THE SYNTHESIS, COMPUTER PREDICTION OF THE BIOLOGICAL ACTIVITY AND THE ACUTE TOXICITY OF

Aim. The aim of present study was to conduct modelling of the virtual library of 4-aryl-5-oxo-4,5-dihyd-ro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides, to determine the most probable biological activity spectrum and the acute toxicity of studied compounds by PASS and GUSAR software, sort out the most perspective substances and develop preparative protocols for their synthesis. Methods. Using the PASS program computer prediction of the biological activity of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides has been performed. Prediction of the acute toxicity has been carried out by the GUSAR software. The structure of the compounds synthesized has been proven by elemental analysis and 1 H NMR spectroscopy data. Results. The synthesis of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides has been conducted starting from corresponding methyl 3-aryl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxy-lates, which were converted into corresponding 3-aryl-2-hydrazino-4-oxo-3,4-dihydroquinazoline-7-carbohy-drazides by treatment with hydrazine hydrate. Heating of these 2-hydrazinoquinazolin-4(3H)-ones with acetylacetone was resulted in 4-aryl-8-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]-1-methyl[1,2,4]triazolo[4,3-a]qui-nazolin-5(4H)-ones formation. Following substitution of pyrazole moiety by interaction of these compounds with primary amines led to destinated 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides. The PASS program computer prediction of the biological activity of 4-aryl-5-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides has allowed identifying the types of activity of studied compounds and sorting out the leaders with potential antineurotic activity, which are perspective for male reproductive and erectile dysfunction treatment. Prediction of the acute toxicity has been carried out by the GUSAR software, which allowed to refer them to slightly toxic (class 4) or practically nontoxic (class 5) substances. Conclusions. The obtained compounds are perspective objects for further investigations as slightly toxic (non-toxic) substances with potential antineurotic activity, which are perspective for male reproductive and erectile dysfunction treatment. Hydrazine functional derivatives are widely used in medical practice as remedies applied for pharmacotherapy of depression, infection diseases, hypertension, diabetes, etc. It is worth mentioning that among obtained 7-R-8-hydrazine derivatives of 1,3-dimethylxantine promising substances have been identified. Due to the fact that lit-erature sources display only results of occasional studies of the reactions between 7-R-8-hydrazine theophyllines and mono- or dicarbonyle substances, the use of other keto reagents for xanthine bicycle at 8 th position function-alization will allow to explore synthetic potential of the last one, and with high probability may lead to obtaining original biologically active substances. Aim. To study types of reaction between 8- hydrazinyl-1,3-dimethyl-7-aryl alkyl-1H-purine-2,6(3H,7H)-diones and a number of carbonyl containing reagents. Methods. A nucleophilic addition reaction followed by dehydration or ethanol splitting was used, as well as the complex of the modern analysis methods to confirm the structure and individuality of the synthesized substances. Results. Different directions of 8-hydrazinyl-1,3,-dimethyl-7(fenetyl-, 3-phenylpropyl-, 3-phenylalyl)- 1H-purine-2,6(3H,7H)-diones chemical transformations in reactions with the appropriate carbonyl containing compounds have been studied experimentally. The structure of synthesized substances was confirmed by chromatog-raphy/mass and 1 H NMR spectroscopy. Conclusion. The group of 7-arylalkyl-8-(3,5-R,R 1 -pyrazole-1-yl)theophyllines, consisting of two functionally substituted bioactive heterocycles, has been synthesized by reaction between initial substances and selected mono- and dicarbonyl compounds


Introduction
Derivatives of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one, which are representatives of the important class of condensed heterocycles possessing wide range of the biological activity, attract particular interest in development of innovative drug substances.

Formulation of the problem in a general way, the relevance of the theme and its connection with important scientific and practical issues
The possibility to synthesize a large amount of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one derivatives leads to the necessity for the rational presynthetic selection the most perspective compounds from defined variety. One of the effective ways to solve this problem is computer prediction of various properties of [1,2,4]triazolo[4,3a]quinazolin-5(4H)-one derivatives, such as biological activity and acute toxicity, that enables to eliminate unpromising substances at the early stages of the research.

Allocation of unsolved parts of the general problem, which is dedicated to the article
The presence of amide group may have a significant impact on biological behavior of compounds. Investigation of influence of amide moiety on the biological activity of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones is important for expancion of knowledge about pharmacological properties of this class of compounds.

Formulation of goals (tasks) of article
Taking into account actuality of searching biological active substances among [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one derivatives and modern advances in software for virtual screening the goal of present study was to conduct modelling of the virtual library of 4-aryl-5-oxo-4,5-dihydro [1,2,4]triazolo[4,3-a]quinazoline-8carboxamides, to determine the most probable biological activity spectrum and the acute toxicity of studied compounds by PASS and GUSAR software, sort out the most perspective substances and develop preparative protocols for their synthesis.
The virtual screening for biological activity of virtual library of studied substances was performed by the PASS Online web-resource, which contains information about structure and biological activity more than 300000 organic compounds [20][21][22]. Computer prediction of the biological activity spectrum of virtual library of 4-aryl-5oxo-4,5-dihydro [1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides 4a-l was performed with probability of demonsration of specific type of therapeutic action exceeding 50 % (Pa > 0,500).
Analysis of the computer prediction results for the virual library of 4-aryl-5-oxo-4,5-dihydro [1,2,4]tria-zo-lo[4,3-a]quinazoline-8-carboxamides by PASS software showed the possibility of searching substances possessing potential antineurotic activity, and perspective for male reproductive and erectile disfunction treatment among these compounds and allowed to generate the library of the most perspective compounds 4a-l for further investigations (Table 2). However, the probability of antiasthmatic and antiallergic activity is diminished compared to previously described library of having no amide group compounds [23].

Conclusions
According to the result of computer prediction of the biological activity spectrum and acute toxicity of 4aryl-5-oxo-4,5-dihydro [1,2,4]triazolo[4,3-a]quinazoline-8-carboxamides the selection of slightly toxic or nontoxic substances with the potential antineurotic activi-ty, and perspective for male reproductive and erectile dysfunction treatment has been performed.