Lesyk R. Synthesis and biological activity of condensed and non-condensed heterocyclic systems based on 4-azolidones

Object - [2+3]-cyclocondensations in synthesis of 4-azolidones, interaction of 4-azolidones with oxocompounds, reactions of acylation, heterocyclization, alkaline hydrolysis, alkylation, heterodiene synthesis, "domino" reactions; aim - synthesis of new condensed and non-condensed heterocyclic systems based on 4-azolidones, search among them effective and non-toxic substances with anticancer, antioxidant, antiradical, antihypoxant, cerebroprotective, anti-inflammatory, anticonvulsant and antimicrobial activities as potential drugs; methods - organic synthesis, spectral methods (UV-, IR-, NMR-, mass-spectroscopies), X-ray analysis, elemental analysis, chromatography, virtual biological screening, traditional and high-throughput pharmacological screening, 2D-QSAR analysis; novelty - group of effective reagents for construction biologically active molecules were proposed, such as 2-carbethoxymethylthio-2-thiazoline-4-one, aroylacrylic acids, maleic anhydride and maleimides, cytraconic anhydride, 2,4-аzolidinedione-5-acetic acids, 5-carboxymethylidene-2,4-thiazolidinedione, 5-аrylidene-2,4-thiazolidinedione-3-аlkancarboxylic acid chlorides, аnhydrides of 5-аrylidenerhodanine-3-succinic acid, aldehydes with dienophilic fragment in molecules, 5-(2-hydroxyphenylmethylidene)іsorhodanines, isothiocoumarine-3-carboxylic acid chlorides. New heterocyclic systems - 3,7-dithia-5-аzatetracyclo[9,2,1,02,10,04.8]tetradecene-4(8) and 3,7-dithia-5,14-diazapentacyclo[9,5,1,02,10, 04,8,012,16]heptadecene-4(8) - were obtained. Fact of "domino" reaction of 5-(2-hydroxyphenylmethylidene)іsorhodanines with anhydrides of unsaturated dicarboxylic acids, combining acylation of phenolic hydroxygroup and spontaneous intermediate [4+2]-cyclocondensation in situ was determined. For the first time it was determined, that 4-azolidinethiones and aldehydes with dienophilic fragment react by tandem-type with cascade passing Knoevenagel and heterodiene synthesis reactions. Focused combinatorial library, which consists of 80 original heterocyclic compounds with anticancer, antioxidant, antiradical, antihypoxant, cerebroprotective, anti-inflammatory, anticonvulsant and antimicrobial activities. Dissertation has priority on anticancer activity of 4-thiazolidones and related heterocyclic systems; results - preparative synthesis methods of 2-arylamino-2-thiazoline-4-ones, 2-imino-4-thiazolidones, 2,4-thia(imida)zolidinediones-3 and 5-carboxylic acids and its functional derivatives, azolothiopyranes, thioisocoumarines were worked out. Group of new pharmacologically active and non-toxic compounds were proposed for in-depth study as potential drugs. Following 2D-QSAR analysis requirements for structures with anti-inflammatory and antimicrobial activity were formulated. For purposeful synthesis of biologically active compounds from azolidine group; applications - used in education and scientific processes in National Pharmaceutical University (аcts from 27.05.04, 03.06.04 and 10.06.04), scientific process in Institute of Molecular Biology NAS of Ukraine (two acts from 14.01.04), Lugansk State Medical University (act from 10.11.03), and also used in educational program "Computer technologies in pharmacy" (program approved СMC of Danylo Halytsky State Medical University from 5.12.02, protocol №2); area - pharmacy.