In-silico Designing, ADMET Analysis, Synthesis and Biological Evaluation of Novel Derivatives of Diosmin Against Urease Protein and Helicobacter pylori Bacterium

Author(s): Ritu Kataria, Anurag Khatkar*.

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 29 , 2019

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Abstract:

Background: Designing drug candidates against the urease enzyme, which has been found responsible for many pathological disorders in human beings as well as in animals, was done by insilico means.

Methods: Studies were carried out on a designed library of diosmin derivatives with the help of Schrodinger’s maestro package of molecular docking software against a crystallographic complex of plant enzyme Jack bean urease (PDB ID: 3LA4). Best twelve derivatives of diosmin were selected for synthesis by considering their interaction energy along with docking score and were further investigated for antioxidant, urease inhibitory and Anti-H. pylori activity by in- vitro method along with ADMET analysis.

Results: In-vitro results of series concluded compounds D2a, D2d and D7 (IC50 12.6 ± 0.002, 14.14 ± 0.001 and 15.64 ± 0.012 µM respectively in urease inhibition and 5.195 ± 0.036, 5.39 ± 0.020 and 5.64± 0.005 µM in antioxidant behavior against DPPH) were found to be significantly potent with excellent docking score -11.721, -10.795, -10.188 and binding energy -62.674, -63.352, -56.267 kJ/ mol as compared to standard drugs thiourea and acetohydroxamic acid (-3.459, -3.049 and -21.156 kJ/mol and - 17.454 kJ/mol) whereas compounds D2b, D5b, D5d and D6 were found moderate in urease inhibitory activity.

Conclusion: Selected candidates from the outcome of in-vitro urease inhibitory were further examined for anti- H. pylori activity by a well diffusion method against H. pylori bacterium (DSM 4867). Compound D2a showed good anti-H. Pylori activity with a zone of inhibition 10.00 ± 0.00 mm and MIC value 500µg/mL as compared to standard drug acetohydroxamic acid having a zone of inhibition 9.00 ± 0.50mm and MIC 1000µg/mL. In- silico studies played an important role in designing the potent ligands against urease protein as well as in explaining the binding pattern of designed and synthesized ligand within the active pocket of jack bean urease protein. ADMET studies were also carried out to check the drug similarity of designed compounds by the means of quikprop module of molecular docking software. Hence, the present investigation studies will provide a new vision for the discovery of potent agents against H. pylori and urease associated diseases.

Keywords: Diosmin, Urease inhibition, Natural phenolic compounds, Antioxidant, Anti-H. pylori activity, Designing drug.

[1]
El-Shafae, A.M.; El-Domiaty, M.M. Improved LC methods for the determination of diosmin and/or hesperidin in plant extracts and pharmaceutical formulations. J. Pharm. Biomed. Anal., 2001, 26(4), 539-545.
[http://dx.doi.org/10.1016/S0731-7085(01)00476-9] [PMID: 11516904]
[2]
Campanero, M.A.; Escolar, M.; Perez, G.; Garcia-Quetglas, E.; Sadaba, B.; Azanza, J.R. Simultaneous determination of diosmin and diosmetin in human plasma by ion trap liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry: Application to a clinical pharmacokinetic study. J. Pharm. Biomed. Anal., 2010, 51(4), 875-881.
[http://dx.doi.org/10.1016/j.jpba.2009.09.012] [PMID: 19800189]
[3]
Gopalakrishnan, V. Pillai, S. I.; Subramanian, S. P. Synthesis, Spectral Characterization, and Biochemical Evaluation of Antidiabetic Properties of a New Zinc-Diosmin Complex Studied in High Fat Diet Fed-Low Dose Streptozotocin Induced Experimental Type 2 Diabetes in Rats. Biochem. Res. Int., 2015, 2015350829
[http://dx.doi.org/10.1155/2015/350829]
[4]
Camarda, L.; Di Stefano, V.; Del Bosco, S.F.; Schillaci, D. Antiproliferative activity of Citrus juices and HPLC evaluation of their flavonoid composition. Fitoterapia, 2007, 78(6), 426-429.
[http://dx.doi.org/10.1016/j.fitote.2007.02.020] [PMID: 17628348]
[5]
del Baño, M.J.; Lorente, J.; Castillo, J.; Benavente-García, O.; Marín, M.P.; Del Río, J.A.; Ortuño, A.; Ibarra, I. Flavonoid distribution during the development of leaves, flowers, stems, and roots of Rosmarinus officinalis. postulation of a biosynthetic pathway. J. Agric. Food Chem., 2004, 52(16), 4987-4992.
[http://dx.doi.org/10.1021/jf040078p] [PMID: 15291464]
[6]
Oesterle, O.A.; Wander, G. Naturally occurring flavonic glycoside rhamnoglycoside of diosmetin, Isolation from various plant sources. Helv. Chim. Acta, 1925, 8, 519.
[http://dx.doi.org/10.1002/hlca.19250080179]
[7]
Monograph. Diosmin. Altern. Med. Rev., 2004, 9(3), 308-311.
[PMID: 15387721]
[8]
Barreca, D.; Laganà, G.; Bruno, G.; Magazù, S.; Bellocco, E. Diosmin binding to human serum albumin and its preventive action against degradation due to oxidative injuries. Biochimie, 2013, 95(11), 2042-2049.
[http://dx.doi.org/10.1016/j.biochi.2013.07.014] [PMID: 23886889]
[9]
Manuel y Keenoy, B.; Vertommen, J.; De Leeuw, I.; De Leeuw, I. The effect of flavonoid treatment on the glycation and antioxidant status in Type 1 diabetic patients. Diabetes Nutr. Metab., 1999, 12(4), 256-263.
[PMID: 10782751]
[10]
Srinivasan, S.; Pari, L. Ameliorative effect of diosmin, a citrus flavonoid against streptozotocin-nicotinamide generated oxidative stress induced diabetic rats. Chem. Biol. Interact., 2012, 195(1), 43-51.
[http://dx.doi.org/10.1016/j.cbi.2011.10.003] [PMID: 22056647]
[11]
Crespo, M.E.; Gálvez, J.; Cruz, T.; Ocete, M.A.; Zarzuelo, A. Anti-inflammatory activity of diosmin and hesperidin in rat colitis induced by TNBS. Planta Med., 1999, 65(7), 651-653.
[http://dx.doi.org/10.1055/s-2006-960838] [PMID: 10575379]
[12]
Cotelle, N.; Bernier, J.L.; Catteau, J.P.; Pommery, J.; Wallet, J.C.; Gaydou, E.M. Antioxidant properties of hydroxy-flavones. Free Radic. Biol. Med., 1996, 20(1), 35-43.
[http://dx.doi.org/10.1016/0891-5849(95)02014-4] [PMID: 8903677]
[13]
Tahir, M.; Rehman, M.U.; Lateef, A.; Khan, R.; Khan, A.Q.; Qamar, W.; Ali, F.; O’Hamiza, O.; Sultana, S. Diosmin protects against ethanol-induced hepatic injury via alleviation of inflammation and regulation of TNF-α and NF-κB activation. Alcohol, 2013, 47(2), 131-139.
[http://dx.doi.org/10.1016/j.alcohol.2012.12.010] [PMID: 23419394]
[14]
Silambarasan, T.; Raja, B. Diosmin, a bioflavonoid reverses alterations in blood pressure, nitric oxide, lipid peroxides and antioxidant status in DOCA-salt induced hypertensive rats. Eur. J. Pharmacol., 2012, 679(1-3), 81-89.
[http://dx.doi.org/10.1016/j.ejphar.2011.12.040] [PMID: 22266490]
[15]
Tanaka, T.; Makita, H.; Kawabata, K.; Mori, H.; Kakumoto, M.; Satoh, K.; Hara, A.; Sumida, T.; Fukutani, K.; Tanaka, T.; Ogawa, H. Modulation of N-methyl-N-amylnitrosamine-induced rat oesophageal tumourigenesis by dietary feeding of diosmin and hesperidin, both alone and in combination. Carcinogenesis, 1997, 18(4), 761-769.
[http://dx.doi.org/10.1093/carcin/18.4.761] [PMID: 9111212]
[16]
Krajewska, B.; Zaborska, W. Double mode of inhibition-inducing interactions of 1,4-naphthoquinone with urease: arylation versus oxidation of enzyme thiols. Bioorg. Med. Chem., 2007, 15(12), 4144-4151.
[http://dx.doi.org/10.1016/j.bmc.2007.03.071] [PMID: 17416528]
[17]
Mobley, H.L.T.; Hausinger, R.P. Microbial ureases: significance, regulation, and molecular characterization. Microbiol. Rev., 1989, 53(1), 85-108.
[PMID: 2651866]
[18]
Amtul, Z.; Kausar, N.; Follmer, C.; Rozmahel, R.F. Atta-Ur-Rahman; Kazmi, S.A.; Shekhani, M.S.; Eriksen, J.L.; Khan, K.M.; Choudhary, M.I. Cysteine based novel noncompetitive inhibitors of urease(s)--distinctive inhibition susceptibility of microbial and plant ureases. Bioorg. Med. Chem., 2006, 14(19), 6737-6744.
[http://dx.doi.org/10.1016/j.bmc.2006.05.078] [PMID: 16859909]
[19]
Wilcox, P.E. Chymotrypsinogens chymotrypsins. Methods Enzymol., 1970, 19, 64-108.
[http://dx.doi.org/10.1016/0076-6879(70)19007-0]
[20]
Bayerdörffer, E.; Ottenjann, R. The role of antibiotics in Campylobacter pylori associated peptic ulcer disease. Scand. J. Gastroenterol. Suppl., 1988, 142, 93-100.
[http://dx.doi.org/10.3109/00365528809091721] [PMID: 3047854]
[21]
Collins, C.M.; D’Orazio, S.E.M. Bacterial ureases: structure, regulation of expression and role in pathogenesis. Mol. Microbiol., 1993, 9(5), 907-913.
[http://dx.doi.org/10.1111/j.1365-2958.1993.tb01220.x] [PMID: 7934918]
[22]
Montecucco, C.; Rappuoli, R. Living dangerously: how Helicobacter pylori survives in the human stomach. Nat. Rev. Mol. Cell Biol., 2001, 2(6), 457-466.
[http://dx.doi.org/10.1038/35073084] [PMID: 11389469]
[23]
Seneviratne, G.; Van Holm, L.H.J.; Ekanayake, E. Agronomic benefits of rhizobial inoculant use over nitrogen fertilizer application in tropical soybean. Field Crops Res., 2000, 68, 199-203.
[http://dx.doi.org/10.1016/S0378-4290(00)00123-4]
[24]
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. Atta-ur-Rahman, Chemical constituents of Stereospermum acuminatissimum and their urease and α-chymotrypsin inhibitions. Fitoterapia, 2012, 83(1), 204-208.
[http://dx.doi.org/10.1016/j.fitote.2011.10.014] [PMID: 22062354]
[25]
Menezes, D.C.; Borges, E.; Torres, M.F.; Braga, J.P. A kinetic study of jack-bean urease denaturation by a new dithiocarbamate bismuth compound. Chem. Phys. Lett., 2012, 548, 85-89.
[http://dx.doi.org/10.1016/j.cplett.2012.07.078]
[26]
Modolo, L.V.; de Souza, A.X.; Horta, L.P.; Araujo, D.P.; de Fátima, Â. An overview on the potential of natural products as ureases inhibitors: A review. J. Adv. Res., 2015, 6(1), 35-44.
[http://dx.doi.org/10.1016/j.jare.2014.09.001] [PMID: 25685542]
[27]
Xiao, Z.P.; Peng, Z.Y.; Dong, J.J.; He, J.; Ouyang, H.; Feng, Y.T.; Lu, C.L.; Lin, W.Q.; Wang, J.X.; Xiang, Y.P.; Zhu, H.L. Synthesis, structure-activity relationship analysis and kinetics study of reductive derivatives of flavonoids as Helicobacter pylori urease inhibitors. Eur. J. Med. Chem., 2013, 63, 685-695.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.016] [PMID: 23567958]
[28]
Yu, X.D.; Zheng, R.B.; Xie, J.H.; Su, J.Y.; Huang, X.Q.; Wang, Y.H.; Zheng, Y.F.; Mo, Z.Z.; Wu, X.L.; Wu, D.W.; Liang, Y.E.; Zeng, H.F.; Su, Z.R.; Huang, P. Biological evaluation and molecular docking of baicalin and scutellarin as Helicobacter pylori urease inhibitors. J. Ethnopharmacol., 2015, 162, 69-78.
[http://dx.doi.org/10.1016/j.jep.2014.12.041] [PMID: 25557028]
[29]
Wu, D.W.; Yu, X.D.; Xie, J.H.; Su, Z.Q.; Su, J.Y.; Tan, L.R.; Huang, X.Q.; Chen, J.N.; Su, Z.R. Inactivation of jack bean urease by scutellarin: elucidation of inhibitory efficacy, kinetics and mechanism. Fitoterapia, 2013, 91, 60-67.
[http://dx.doi.org/10.1016/j.fitote.2013.08.012] [PMID: 23978581]
[30]
Ahmad, M.; Muhammad, N.; Ahmad, M.; Arif Lodhi, M.; Jehan, N.; Khan, Z.; Ranjit, R.; Shaheen, F.; Iqbal Choudhary, M. Urease inhibitor from Datisca cannabina linn. J. Enzyme Inhib. Med. Chem., 2008, 23(3), 386-390.
[http://dx.doi.org/10.1080/14756360701536513] [PMID: 18569344]
[31]
Nile, S.H.; Nile, A.S.; Keum, Y.S.; Sharma, K. Utilization of quercetin and quercetin glycosides from onion (Allium cepa L.) solid waste as an antioxidant, urease and xanthine oxidase inhibitors. Food Chem., 2017, 235, 119-126.
[http://dx.doi.org/10.1016/j.foodchem.2017.05.043] [PMID: 28554615]
[32]
Perveen, S.; El-Shafae, A.M.; Al-Taweel, A.; Fawzy, G.A.; Malik, A.; Afza, N.; Latif, M.; Iqbal, L. Antioxidant and urease inhibitory C-glycosylflavonoids from Celtis africana. J. Asian Nat. Prod. Res., 2011, 13(9), 799-804.
[http://dx.doi.org/10.1080/10286020.2011.593171] [PMID: 21830883]
[33]
Mohammed, M. Ansari, Shirish, P.; Deshmukh, R. K. Synthesis Antimicrobial and Anticancer Evaluation of 1-Aryl-5-(o-methoxyphenyl)-2-S-benzyl Isothiobiurets. Int. J. Med. Chem., 2014, •••352626
[http://dx.doi.org/10.1155/2014/352626]
[34]
Ullah Mughal, E.; Ayaz, M.; Hussain, Z.; Hasan, A.; Sadiq, A.; Riaz, M.; Malik, A.; Hussain, S.; Choudhary, M.I. Synthesis and antibacterial activity of substituted flavones, 4-thioflavones and 4-iminoflavones. Bioorg. Med. Chem., 2006, 14(14), 4704-4711.
[http://dx.doi.org/10.1016/j.bmc.2006.03.031] [PMID: 16603364]
[35]
Brodowska, K.; Sykuła, A.; Garribba, E.; Łodyga-Chruścińska, E.; Sójka, M. Naringenin Schiff base: antioxidant activity, acid–base profile, and interactions with DNA. Transition Metal Chemistry, 2016, 41(2), 179-189.
[http://dx.doi.org/10.1007/s11243-015-0010-7]
[36]
Weatherburn, M.W. Phenol-hypochlorite reaction for determination of ammonia. Anal. Chem., 1967, 39(8), 971-974.
[http://dx.doi.org/10.1021/ac60252a045]
[37]
Hanif, M.; Shoaib, K.; Saleem, M.; Hasan Rama, N.; Zaib, S.; Iqbal, J. Synthesis, urease inhibition, antioxidant, antibacterial, and molecular docking studies of 1,3,4-oxadiazole derivatives. ISRN Pharmacol., 2012, 2012928901
[http://dx.doi.org/10.5402/2012/928901] [PMID: 22934191]
[38]
Choudhary, M.I.; Begum, A.; Abbaskhan, A.; Musharraf, S.G.; Ejaz, A. Atta-ur-Rahman. Two new antioxidant phenylpropanoids from Lindelofia stylosa. Chem. Biodivers., 2008, 5(12), 2676-2683.
[http://dx.doi.org/10.1002/cbdv.200890221] [PMID: 19089825]
[39]
Maestro, version 10.2, Schrödinger, LLC: New York. 2015.
[40]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID: 15027865]
[41]
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem., 2004, 47(7), 1750-1759.
[http://dx.doi.org/10.1021/jm030644s] [PMID: 15027866]
[42]
Glide, version 6.6, Schrödinger, LLC: New York. 2015.
[43]
Godschalk, F.; Genheden, S.; Söderhjelm, P.; Ryde, U. Comparison of MM/GBSA calculations based on explicit and implicit solvent simulations. Phys. Chem. Chem. Phys., 2013, 15(20), 7731-7739.
[http://dx.doi.org/10.1039/c3cp00116d] [PMID: 23595060]
[44]
Sengupta, D.; Verma, D.; Naik, P.K. Docking-MM-GB/SA and ADME screening of HIV-1 NNRTI inhibitor: nevirapine and its analogues. In: In Silico Biol. (Gedrukt); , 2008. 8(3-4), 275-289.
[PMID: 19032162]
[45]
Cecchelli, R.; Berezowski, V.; Lundquist, S.; Culot, M.; Renftel, M.; Dehouck, M.P.; Fenart, L. Modelling of the blood-brain barrier in drug discovery and development. Nat. Rev. Drug Discov., 2007, 6(8), 650-661.
[http://dx.doi.org/10.1038/nrd2368] [PMID: 17667956]
[46]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2012, 64, 4-17.
[http://dx.doi.org/10.1016/j.addr.2012.09.019] [PMID: 11259830]
[47]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID: 17034125]
[48]
Hanif, M.; Saleem, M.; Hussain, M.T.; Rama, N.H.; Zaib, S.; Aslam, M.A.; Jones, P.G.; Iqbal, J. Synthesis, urease inhibition, antioxidant and antibacterial studies of some 4-amino-5-aryl-3H-1, 2, 4-triazole-3-thiones and their 3, 6-disubstituted 1, 2, 4-triazolo [3, 4-b] 1, 3, 4-thiadiazole derivatives. J. Braz. Chem. Soc., 2012, 23(5), 854-860.
[http://dx.doi.org/10.1590/S0103-50532012000500010]
[49]
Xiao, Z.P.; Shi, D.H.; Li, H.Q.; Zhang, L.N.; Xu, C.; Zhu, H.L. Polyphenols based on isoflavones as inhibitors of Helicobacter pylori urease. Bioorg. Med. Chem., 2007, 15(11), 3703-3710.
[http://dx.doi.org/10.1016/j.bmc.2007.03.045] [PMID: 17400458]
[50]
Li, H.Q.; Xiao, Z.P. Yin-Luo; Yan, T.; Lv, P.C.; Zhu, H.L. Amines and oximes derived from deoxybenzoins as Helicobacter pylori urease inhibitors. Eur. J. Med. Chem., 2009, 44(5), 2246-2251.
[http://dx.doi.org/10.1016/j.ejmech.2008.06.001] [PMID: 18625539]
[51]
Xiao, Z.P.; Wang, X.D.; Peng, Z.Y.; Huang, S.; Yang, P.; Li, Q.S.; Zhou, L.H.; Hu, X.J.; Wu, L.J.; Zhou, Y.; Zhu, H.L. Molecular docking, kinetics study, and structure-activity relationship analysis of quercetin and its analogous as Helicobacter pylori urease inhibitors. J. Agric. Food Chem., 2012, 60(42), 10572-10577.
[http://dx.doi.org/10.1021/jf303393n] [PMID: 23067328]
[52]
Numao, N.; Iwahori, A.; Hirota, Y.; Sasatsu, M.; Kondo, I.; Onimura, K.; Sampe, R.; Yamane, S.; Itoh, S.; Katoh, T.; Kobayashi, S. Antibacterial activity of two alkylamines integrated an indane scaffold: mimicry of a complementary unit on magainin 2. Biol. Pharm. Bull., 1997, 20(7), 800-804.
[http://dx.doi.org/10.1248/bpb.20.800] [PMID: 9255423]


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VOLUME: 19
ISSUE: 29
Year: 2019
Page: [2658 - 2675]
Pages: 18
DOI: 10.2174/1568026619666191114123452
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