| Autor: |
Homolya L; Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary., Mathomes RT; School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK., Varga L; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary., Docsa T; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary., Juhász L; Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary., Hayes JM; School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK., Somsák L; Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary. |
| Abstrakt: |
Recently studied N -(β-d-glucopyranosyl)-3-aryl-1,2,4-triazole-5-carboxamides have proven to be low micromolar inhibitors of glycogen phosphorylase (GP), a validated target for the treatment of type 2 diabetes mellitus . Since in other settings, the bioisosteric replacement of the 1,2,4-triazole moiety with imidazole resulted in significantly more efficient GP inhibitors, in silico calculations using Glide molecular docking along with unbound state DFT calculations were performed on N -(β-d-glucopyranosyl)-arylimidazole-carboxamides, revealing their potential for strong GP inhibition. The syntheses of the target compounds involved the formation of an amide bond between per- O -acetylated β-d-glucopyranosylamine and the corresponding arylimidazole-carboxylic acids. Kinetics experiments on rabbit muscle GP b revealed low micromolar inhibitors, with the best inhibition constants ( K i s) of ~3-4 µM obtained for 1- and 2-naphthyl-substituted N -(β-d-glucopyranosyl)-imidazolecarboxamides, 2b - c . The predicted protein-ligand interactions responsible for the observed potencies are discussed and will facilitate the structure-based design of other inhibitors targeting this important therapeutic target. Meanwhile, the importance of the careful consideration of ligand tautomeric states in binding calculations is highlighted, with the usefulness of DFT calculations in this regard proposed. |
