THE SYNTHESIS, COMPUTER PREDICTION OF THE BIOLOGICAL ACTIVITY AND THE ACUTE TOXICITY OF 1-Ar-4-R-[1,2,4] TRIAZOLO[4,3-a] QUINAZOLIN-5(4H)-ONES

Using the PASS programme computer prediction of the biological activity of 1-Ar-4-R-[1,2,4]triazolo[4,3-a] quinazolin-5(4H)-ones has been performed; it has allowed to identify the types of the biological activity of the compounds studied and sort out the most promising compounds 5{1-20} with the potential anti-asthmatic and anti-allergic activity. Prediction of the acute toxicity of 1-Ar-4-R-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones 5{120} has been carried out by the GUSAR software, which allows to refer them to slightly toxic (toxicity class 4) or practically nontoxic (toxicity class 5) substances. The synthesis of the most promising compounds 5{1-20} studied іn silico for the biological activity and the acute toxicity has been conducted by interaction of the corresponding 2-hydrazinoquinazolin-4(3H)-ones 1{1-5} with imidazolides 3{1, 2} of aromatic acids 2{1, 2}, or with aromatic aldehydes 4{1, 2} followed by oxidation in the presence of FeCl3. The structure of the compounds 5{1-20} synthesized has been proven by the data of the elemental analysis and 1H NMR spectroscopy. The compounds obtained are promising objects for further investigations as slightly toxic or nontoxic substances with the potential anti-asthmatic and anti-allergic activity.

The possibility to synthesize a large amount of [1,2,4]triazolo [4,3-a]quinazolin-5(4H)-one derivatives leads to understanding of the necessity for the rational presynthetic selection of the most promising compounds of this class. One of the effective ways to solve this problem is computer prediction of various properties of [1,2,4]triazolo [4,3-a]quinazolin-5(4H)-one derivatives, such as the biological activity [18] and the acute toxicity [19]; it allows to eliminate unpromising substances at the early stages of the research.
Taking into account the 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 was to conduct modelling of the virtual library of 1-Ar-4-R- [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones, to determine the most probable biological activity spectrum and the acute toxicity of the compounds studied using the PASS and GUSAR software, sort out the most promising substances and develop preparative methods for their synthesis.
Analysis of the computer prediction results for the virual library of 1-Ar-4-R- [1,2,4]triazolo [4,3-a] quinazolin-5(4H)-ones by the PASS software showed the possibility of searching substances possessing the anti-asthmatic and anti-allergic activity among these compounds and allowed to generate the library of the most promising compounds 5{1-20} for further research (Table 1) [18].

Experimental Part
The virtual screening for the biological activity of the virtual library of the substances studied was performed by the PASS Online web-resource. It enables to predict more than 4000 types of the biological activity with the average accuracy of more than 95% based on the analysis of the structure -activity relationships in a training set (drug substances, drug candidates being at various stages of clinical or preclinical trials, pharmacological substances and biochemical reagents, substances with the known specific toxicity data), which contains information about the structure and the biological activity of more than 300000 organic compounds [23][24][25].
Computer prediction of the biological activity spectrum of the virtual library of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one derivatives was performed with probability of demonstration of the specific type of the therapeutic action exceeding 50% (Pa>0.500). It al- Table 1 Prediction of the biological activity spectrum of 1-Ar-4-R- [1,2,4] Continuation of the Table 1 Prediction The training set of the programme was developed based on SYMYX MDL Toxicity Database contai- Table 2 The values of acute toxicity of 1-Ar-4-R- [1,2,4]  ning information about the acute toxicity of more than 10000 chemical structures. The baseline information regarding the acute toxicity of the compounds under study are presented by LD 50 values (log 10 (mmol/kg) and mg/kg) and the toxicity class according to the OECD classification project of chemical substances by acute toxicity values [19,20]. The 1 H NMR-spectra of compounds 5{1-20} were recorded on a Varian WXR-400 (200 MHz) spectrometer in DMSO-d6 solution with TMS as an internal standard, chemical shifts were reported in ppm. Melting points were measured with a Buchi B-520 melting point apparatus. Elemental analysis was performed on an Euro EA-3000 apparatus. Starting 2-hydrazinoquinazolin-4(3H)-ones 1{1-5} were obtained according to the method [21].
The general procedure for the synthesis of 1-Ar- 5{1, 4, 5, 8, 9, 12, 13, 16, 17, 20}. Dissolve the mixture of 1.5 mmol of the corresponding acid 2{1, 2} and 0.24 g (1.5 mmol) of carbonyldiimidazole (CDI) in 5 ml of anhydrous DMFA. Heat the solution at 100°C for 1 h, then add 1 mmol of the corresponding 2-hydrazinoquinazolin-4(3H)-one 1{1-5}. Reflux the reaction mixture for 24 h. After cooling dilute the reaction mixture with 10 ml of water. The next day filter the precipitate formed, wash with 20 ml of i-propanol and recrystallize from the mixture of 5 ml of DMFA and 10 ml of i-propanol. Yields and 1 H NMR data are given in Table 3.

Conclusions
According to the result of computer prediction of the biological activity spectrum and the acute toxicity of 1-Ar-4-R- [1,2,4]triazolo[4,3-a]quinazolin-5(4H)ones the selection of slightly toxic or nontoxic substances with the potential anti-asthmatic and antiallergic activity has been performed.