The synthesis, reactivity and the antimicrobial activity of substituted thieno[2,3-d]pyrimidine-4(3H)-thio(seleno)nes

ISSN 2308-8303 Journal of Organic and Pharmaceutical Chemistry. – 2015. – Vol. 13, Iss. 4 (52) UDC 547.854.83 THE SYNTHESIS, REACTIVITY AND THE ANTIMICROBIAL ACTIVITY OF SUBSTITUTED THIENO[2,3-d]PYRIMIDINE4(3H)-THIO(SELENO)NES D.O.Kolomieitsev1, V.I.Markov1, V.O.Astakhina1, S.I.Kovalenko2, S.A.Varenichenko1, O.V.Kharchenko1 Ukrainian State University of Chemical Technology 8, av. Gagarina, Dnepropetrovsk, 49005, Ukraine. E-mail: 2 Zaporozhye State Medical University 1 Key words: thieno[2,3-d]pyrimidine-4(3H)-thio(seleno)nes; alkylation; antibacterial activity A new series of R1,R2-thieno[2,3-d]pyrimidine-4(3H)-one, thione and selenone derivatives have been synthesized; the reaction of alkylation of the compounds obtained has been studied. Their structures have been confirmed by the NMR 1H and mass spectra, and elemental analysis. The antibacterial and antifungal activities in vitro against three bacterial and two fungal pathogens have been revealed using the stiff plate agar diffusion method and the serial dilution method. The minimal bactericidal, fungicidal and bacteriostatic concentrations have been obtained. The pharmacological screening has shown that some of the compounds obtained possess a good antimicrobial activity. The culture of S.aureus. appeared to be the most sensitive to compound 10a. The best fungistatic indicators against A.niger have been found for compounds 4a and 9a. СИНТЕЗ, РЕАКЦІЙНА ЗДАТНІСТЬ ТА АНТИМІКРОБНА АКТИВНІСТЬ ЗАМІЩЕНИХ ТІЄНО[2,3-d]ПІРИМІДИН4(3Н)-ТІО(СЕЛЕНО)НІВ Д.О.Коломійцев, В.І.Марков, В.О.Астахіна, С.І.Коваленко, С.А.Варениченко, О.В.Харченко Ключові слова: тієно[2,3-d]піримідин-4(3Н)-тіо(селено)ни; алкілування; антибактеріальна активність Синтезовано ряд нових похідних R1,R2-тієно[2,3-d]піримідин-4(3Н)-онів, тіонів і селенонів та вивчено реакцію алкілування отриманих продуктів. Структури отриманих продуктів встановлені за допомогою даних ЯМР 1Н та мас-спектрів і даних елементного аналізу. Антибактеріальну і фунгістатичну активність in vitro проти 3 культур бактерій і двох видів грибів було встановлено за допомогою методу дифузії речовини в агар і методу серійних розведень. Були визначені мінімальні концентрації бактеріальної, фунгістатичної і бактеріостатичної активності. Фармакологічне дослідження підтвердило, що деякі з отриманих продуктів проявляють добру антимікробну активність. Культура бактерії S.aureus. найбільш чутлива до сполуки 10а. Найкращі фунгістатичні показники проти цвільового гриба A.niger виявлені для сполук 4а і 9а. СИНТЕЗ, РЕАКЦИОННАЯ СПОСОБНОСТЬ И АНТИМИКРОБНАЯ АКТИВНОСТЬ ЗАМЕЩЕННЫХ ТИЕНО[2,3-d] ПИРИМИДИН-4(3Н)-ТИО(СЕЛЕНО)НОВ Д.О.Коломейцев, В.И.Марков, В.О.Астахина, С.И.Коваленко, С.А.Варениченко, А.В.Харченко Ключевые слова: тиено[2,3-d]пиримидин-4(3Н)-тио(селено)ны; алкилирование; антибактериальная активность Синтезирован ряд новых производных R1,R2-тиено[2,3-d]пиримидин-4(3Н)-онов, тионов и селенонов, изучена реакция алкилирования полученных соединений. Структуры полученных соединений установлены с помощью данных ЯМР 1Н и масс-спектров, а также данных элементного анализа. Антибактериальная и фунгистатическая активность in vitro против трёх видов бактерий и двух видов грибов была обнаружена с помощью метода диффузии вещества в агар и метода серийного разведения. Определены минимальные концентрации бактериальной, фунгицидной и бактериостатической активности. Фармакологическое исследование подтвердило, что некоторые из полученных продуктов проявляют хорошую антимикробную активность. Культура бактерии S.aureus наиболее чувствительна к соединению 10а. Наилучшие фунгистатические показатели против цвелевого гриба A.niger определены для соединений 4а и 9а. Thieno[2,3-d]pyrimidines are of great interest in pharmaceutical industry due to the potent physiological properties such as blood platelet aggregation inhibition, the antiviral and anti-inflammatory activity [1-3]. Molecular docking also shows that thieno[2,3-d] pyrimidines reveal the increased activity as inhibitors for PARP-1 (poly(ADP-ribose)-polymerase-1) [4]. Although the synthesis of thieno[2,3-d]pyrimidines has attracted much attention in organic synthesis, so far 32 only few methods have been reported for the synthesis of benzothieno[2,3-d]pyrimidines [5, 6]. Moreover, thieno[2,3-d]pyrimidines containing active functional groups are especially of great interest. The presence of different groups (R=O, S, Se) in position 4 of thieno[2,3-d]pyrimidine causes the possibility of further structural modification by different reagents. Thus, as part of our ongoing research in discovery of new biologically active thienopyrimidine deriva- Журнал органічної та фармацевтичної хімії. – 2015. – Т. 13, вип. 4 (52) tives the aim of this work was to develop several simple and highly efficient methods of the synthesis of R1,R2-thieno[2,3-d]pyrimidines 3a-c and 4a-c, the study their alkylation and antibacterial properties depending on atom in position 4 of the heterocycle. The synthesis strategy of the starting thieno[2,3-d] pyrimidin-4(3H)-ones 1a-c was based on the classical Hewald reaction reported in the literature [7, 8]. Treatment of ketones with ethyl 2-cyanoacetate gave the corresponding 2-aminothiophene carboxylic esters that, in turn, gave compounds 1a-c upon refluxing in formamide. Further compounds 1a-c were converted into the corresponding 4-chlorothieno[2.3-d] pyrimidines 2a-c under the action of phosphorus oxychloride and dimethylaniline. Thieno[2,3-d]pyrimidine-4(3H)-thiones 3a-c and benzothieno[2,3-d] pyrimidine-4(3Н)-selenones 4a-c were obtained upon treatment with such nucleophile compounds as NaHS(NaHSe) and Lawsan reagent, respectively (Scheme 1). The presence of different reaction centres in thieno[2,3-d]pyrimidines 1a-c and 3,4a-c made possible to obtain a number of new potential biologically active compounds. The alkylation of the starting compounds 1a-c was studied at 50-70°C in the presence of alkali (Scheme 2). The acidity of the NH group under these conditions provided the easy formation of the anion, which underwent alkylation. Since substance 3а-с can exist in the form of thiole and thione, the formation of both S- and N- derivatives could be expected depending on the reaction conditions. Thus, when pyrimidine-4(3H)-thiones 3a-c are refluxed with NaOH and the corresponding derivatives of chloroacetic acid in ethanol, S-substituted derivatives are supposed to be obtained. However, the use of NaHCO3 and DMF as a solvent did not lead to formation of N-substituted derivatives as it was expected. It was found that the alkylation occurred at the more nucleophilic sulphur atom in both cases (Scheme 3). All the final products were isolated as crystalline substances with a high melting point (Table 4). The structures of the compounds obtained were confirmed by IR- and NMR 1H spectroscopy (Table 5). The formation of the energetically preferable aromatic system was confirmed by the chemical shift of the signal of protons of the -CH group (8.7-8.9 (...truncated)