Renata Studzińska

Synthesis of new thiazolo〔3,2-a〕pyrimidin-5-one derivatives in reaction of 3-allyl-2-thiouracils cyclization

- The series ofthiazolo[3,2-a]pyrimidin-5-one derivatives in cyclization reaction of 3-allyl-2-thiouracil derivatives with iodine monochloride, and then hydrogen iodide elimination from intermediate reaction product has been obtained. On the basis of the studies of reaction kinetics, the elimination reaction mechanism has been proposed. Moreover, the influence of substituent on the reaction elimination rate has been investigated.

2-Allylaminothiazole and 2-allylaminodihydrothiazole derivatives: synthesis, characterization, and evaluation of bioactivity.

Some reactions of selected chlorooxoesters and haloesters with a 1-allylthiourea under various conditions have been performed. The reactions have been performed in methanol in alkaline and neutral environment. Condensation of 1-allylthiourea with chlorooxoesters has been further led via acetal as intermediate compound. As a result, the compounds containing thiazole and a 4,5-dihydrothiazole ring with a good yield have been obtained. The structures of the compounds were verified by 1H NMR, 13C NMR as well as X-ray diffraction analysis. Due to the potential biological activity of the synthesized compounds, the parameters of their bioavailability have been determined, and the probability of pharmacological action has been defined. All of the obtained compounds fulfilled the rule of five, which indicate their good absorption after oral intake. The probability of pharmacological action and potential targets calculated for the obtained compounds show that they can be potential drugs.Graphical abstract

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

Lipophilicity Study of Thiazolo[3,2-a]pyrimidine Derivatives as Potential Bioactive Agents

Systems containing fused thiazole and pyrimidine rings play a significant role in organisms due to their biological activity. Lipophilicity, as important parameter to expect biological activity of the compounds, was evaluated for 27 potentially active thiazolo[3,2-a]pyrimidine derivatives using chromatographic methods: reversed phase thin layer chromatography (RP-TLC) and reversed phase high performance liquid chromatography (RP-HPLC) methods. Methanol was used as the organic modifier of the mobile phases. The corresponding relationship between compounds structure and lipophilicity parameters (RM0 and log kw) values were observed and featured. RM0 and log kw parameters were compared with computed log P values. For all of analyzed compounds, determined lipophilicitys parameters values are > 0 which means that there are hydrophobic substances, soluble in the lipid phase. Simultaneously, these values are < 5, i.e., are in accordance with Lipinskis rule in the range of lipophilicity. In the case of the possibility of their use as drugs, they will be active after oral application.

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.

Reverse Stereoselectivity in the Lipase‐Catalyzed Hydrolysis of Diacetylated Pyrimidine Acyclonucleosides

The enzymatic hydrolysis of the prochiral acetyl groups of pyrimidine acyclonucleoside derivatives was catalyzed effectively by lipase Amano PS from Burkholderia cepacia (BCL) to give monoacetates with a high optical purity. The stereopreference of BCL depends on the structure of the substrates. The BCL‐catalyzed hydrolysis of the unsubstituted acyclonucleoside 2‐{[2,4‐dioxo‐3,4,5,6,7,8‐hexahydroquinazolin‐1(2H)‐yl]methoxy}propane‐1,3‐diyl diacetate is enantiotopically selective (pro‐R). After the reaction, the enantiomerically pure 2‐S isomer was obtained. The additional group on the ring caused a dramatic change in the stereopreference of the enzyme‐catalyzed deacylation compared to that of the unsubstituted compound, and the reverse chiral preference was observed. The enzymatic deacylation of prochiral ester groups of acyclonucleoside analogs substituted at C‐6 and C‐8 in 2,4‐dioxo‐3,4,5,6,7,8‐hexahydroquinazoline ring led to the 2‐R isomer (pro‐S selectivity).