Generic placeholder image

Medicinal Chemistry

Author(s): Sajjad Esmaeili, Nazanin Ghobadi, Donya Nazari, Alireza Pourhossein, Hassan Rasouli, Hadi Adibi* and Reza Khodarahmi*

DOI: 10.2174/1573406416666200506083718

DownloadDownload PDF Flyer Cite As
Curcumin-based Antioxidant and Glycohydrolase Inhibitor Compounds: Synthesis and In Vitro Appraisal of the Dual Activity Against Diabetes

Page: [677 - 698] Pages: 22

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Background: Curcumin, as the substantial constituent of the turmeric plant (Curcuma longa), plays a significant role in the prevention of various diseases, including diabetes. It possesses ideal structure features as an enzyme inhibitor, including a flexible backbone, hydrophobic nature, and several available hydrogen bond (H-bond) donors and acceptors.

Objective: The present study aimed at synthesizing several novel curcumin derivatives and further evaluation of these compounds for possible antioxidant and anti-diabetic properties along with inhibitory effect against two carbohydrate-hydrolyzing enzymes, α-amylase and α-glucosidase, as these enzymes are therapeutic targets for attenuation of postprandial hyperglycemia.

Methods: Therefore, curcumin-based pyrido[2,3-d]pyrimidine derivatives were synthesized and identified using an instrumental technique like NMR spectroscopy and then screened for antioxidant and enzyme inhibitory potential. Total antioxidant activity, reducing power assay and 1,1-diphenyl-2- picrylhydrazyl (DPPH•) radical scavenging activity were done to appraise the antioxidant potential of these compounds in vitro.

Results: Compounds L6-L9 showed higher antioxidant activity while L4, L9, L12 and especially L8 exhibited the best selectivity index (lowest α-amylase/α-glucosidase inhibition ratio).

Conclusion: These antioxidant inhibitors may be potential anti-diabetic drugs, not only to reduce glycemic index but also to limit the activity of the major reactive oxygen species (ROS) producing pathways.

Keywords: Curcumin derivatives, diabetes, enzyme inhibition, antioxidant activity, α-amylase, α-glucosidase.

Graphical Abstract

[1]
Olokoba, A.B.; Obateru, O.A.; Olokoba, L.B. Type 2 diabetes mellitus: a review of current trends. Oman Med. J., 2012, 27(4), 269-273.
[http://dx.doi.org/10.5001/omj.2012.68] [PMID: 23071876]
[2]
Maritim, A.C.; Sanders, R.A.; Watkins, J.B. III Diabetes, oxidative stress, and antioxidants: a review. J. Biochem. Mol. Toxicol., 2003, 17(1), 24-38.
[http://dx.doi.org/10.1002/jbt.10058] [PMID: 12616644]
[3]
Giacco, F.; Brownlee, M. Oxidative stress and diabetic complications. Circ. Res., 2010, 107(9), 1058-1070.
[http://dx.doi.org/10.1161/CIRCRESAHA.110.223545] [PMID: 21030723]
[4]
Jiang, Z-Y.; Woollard, A.C.; Wolff, S.P. Hydrogen peroxide production during experimental protein glycation. FEBS Lett., 1990, 268(1), 69-71.
[http://dx.doi.org/10.1016/0014-5793(90)80974-N] [PMID: 2384174]
[5]
Wolff, S.P.; Dean, R.T. Glucose autoxidation and protein modification. The potential role of ‘autoxidative glycosylation’ in diabetes. Biochem. J., 1987, 245(1), 243-250.
[http://dx.doi.org/10.1042/bj2450243] [PMID: 3117042]
[6]
Lee, H.B.; Ha, H.; King, G.L. Reactive oxygen species and diabetic nephropathy. Am. Soc. Nephrol., 2003, 14(suppl. 3), S209-S210.
[http://dx.doi.org/10.1097/01.ASN.0000077403.06195.D2]
[7]
Sesti, F.; Tsitsilonis, O.E.; Kotsinas, A.; Trougakos, I.P. Oxidative stress-mediated biomolecular damage and inflammation in tumorigenesis. In Vivo, 2012, 26(3), 395-402.
[PMID: 22523291]
[8]
Zielinski, H. Low molecular weight antioxidants in the cereal grains: A review. Pol. J. Food Nutr. Sci., 2002, 11, 3-9.
[9]
Mates, J.M.; Pérez-Gómez, C.; De Castro, I.N. Antioxidant enzymes and human diseases. Clin. Biochem., 1999, 32, 595-603.
[http://dx.doi.org/10.1016/S0009-9120(99)00075-2]
[10]
Kajaria, D.; Ranjana, J.T.; Tripathi, J.; Tripathi, Y.B.; Tiwari, S. In-vitro α amylase and glycosidase inhibitory effect of ethanolic extract of antiasthmatic drug - Shirishadi. J. Adv. Pharm. Technol. Res., 2013, 4(4), 206-209.
[http://dx.doi.org/10.4103/2231-4040.121415] [PMID: 24350051]
[11]
Dalu, D.; Dhulipala, S. Evaluation of possible mechanisms of three plants for blood glucose control in diabetes. Bangladesh J. Pharmacol., 2016, 11, 224-230.
[http://dx.doi.org/10.3329/bjp.v11i1.24932]
[12]
Standl, E.; Schnell, O. Alpha-glucosidase inhibitors 2012 - cardiovascular considerations and trial evaluation. Diab. Vasc. Dis. Res., 2012, 9(3), 163-169.
[http://dx.doi.org/10.1177/1479164112441524] [PMID: 22508699]
[13]
Senger, M.R. Gomes, Lda.C.; Ferreira, S.B.; Kaiser, C.R.; Ferreira, V.F.; Silva, F.P., Jr Kinetics studies on the inhibition mechanism of pancreatic α-amylase by glycoconjugated 1H-1,2,3-triazoles: a new class of inhibitors with hypoglycemiant activity. ChemBioChem, 2012, 13(11), 1584-1593.
[http://dx.doi.org/10.1002/cbic.201200272] [PMID: 22753086]
[14]
Zhang, L.; Hogan, S.; Li, J.; Sun, S.; Canning, C.; Zheng, S.J.; Zhou, K. Grape skin extract inhibits mammalian intestinal α-glucosidase activity and suppresses postprandial glycemic response in streptozocin-treated mice. Food Chem., 2011, 126, 466-471.
[http://dx.doi.org/10.1016/j.foodchem.2010.11.016]
[15]
Konya, H.; Miuchi, M.; Konishi, K.; Nagai, E.; Ueyama, T.; Kusunoki, Y.; Kimura, Y.; Nakamura, Y.; Ishikawa, T.; Inokuchi, C.; Katsuno, T.; Hamaguchi, T.; Miyagawa, J.; Namba, M. Pleiotropic effects of mitiglinide in type 2 diabetes mellitus. J. Int. Med. Res., 2009, 37(6), 1904-1912.
[http://dx.doi.org/10.1177/147323000903700628] [PMID: 20146890]
[16]
Yagi, S.; Drouart, N.; Bourgaud, F.; Henry, M.; Chapleur, Y.; Laurain-Mattar, D. Antioxidant and antiglycation properties of Hydnora johannis roots. S. Afr. J. Bot., 2013, 84, 124-127.
[http://dx.doi.org/10.1016/j.sajb.2012.10.006]
[17]
Kowluru, R.A.; Kanwar, M. Effects of curcumin on retinal oxidative stress and inflammation in diabetes. Nutr. Metab. (Lond.), 2007, 4, 8.
[http://dx.doi.org/10.1186/1743-7075-4-8] [PMID: 17437639]
[18]
Gupta, S.C.; Patchva, S.; Aggarwal, B.B. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J., 2013, 15(1), 195-218.
[http://dx.doi.org/10.1208/s12248-012-9432-8] [PMID: 23143785]
[19]
Du, Z.Y.; Liu, R.R.; Shao, W.Y.; Mao, X.P.; Ma, L.; Gu, L.Q.; Huang, Z.S.; Chan, A.S. α-glucosidase inhibition of natural curcuminoids and curcumin analogs. Eur. J. Med. Chem., 2006, 41(2), 213-218.
[http://dx.doi.org/10.1016/j.ejmech.2005.10.012] [PMID: 16387392]
[20]
Lin, J.; Tang, Y.; Kang, Q.; Feng, Y.; Chen, A. Curcumin inhibits gene expression of receptor for advanced glycation end-products (RAGE) in hepatic stellate cells in vitro by elevating PPARγ activity and attenuating oxidative stress. Br. J. Pharmacol., 2012, 166(8), 2212-2227.
[http://dx.doi.org/10.1111/j.1476-5381.2012.01910.x] [PMID: 22352842]
[21]
Muthenna, P.; Suryanarayana, P.; Gunda, S.K.; Petrash, J.M.; Reddy, G.B. Inhibition of aldose reductase by dietary antioxidant curcumin: mechanism of inhibition, specificity and significance. FEBS Lett., 2009, 583(22), 3637-3642.
[http://dx.doi.org/10.1016/j.febslet.2009.10.042] [PMID: 19850041]
[22]
Mahmoud, A.A.; Nor El-Din, A.K. Glucose-6-phosphate dehydrogenase activity and protein oxidative modification in patients with type 2 diabetes mellitus. J. Biomark., 2013, 2013, 430813.
[http://dx.doi.org/10.1155/2013/430813] [PMID: 26317017]
[23]
Menon, V.P.; Sudheer, A.R. Antioxidant and anti-inflammatory properties of curcumin.The molecular targets and therapeutic uses of curcumin in health and disease; Springer, 2007, pp. 105-125.
[http://dx.doi.org/10.1007/978-0-387-46401-5_3]
[24]
Aziz, M.T.; El-Asmar, M.F.; Rezq, A.M.; Wassef, M.A.; Fouad, H.; Roshdy, N.K.; Ahmed, H.H.; Rashed, L.A.; Sabry, D.; Taha, F.M.; Hassouna, A. Effects of a novel curcumin derivative on insulin synthesis and secretion in streptozotocin-treated rat pancreatic islets in vitro. Chin. Med., 2014, 9(1), 3.
[http://dx.doi.org/10.1186/1749-8546-9-3] [PMID: 24422903]
[25]
Yousefi, R.; Alavian-Mehr, M-M.; Mokhtari, F.; Panahi, F.; Mehraban, M.H.; Khalafi-Nezhad, A. Pyrimidine-fused heterocycle derivatives as a novel class of inhibitors for α-glucosidase. J. Enzyme Inhib. Med. Chem., 2013, 28(6), 1228-1235.
[http://dx.doi.org/10.3109/14756366.2012.727812] [PMID: 23043430]
[26]
Wang, Y-J.; Pan, M-H.; Cheng, A-L.; Lin, L-I.; Ho, Y-S.; Hsieh, C-Y.; Lin, J-K. Stability of curcumin in buffer solutions and characterization of its degradation products. J. Pharm. Biomed. Anal., 1997, 15(12), 1867-1876.
[http://dx.doi.org/10.1016/S0731-7085(96)02024-9] [PMID: 9278892]
[27]
Aggarwal, B.B.; Surh, Y-J.; Shishodia, S. The molecular targets and therapeutic uses of curcumin in health and disease; Springer Science & Business Media, 2007, Vol. 595, .
[http://dx.doi.org/10.1007/978-0-387-46401-5_1]
[28]
Panahi, F.; Yousefi, R.; Mehraban, M.H.; Khalafi-Nezhad, A. Synthesis of new pyrimidine-fused derivatives as potent and selective antidiabetic α-glucosidase inhibitors. Carbohydr. Res., 2013, 380, 81-91.
[http://dx.doi.org/10.1016/j.carres.2013.07.008] [PMID: 23978663]
[29]
Yousefi, A.; Yousefi, R.; Panahi, F.; Sarikhani, S.; Zolghadr, A.R.; Bahaoddini, A.; Khalafi-Nezhad, A. Novel curcumin-based pyrano[2,3-d]pyrimidine anti-oxidant inhibitors for α-amylase and α-glucosidase: Implications for their pleiotropic effects against diabetes complications. Int. J. Biol. Macromol., 2015, 78, 46-55.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.03.060] [PMID: 25843662]
[30]
Dubowski, K.M. An o-toluidine method for body-fluid glucose determination. Clin. Chem., 1962, 8, 215-235.
[http://dx.doi.org/10.1093/clinchem/8.3.215] [PMID: 13888102]
[31]
Blois, M.S. Antioxidant determinations by the use of a stable free radical. Nature, 1958, 181, 1199-1200.
[http://dx.doi.org/10.1038/1811199a0]
[32]
Burits, M.; Bucar, F. Antioxidant activity of Nigella sativa essential oil. Phytother. Res., 2000, 14(5), 323-328.
[http://dx.doi.org/10.1002/1099-1573(200008)14:5<323::AIDPTR621>3.0.CO;2-Q] [PMID: 10925395]
[33]
Gülçin, I. Comparison of in vitro antioxidant and antiradical activities of L-tyrosine and L-Dopa. Amino Acids, 2007, 32(3), 431-438.
[http://dx.doi.org/10.1007/s00726-006-0379-x] [PMID: 16932840]
[34]
Ancerewicz, J.; Migliavacca, E.; Carrupt, P-A.; Testa, B.; Brée, F.; Zini, R.; Tillement, J-P.; Labidalle, S.; Guyot, D.; Chauvet-Monges, A-M.; Crevat, A.; Le Ridant, A. Structure-property relationships of trimetazidine derivatives and model compounds as potential antioxidants. Free Radic. Biol. Med., 1998, 25(1), 113-120.
[http://dx.doi.org/10.1016/S0891-5849(98)00072-0] [PMID: 9655529]
[35]
Association, A.D. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care, 2014, 37(Suppl. 1), S81-S90.
[http://dx.doi.org/10.2337/dc14-S081] [PMID: 24357215]
[36]
Cho, H.; Mu, J.; Kim, J.K.; Thorvaldsen, J.L.; Chu, Q.; Crenshaw, E.B., III; Kaestner, K.H.; Bartolomei, M.S.; Shulman, G.I.; Birnbaum, M.J. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB β). Science, 2001, 292(5522), 1728-1731.
[http://dx.doi.org/10.1126/science.292.5522.1728] [PMID: 11387480]
[37]
Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.; Matsui, K. Synthesis and alpha-D-glucosidase inhibitory activity of N-substituted valiolamine derivatives as potential oral antidiabetic agents. J. Med. Chem., 1986, 29(6), 1038-1046.
[http://dx.doi.org/10.1021/jm00156a023] [PMID: 3519969]
[38]
van de Laar, F.A. Alpha-glucosidase inhibitors in the early treatment of type 2 diabetes. Vasc. Health Risk Manag., 2008, 4(6), 1189-1195.
[http://dx.doi.org/10.2147/VHRM.S3119] [PMID: 19337532]
[39]
Tundis, R.; Loizzo, M.R.; Menichini, F. Natural products as α-amylase and α-glucosidase inhibitors and their hypoglycaemic potential in the treatment of diabetes: an update. Mini Rev. Med. Chem., 2010, 10(4), 315-331.
[http://dx.doi.org/10.2174/138955710791331007] [PMID: 20470247]
[40]
Shobana, S.; Sreerama, Y.; Malleshi, N. Composition and enzyme inhibitory properties of finger millet (Eleusine coracana L.) seed coat phenolics: Mode of inhibition of α-glucosidase and pancreatic amylase. Food Chem., 2009, 115, 1268-1273.
[http://dx.doi.org/10.1016/j.foodchem.2009.01.042]
[41]
Chuengsamarn, S.; Rattanamongkolgul, S.; Luechapudiporn, R.; Phisalaphong, C.; Jirawatnotai, S. Curcumin extract for prevention of type 2 diabetes. Diabetes Care, 2012, 35(11), 2121-2127.
[http://dx.doi.org/10.2337/dc12-0116] [PMID: 22773702]
[42]
Kim, J.S.; Kwon, C.S.; Son, K.H. Inhibition of alpha-glucosidase and amylase by luteolin, a flavonoid. Biosci. Biotechnol. Biochem., 2000, 64(11), 2458-2461.
[http://dx.doi.org/10.1271/bbb.64.2458] [PMID: 11193416]
[43]
McCue, P.P.; Shetty, K. Inhibitory effects of rosmarinic acid extracts on porcine pancreatic amylase in vitro. Asia Pac. J. Clin. Nutr., 2004, 13(1), 101-106.
[PMID: 15003922]
[44]
Machius, M.; Vértesy, L.; Huber, R.; Wiegand, G. Carbohydrate and protein-based inhibitors of porcine pancreatic α-amylase: structure analysis and comparison of their binding characteristics. J. Mol. Biol., 1996, 260(3), 409-421.
[http://dx.doi.org/10.1006/jmbi.1996.0410] [PMID: 8757803]
[45]
Okuyama, M.; Saburi, W.; Mori, H.; Kimura, A. α-Glucosidases and α-1,4-glucan lyases: structures, functions, and physiological actions. Cell. Mol. Life Sci., 2016, 73(14), 2727-2751.
[http://dx.doi.org/10.1007/s00018-016-2247-5] [PMID: 27137181]
[46]
Jhong, C.H.; Riyaphan, J.; Lin, S.H.; Chia, Y.C.; Weng, C.F. Screening alpha-glucosidase and alpha-amylase inhibitors from natural compounds by molecular docking in silico. Biofactors, 2015, 41(4), 242-251.
[http://dx.doi.org/10.1002/biof.1219] [PMID: 26154585]
[47]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[48]
Mollica, A.; Zengin, G.; Locatelli, M.; Stefanucci, A.; Mocan, A.; Macedonio, G.; Carradori, S.; Onaolapo, O.; Onaolapo, A.; Adegoke, J. Anti-diabetic and anti-hyperlipidemic properties of Capparis spinosa L.: In vivo and in vitro evaluation of its nutraceutical potential. J. Funct. Foods, 2017, 35, 32-42.
[http://dx.doi.org/10.1016/j.jff.2017.05.001]
[49]
Rasouli, H.; Hosseini-Ghazvini, S.M-B.; Adibi, H.; Khodarahmi, R. Differential α-amylase/α-glucosidase inhibitory activities of plant-derived phenolic compounds: a virtual screening perspective for the treatment of obesity and diabetes. Food Funct., 2017, 8(5), 1942-1954.
[http://dx.doi.org/10.1039/C7FO00220C] [PMID: 28470323]
[50]
Rasouli, H.; Parvaneh, S.; Mahnam, A.; Rastegari-Pouyani, M.; Hoseinkhani, Z.; Mansouri, K. Anti-angiogenic potential of trypsin inhibitor purified from Cucumis melo seeds: Homology modeling and molecular docking perspective. Int. J. Biol. Macromol., 2017, 96, 118-128.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.12.027] [PMID: 27965128]
[51]
Rasouli, H.; Mehrabi, M.; Arab, S.S.; Khodarahmi, R. Are Pro8/Pro18 really critical for functional dynamic behavior of human endostatin N-terminal peptide? A comparative molecular dynamics study. J. Iranian Chem. Soc., 2017, 14, 1-17.
[52]
Zhang, D.W.; Fu, M.; Gao, S-H.; Liu, J-L. Curcumin and diabetes: a systematic review. Evid. Based Complement. Alternat. Med., 2013, 2013, 636053.
[http://dx.doi.org/10.1155/2013/636053] [PMID: 24348712]
[53]
Ponnusamy, S.; Zinjarde, S.; Bhargava, S.; Rajamohanan, P.R.; Ravikumar, A. Discovering Bisdemethoxycurcumin from Curcuma longa rhizome as a potent small molecule inhibitor of human pancreatic α-amylase, a target for type-2 diabetes. Food Chem., 2012, 135(4), 2638-2642.
[http://dx.doi.org/10.1016/j.foodchem.2012.06.110] [PMID: 22980852]
[54]
Van de Laar, F.A.; Lucassen, P.L.; Akkermans, R.P.; Van de Lisdonk, E.H.; Rutten, G.E.; Van Weel, C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst. Rev., 2005, (2), CD003639.
[http://dx.doi.org/10.1002/14651858.CD003639.pub2] [PMID: 15846673]
[55]
Carella, A.; Roviello, V.; Iannitti, R.; Palumbo, R.; La Manna, S.; Marasco, D.; Trifuoggi, M.; Diana, R.; Roviello, G.N. Evaluating the biological properties of synthetic 4-nitrophenyl functionalized benzofuran derivatives with telomeric DNA binding and antiproliferative activities. Int. J. Biol. Macromol., 2019, 121, 77-88.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.09.153] [PMID: 30261256]
[56]
Vicidomini, C.; Cioffi, F.; Broersen, K.; Roviello, V.; Riccardi, C.; Montesarchio, D.; Capasso, D.; Di Gaetano, S.; Musumeci, D.; Roviello, G.N. Benzodifurans for biomedical applications: BZ4, a selective anti-proliferative and anti-amyloid lead compound. Future Med. Chem., 2019, 11, 285-302.
[http://dx.doi.org/10.4155/fmc-2018-0473] [PMID: 30801198]