Computationally motivated synthesis and enzyme kinetic evaluation of N-(β-d-glucopyranosyl)-1,2,4-triazolecarboxamides as glycogen phosphorylase inhibitors

Following our recent study of N-(β-D-glucopyranosyl)-oxadiazole-carboxamides (Polyák et al., Biorg. Med. Chem. 2013, 21, 5738) revealed as moderate inhibitors of glycogen phosphorylase (GP), in silico docking calculations using Glide have been performed on N-(β-D-glucopyranosyl)-1,2,4-triazolecarboxamides with different aryl substituents predicting more favorable binding at GP. The ligands were subsequently synthesized in moderate yields using N-(2,3,4,6-terta-O-acetyl-β-D-glucopyranosyl)-tetrazole-5-carboxamide as starting material. Kinetics experiments against rabbit muscle glycogen phosphorylase b (RMGPb) revealed the ligands to be low µM GP inhibitors; the phenyl analogue (Ki = 1 µM) is one of the most potent N-(β-D-glucopyranosyl)-heteroaryl-carboxamide-type inhibitors of the GP catalytic site discovered to date. Based on QM and QM/MM calculations, the potency of the ligands is predicted to arise from favorable intra- and intermolecular hydrogen bonds formed by the most stable solution phase tautomeric (t2) state of the 1,2,4-triazole in a conformationally dynamic system. ADMET property predictions revealed the compounds to have promising pharmacokinetic properties without any toxicity. This study highlights the benefits of a computationally lead approach to GP inhibitor design

Advances in Spiro Compounds

Spiro compounds (also named as spiranes following the suggestion of Adolf von Baeyer as early as 1900) are ubiquitous molecules, which contain a fused bicyclic system that share a single atom. A search for the key term “spiro” in the SciFinder database at the beginning of April 2017 resulted in more than 147,000 hits including 5000–6000 publications per annum after 2010. This enormous research activity encompasses a large number of fields in chemistry (especially organic and medicinal chemistry—with an emphasis on heterocyclic systems), but also includes pharmacology, crystallography, materials science, physics, biochemistry, molecular biology, engineering, energy and fuels, just to mention the most active areas. The immense interest in spirocycles, besides their unique features related to isolation from natural sources, synthesis and stereochemistry, is fuelled by an extremely wide range of useful properties, that comprise among others anti-cancer, antibacterial, antifungal, anti-diabetic, anti-HIV, cytotoxic, diuretic, spasmolytic, antiphlogistic, anti-hypertensive, anti-depressant, anxiolytic, anti-fouling, anti-feedant, herbicidal, plant growth regulatory effects; photochromism; and hole-transporting ability

Szelektív szintézismódszerek kifejlesztése vizes közegben átmenetifém-komplexek jelenlétében = Development of selective synthetic methods in aqueous medium in the presence os transition metal complexes

Kutatómunkánkat króm(II) komplexek szelektív szintézisreakcióinak fejlesztésén végeztük. Kidolgoztuk a Nozaki-Hiyama reakció szén-szén kötések enantioszelektív kialakítására alkalmas módszerét karbonil- és halogénszármazékok kapcsolásában, króm(II) komplexek jelenlétében. Tanulmányoztuk szénhidrátszármazékok anomer centrumának reaktivitását CrIIEDTA komplex jelenlétében, semleges-vizes közegben és új módszereket dolgoztunk ki glikálok és C-glikozidok előállítására. Természetes aminosavak króm(II) komplexeinek királis információját aminok enantioszelektív szintézisére alkalmaztuk. Tanulmányoztuk az enantioszelektív autokatalízis törvényszerűségeit, empirikus összefüggést dolgoztunk ki a királis erősítés jellemzésére. | Selective synthetic reactions could be developed in our research work in the present of chromium(II) complexes. The Nozaki-Hiyama reaction could be developed for enantioselective carbon-carbon coupling in the reactions of carbonyl- and halogen derivatives using chromium(II) complexes. Reactivity of the anomeric centre of carbohydrate derivatives was investigated with CrIIEDTA complex in neutral aqueous medium and new methods could be developed for preparation of glycals and C-glycosides. Amino acid induced enantioselective amine synthesis could be developed in the presence of Cr(II) in aqueous medium. The principles of the enantioselective autocatalytic reactions could be investigated and empirical relation proposed for the chiral amplification

C-Glycosyl 1,2,4-triazoles: Synthesis of the 3-β-d-glucopyranosyl-1,5-disubstituted and 5-β-d-glucopyranosyl-1,3-disubstituted variants

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