in Wiley Online Library (wileyonlinelibrary.com).Synthesis of 1-methyl-6-((2-(aryl-(heteryl-))-2-oxoethyl) pteridine-2,4,7(1H,3H,8H)-triones via [4 + 2]-cycloaddition of 1-methyl-5,6-diaminouracil with ethyl 4-aryl(heteryl)-2,4-dioxobutanoates is described in presented work. It was established that the reaction occurs regioselectively and proceeds under refluxing of starting compounds in acetic acid for 60 min. The structures of synthesized compounds were proven by complex of physicochemical methods including infrared, 1 H-, 13 C-NMR spectroscopy, liquid chromatographymass spectrometry, and electron impact-mass spectrometry. Based on the detail analysis of the correlational NMR spectral data (correlation spectroscopy, heteronuclear single quantum coherence, heteronuclear multiple bond correlation, and Nuclear Overhauser effect spectroscopy), it was determined that in dimethyl sulfoxide solution, the 1-methyl-6-((2-(aryl-(heteryl-))-2-oxoethyl)pteridine-2,4,7(1H,3H,8H)-triones exist in two tautomeric forms: ketone (A) and enol (B). It was also found that tautomeric behavior of aforementioned compounds in hexadeuterated dimethyl sulfoxide is sensitive to the nature of the aryl or heteryl substituent at the position 6 of ring. The electron donating groups shift equilibrium to the tautomer A, while electron withdrawingto the tautomer B. The synthesized compounds were tested on antiradical activity. It was found that obtained compounds reveal radical scavenging activity comparable or higher than ascorbic acid.

A synthesis method of novel N‐cycloalkylcarbonyl‐N′‐arylthioureas was developed. It consists of sequential addition of equimolecular amounts of ammonium isothiocyanate and substituted anilines to cycloalkylcarbonyl chlorides. The identity and purity of products were confirmed by LC/MS spectra, their structure by elemental analysis, IR and 1H‐NMR spectra. Preliminary antimicrobial screening for standard microorganisms and molecular docking allowed to select several structures for antifungal and genetic toxicity studies. Conducted in vitro screening of 9 compounds for antifungal potential against 11 phytopathogenic fungi and three Phytophthora strains revealed that two N‐(arylcarbamothioyl) cyclopropanecarboxamides at a concentration of 50 μg/ml exhibited activities comparable to the standard antifungal agent ‘Cyproconazole’. Analysis of mutagenicity of novel thioureas using the Salmonella reverse mutagenicity assay (‘Ames Test’) showed a low gene‐toxicity profile.

2-([1,2,4]triazolo[1,5-c]quinazolin-2-yl-)alkyl-(alkaryl-, aryl-)-amines and their derivatives. (3Н-quinazolin-4-yliden)hydrazides (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)alkyl-(alkaryl-, aryl-)carboxylic acids: features of synthesis, modifi cation and antibacterial activity of synthesized compounds Zaporizhzhia State Medical UniversityKey words: Aminoacіds, (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)alkyl-(alkaryl-, aryl-)carboxylic acids, (3Н-quinazolin-4-yliden) hydrazides, 2-substituted [1,2,4]triazolo [1,5-c]quinazolines, Antimicrobial And Antifungal Activity.The combination of different "pharmacophore" components in one structure connected via "linker" functional groups is one of the major and justifi ed approaches for the synthesis of new biologically active substances. In this area (3Н-quinazoline-4-yliden)hydrazides (1,3-dioxo-1,3-dihydro-2H-іsoindol-2-yl-)alkyl-(aralkyl-, aryl-)carboxylic acids are the most interesting compounds. They contain quinazoline and іsoindole fragments united through аlkyl, аlkaryl and аryl groups and furthermore can be used for the synthesis of new heterocycles.Aim. The purpose of this work is to fi nd antimicrobial and antifungal agents among (3H-quinazolin-4-ylidene)hydrazides (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl-)alkyl-(alkaryl-, aryl-)carboxylic acids and their fused derivatives and to establish physical-chemical properties of these compounds and to correlate "structure -activity relationship" for structure optimization.Methods and results. The study of microbiological activity was conducted by disco-diffusion method on Mueller-Hinton agar on the following strains of microorganisms: gram-positive cocci (Staphylococcus aureus ATCC 25923, Enterococcus aeruginosa, E. faecalis ATCC 29212), gram-negative bacteria (Pseudomonas aeruginosa PSS27853, Escherichia coli ATCC 25922), facultative anaerobic gram-negative bacteria (Klebsiella pneumoniaе) and fungi (Candida albicans ATCC 885653).Conclusion. The protected aminoacids were used to synthesize unknown (3H-quinazolin-4-ylidene)hydrazides (1,3-dioxo-1,3-dihydroisoindolo-2-yl-)alkyl-(alkaryl-, aryl-)carboxylic acids in the reactions of nucleophilic substitution for the fi rst time. While new [1,2,4] triazolo[1,5-c]quinazolin-2-yl-)alkyl-(alkaryl-, aryl-)isoindol-1,3(2H)-diones were received by heterocyclization of the last. Structure and identity have been confi rmed by elemental analysis, physical and chemical methods ( 1 H NMR spectroscopy, mass-spectrometry). Analysis of the results of microbiological study shows, that the synthesized compounds have never been active against St. aureus, E. aerogenes, P. aeruginosa, E. coli, K. pneumoniaе (growth inhibition zone 6 mm). However, compounds 2.1, 2.2 are found among the (3H-quinazoline-4-ylidene)hydrazides (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl-)alkyl-(aralkyl-, aryl-)carboxylic acids (2.1-2.9) and inhibit the growth of E. faecalis zone 7 mm. Conducted cyclocondensation of 2.1-2.9 compounds does not lead to increase of antibacterial activity of corresponding [1,2,4]triazolo[1,5-...

The synthesis of 6-(2-hydroxy-2-aryl (heteryl)ethyl)-1-methylpteridine-2,4,7 (1H,3H,8H)-triones by the reduction of the corresponding ketones and the peculiarities of conversion of the synthesized alcohols to (E)-1-methyl-6-(2-aryl (heteryl)ethenyl)pteridine-2,4,7(1H,3H,8H)-triones was reported. The mechanism of monomolecular elimination that occurred in the presence of hydrogen halides was discussed, namely, the competitive formation of an energyefficient conjugated system by deprotonation of a stable benzyl-type carbocation.Alternative synthesis methods of pteridine-2,4,7(1H,3H,8H)-triones were developed. Abovementioned approach involved [4+2]-cyclocondensation of 1methyl-5,6-diaminouracil to 2-oxo-4-R-but-3-enoic acids and Knoevenagel condensation of 1,6-dimethylpteridine-2,4,7(1H,3H,8H)-trione with aromatic aldehydes. The antiradical, antimicrobial, and antifungal activities were studied for the synthesized compounds.

A targeted search for anticonvulsant agents among unknown diacylthiosemicarbazides with the analysis of the structure-activity relationship (SAR-analysis). Methods. Organic synthesis; molecular docking; spectral methods; pentylenetetrazole convulsions, statistical methods. Results. A strategy of search for new anticonvulsant agents among unknown diacylthiosemicarbazides has been developed. It included virtual-oriented screening towards [the] active centers of enzymes and sodium channels that underlie the mechanism of antiepileptic drugs activity. The synthesis of diacylthiosemicarbazides was carried out by the in situ method, namely, accomplishing the interaction of cycloalkanecarbonyl chlorides with ammonium isothiocyanate and the subsequent nucleophilic addition of cycloalkyl-(aralkyl-, aryl-, hetaryl-) carboxylic acid hydrazides. The peculiarities of the structure of the synthesized compounds were confirmed by spectral methods (LCMS and 1 H NMR spectra). Biological screening showed that diacylthiosemicarbazides (2) in the experimental model of pentyleneterazole seizures in rats increased the latency period of seizures by 2.77-7.82 times, reduced the duration of tonic-clonic seizures by 1.23-5.59 minutes and prevented mortality by 30-60 %, relative to the control group of animals. It was shown that diacylthiosemicarbazides (2.6, 2.15, 2.22, 2.18) with cyclopropane-or cyclopentanecarboxamide groups show the anticonvulsant activity that exceeds that of the reference drug Depakine or competes with it. Conclusions. A range of new diacylthiosemicarbazides were obtained and the primary screening of their anticonvulsant activity was performed, the SAR-analysis was provided, and the hit-compound was identified for further in-depth pharmacological studies.

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2- ([1,2,4]triazolo [1,5-c]quinazoline-2-yl-)alkyl-(alkaryl-,aryl-)-amines and their derivatives. The synthesis of (3Н-quinazoline-4-ylidene) hydrazides N-protected aminoacids, using a variety of amine-protecting approaches. Physical-chemical properties and biological activity of synthesized compounds (Message 2) 2- ([1,2,4]тріазоло [1,5-c]хіназолін-2-іл-)алкіл-(алкарил-,арил-)-аміни та їхні похідні. Cинтез (3Н-хіназолін-4-іліден)гідразидів ациламінокислот із використанням різноманітних підходів захисту аміногрупи. Фізико-хімічні властивості та біологічна активність синтезованих сполук (Повідомлення 2)Синтетичний потенціал (3Н-хіназолін-4-іліден)гідразидів карбонових кислот є значущим у контексті cтворення на їх основі нових s-тріазолохіназолінів, а дані щодо біологічної активності є підставою для розробки нових методів їх побудови з використанням різноманітних реагентів. Важливим аспектом, що вирішує цю проблему та розширює межі застосування гідразидів, є введення залишків N-захищених амінокислот у молекулу 4-гідразинохіназоліну. Це дасть змогу цілеспрямовано змінити фізико-хімічні та біологічні властивості відповідних гідразидів і відкрити нові перспективи їх практичного застосування та наступних хімічних перетворень.Мета роботи -синтез невідомих (3Н-хіназолін-4-іліден)гідразидів N-захищених амінокислот із використанням різних підходів щодо захисту аміногрупи, вивчення особливостей їхньої будови та пошук серед них ефективних біологічно активних речовин із протимікробною та антирадикальною дією.Матеріали та методи. Індивідуальність і будова синтезованих сполук доведена елементним аналізом, хромато-маста 1 H ЯМР-спектрами. Дослідження антирадикальної активності in vitro базується на взаємодії синтезованих сполук з 2,2-дифеніл-1-пікрилгідразилом (DPPH). Мікробіологічну активність вивчили методом серійних розведень на середовищі Мюллера-Хінтона на стандартних штамах мікроорганізмів і грибів: St. aureus ATCC 25923, E. coli ATCC 25922, P. aeruginosa ATCC 27853, C. albicans ATCC 885653.Висновки. Уперше розроблений препаративний метод cинтезу (3Н-хіназолін-4-іліден)гідразидів N-захищених амінокислот як результат взаємодії 4-гідразино хіназоліну та «активованих» N-захищених амінокислот із використанням різноманітних підходів захисту аміногрупи. Встановили, що найбільш надійними субстратами для синтезу відповідних Ключові слова:The synthetic potential of (3H-quinazoline-4-ylidene)hydrazides of carboxylic acids is significant in the context of new s-triazoloquinazolines creation and the obtained data of biological activity is a valid reason for the development of new methods of their synthesis, using a variety of reage nts. The introduction of N-protected aminoacids moieties into 4-hydrazinoquinazoline molecule is an important aspect, which solves this problem and extends the limits of hydrazides usage. The above would allow to change physical-chemical and biological properties of the corresponding hydrazides and it opens new perspectives of their practical application and further chemical transformations.The aim of the w...

To the purposeful search for the DHFR-inhibitors among substituted pteridine-2,4,7triones and 7-aryl-(hetaryl-)furo[3,2-g]pteridine-2,4(1H,3H)-diones for further biological research. Methods. In vitro methods, molecular docking, SAR-analysis, statistical methods. Results. The DHFR-inhibitory activity of substituted 1-methylpteridine-2,4,7-triones (2, 3, 4) and 7-aryl-(hetaryl-)furo[3,2-g]pteridine-2,4(1H,3H)-diones (5, 6) was studied. It was estab- 6) inhibited DHFR by 14.59-52.11 %, and were less active comparing to methotrexate. It was found that the introduction of aryl moiety with electron-accepting group, naphthyl substituent or electron-accepting heterocycle (furan, thiophene and benzofuran) caused an increase in the DHFR-inhibitory activity. Additionally, it was shown, that annulation of the furan cycle to the pteridine system was reasonable in the scope of new DHFR-inhibitors synthesis. Thereby it may be concluded that the calculated values of affinity are not reliable predictors for the DHFR-inhibiting activity of studied compound. However, the molecular docking study may be used for evaluation of the interactions between the studied inhibitor and active center of DHFR. Conclusions. The conducted primary in vitro screening revealed low or moderate DHFR-inhibiting activity of the synthesized compounds. The visualization of molecular docking showed that despite the structural similarity to methotrexate, the obtained compounds form different ligand-enzyme interactions. The calculated values of affinity cannot be used as predictors of DHFR-inhibiting activity because of the absence of correlation between the abovementioned indicators. The obtained compounds may be of interest for further studies aimed at the search for anti-inflammatory, anti-viral, hypoglycemic, hypotensive, anti-ische mic agents due to the expected low-toxicity associated with the slight DHFR-inhibiting activity.