Dataset Information

C-Glucopyranosyl-1,2,4-triazoles As New Potent Inhibitors of Glycogen Phosphorylase.

ABSTRACT: Glycogen phosphorylase inhibitors are considered as potential antidiabetic agents. 3-(?-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles were prepared by acylation of O-perbenzoylated N (1)-tosyl-C-?-d-glucopyranosyl formamidrazone and subsequent removal of the protecting groups. The best inhibitor was 3-(?-d-glucopyranosyl)-5-(2-naphthyl)-1,2,4-triazole (K i = 0.41 ?M against rabbit muscle glycogen phosphorylase b).

SUBMITTER: Bokor E

PROVIDER: S-EPMC4027562 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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C-Glucopyranosyl-1,2,4-triazoles As New Potent Inhibitors of Glycogen Phosphorylase.

Bokor Eva E Docsa Tibor T Gergely Pál P Somsák László L

ACS medicinal chemistry letters 20130517 7

Glycogen phosphorylase inhibitors are considered as potential antidiabetic agents. 3-(β-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles were prepared by acylation of O-perbenzoylated N (1)-tosyl-C-β-d-glucopyranosyl formamidrazone and subsequent removal of the protecting groups. The best inhibitor was 3-(β-d-glucopyranosyl)-5-(2-naphthyl)-1,2,4-triazole (K i = 0.41 μM against rabbit muscle glycogen phosphorylase b). ...[more]

PMID: 24900719

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Project description:IntroductionHeterocyclic compounds have diverse biological activities and potential in drug development. This study aims to synthesize novel compounds with two 1,2,4-triazole cores and evaluate their biological properties, particularly their inhibitory activity against thymidine phosphorylase (TP), an enzyme involved in various physiological processes.MethodsThe compounds were synthesized by reacting 5,5'-butane-bis-1,2,4-triazole derivatives with prenyl bromide. Characterization involved various techniques, including spectroscopy and elemental analysis. Antimicrobial potential was evaluated against bacteria and fungi, with comparative antibiotics as references. Inhibitory activity against TP was assessed, and molecular docking studies were conducted.ResultsSix compounds were successfully synthesized and their structures confirmed. The synthesized triazole derivatives exhibited high biological activity, with compounds 2 and 6 showing the most promising TP inhibition. Molecular docking studies revealed interactions between compound 2 and TP, involving nine amino acids.DiscussionThe synthesis of novel compounds with two 1,2,4-triazole cores contributes significantly to bis-triazole research. These compounds have potential as anti-tumor agents due to their inhibitory activity against TP, a crucial enzyme in tumor growth and metastasis. Comparative evaluation against antibiotics highlights their potency. Docking results provide insights into their interactions with TP, supporting their potential as potent TP inhibitors. Further research should focus on evaluating their efficacy in biological models, understanding their mechanisms of action, and optimizing their activities.ConclusionThe synthesized compounds with two 1,2,4-triazole cores exhibit significant biological activity, including strong TP inhibition and broad-spectrum antimicrobial effects. These findings emphasize their potential as anti-tumor agents and the need for further exploration and optimization. Future research should focus on evaluating their efficacy in biological models, understanding their mechanisms of action, and developing more potent bis-triazole derivatives for drug discovery efforts. The combined results from assays and docking studies support the therapeutic potential of these compounds as anti-tumor agents.

Project description:Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes. β-d-Glucopyranosyl derivatives have provided some of the most potent GP inhibitors discovered to date. In this regard, C-β-d-glucopyranosyl azole type inhibitors proved to be particularly effective, with 2- and 4-β-d-glucopyranosyl imidazoles among the most potent designed to date. His377 backbone C=O hydrogen bonding and ion-ion interactions of the protonated imidazole with Asp283 from the 280s loop, stabilizing the inactive state, were proposed as crucial to the observed potencies. Towards further exploring these features, 4-amino-3-(β-d-glucopyranosyl)-5-phenyl-1H-pyrazole (3) and 3-(β-d-glucopyranosyl)-4-guanidino-5-phenyl-1H-pyrazole (4) were designed and synthesized with the potential to exploit similar interactions. Binding assay experiments against rabbit muscle GPb revealed 3 as a moderate inhibitor (IC50 = 565 µM), but 4 displayed no inhibition at 625 µM concentration. Towards understanding the observed inhibitions, docking and post-docking molecular mechanics-generalized Born surface area (MM-GBSA) binding free energy calculations were performed, together with Monte Carlo and density functional theory (DFT) calculations on the free unbound ligands. The computations revealed that while 3 was predicted to hydrogen bond with His377 C=O in its favoured tautomeric state, the interactions with Asp283 were not direct and there were no ion-ion interactions; for 4, the most stable tautomer did not have the His377 backbone C=O interaction and while ion-ion interactions and direct hydrogen bonding with Asp283 were predicted, the conformational strain and entropy loss of the ligand in the bound state was significant. The importance of consideration of tautomeric states and ligand strain for glucose analogues in the confined space of the catalytic site with the 280s loop in the closed position was highlighted.

Dataset Information

C-Glucopyranosyl-1,2,4-triazoles As New Potent Inhibitors of Glycogen Phosphorylase.

Publications

C-Glucopyranosyl-1,2,4-triazoles As New Potent Inhibitors of Glycogen Phosphorylase.

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