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Medicinal Chemistry

Author(s): Sahar M. Abou-Seri, AlShaimaa M. Taha, Mona A. Mohamed* and Nour M. Abdelkader

DOI: 10.2174/1573406415666181208104543

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New Quinazoline-Sulfonylurea Conjugates: Design, Synthesis and Hypoglycemic Activity

Page: [634 - 647] Pages: 14

  • * (Excluding Mailing and Handling)

Abstract

Background: Sulphonylureas are the oldest and commonly used to treat diabetic patients, but its efficacy declines by time. It was reported that quinazoline nucleus exhibits a potent hypoglycemic effect in diabetic animal models.

Objective: The current study aimed to synthesize new quinazoline-sulfonylurea conjugates and evaluate their hypoglycemic effects in alloxan-induced diabetic rats.

Methods: The conjugates were synthesized by bioisosteric replacement of 5-chloro-2-methoxybenzamide moiety in glibenclamide or 1,3-dioxo-3,4-dihydroisoquinoline moiety in gliquidone with 6,7-dimethoxy-4-oxoquinazoline moiety (compounds 4a-4d, 9b-9c and 10b-10d). Diabetes was induced in rats by a single i.p. administration of alloxan, followed by treatment with the synthesized conjugates (5mg/kg Body weight).

Results: All conjugates showed hypoglycemic effects with different efficacy indicated by the reduction in blood glucose and elevation of insulin levels. Moreover, these conjugates up-regulated the expression of pancreatic glucose transporter 2, muscle glucose transporter 4, and insulin receptor substrate-1 genes, compared to the diabetic group. A normal pancreatic tissue pattern was noticed in diabetic rats treated with compounds 9b, 9c, and 10c.

Conclusion: Conjugation of sulfonylurea with quinazoline (especially 9b, 9c, 10c) possessed a significant hypoglycemic effect through improving blood insulin level and insulin action and consequently increased the glucose uptake by the skeletal muscles.

Keywords: Sulfonylurea, quinazoline, bioisoster, hypoglycemic, heterocyclic compounds, insulin receptor substrate-1.

Graphical Abstract

[1]
Lin, Y.; Sun, Z. Current views on type 2 diabetes. J. Endocrinol., 2010, 204, 1-11.
[2]
Cefalu, W.T. Pharmacotherapy for the treatment of patients with type 2 diabetes mellitus: Rationale and specific agents. Clin. Pharmacol. Ther., 2007, 81, 636-649.
[3]
Chaudhury, A.; Duvoor, C.; Dendi, V.S.; Kraleti, S.; Chada, A.; Ravilla, R.; Marco, A.; Shekhawat, N.S.; Montales, M.T.; Kuriakose, K.; Sasapu, A.; Beebe, A.; Patil, N.; Musham, C.K.; Lohani, G.P.; Mirza, W. Clinical review of antidiabetic drugs: Implications for type 2 diabetes mellitus management. Front. Endocrinol., 2017, 8, 6.
[4]
Reis, A.F.; Velho, G. Sulfonylurea receptor -1 (SUR1): Genetic and metabolic evidences for a role in the susceptibility to type 2 diabetes mellitus. Diabetes Metab., 2002, 28, 14-19.
[5]
May, M.; Schindler, C. Clinically and pharmacologically relevant interactions of antidiabetic drugs. Ther. Adv. Endocrinol. Metab., 2016, 7, 69-83.
[6]
Vijayakumar, B.; Prasanthi, P.; Teja, K.M.; Reddy, M.K.; Nishanthi, P.; Nagendramma, M.; Nishanthi, M. Quinazoline derivatives and pharmacological activities: A review. Inter. J. Med. Chem. Anal., 2013, 3, 10-21.
[7]
Guan, J.; Zhang, Q.; Neil, O.M.; Obaldia, N.; Ager, A.; Lin, J.A. Antimalarial activities of new pyrrolo[3,2-f] quinazoline-1,3-diamine derivatives. Antimicrob. Agents Chemother., 2005, 49, 4928-4933.
[8]
Refaie, F.M.; Esmat, A.Y.; Abdel Gawad, S.M.; Ibrahim, A.M.; Mohamed, M.A. The antihyperlipidemic activities of 4(3H) quinazol-inone and two halogenated derivatives in rats. Lipids Health Dis., 2005, 4, 22.
[9]
Zhang, N.; Wu, B.; Powell, D.; Wissner, A.; Floyd, M.B.; Kovacs, E.D.; Toral-Barza, L.; Kohler, C. Synthesis and structure-activity relationships of 3-cyano -4-(phenoxyanilino) quinolines as MEK (MAPKK) inhibitors. Bioorg. Med. Chem. Lett., 2000, 10, 2825-2828.
[10]
Allendörfer, N.; Es-Sayed, M.; Nieger, M.; Braese, S. Nucleophilic ring-opening reaction of benzoxazinones-access to o-amino-2,2,2-trifluoroacetophenones. Tetrahedron Lett., 2012, 53, 388-391.
[11]
Mosley, C.A.; Acker, T.M.; Hansen, K.B.; Mullasseril, P.; Andersen, K.T.; Le, P.; Vellano, K.M.; Braeuner-Osborne, H.; Liotta, D.C.; Traynelis, S.F. Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-d-aspartate receptor antagonists. J. Med. Chem., 2010, 53, 5476-5490.
[12]
Sheweita, S.A.; Newairy, A.A.; Mansour, H.A.; Youssif, M.I. Effect of some hypoglycemic herbs on the activity of phase I and II drug-metabolizing enzymes in alloxan- induced diabetic rats. Toxicol., 2002, 174, 131-139.
[13]
Banchroft, J.D.; Stevens, A.; Turner, D.R. Theory and practice of histological techniques, 4th ed; Churchil Livingstone: New York, 1996.
[14]
Dhahir, F.J.; Cook, D.B.; Self, C.H. Amplified enzyme-linked immunoassay of human proinsulin in serum. Clin. Chem., 1992, 38, 227-232.
[15]
Yoshioka, T.; Kawada, K.; Shimada, T.; Mori, M. Lipid peroxidation in maternal cord blood and protective mechanism against activated oxygen toxicity in blood. Am. J. Obstet. Gynecol., 1979, 135, 372-376.
[16]
Koracevic, D.I.; Koracevic, G.; Djordjevic, V.; Andrejevic, S.; Cosic, V. Method for measurement of antioxidant activity in human fluids. J. Clin. Chem. Path., 2001, 54, 356-361.
[17]
Beutler, E.; Duron, O.; Kelly, M.B. Improved method for the determination of blood glutathione. J. Lab. Clin. Med., 1963, 61, 882-888.
[18]
DuBois, M.; Gilles, K.; Hamilton, J.; Rebers, P.; Smith, F. Colorimetric method for determination of sugars and related substances. Anal. Chem., 1956, 28, 350-356.
[19]
Allain, C.C.; Poon, L.S.; Chan, C.S.; Richmond, W. FU, P.C. Enzymatic determination of total serum cholesterol. Clin. Chem., 1974, 20, 470-475.
[20]
MGowan M.W.; Artiss, J.D.; Standbergh, D.R.; Zak, B. A peroxidase-coupled method for colorimetric determination of serum triglycerides. Clin. Chem., 1983, 29, 538-452.
[21]
Nagy, M.A.; Mohamed, S.A. Momordica charantia (cucurbitaceae) methanolic extract alleviates alloxan-induced oxidative stress and β-cell damage in rat pancreas. A.A.M.J., 2012, 10, 173-196.
[22]
Shah, N.A.; Khan, M.R. Antidiabetic effect of Sida cordata in Alloxan induced diabetic rats. BioMed Res. Int., 2014, 2014, 15.
[23]
Al-Qudah, M.M.; Haddad, M.A. EL-Qudah, J.M. The effects of aqueous ginger extract on pancreas histology and on blood glucose in normal and alloxan monohydrate-induced diabetic rats. Biomed. Res., 2016, 27, 350-356.
[24]
Gai, W.; Schott-Ohly, P. Schulte im Walde, S.; Gleichmann, H. Differential target molecules for toxicity induced by streptozotocin and alloxan in pancreatic islets of mice in vitro. Exp. Clin. Endocrinol. Diabetes, 2004, 112, 29-37.
[25]
Guillam, M.T.; Hümmler, E.; Schaerer, E.; Yeh, J.I.; Birnbaum, M.J.; Beermann, F.; Schmidt, A.; Dériaz, N.; Thorens, B.; Wu, J.Y. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat. Genet., 1997, 17, 327-330.
[26]
Efrat, S. Making sense of glucose sensing. Nat. Genet., 1997, 17, 249-250.
[27]
Elsner, M.; Tiedge, M.; Guldbakke, B.; Munday, R.; Lenzen, S. Importance of the GLUT2 glucose transporter for pancreatic beta cell toxicity of alloxan. Diabetologia, 2002, 45, 1542-1549.
[28]
Szkudelski, T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol. Res., 2001, 50, 537-546.
[29]
Lenzen, S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia, 2008, 51, 216-226.
[30]
Winterbourn, C.C.; Munday, R. Glutathione-mediated redox cycling of alloxan. Mechanisms of superoxide dismutase inhibition and of metal-catalyzed OH formation. Biochem. Pharmacol., 1989, 38, 271-277.
[31]
Yang, H.; Jin, X.; Lam, C.W.; Yan, S.K. Oxidative stress and diabetes mellitus. Clin. Chem. Lab. Med., 2011, 49, 1773-1782.
[32]
Hosseini, A.; Shafiee-Nick, R.; Ghorbani, A. Pancreatic beta cell protection/regeneration with phytotherapy. Braz. J. Pharm. Sci., 2015, 51(1), 1-16.
[33]
Pushparaj, P.N.; Low, H.K.; Manikandan, J.; Tan, P.K.; Tan, C.H. Anti-diabetic effects of Cichorium intybus in streptozotocin-induced diabetic rats. J. Ethnopharmacol., 2007, 111, 430-434.
[34]
Murali, B.; Upadhyaya, U.M.; Goyal, R.K. Effect of chronic treatment with Enicostemma littorale in non-insulin dependent diabetic (NIDDM) rats. J. Ethnopharmacol., 2002, 81, 199-204.
[35]
Frayn, K.N. The glucose-fatty acid cycle: A physiological perspective. Biochem. Soc. Trans., 2003, 31, 1115-1119.
[36]
Yili, G.; Hong, P.; Xiqun, S.; Gongchen, Z.; Jun, Z.; Miao, W.; Xiaoping, Z.; Kaixun, H. Effects of alloxan-induced diabetes on the expression of insulin signal transmission molecules. Wuhan University. J. Nat. Sci., 2009, 14, 447-451.
[37]
Mohammad, S.; Taha, A.; Akhtar, K.; Bamezai, R.N. In vivo effect of Trigonella foenum graecum on the expression of pyruvate kinase, phosphoenolpyruvate carboxykinase, and distribution of glucose transporter (GLUT4) in alloxan-diabetic rats. Can. J. Physiol. Pharmacol., 2006, 84, 647-654.
[38]
Michel, A. Tests of liver use and misuse. Gastroenterol., 1998, 6, 34-39.