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Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Pyrano[3,2-c]quinoline Derivatives as New Class of α-glucosidase Inhibitors to Treat Type 2 Diabetes: Synthesis, in vitro Biological Evaluation and Kinetic Study

Author(s): Zahra Heydari, Maryam Mohammadi-Khanaposhtani, Somaye Imanparast, Mohammad A. Faramarzi, Mohammad Mahdavi *, Parviz R. Ranjbar* and Bagher Larijani

Volume 15, Issue 1, 2019

Page: [8 - 16] Pages: 9

DOI: 10.2174/1573406414666180528110104

Price: $65

Abstract

Background: Pyrano[3,2-c]quinoline derivatives 6a–n were synthesized via simple two-step reactions and evaluated for their in vitro α-glucosidase inhibitory activity.

Methods: Pyrano[3,2-c]quinoline derivatives 6a–n derivatives were prepared from a two-step reaction: cycloaddition reaction between 1-naphthyl amine 1 and malonic acid 2 to obtain benzo[h]quinoline-2(1H)-one 3 and reaction of 3 with aryl aldehydes 4 and Meldrum’s acid 5. The anti- α-glucosidase activity and kinetic study of the synthesized compounds were evaluated using α-glucosidase from Saccharomyces cerevisiae and p-nitrophenyl-a-D-glucopyranoside as substrate. The α-glucosidase inhibitory activity of acarbose was evaluated as positive control.

Results: All of the synthesized compounds, except compounds 6i and 6n, showed more inhibitory activity than the standard drug acarbose and were also found to be non-cytotoxic. Among the synthesized compounds, 1-(2-bromophenyl)-1H-benzo[h]pyrano[3,2-c]quinoline-3,12(2H,11H)-dione 6e displayed the highest α-glucosidase inhibitory activity (IC50 = 63.7 ± 0.5 µM). Kinetic study of enzyme inhibition indicated that the most potent compound, 6e, is a non-competitive inhibitor of α-glucosidase with a Ki value of 72 µM. Additionally, based on the Lipinski rule of 5, the synthesized compounds were found to be potential orally active drugs.

Conclusion: Our results suggest that the synthesized compounds are promising candidates for treating type 2 diabetes.

Keywords: α-Glucosidase, type 2 diabetes, kinetic study, pyrano[3, 2-c]quinoline, coumarin, xanthones.

Graphical Abstract
[1]
Vijan, S. Type 2 diabetes. Ann. Intern. Med., 2010, 152, ITC3-ITC1.
[2]
Ciechanowski, P.S.; Katon, W.J.; Russo, J.E.; Hirsch, I.B. The relationship of depressive symptoms to symptom reporting, self-care and glucose control in diabetes. Gen. Hosp. Psychiatry, 2003, 25, 246-252.
[3]
Look AHEAD Research Group. Long term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes: four year results of the Look AHEAD trial. Arch. Intern. Med., 2010, 170, 1566.
[4]
Rabasa-Lhoret, R.; Chiasson, J.L. a-Glucosidase Inhibitors. International textbook of diabetes mellitus. 2004.
[5]
Humphries, M.J.; Matsumoto, K.; White, S.L.; Olden, K. Inhibition of experimental metastasis by castanospermine in mice: blockage of two distinct stages of tumor colonization by oligosaccharide processing inhibitors. Cancer Res., 1986, 46, 5215-5222.
[6]
Park, H.; Hwang, K.Y.; Oh, K.H.; Kim, Y.H.; Lee, J.Y.; Kim, K. Discovery of novel α-glucosidase inhibitors based on the virtual screening with the homology-modeled protein structure. Bioorg. Med. Chem., 2008, 16, 284-292.
[7]
Storr, S.J.; Royle, L.; Chapman, C.J.; Hamid, U.M.A.; Robertson, J.F.; Murray, A.; Dwek, R.A.; Rudd, P.M. The O-linked glycosylation of secretory/shed MUC1 from an advanced breast cancer patient’s serum. Glycobiology, 2008, 18, 456-462.
[8]
Kostova, I.; Bhatia, S.; Grigorov, P.; Balkansky, S.; Parmar, V.S.; Prasad, A.K.; Saso, L. Coumarins as antioxidants. Curr. Med. Chem., 2011, 18, 3929-3951.
[9]
Kontogiorgis, C.A.; Hadjipavlou-Litina, D.J. Synthesis and antiinflammatory activity of coumarin derivatives. J. Med. Chem., 2005, 48, 6400-6408.
[10]
Cravotto, G.; Nano, G.M.; Palmisano, G.; Tagliapietra, S. An asymmetric approach to coumarin anticoagulants via hetero-Diels–Alder cycloaddition. Tetrahedron Asymmetry, 2001, 12, 707-709.
[11]
Shi, Y.; Zhou, C.H. Synthesis and evaluation of a class of new coumarin triazole derivatives as potential antimicrobial agents. Bioorg. Med. Chem. Lett., 2011, 21, 956-960.
[12]
Belluti, F.; Fontana, G.; Dal Bo, L.; Carenini, N.; Giommarelli, C.; Zunino, F. Design, synthesis and anticancer activities of stilbene-coumarin hybrid compounds: Identification of novel proapoptotic agents. Bioorg. Med. Chem., 2010, 18, 3543-3550.
[13]
Yu, D.; Suzuki, M.; Xie, L.; Morris-Natschke, S.L.; Lee, K.H. Recent progress in the development of coumarin derivatives as potent an-ti‐HIV agents. Med. Res. Rev., 2003, 23, 322-345.
[14]
Sashidhara, K.V.; Kumar, M.; Modukuri, R.K.; Srivastava, A.; Puri, A. Discovery and synthesis of novel substituted benzocoumarins as orally active lipid modulating agents. Bioorg. Med. Chem. Lett., 2011, 21, 6709-6713.
[15]
Razavi, S.F.; Khoobi, M.; Nadri, H.; Sakhteman, A.; Moradi, A.; Emami, S.; Foroumadi, A.; Shafiee, A. Synthesis and evaluation of 4-substituted coumarins as novel acetylcholinesterase inhibitors. Eur. J. Med. Chem., 2013, 64, 252-259.
[16]
Kostova, I. Synthetic and natural coumarins as cytotoxic agents. Curr. Med. Chem. Anticancer Agents, 2005, 5, 29-46.
[17]
Smyth, T.; Ramachandran, V.N.; Smyth, W.F. A study of the antimicrobial activity of selected naturally occurring and synthetic couma-rins. Int. J. Antimicrob. Agents, 2009, 33, 421-426.
[18]
Lee, S.O.; Choi, S.Z.; Lee, J.H.; Chung, S.H.; Park, S.H.; Kang, H.C.; Yang, E.Y.; Cho, H.J.; Lee, K.R. Antidiabetic coumarin and cyclitol compounds from Peucedanum japonicum. Arch. Pharm. Res., 2004, 27, 1207-1210.
[19]
Aminudin, N.I.; Ahmad, F.; Taher, M.; Zulkifli, R.M. Incrassamarin A–D: Four new 4-substituted coumarins from Calophyllum incrassa-tum and their biological activities. Phytochem. Lett., 2016, 16, 287-293.
[20]
Pinto, M.M.M.; Sousa, M.E.; Nascimento, M.S.J. Xanthone derivatives: new insights in biological activities. Curr. Med. Chem., 2005, 12, 2517-2538.
[21]
Khan, M.T.H.; Orhan, I.; Şenol, F.S.; Kartal, M.; Şener, B.; Dvorská, M.; Šmejkal, K.; Šlapetová, T. Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies. Chem. Biol. Interact., 2009, 181, 383-389.
[22]
Akao, Y.; Nakagawa, Y.; Nozawa, Y. Anti-cancer effects of xanthones from pericarps of mangosteen. Int. J. Mol. Sci., 2008, 9, 355-370.
[23]
Jung, H.A.; Su, B.N.; Keller, W.J.; Mehta, R.G.; Kinghorn, A.D. Antioxidant xanthones from the pericarp of Garcinia mangostana (Mango-steen). J. Agric. Food Chem., 2006, 54, 2077-2082.
[24]
Liu, Y.; Ma, L.; Chen, W-H.; Wang, B.; Xu, Z-L. Synthesis of xanthone derivatives with extended π-systems as α-glucosidase inhibitors: Insight into the probable binding mode. Bioorg. Med. Chem., 2007, 15, 2810-2814.
[25]
Liu, Y.; Ke, Z.; Cui, J.; Chen, W.H.; Ma, L.; Wang, B. Synthesis, inhibitory activities, and QSAR study of xanthone derivatives as α-glucosidase inhibitors. Bioorg. Med. Chem., 2008, 16, 7185-7192.
[26]
Mohammadi-Khanaposhtani, M.; Saeedi, M.; Zafarghandi, N.S.; Mahdavi, M.; Sabourian, R.; Razkenari, E.K.; Alinezhad, H.; Khanavi, M.; Foroumadi, A.; Shafiee, A.; Akbarzadeh, T. Potent acetylcholinesterase inhibitors: design, synthesis, biological evaluation, and docking study of acridone linked to 1, 2, 3-triazole derivatives. Eur. J. Med. Chem., 2015, 92, 799-806.
[27]
Mohammadi-Khanaposhtani, M.; Mahdavi, M.; Saeedi, M.; Sabourian, R.; Safavi, M.; Khanavi, M.; Foroumadi, A.; Shafiee, A.; Akbarza-deh, T. Design, Synthesis, Biological Evaluation, and Docking Study of Acetylcholinesterase Inhibitors: New Acridone-1, 2, 4-oxadiazole-1, 2, 3-triazole Hybrids. Chem. Biol. Drug Des., 2015, 86, 1425-1432.
[28]
Mohammadi-Khanaposhtani, M.; Shabani, M.; Faizi, M.; Aghaei, I.; Jahani, R.; Sharafi, Z.; Zafarghandi, N.S.; Mahdavi, M.; Akbarzadeh, T.; Emami, S.; Shafiee, A. Design, synthesis, pharmacological evaluation, and docking study of new acridone-based 1, 2, 4-oxadiazoles as potential anticonvulsant agents. Eur. J. Med. Chem., 2016, 112, 91-98.
[29]
Arab, S.; Sadat-Ebrahimi, S.E.; Mohammadi-Khanaposhtani, M.; Moradi, A.; Nadri, H.; Mahdavi, M.; Moghimi, S.; Asadi, M.; Firoozpour, L.; Pirali-Hamedani, M.; Shafiee, A. Synthesis and evaluation of chroman-4-one linked to N-benzyl pyridinium derivatives as new acetylcholinesterase inhibitors. Arch. Pharm., 2015, 348, 643-649.
[30]
Akbarzadeh, T. Noushini. S, Taban, S.; Mahdavi, M.; Khoshneviszadeh, M.; Saeedi, M.; Emami, S.; Eghtedari, M.; Sarrafi, Y.; Khoshne-viszadeh, M.; Safavi, M. Synthesis and cytotoxic activity of novel poly-substituted imidazo [2, 1-c][1, 2, 4] triazin-6-amines. Mol. Divers., 2015, 19, 273-281.
[31]
Nikookar, H.; Mohammadi-Khanaposhtani, M.; Imanparast, S.; Faramarzi, M.A.; Ranjbar, P.R.; Mahdavi, M.; Larijani, B. Design, synthe-sis and in vitro α-glucosidase inhibition of novel dihydropyrano [3, 2-c] quinoline derivatives as potential anti-diabetic agents. Bioorg. Chem., 2018, 77, 280-286.
[32]
ChemOffice, CambridgeSoftCorporation, Cambridge, USA, 2009.
[33]
Mohammadi-Khanaposhtani, M.; Safavi, M.; Sabourian, R.; Mahdavi, M.; Pordeli, M.; Saeedi, M.; Ardestani, S.K.; Foroumadi, A.; Shafi-ee, A.; Akbarzadeh, T. Design, synthesis, in vitro cytotoxic activity evaluation, and apoptosis-induction study of new 9 (10H)-acridinone-1, 2, 3-triazoles. Mol. Divers., 2015, 19, 787-795.
[34]
Yavari, I.; Sabbaghan, M.; Hossaini, Z. Proline-promoted efficient synthesis of 4-aryl-3, 4-dihydro-2H, 5H-pyrano [3, 2-c] chromene-2, 5-diones in aqueous media. Synlett, 2008, 8, 1153-1154.
[35]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permea-bility in drug discovery and development settings. Adv. Drug Deliv. Rev., 1997, 23, 3-25.
[36]
Lipinski, C.A. Drug-like properties and the causes of poor solubility and poor Permeability. J. Pharmacol. Toxicol. Methods, 2000, 44, 235-249.

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