wishart, D.S. VADAR: a web server for quantitative evaluation of protein structure quality. Nucleic Acids Res., 2003, 31(13), 3316-3319.
[http://dx.doi.org/10.1093/nar/gkg565] [PMID: 12824316]
Dallakyan, S.; Olson, A.J. Small-molecule library screening by docking with PyRx. Methods Mol. Biol., 2015, 1263, 243-250.
[http://dx.doi.org/10.1007/978-1-4939-2269-7_19] [PMID: 25618350]
Pronk, S.; Páll, S.; Schulz, R.; Larsson, P.; Bjelkmar, P.; Apostolov, R.; Shirts, M.R.; Smith, J.C.; Kasson, P.M.; van der Spoel, D.; Hess, B.; Lindahl, E. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics, 2013, 29(7), 845-854.
[http://dx.doi.org/10.1093/bioinformatics/btt055] [PMID: 23407358]
Chiu, S.W.; Pandit, S.A.; Scott, H.L.; Jakobsson, E. An improved united atom force field for simulation of mixed lipid bilayers. J. Phys. Chem. B, 2009, 113(9), 2748-2763.
[http://dx.doi.org/10.1021/jp807056c] [PMID: 19708111]
Schüttelkopf, A.W.; van Aalten, D.M. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D Biol. Crystallogr., 2004, 60(Pt 8), 1355-1363.
[http://dx.doi.org/10.1107/S0907444904011679] [PMID: 15272157]
Wang, H.; Dommert, F.; Holm, C. Optimizing working parameters of the smooth particle mesh Ewald algorithm in terms of accuracy and efficiency. J. Chem. Phys., 2010, 133(3)034117
[http://dx.doi.org/10.1063/1.3446812] [PMID: 20649318]
Banavath, H.N.; Sharma, O.P.; Kumar, M.S.; Baskaran, R. Identification of Potent Inhibitors for Resistant Form of Chronic Myelogenous Leukaemia (CML). Proceedings IWBBIO 2014, Granada2014.
Almeida, P.A.; Silva, T.M.S.; Echevarria, A. Mesoionic 5-alkyl-1,3-dithiolium-4-thiolates: synthesis and brine shrimp toxicity. Heterocycl. Commun., 2002, 8, 593-600.
Meyer, B.N.; Ferrigni, N.R.; Putnam, J.E.; Jacobsen, L.B.; Nichols, D.E.; McLaughlin, J.L. Brine shrimp: a convenient general bioassay for active plant constituents. Planta Med., 1982, 45, 31-34.
Bjellqvist, B.; Hughes, G.J.; Pasquali, C.; Paquet, N.; Ravier, F.; Sanchez, J.C.; Frutiger, S.; Hochstrasser, D. The focusing positions of polypeptides in immobilized pH gradients can be predicted from their amino acid sequences. Electrophoresis, 1993, 14(10), 1023-1031.
[http://dx.doi.org/10.1002/elps.11501401163] [PMID: 8125050]
Xiong, X.; Huang, S.; Zhang, H.; Li, J.; Shen, J.; Xiong, J.; Lin, Y.; Jiang, L.; Wang, X.; Liang, S. Enrichment and proteomic analysis of plasma membrane from rat dorsal root ganglions. Proteome Sci., 2009, 7, 41.
[http://dx.doi.org/10.1186/1477-5956-7-41] [PMID: 19889238]
Kyte, J.; Doolittle, R.F. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol., 1982, 157(1), 105-132.
[http://dx.doi.org/10.1016/0022-2836(82)90515-0] [PMID: 7108955]
Ghose, A.K.; Herbertz, T.; Hudkins, R.L.; Dorsey, B.D.; Mallamo, J.P. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem. Neurosci., 2012, 3(1), 50-68.
[http://dx.doi.org/10.1021/cn200100h] [PMID: 22267984]
Kadam, R.U.; Roy, N. Recent trends in drug-likeness prediction: A comprehensive review of in silico methods. Indian J. Pharm. Sci., 2007, 69, 609-615.
Bakht, M.A.; Yar, M.S.; Abdel-Hamid, S.G.; Al Qasoumi, S.I.; Samad, A. Molecular properties prediction, synthesis and antimicrobial activity of some newer oxadiazole derivatives. Eur. J. Med. Chem., 2010, 45(12), 5862-5869.
[http://dx.doi.org/10.1016/j.ejmech.2010.07.069] [PMID: 20965619]
Tian, S.; Wang, J.; Li, Y.; Li, D.; Xu, L.; Hou, T. The application of in silico drug-likeness predictions in pharmaceutical research. Adv. Drug Deliv. Rev., 2015, 86, 2-10.
[http://dx.doi.org/10.1016/j.addr.2015.01.009] [PMID: 25666163]
Selick, H.E.; Beresford, A.P.; Tarbit, M.H. The emerging importance of predictive ADME simulation in drug discovery. Drug Discov. Today, 2002, 7(2), 109-116.
[http://dx.doi.org/10.1016/S1359-6446(01)02100-6] [PMID: 11790621]
Pires, D.E. lundell, T.L.; Ascher, D.B. pkCSM. J. Med. Chem., 2015, 58, 4066-4072.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00104] [PMID: 25860834]
Hameed, A.; Khan, K.M.; Zehra, S.T.; Ahmed, R.; Shafiq, Z.; Bakht, S.M.; Yaqub, M.; Hussain, M.; de la Vega de León, A.; Furtmann, N.; Bajorath, J.; Shad, H.A.; Tahir, M.N.; Iqbal, J. Synthesis, biological evaluation and molecular docking of N-phenyl thiosemicarbazones as urease inhibitors. Bioorg. Chem., 2015, 61, 51-57.
[http://dx.doi.org/10.1016/j.bioorg.2015.06.004] [PMID: 26119990]
Abdul Fattah, T.; Saeed, A.; Channar, P.A.; Ashraf, Z.; Abbas, Q.; Hassan, M.; Larik, F.A. Synthesis, enzyme inhibitory kinetics, and computational studies of novel 1-(2-(4-isobutylphenyl)propanoyl)-3-arylthioureas as Jack bean urease inhibitors. Chem. Biol. Drug Des., 2018, 91, 434-447.
a)Channar, P.A.; Saeed, A.; Albericio, F.; Larik, F.A.; Abbas, Q.; Hassan, M.; Raza, H.; Seo, S.Y. Sulfonamide-linked ciprofloxacin, sulfadiazine and amantadine derivatives as a novel class of inhibitors of jack bean urease; Synthesis, Kinetic mechanism and molecular docking. Molecules, 2017, 22(8), 1352.
[http://dx.doi.org/10.3390/molecules22081352] [PMID: 28813027]
b)An expedient synthesis of N-(1-(5-mercapto-4-((substituted benzylidene)amino)-4H-1,2,4-triazol-3-yl)-2-phenylethyl)benzamides as jack bean urease inhibitors and free radical scavengers: Kinetic mechanism and molecular docking studies. Chem. Biol. Drug Des., 2017, 90, 764-777.
a)Saeed, A.; Ur-Rehman, S.; Channar, P.A.; Larik, F.A.; Abbas, Q.; Hassan, M.; Raza, H.; Seo, S.Y. Jack bean urease inhibitors, and antioxidant activity based on palmitic acid derived 1-acyl-3-arylthioureas: Synthesis, kinetic mechanism and molecular docking studies. Drug Res. (Stuttg.), 2017, 67(10), 596-605.
[http://dx.doi.org/10.1055/s-0043-113832] [PMID: 28672409]
b)Saeed, A.; Mahesar, P.A.; Channar, P.A.; Abbas, Q.; Larik, F.A.; Hassan, M.; Raza, H.; Seo, S-Y. Synthesis, molecular docking studies of coumarinyl-pyrazolinyl substituted thiazoles as non-competitive inhibitors of mushroom tyrosinase. Bioorg. Chem., 2017, 74, 187-196.
[http://dx.doi.org/10.1016/j.bioorg.2017.08.002] [PMID: 28837887]
Saeed, A. Rehman, S-u.; Channar, P.A.; Larik, F.A.; Abbas, Q.; Hassan, M.; Raza, H.; Flörke, U.; Seo, S-Y. Long chain 1-acyl-3-arylthioureas as jack bean urease inhibitors, synthesis, kinetic mechanism and molecular docking studies. J. Taiwan Inst Chem Eng., 2017, 77, 54-63.

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Year: 2020
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DOI: 10.2174/1573406415666190715164834
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