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Medicinal Chemistry

Author(s): Muhammad A. Bashir, Kulsoom Javaid, Muniza Shaikh, Muhammad I. Choudhary* and Hina Siddiqui*

DOI: 10.2174/1573406416666200128114422

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Tyramine Derivatives as Potent Therapeutics for Type 2 Diabetes: Synthesis and In Vitro Inhibition of α-Glucosidase Enzyme

Page: [1124 - 1135] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: Tyramine derivatives 3-16 were prepared and tested first time for their α- glucosidase (Sources: Saccharomyces cerevisiae) inhibitory activity by using an in vitro mechanismbased biochemical assay. All the compounds were found to be new, except compounds 3, 10-12 and 16.

Objective: In continuation of our research to synthesize and identify potent inhibitors of α-glucosidase enzyme, we intended to synthesize new inhibitors of α-glucosidase enzyme with enhanced efficacy in order to provide the basis for the better treatment of the type-II diabetic.

Methods: Tyramine (1) was allowed to react with a variety of aryl chlorides (2) to yield the corresponding amides. Synthesized compounds were then purified through normal phase column chromatography. Compounds 3-16 were then assessed for their α-glucosidase inhibitory activity in an in vitro biochemical assay. The cytotoxicity of compounds 3-16 was determined by using 3T3 mouse fibroblast cell lines.

Results: Compounds 3-5, 8, 13, and 15-16 were found to be more active (IC50 = 103.1±0.46, 37.3±4.51, 56.7±4.2, 23.9±2.31, 43.6±2.88, 55.8±1.73, and 38.2±0.86 μM, respectively) than the acarbose, the standard inhibitor of α-glucosidase enzyme, (IC50= 840.0±1.73 μM). To determine the dissociation constants and mode of inhibition, the kinetic studies were also performed for compounds 4 and 8 (the most potent inhibitors). It was observed that compounds 4 and 8 possess noncompetitive properties as the inhibitors of α-glucosidase. All the compounds were found to be noncytotoxic, except 5 and 12 (IC50= 14.7± 0.24 and 6.6± 0.38 μM, respectively).

Conclusion: The current study gives the facile synthesis and identification of potent inhibitors of α- glucosidase. The new inhibitors reported here may be investigated further for the designing and development of novel anti-diabetic agents.

Keywords: Tyramine, molecular docking, post-prandial hyperglycemia, α-glucosidase inhibition, diabetes, postprandial hyperglycemia.

Graphical Abstract

[1]
Ortiz-Andrade, R.R.; García-Jiménez, S.; Castillo-España, P.; Ramírez-Avila, G.; Villalobos-Molina, R.; Estrada-Soto, S. α-Glucosidase inhibitory activity of the methanolic extract from Tournefortia hartwegiana: an anti-hyperglycemic agent. J. Ethnopharmacol., 2007, 109(1), 48-53.
[http://dx.doi.org/10.1016/j.jep.2006.07.002] [PMID: 16920301]
[2]
Bhandari, M.R.; Jong-Anurakkun, N.; Hong, G.; Kawabata, J. α-Glucosidase and α-amylase inhibitory activities of Nepalese medicinal herb Pakhanbhed (Bergenia ciliata, Haw.). Food Chem., 2008, 106(1), 247-252.
[http://dx.doi.org/10.1016/j.foodchem.2007.05.077]
[3]
Gao, H.; Huang, Y-N.; Gao, B.; Xu, P-Y.; Inagaki, C.; Kawabata, J. α-Glucosidase inhibitory effect by the flower buds of Tussilago farfara L. Food Chem., 2008, 106(3), 1195-1201.
[http://dx.doi.org/10.1016/j.foodchem.2007.07.064]
[4]
Gao, H.; Huang, Y-N.; Gao, B.; Li, P.; Inagaki, C.; Kawabata, J. Inhibitory effect on α-glucosidase by Adhatoda vasica Nees. Food Chem., 2008, 108(3), 965-972.
[http://dx.doi.org/10.1016/j.foodchem.2007.12.002] [PMID: 26065759]
[5]
Siddiqui, H.; Bashir, M.A.; Javaid, K.; Nizamani, A.; Bano, H.; Yousuf, S.; Rahman, A.U.; Choudhary, M.I. Ultrasonic synthesis of tyramine derivatives as novel inhibitors of α-glucosidase in vitro. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1392-1403.
[http://dx.doi.org/10.3109/14756366.2016.1142983] [PMID: 26912275]
[6]
Huang, J.; Xing, X.; Zhang, X.; He, X.; Lin, Q.; Lian, W.; Zhu, H. A molecularly imprinted electrochemical sensor based on multiwalled carbon nanotube-gold nanoparticle composites and chitosan for the detection of tyramine. Food Res. Int., 2011, 44(1), 276-281.
[http://dx.doi.org/10.1016/j.foodres.2010.10.020]
[7]
Qu, Y.h.; Yang, J.h.; Chen, S.s. Synthesis of octopamine derivatives and investigation of their antioxidation activities. Chinese J. Marine Drugs,, 2012. 3, 006
[8]
Bryar, B.A.; Fregly, M.J.; Field, F.P. Changes in vascular responsiveness following chronic exposure to cold in the rat. J. Appl. Physiol., 1983, 55(3), 823-829.
[http://dx.doi.org/10.1152/jappl.1983.55.3.823] [PMID: 6629919]
[9]
Kim, J.S.; Hirano, M.; Uchimura, H.; Saito, M.; Nakahara, T.; Itoh, M. Effects of thyroidectomy on monoamine oxidase activities toward tyramine and serotonin in the circumventricular nuclei of the rat. Experientia, 1979, 35(3), 302-303.
[http://dx.doi.org/10.1007/BF01964312] [PMID: 446597]
[10]
Lino, C.; Sales, T.; Gomes, P.; do Amaral, J.; Alexandre, F.; Silveira, E.; Ferreira, J.; de Sousa, D.; de Queiroz, M.; de Sousa, F. Anti-diabetic activity of a fraction from Cissus verticillata and tyramine, its main bioactive constituent, in alloxan-induced diabetic rats. Am. J. Pharmacol. Toxicol., 2007, 2, 178-188.
[http://dx.doi.org/10.3844/ajptsp.2007.178.188]
[11]
Choudhary, M.I.; Shah, S.A. Atta-ur-Rahman.; Khan, S.N.; Khan, M.T. Alpha-glucosidase and tyrosinase inhibitors from fungal hydroxylation of tibolone and hydroxytibolones. Steroids, 2010, 75(12), 956-966.
[http://dx.doi.org/10.1016/j.steroids.2010.05.017] [PMID: 20685216]
[12]
Pauwels, R.; Balzarini, J.; Baba, M.; Snoeck, R.; Schols, D.; Herdewijn, P.; Desmyter, J.; De Clercq, E. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods, 1988, 20(4), 309-321.
[http://dx.doi.org/10.1016/0166-0934(88)90134-6] [PMID: 2460479]
[13]
LigPrep, version 3.6; Schrödinger, LLC: New York, NY, 2015.
[14]
Wizard, P.P. 2015-4; Epik version 2.4, Schrödinger, LLC, New York, NY, 2015; Impact version 5.9, Schrödinger, LLC, New York, NY, 2015; Prime version 3.2; Schrödinger, LLC: New York, NY, 2015.
[15]
Sastry, G.M.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des., 2013, 27(3), 221-234.
[http://dx.doi.org/10.1007/s10822-013-9644-8] [PMID: 23579614]
[16]
Halgren, T.A. Identifying and characterizing binding sites and assessing druggability. J. Chem. Inf. Model., 2009, 49(2), 377-389.
[http://dx.doi.org/10.1021/ci800324m] [PMID: 19434839]
[17]
Release, S. 2015-4: SiteMap, version 3.7; Schrodinger, LLC: New York, NY, 2015.
[18]
Glide, version 6.9; Schrodinger, LLC: New York, NY, 2015.
[19]
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]
[20]
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. Chapter 1: Introduction 6 Schrödinger Software Release 2015-4 Enrichment Factors in Database Screening. J. Med. Chem., 2004, 47, 1750-1759.
[http://dx.doi.org/10.1021/jm030644s] [PMID: 15027866]
[21]
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]
[22]
Song, Y.H.; Kim, D.W.; Curtis-Long, M.J.; Park, C.; Son, M.; Kim, J.Y.; Yuk, H.J.; Lee, K.W.; Park, K.H. Cinnamic acid amides from Tribulus terrestris displaying uncompetitive α-glucosidase inhibition. Eur. J. Med. Chem., 2016, 114, 201-208.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.044] [PMID: 26974386]
[23]
Zhang, L.; Tu, Z.C.; Yuan, T.; Wang, H.; Xie, X.; Fu, Z.F. Antioxidants and α-glucosidase inhibitors from Ipomoea batatas leaves identified by bioassay-guided approach and structure-activity relationships. Food Chem., 2016, 208, 61-67.
[http://dx.doi.org/10.1016/j.foodchem.2016.03.079] [PMID: 27132824]
[24]
Panidthananon, W.; Chaowasku, T.; Sritularak, B.; Likhitwitayawuid, K. A new benzophenone c-glucoside and other constituents of Pseuduvaria fragrans and their α-glucosidase inhibitory activity. Molecules, 2018, 23(7), 1600.
[http://dx.doi.org/10.3390/molecules23071600] [PMID: 30004411]