Tomasz Kosmalski

A novel derivatives of thiazol-4(5 H )-one and their activity in the inhibition of 11β-hydroxysteroid dehydrogenase type 1

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that catalyzes the conversion of inactive cortisone into physiologically active cortisol. Inhibiting the activity of this enzyme plays a key role in the treatment of Cushings syndrome, metabolic syndrome and type 2 diabetes. Therefore, new compounds that are selective inhibitors of this enzyme are constantly being looked for. In this work we present the synthesis of 2-(allylamino)thiazol-4(5H)-one derivatives by the reaction of N-allylthiourea with appropriate α-bromoesters. In the case of using of aliphatic α-bromoesters and α-bromo-β-phenylesters, the reactions were carried out in a basic medium (sodium ethoxide) and the products were isolated with a yield of up to 68%. Derivatives containing spiro systems in which carbon C-5 of the thiazole ring is the linker atom were obtained in the presence of N,N-diisopropylethylamine. Some of the obtained compounds, at a concentration of 10 μM have activity in the inhibition of 11β-HSD1 up to 71%. IC50 value for the most active compound: 2-(allylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one is 2.5 µM. With a high degree of 11β-HSD1 inhibition and a relatively large difference in the inhibition of 11β-HSD1 and 11β-HSD2 activity, this compound appears to be promising and should be subjected to further testing.

Novel O-Benzyl Oxime Ethers of 1-(Thiophen-2-yl)ethan-1-one – Synthesis, Structure and Antimicrobial Activity

1 Department of Organic Chemistry, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-094 Bydgoszcz, Poland, *E-mail: tpkos@wp.pl 2 Department of Genetic and Microbiology, Faculty of Biology and Biotechnology, Sklodowska-Curie University, Akademicka 19, 20-033 Lublin, Poland 3 Medicinal Chemistry Department, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-094 Bydgoszcz, Poland 4 Department of Organic Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland

Study of the Room-Temperature Synthesis of Oxime Ethers by using a Super Base

Abstract In this study, we present a convenient method for the synthesis of oxime ethers by reacting oximes with various chlorides (alkyl, functionalized alkyl, and benzyl) and with the subsequent use of a super base—pulverized potassium hydroxide in DMSO. The reactions take place at room temperature and the products are obtained in high yields. The final products were received within 2 min to 3 h. In addition, the compounds do not require chromatographic separation. The structure elucidation of the titled compounds was performed by using 1H NMR and 13C NMR spectroscopy as well as mass spectrometry. The presented method of synthesis for oxime ethers is environmentally friendly, because neither water cooling or heating of the reaction mixture/solvents (necessary for chromatographic purification) is required. The synthesis can be carried out very easily on a large scale.

Thiazolo[3,2-a]pyrimidin-5-one derivatives as a novel class of 11β-hydroxysteroid dehydrogenase inhibitors

11β-hydroxysteroid type 1 dehydrogenase (11β-HSD1) is an enzyme that increases tissue concentrations of cortisol. Selective inhibitors of this enzyme regulate the level of cortisol and thus play a key role in the treatment of Cushings syndrome, metabolic syndrome and type 2 diabetes. In this study the inhibitory activity of 29 thiazolo[3,2-a]pyrimidin-5-one derivatives on 11β-HSD1 were investigated. Studies were carried out with pooled human liver microsomes. A lot of analyzed compounds show activity for inhibiting 11β-HSD1 (up to 59.15% at concentration 10 µmol/l). Molecular docking simulation show that the molecule of the most active compound: 7-(cyclohexylmethyl)-2-iodomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one forms hydrogen bonds with Ala172, Leu171, Leu215 or Tyr177. In addition, the cycloalkane moiety can create the hydrophobic contacts with NADP+. For this compound also the most favourable Docking Score value was obtained. The most active compound only in the slight degree inhibits 11β-HSD2 activity and is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1. Consequently it can have a real effect on the regulation of the cortisol level in the body.

1-(1-Benzo-furan-2-yl)ethanone O-(2,6-di-fluoro-benz-yl)oxime.

In the title compound, C17H13F2NO2, the 2,2-difluorobenzyloxy residue assumes an E configuration with respect to the benzofuran system. The benzene ring makes a dihedral angle of 61.70 (4)° with the fused ring system (r.m.s. deviation = 0.008 Å). In the crystal, molecules are connected by weak C—H⋯F hydrogen bonds into chains extending parallel to the b-axis direction.

1-(1-Benzofuran-2-yl)ethanone O-(4-chloro­benz­yl)oxime

In the title compound, C17H14ClNO2, the p-chlorobenzyloxy residue assumes an E conformation with respect to the benzofuran system. The carbo- and heterocyclic systems make a dihedral angle of 47.99 (4)°. In the crystal, there are no significant intermolecular interactions present.