Mykhalchenko Y. Syntheses, properties and transformation of 7-substituted 3-benzyl-8-propylxanthines

Українська версія

Thesis for the degree of Doctor of Philosophy (PhD)

State registration number

0820U100282

Applicant for

Specialization

  • 226 - Фармація, промислова фармація

15-10-2020

Specialized Academic Board

ДФ 17.600.13

Zaporizhzhya State Medical University

Essay

compound with halogenated derivants of alkanes, alkenes, aryl(heteryl)alkanes and aromatic ketones enabled to obtain more polar 7-substituted derivants of 3-benzyl-8-propylxanthine. Three methods for the synthesis of 3-benzyl-8-propylxanthine-7-yl ethanoic acid have been proposed. In order to further expand the range of prospective biologically active compounds, 3-benzyl-8-propylxanthin-7-yl acetic acid hydrazide was obtained. It was proposed as a basic structure, which allowed to obtain xanthine derivants containing heterocyclic substituents in the side carbon chain. For instance, to obtain previously not described 3-benzyl-8-propyl-7-[2'-oxo-2'-(3'',5''-dimethylpyrazole-1''-yl)ethyl]xanthine, two easy-to-perform methods of synthesis by the interaction of 3-benzyl-8-propylxanthine-7-yl acetic acid hydrazide with acetylacetone were developed. Grounding on the quantum chemical calculations by DFT method, a probable mechanism of reactions behavior was suggested. Preparative methods for the synthesis of 3-benzyl-8-propylxanthin-7-yl acetic acid hydrazideylidenederivants were adapted to obtain potential biologically active compounds with low toxicity. The author has shown the potential of using these ylidenehydrazides in heterocyclization reactions to obtain previously undescribed 7-([4'-acetyl-5'-R-4',5'-dihydro-1',3',4'-oxadiazol-2'-yl]methyl)-3-benzyl-8-propylxanthines, which structurally combine two pharmacologically prospective heterocycles. It is for the first time that 3-benzyl-7-[(4'-R-5'-mercapto-1',2',4'-triazole-3'-yl)methyl]-8-propylxanthines were obtained. Basing on the obtained 3-benzyl-8-propylxanthine N-alkyl(phenyl)hydrazinocarbothioamides, compounds that combine xanthine and thiazole or dihydrothiazole cycles in one molecule, have been synthesized for the first time. In the course of the dissertation research, 111 new compounds were synthesized for which the study of different types of biological activity was performed, which allowed to reveal the most active structures and to establish the regularities of "structure-action". Pharmacological screening of the synthesized compounds for antioxidant (63), diuretic (24), antimicrobial (20), antifungal (20), and hypoglycemic effects (7) was performed. As a result, it was found that 3-benzyl-8-propylxanthine, its xanthinides, 7-alkyl(aralkyl)substituted, 3-benzyl-8-propylxanthin-7-yl acetic acid and its derivants, as well as 7-substituted 3-benzyl-8-propylxanthines that contained heterocyclic substituents in the side chain, demonstrate the studied activities and in some cases exceed the reference standards. The dependence of biological action of the synthesized compounds on their structure has been analyzed. Discovered regularities allowed to reveal a number of perspective directions for further search of new biologically active compounds. According to the results of in vitro studies of AOA, the most active compound was selected, the actoprotective and cardioprotective properties of which were studied on a model pathology. L-arginine 3-benzyl-8-propylxanthin-7-yl acetate, which has a pronounced actoprotective effect and belongs to practically non-toxic substances, has been proposed for further in-depth pharmacological research. In order to standardize the "leader-compound" substance, a project of quality control methods for powder (substance) for the production of sterile medications has been designed. The results of the biological action study, as well as the established patterns of "structure-action" dependence, can be used for a targeted search for biologically active compounds among 7-substituted derivants of 3-R-8-R'xanthines.

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