N-(Β-D-Glucopyranosyl)-Azolecarboxamides as Glycogen Phosphorylase Inhibitors: Computational Prediction, Synthesis and Enzymatic Evaluation

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N-(Β-D-Glucopyranosyl)-Azolecarboxamides as Glycogen Phosphorylase Inhibitors: Computational Prediction, Synthesis and Enzymatic Evaluation

Levente Homolya 1 , Rachel Mathomes 2 , Ádám Sipos 3 , Tibor Docsa 3 , László Juhász 1 , Joseph M. Hayes 2 , László Somsák 1

1 Department of Organic Chemistry, University of Debrecen, Debrecen, Hungary, 2 School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston, United Kingdom, 3 Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

Type II diabetes mellitus characterized by hyperglycemia and peripheral insulin resistance is one of the major concerns of our society [1]. Since the disease is not curable, without the control of blood glucose levels serious complications may appear, therefore, the most important task in the treatment of diabetes mellitus is to normalize blood glucose levels. Glycogen phosphorylase (GP) is the rate determining enzyme of glycogen metabolism, therefore its inhibitors are potential antidiabetic agents.

Several compounds, with potential GP inhibitor activity were synthesized earlier, such as N-(β-D-glucopyranosyl)-aryl-oxadiazolecarboxamides (aryl: phenyl, 1-naphthyl, 2-naphthyl) and N-(β-D-glucopyranosyl)-5-aryl-1,2,4-triazole-3-carboxamides (aryl: phenyl, 2-naphthyl) [2, 3]. In continuation of this research, based on the computational prediction of GP inhibitor activities of new molecules, the synthesis of N-(β-D-glucopyranosyl)-5-(1-naphthyl)-1,2,4-triazole-3-carboxamide (2c), N-(β-D-glucopyranosyl)-2-arylimidazole-4(5)-carboxamide (3a-c) and N-(β-D-glucopyranosyl)-4(5)-arylimidazole-2-carboxamide (4a-c) (aryl: phenyl, 1-naphthyl, 2-naphthyl) were planned and performed. Details of the syntheses and enzyme kinetic results will be presented on the poster.

Figure 1.: Structure of N-(β-D-glucopyranosyl)-azolecarboxamides

Karuranga, S.; Fernandes, J. R.; Huang, Y.; Malanda, B.; IDF Diabetes Atlas – 8th edition, International Diabetes Federation, 2017.

Polyák, M.; Varga, G.; Szilágyi, B.; Juhász, L.; Docsa, T.; Gergely, P.; Begum, J.; Hayes, J. M.; Somsák, L.; Bioorganic & Medicinal Chemistry, 2013, 21, 5738.

Begum, J.; Varga, G.; Docsa, T.; Gergely, P.; Hayes, J. M.; Juhász, L.; Somsák.L.; MedChemComm, 2015, 6, 80.

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