Yushyn I. Synthesis and biological activity of thiazolidine derivatives with a pyrazoline fragment in molecules

The dissertation is devoted to synthesizing new pyrazoline-containing derivatives of thiazolidine and thiazole and studying their physicochemical parameters and biological properties. Based on the analysis of literature data, the directions and methods of synthesis of targeted compounds via [2+3]-cyclocondensation, Knoevenagel reaction, Claisen-Schmidt reaction, hetero-Diels-Alder reaction, aminolysis, acylation, alkylation, azo coupling are outlined. It was established that 4-(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)thiosemicarbazide, depending on the conditions of the heterocyclization reaction, can be used for the synthesis of various antipyryl-substituted bicyclic thiazolidinones and 1,3,4-thiadiazoles, which justifies the further use of the compound as a versatile "building block" in the design of "drug-like molecules". For the first time, the chemical features of 3-methyl-1H-pyrazol-5-amine were studied in detail in the aminolysis, Knoevenagel, and Michael reactions with various thiazolidinones, which made it possible to obtain new unfused 5-substituted 4-[(3-methyl-1H-pyrazol-5-yl)amino]-5H-thiazol-2-ones, as well as to propose an effective method for the synthesis of condensed pyrazolo[3,4-b]thiazolo[5,4-e]pyridin-6-ones/thiones. Furthermore, it is shown that the enone fragment of (E)-3-aryl-1-[4-methyl-2-(2-pyridylamino)-thiazol-5-yl]-2-propen-1-ones is essential for the synthesis of pharmacologically attractive Michael pro-acceptors, which was demonstrated by the synthesis of biologically active pyrazoline-thiazole-pyridine hybrid molecules and Michael adducts. It was established that pyrazoline-containing dienophiles are effective reagents for synthesizing new thiopyrano[2,3-d]thiazoles in the hetero-Diels-Alder reaction, for which the regio- and diastereoselective course was confirmed. It was shown for the first time that as an alternative option for obtaining thiopyrano[2,3-d]thiazoles, 5-chloro-3-methyl-1-phenylpyrazole-4-carbaldehyde can be used under the conditions of the Knoevenagel reaction with 4-thioxo-2-thiazolidinone. It was established that the specified pyrazoline-containing aldehyde forms original thieno[2,3-c]pyrazoles upon interaction with 2-mercapto-N-phenylacetamides and 2-(2-mercaptoacetyl)hydrazine-1-carbothioamide. Directed synthesis of 70 compounds was carried out. Based on biological screening, 20 "hit compounds" with antitumor, antimicrobial, antifungal effects in vitro and anti-inflammatory effects in vivo were identified. Based on molecular docking, the mechanisms of potential anticancer activity are substantiated, and recommendations for the rational design of anticancer agents are proposed.