Synthesis, enzyme kinetics and computational evaluation of N-(β-d-glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors

Polyak, M. S.; Varga, Gergely; Szilágyi, Bence; Juhász, László; Docsa, Tibor; Gergely, Pál; Begum, J.P. Shabaaz; Hayes, Joseph M.; Somsák, László

doi:10.1016/j.bmc.2013.07.024

Cited by 18 publications

(13 citation statements)

References 53 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The other compounds (9b, 9e, 12b, 13b, 13c Potential permeability issues for glucose analogues have been highlighted in the past. 15,23,46,47 Here, log P in particular was identified as an important benchmark, but with exceptions such Veber's Rules & Violations (V) [b] M r [Da] HBD [c] HBA [d] log as for 12b. The log P range of the ten compounds tested was -0.67 -1.21 which is outside the proposed log P (~2-4) sweet spot range in medicinal chemistry, 48 and is proposed as a target range in future inhibitor design efforts.…”

Section: Cellular and Pharmacokinetic Evaluationmentioning

confidence: 99%

Identification of C-β-d-Glucopyranosyl Azole-Type Inhibitors of Glycogen Phosphorylase That Reduce Glycogenolysis in Hepatocytes: In Silico Design, Synthesis, in Vitro Kinetics, and ex Vivo Studies

et al. 2019

Self Cite

View full text Add to dashboard Cite

Several C-β-D-glucopyranosyl azoles have recently been unravelled among the most potent glycogen phosphorylase (GP) catalytic site inhibitors discovered to date. Towards further exploring their translational potential, ex-vivo experiments have been performed for their effectiveness in reduction of glycogenolysis in hepatocytes. New compounds for these experiments were predicted in silico where, for the first time, effective ranking of GP catalytic site inhibitor potencies using the MM-GBSA method has been demonstrated. For a congeneric training set of 27 ligands, excellent statistics in terms of Pearson (Rp) and Spearman (Rs) correlations (both 0.98), predictive index (PI = 0.99) and AU-ROC (0.99) for predicted versus experimental binding affinities were obtained, with ligand tautomeric/ionization states additionally considered using DFT calculations. Seven 2-aryl-4(5)-(β-D-glucopyranosyl)imidazoles and 2-aryl-4-(β-D-glucopyranosyl)-thiazoles were subsequently synthesized and kinetics experiments against rabbit muscle GPb revealed new potent inhibitors with best Ki-s in the low µM range (5c = 1.97 µM; 13b = 4.58 µM). Ten C-β-D-glucopyranosyl azoles were then tested ex-vivo in mouse primary hepatocytes. Four of these (5a-c and 9d) demonstrated significant reduction of glucagon stimulated glycogenolysis (IC50 = 30-60 µM). Structural and predicted physicochemical properties associated with their effectiveness was analysed, with permeability related parameters identified as crucial factors. The most effective ligand series 5 contained an imidazole ring and the calculated pKa (Epik: 6.2; Jaguar 5.5) for protonated imidazole suggests that cellular permeation through the neutral state is favoured, while within the cell there is predicted more favourable binding to GP in the protonated form.

show abstract

Section: Cellular and Pharmacokinetic Evaluationmentioning

confidence: 99%

Identification of C-β-d-Glucopyranosyl Azole-Type Inhibitors of Glycogen Phosphorylase That Reduce Glycogenolysis in Hepatocytes: In Silico Design, Synthesis, in Vitro Kinetics, and ex Vivo Studies

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Also, considering the involvement of carbohydrates in various interactions, sugars are often incorporated in various simpler molecules to deal with the targeting mechanism of action and/or pharmacology . 1,3,4‐Oxadiazoles linked to sugar skeleton such as a glucofuranose, glucopyranose, xylopyranose, psicopyranose, thioglycosides and fructopyranose are documented in literature, and many of these derivatives have showed potential antibacterial, anticancer, antitumor, and antidiabetic activity . Considering the aforementioned facts and our previous experience on click‐mediated development of glycoconjugates of diverse application , we intend to conjugate the orthogonally protected saccharide residue with biologically privileged 1,3,4‐oxadiazole framework using Cu(I)‐catalyzed click reaction to obtain glycohybrids, which may exhibit the medicinal properties of both the parent components.…”

Section: Introductionmentioning

confidence: 99%

Click Inspired Synthesis of 1,2,3‐Triazole‐linked 1,3,4‐Oxadiazole Glycoconjugates

Kushwaha

Tiwari

2017

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

The glycoconjugation of biologically privileged 1,3,4‐oxadiazole scaffold is described via Cu(I)‐catalyzed azide–alkyne cycloaddition. A series of glycosyl alkynes 1b–i, obtained from various commercial sugars, were treated with azide functionalized 1,3,4‐oxadiazole using click chemistry to access triazole‐linked glycosylated 1,3,4‐oxadiazoles 10b–i in good yields. The structure of the developed glycoconjugates has been ascertained by extensive spectroscopic analysis (1H &13C NMR, IR, and MS).

show abstract

“…The 3-(β-D-glucopyranosyl)-5substituted-1,2,4-triazoles studied here are predicted to have drug-like potential with only permeability flagged as a potential issue to efficacy. However, the compounds have in general (for six of the nine synthesized) better predicted Caco-2 cell permeabilities (by a factor of 3)than previously reported glucose analogues[10,55,56] and accordingly are to be considered in further follow up experiments (cellular and in vivo) for efficacy.…”

mentioning

confidence: 79%

A multidisciplinary study of 3-(β- d -glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors

Kun

Begum

Kyriakis

et al. 2018

European Journal of Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

3-(β-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles have been revealed as an effective scaffold for the development of potent glycogen phosphorylase (GP) inhibitors but with the potency very sensitive to the nature of the alkyl/aryl 5-substituent (Kun et al., Eur. J. Med. Chem. 2014, 76, 567). For a training set of these ligands, quantum mechanics-polarized ligand docking (QM-PLD) demonstrated good potential to identify larger differences in potencies (predictive index PI = 0.82) and potent inhibitors with K's < 10 μM (AU-ROC = 0.86). Accordingly, in silico screening of 2335 new analogues exploiting the ZINC docking database was performed and nine predicted candidates selected for synthesis. The compounds were prepared in O-perbenzoylated forms by either ring transformation of 5-β-d-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(β-d-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(β-d-glucopyranosylcarbonyl)arenethiocarboxamides by hydrazine, followed by deprotections. Kinetics experiments against rabbit muscle GPb (rmGPb) and human liver GPa (hlGPa) revealed five compounds as potent low μM inhibitors with three of these on the submicromolar range for rmGPa. X-ray crystallographic analysis sourced the potency to a combination of favorable interactions from the 1,2,4-triazole and suitable aryl substituents in the GP catalytic site. The compounds also revealed promising calculated pharmacokinetic profiles.

show abstract

Synthesis, enzyme kinetics and computational evaluation of N-(β-d-glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors

Cited by 18 publications

References 53 publications

Identification of C-β-d-Glucopyranosyl Azole-Type Inhibitors of Glycogen Phosphorylase That Reduce Glycogenolysis in Hepatocytes: In Silico Design, Synthesis, in Vitro Kinetics, and ex Vivo Studies

Identification of C-β-d-Glucopyranosyl Azole-Type Inhibitors of Glycogen Phosphorylase That Reduce Glycogenolysis in Hepatocytes: In Silico Design, Synthesis, in Vitro Kinetics, and ex Vivo Studies

Click Inspired Synthesis of 1,2,3‐Triazole‐linked 1,3,4‐Oxadiazole Glycoconjugates

A multidisciplinary study of 3-(β- d -glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors

Contact Info

Product

Resources

About