Tarasenko D. Modification of thiazole carbonyl derivatives: synthesis and properties of benzimidazoles and chromones

The dissertation is devoted to derivatives of 5-formylthiazoles that have fluorescent properties, namely benzimidazoles and chromones. The thiazole fragment is part of many natural substances such as enzymes, vitamins, etc. Therefore, a large number of preparations of many drugs have already been developed on its basis. It is very convenient to obtain them from carbonyl derivatives of thiazole because the C=O group can be very easily modified into a wide range of other functional groups. Thus, the preparation of formylthiazoles has been an important issue for the past several decades, and many approaches have been proposed to solve it. However, they still do not allow the preparation of 5- formylthiazoles with some substituents. In this work, different approaches were used to obtain various 5- formylthiazoles. The first is the preparation of 5-formylthiazoles without substitutes in the 4th position; for this, the interaction of the corresponding thioureas with chlormalonaldehyde was used. Next, 4-bromo and 4-chloro 5- formylthiazole derivatives were synthesized from dibromo/dichloro-5- formylthiazole to study the influence of the halogen in the 4th position on the properties of benzimidazoles and chromones based on them. Also, to study the influence of the diheterocyclic system, thiazole-thiazole and thiazole-Nmethylpyrrolidine derivatives were synthesized. For this purpose, cross-coupling reactions of 5-formyl thiazole and its derivatives were investigated. It was found that the Stille reaction is the best for their modification. In addition, the aldehyde itself cannot be used because side reactions occur under the reaction conditions leading to resinification. Therefore, acetal protection of the carbonyl group is necessary, among the options for such protection, dioxolane is the best, since the removal of this protection takes place in milder conditions and it is not a reversible reaction, unlike acetal with methanol. For the cross-coupling reaction, an analysis of the effectiveness of many catalysts was carried out and the most effective of them were found. We also noticed that under the conditions of this reaction, the addition of a stannane fragment by the carbonyl group can also take place, but this reaction is specific for some carbonyl compounds, does not depend on the substituent in the stannane, and proceeds with very low yields. Therefore, the modification of the carbonyl group by this method is less effective compared to other modern synthetic approaches. Various systems of solvents and cocatalysts have been tested to scale up such a reaction. When trying to scale the reaction, the yields dropped significantly. To solve this problem, a series of experiments was conducted and it was found that in order to maintain the yield, it is necessary to carry out the reaction in dim ethyl form of copper and add the co-catalyst CuI. As result, a synthetic approach to the preparation of 2-hetarylthiazoles was developed. The final stage of the work is the glycosylation of the obtained chromones and the study of the interaction of the derivatives with β-glucosidase. All glycosylation methods available in the literature were tested, but none of them allowed obtaining products with sufficient yields. Therefore, a modification of the method, which showed the best result - direct esterification, was carried out. For this, various bases and solvents used in the reaction, as well as the temperature regime, were tested. As a result, a more efficient method of synthesizing the glycoside of chromones was developed. By this method, both flavonol derivatives for model studies and thiazolyl-chromone derivatives were obtained. Due to the fact that the intensity of the short-wavelength band remains constant during hydrolysis, it can be used as an internal fluorescent standard. This makes possible to use flavonol glucosides not only for the detection of β-glucosidase activity in biological samples, but also for several assessments of this activity. The binding affinity of flavonols to the β-glucosidase protein depends on its structure, so the addition of a 4'-benzyloxy group to the flavonol glycoside increased the binding affinity from -9.9 to -10.8 kcal/mol. However, the stronger connection of the benzyloxy-substituted glucoside compared with its unsubstituted analogue requires a high energy barrier for activation for the formation of the substrate-receptor transition stage for the enzymatic hydrolysis reaction It can be observed as a 2.3-fold decrease in the specific fluidity constant. Such conclusions reveal the possibility of corresponding flavonols glucosides as simple indicators for rapid fluorescent monitoring of the activity of other enzymes from glucosidases family.