Nowadays, the prevalence of metabolic syndrome (MS) is a serious problem among the world’s population. Metabolic syndrome includes the so-called “deadly” quartet – hypertension, type 2 diabetes mellitus (diabetes mellitus), dyslipidemia and alimentary obesity. After all, type 2 diabetes is included in the list of pathologies of the metabolic syndrome, it is important to find ways to alleviate the disease. Derivatives of such a heterocyclic system as xanthine are of great interest in this aspect. The aim of the study was to explore the hypoglycemic activity of newly synthesized water-soluble derivatives of 3-benzyl-8-substituted xanthines. Materials and methods. We obtained water-soluble potassium 3-benzyl-8-R-xanthin-7-ides, the structure and individuality of which were confirmed by a set of physical-chemical studies. Results. The hypoglycemic effect of the newly synthesized compounds was assessed by an oral glucose tolerance test. The obtained data were processed using modern statistical in silico-methods. Conclusions. The results of the hypoglycemic activity study among the potassium salts of 3-benzyl-8-substituted xanthine derivatives showed, that some new compounds are in close vicinity to the reference drug’s hypoglycemic action.

One of the most important tasks of our indigenous pharmaceutical science is the necessity for new medicines because existing drugs are characterized by various side effects, resistance, high toxicity, and so on. New bioactive molecule synthesis utilizes substances of natural origin as well as chemically modified ones. Thus, the researcher’s attention is mainly focused on 3-,7-,8-substituted derivatives of the natural heterocyclic xanthine system, which possess a wide range of pharmacological action. Synthesis of a novel of (3-benzyl-8-propylxanthin-7-yl)acetohydrazides with antimicrobial and diuretic activities described in the paper. The aim of this work is to develop efficient methods for synthesis of (3-benzyl-8-propylxanthin-7-yl)acetohydrazide derivatives, and to study their physical-chemical properties. Materials and methods. Two-hour boiling of propyl 2-(3-benzyl-8-propylxanthine-7-yl)acetate by excess hydrazine hydrate in propan-2-ol medium have yielded the key the key intermediate 2-(3-benzyl-8-propylxanthine-7-yl)acetohydrazide. Further transformation of the latter has led to formation of corresponding acetohydrazide derivatives achieved by the reaction with aliphatic, aromatic, heterocyclic aldehydes, and ketones. The structure and the relative configuration of the synthesized compounds were elucidated by analyzing their physical-chemical data. Results. The synthesis and optimization of reaction conditions of (3-benzyl-8-propylxanthin-7-yl)acetohydrazide derivatives were conducted. The identification of all synthesized compounds was aided by various physical-chemical methods (thin layer chromatography, elemental analysis, IR, and 1H NMR spectroscopy). Conclusions. As a result of synthetic research the preparative synthesis method of (3-benzyl-8-propylxanthin-7-yl)acetohydrazide derivatives possessing antimicrobic, and diuretic activities was developed.

Aim – the search for biologically active compounds with diuretic and hypoglycemic action among 7-substituted of 3-benzyl-8-propylxanthines, which can be used for the treatment of pathologies of “metabolic syndrome”. Materials and methods. 30 new chemical compounds among derivatives of 7-substituted of 3-benzyl-8-propylxanthines by PASS prediction filter were chosen for diuretic and hypoglycemic activity researches. Diuretic, hypoglycemic activity and for the most active compounds – the acute toxicity were studied in vivo. The molecular docking, which is based on EADock DSS mechanism of the modulation displayed the interaction between some of functional groups inside discovered xanthine ligands and known receptors and enzymes presented in Ligand-protein Database of Swiss Institute of Bioinformatics. Results. It has been shown that synthesized compounds displayed strong diuretic and medium hypoglycemic activities. The molecular docking modulation (SwissDock) of interaction of xanthine derivatives hits with proposed receptors and enzymes revealed prospective of using 7-substituted of 3-benzyl-8-propylxanthines as potential drugs for treatment of metabolic syndrome pathologies. Conclusion. The diuretic activity of the new 23 compounds of 7-substituted of 3-benzyl-8-propylxanthines and hypoglycemic activity of the new 7 derivatives of 7-substituted of 3-benzyl-8-propylxanthines was studied. Results of performed investigation illustrate that 7-substituted of 3-benzyl-8-propylxanthines demonstrate biological activity comparable to standard drugs. We also proposed probable molecular targets for the most active compounds by molecular docking method. It was shown that derivatives of 7-substituted of 3-benzyl-8-propylxanthines can be used for metabolic syndrome disorders prevention.

У статті наведено результати дослідження енерготропної дії потенційних нейропротекторних сполук - похідних ксантину С -3 та С -4 порівняно з референс - препаратом мексидолом на моделі ішемічного інсульту , яку відтворювали шляхом двобічного перев ' язування загальних сонних артерій .

Diabetes mellitus is a chronic endocrine disease. It etiology is the impact of both endogenous (genetic) and exogenous factors that cause absolute or relative shortage of insulin or not effective use of it, which in turn leads to disruption of all kinds of substances exchange. The study of this problem is actual due to the high prevalence of diabetes, chronic disease, the tendency to increase the number of patients, their high morbidity and mortality. Diabetes is characterized by high blood glucose levels, which eventually leads to various complications associated with many human systems damage. Hormones (insulin and its analogues) and synthetic drugs (sulfonylureas, biguanides etc.) are used For the treatment of diabetes, but their high toxicity, cumulativeness, various side effects (autoimmunization, cutaneous allergic reactions, disturbance of the micro flora of the digestive tract), and the formation of insulin resistance restrict the use of these drugs in clinical practice. On this aspect the attention of researchers is attracted to xanthine derivatives, which are known as substances with wide range of biological activities including hypoglycemic.Based on the above, the search and development of new drugs among new 3-R-substituted xanthine, which would have hypoglycemic effect and would be deprived of most side effects is an acute problem of modern medical and pharmaceutical sciences.The aim of this study was to investigate the hypoglycemic activity of newly synthesized derivatives of 3-benzyl-8-methylxanthine and establish certain patterns "structure-activity" relationship.Materials and methodsAs objects of study for hypoglycemic activity we used derivatives of 3-benzyl-8-methylxanthine synthesized at the Department of Biochemistry and LaboratoryDiagnostics ofZaporizhzhyaStateMedicalUniversity.Hypoglycemic action of xanthine derivatives evaluated by intraperitoneal glucose tolerance test, which was reproduced by injection to animals (white rats weighing 160-230 g) glucose at a dose of 2 g/kg. The experimental animals were divided in 14 groups of 7 animals in each:1. Intact – animals administered saline;2. Control – modeling hyperglycemia without treatment.3-13. Animals were injected xanthine derivatives at the background of hyperglycemia modeling.14. The animals were injected metformin at the background of hyperglycemia modeling.We determined glucose level in blood using a glucometer «Accu Chek Active» after 30 and 60 minutes.Research results processed by modern methods of analysis using Student t-test. We used the level of statistical significance of differences of research results - p<0.05.Results and their discussion Presence of methyl and benzyl group or acetate residue at position 7 of xanthine bicycle resulted in incresing of glycemia in the blood of experimental animals. Replacing carboxyl hydroxyl to propoxy group or adding naphtylmethyl substituent reduced glycemia (compound 8 and compound 3) after 30 min glucose injection.ConclusionsAs a result of the research it was found that most hypoglycemic activity among the compounds that were studied, has 3-benzyl-7-(2-naphtylmethyl)-8-metylxanthine. Obtained results can be used in further searching of potential biologically active substances with hypoglycemic properties among derivatives of 3-benzylxanhine.

Одним из основных направлений поиска новых малотоксичных биологически активных веществ является создание растворимых в воде соединений. С этой целью разработана методика синтеза не описанных в специализированной литературе водорастворимых 3-бензил-8-метилксантинидов-7 взаимодействием 3-бензил-8-метилксантина с основаниями в водной или водно-спиртовой среде. Разработан универсальный метод получения 3-бензил-8-метилксантинил-7-ацетатной кислоты, ее амида и водораствормых солей. На примере 3-бензил-8-метилксантинил-7-уксусной кислоты предложен альтернативный метод получения ее алкиловых эфиров. Структура и индивидуальность синтезированных соединений подтверждены данными элементного анализа, ИК-, 1 Н ЯМР-спектроскопии и хроматографией в тонком слое сорбента.

Introduction Nowadays, research of novel biological active compounds with low toxicity, are carried out among different classes of organic compounds of natural and synthetic genesis. One of the main ways of these studies is search of water-soluble compounds – convenient objects for pharmacological researches. In recent years researchers paid attention to xanthine derivatives, because of their high variativity of possible chemical modification and ability to form different salts with wide spectrum of biological action. Thus, among water-soluble xanthine derivatives were found compounds with pronounced antioxidant, diuretic and analeptic properties. Primary methods of obtaining water-soluble xanthine derivatives are direct interaction of bases with xanthine molecule or insertion basic or acidic residues in positions 7 or 8 of xanthine bicycle. According from the above, search of biologically active compounds among water-soluble substituted xanthines is prospective and actual. The aim of the study was development of synthetic ways of obtaining novel water-soluble derivatives of 3-benzyl-8-methylxanthine and studying their physical and chemical properties. Material and methods Melting points of obtained compounds were determined by capillary method on PTP (M) device. ІR-spectra of synthesized compounds were recorded on the Bruker Alpha device (company «Bruker» – Germany) on 4000-400 sm-1 with using console ATR (direct insertion of compound). 1Н NMR-spectra were recorded on the Varian Mercury VX-200 device (company «Varian» – USA) solvent – (DMSO-d6), internal standart – ТМС. Elemental analysis was made on Elementar Vario L cube device. Chromatoraphic studies were made on the plates Sorbfil-AFV-UV (company «Sobrpolimer» –Russia). Systhems for chromatography: «acetone-propanol-2» in ratio 2:3, «propanol-2-benzene» in ratio 10:1 and exersized in UV-light in wave 200-300 nm. Results and discussion We developed methodic of synthesis of water-soluble salts of 3-benzyl-8-methylxanthine. Reflux of 3-benzyl-8-methylxanthine 1 with sodium hydrooxide or ammonium hydroxide in the aqueous solution and ethanolamine, diaethylamine or morpholine in the aqueous propanol-2 led to formation of 3-benzyl-8-methylxanthinides-7 2a-e. The next stage of our study was synthesis of 3-benzyl-8-methylxanthinyl-7-acetic acid 3 with the next obtaining of acetates 5a-h. Acid 3 were synthesized by direct interaction of 3-benzyl-8-methylxanthine 1 or xanthinides-7 2a-e with chloroacetic acid and by hydrolysis of its amide 4 or propyl ester 6. Water-soluble 3-benzyl-8-methylxanthinyl-7-acetates 5а-h were obtained by heating acid 3 with primary, secondary and tertiary amines and ammonium in aqueous or aqueous-alcohol solutions. We also developed alternative method of synthesis of propyl 3-benzyl-8-methylxanthinyl-7-acetate 6, by reflux of acid 3 in propanol-1 with catalytic quantity of dioxane and sulfuric acid. Conclusions Methodic of synthesis of novel water-soluble 3-benzyl-8-methylxanthinides-7 has been developed by interaction of 3-benzyl-8-methylxanthine with bases in aqueous or aqueous alcohol solution. We developed universal method of obtaining of 3-benzyl-8-methylxanthilnyl-7-acetic acid, its amide and water-soluble salts. On example of 3-benzyl-8-methylxanthinyl-7-acetic acid we proposed alternative method of synthesis of alkyl esters – convenient objects for next chemical modification. Structure and identity of all synthesized compounds has been proved by elemental analysis, IR-, 1Н NMR-spectroscopy data and by thin layer chromatography.