DOI: https://doi.org/10.15587/2519-4852.2016.72700

Synthesis and antimicrobial activity of 3-benzyl-5-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-сarboxylic acid amides

Сергій Віталійович Власов, Валентин Петрович Черних

Abstract


Aim. Targeted preparation of the novel antimicrobial agents among the derivatives of 2-thiothieno[2,3-d]pyrimidine-6-carboxylic acids.

Materials and methods of research. The routine methods of organic synthesis and structural chemistry, the screening methods recommended by WHO for antimicrobial activity studies were used for this work.

Results. The series of the novel amides of 3-benzyl-5-methyl-4-oxo-2-thioxo-1,2,3,4-terahydrothieno[2,3-d]pyrimidine-6-carboxylic acid has been performed using the 1,1'-carbonyldiimidazole promoted interaction of the corresponding acid with amines in the DMF media and their antimicrobial activity was studied.

Conclusions. The study for the amides obtained allowed identification of some derivatives with the wide range of antibacterial activity and no influence on the growth of Candida fungi; the ethyl ester of 3-benzyl-5-methyl-4-oxo-2-thioxo-1,2,3,4-terahydrothieno[2,3-d]pyrimidine-6-carboxylic acid was found to be the most active compound against the strains of Bacillus subtilis and Candida albicans


Keywords


thiophene; pyrimidine; carboxylic acids; amides; imidazolides; mercaptans; alkylation; antimicrobial agents

References


Lewis, K. (2013). Platforms for antibiotic discovery. Nature Reviews Drug Discovery, 12 (5), 371–387. doi: 10.1038/nrd3975

Coates, A. R. M., Hu, Y. (2006). New Strategies for Antibacterial Drug Design. Drugs in R & D, 7 (3), 133–151. doi: 10.2165/00126839-200607030-00001

Gladki, A., Kaczanowski, S., Szczesny, P., Zielenkiewicz, P. (2013). The evolutionary rate of antibacterial drug targets. BMC Bioinformatics, 14 (1), 36. doi: 10.1186/1471-2105-14-36

Krogsgaard-Larsen, P., Stromgaard, K., Madsen, U. (2010). Textbook of Drug Design and Discovery. FL.: CRC Press, 460.

Ghorab, M. M., Osman, A. N., Noaman, E., Heiba, H. I., Zaher, N. H. (2006). The Synthesis of Some New Sulfur Heterocyclic Compounds as Potential Radioprotective and Anticancer Agents. Phosphorus, Sulfur, and Silicon and the Related Elements, 181 (8), 1935–1950. doi: 10.1080/10426500500544014

Jin, J., Schulz, M. J., Wang, Y. (2009). Pat. 2010022308, WO. МПК A01N43/54, A01N43/48. Prolyl hydroxylase inhibitors. rep. 21.08.2009; publ. 25.02.2010.

Tkachenko, O. V., Vlasov, S. V., Kovalenko, S. M. et. al (2013). Synthesis and antimicrobial activity of ethyl 5-methyl-2-(alkylthio)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylates. Journal of organic and pharmaceutical chemistry, 11/3 (43), 9–15.

Vlasov, S. V., Kovalenko, S. M., Osolodchenko, T. P., Chernykh, V. P. (2015). Synthesis and the study of the antimicrobial activity of 3-amino-5-methyl-2-(alkylthio)-4-oxo-N-aryl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamides. News of pharmacy, 1 (81), 6–10.

Vlasov, S. V., Chernykh, V. P., Osolodchenko, T. P. (2015). Synthesis and the antimicrobial activity of ethyl 3-alkyl-2-(alkylthio)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate derivatives. News of pharmacy, 3 (83), 3–8.

Kovalenko, S. M., Vlasov, S. V., Fedocov, A. I. et. al (2008). The synthesis and antimicrobial activities of 7-methyl-6-oxo-2H,6H-thieno[2',3':4,5]pyrimido[2,1-b][1,3,4]thiadiazine-8-carboxylic acid derivatives. Visnik Farmatsii, 1 (53), 3–7.

Ivachtchenko, A., Kovalenko, S., Tkachenko, O. V., Parkhomenko, O. (2004). Synthesis of Substituted Thienopyrimidine-4-ones. Journal of Combinatorial Chemistry, 6 (4), 573–583. doi: 10.1021/cc049946l

Tkachenko, O. V., Vlasov, S. V., Svechnikova, O. M., Zhuravel, A. V. (2013). Determination of ionization constants for derivatives of 5-methylthieno[2,3-d]pyrimidine-6-carboxylic acids. Management, economy and quality assurance in pharmacy, 3 (29), 23–28.

Bacteriological growth media control (2000). Kyiv, 4.

Volianskyi, Y. L., Gritsenko, I. S., Shyrobokov, V. P. et. al (2004). Study the specific activity of antimicrobial medications. Kyiv, 38.

The order «On approval of methodical instructions "Determining the sensitivity of microorganisms to antibacterial preparations"» (2007). Ministry of Health of Ukraine, 167.


GOST Style Citations


1. Lewis, K. Platforms for antibiotic discovery [Text] / K. Lewis // Nature Reviews Drug Discovery. – 2013. – Vol. 12, Issue 5. – P. 371–387. doi: 10.1038/nrd3975

2. Coates, A. R. M. New strategies for antibacterial drug design: targeting non-multiplying latent bacteria [Text] / A. R. M. Coates, Y. Hu // Drugs in R & D. – 2006. – Vol. 7, Issue 3. – P. 133–151. doi: 10.2165/00126839-200607030-00001

3. Gladki, A.The evolutionary rate of antibacterial drug targets [Text] / A. Gladki, S. Kaczanowski, P. Szczesny, P. Zielenkiewicz // BMC Bioinformatics. – 2013. Vol. 14, Issue 1. – P. 36. doi: 10.1186/1471-2105-14-36

4. Krogsgaard-Larsen, P. Textbook of Drug Design and Discovery [Text] / P. Krogsgaard-Larsen, K. Stromgaard, U. Madsen. – FL.: CRC Press, 2010. – 460 p.

5. Ghorab, M. M. The synthesis of some new sulfur heterocyclic compounds as potential radioprotective and anticancer agents [Text] / M. M. Ghorab, A. N. Osman, E. Noaman, H. I. Heiba, N. H. Zaher // Phosphorus, Sulfur, and Silicon and the Related Elements. – 2006. – Vol. 181, Issue 8. – P. 1935–1950. doi: 10.1080/10426500500544014

6. Pat. 2010022308, WO. МПК A01N43/54, A01N43/48. Prolyl hydroxylase inhibitors [Text] / Jin J., Schulz M. J., Wang Y.; Smithkline Beecham Corporation. – rep. 21.08.2009; publ. 25.02.2010.

7. Tkachenko, O. V. Synthesis and antimicrobial activity of ethyl 5-methyl-2-(alkylthio)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylates [Text] / O. V. Tkachenko, S. V. Vlasov, S. M. Kovalenko et. al // Journal of organic and pharmaceutical chemistry. – 2013. – Vol. 11, Issue 3 (43). – P. 9–15.

8. Vlasov, S. V. Synthesis and the study of the antimicrobial activity of 3-amino-5-methyl-2-(alkylthio)-4-oxo-N-aryl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamides [Text] / S. V. Vlasov, S. M. Kovalenko, T. P. Osolodchenko, V. P. Chernykh // News of pharmacy. – 2015. – Issue 1 (81). – P. 6–10.

9. Vlasov, S. V. Synthesis and the antimicrobial activity of ethyl 3-alkyl-2-(alkylthio)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate derivatives [Text] / S. V. Vlasov, V. P. Chernykh, T. P. Osolodchenko // News of pharmacy. – 2015. – Issue 3 (83). – P. 3–8.

10. Коваленко, С. М. Синтез та антимікробна активність похідних 7-метил-6-оксо-2H,6H-тієно[2',3':4,5]піримідо[2,1-b][1,3,4]тіа­діазин-8-карбонової кислоти [Текст] / С. М. Коваленко, С. В. Власов, А. І. Федоcов та ін. // Вісник фармації. – 2008. – № 1 (53). – С. 3–7.

11. Ivachtchenko, A. V. Synthesis of Substituted Thienopyrimidine-4-ones [Text] / A. V. Ivachtchenko, S. M. Kovalenko, O. V. Tkachenko, O. O. Parkhomenko // Journal of Combinatorial Chemistry. – 2004. – Vol. 6, Issue 4. – Р. 573–583. doi: 10.1021/cc049946l

12. Ткаченко, О. В. Визначення констант іонізації похідних 5-метилтієно[2,3-d]піримідин-6-карбонових кислот [Текст] / О. В. Ткаченко, С. В. Власов, О. М. Свєчнікова, А. В. Журавель // Управління, економіка та забезпечення якості в фармації. – 2013. – № 3 (29). – С. 23–28.

13. Бактеріологічний контроль поживних середовищ [Текст]: інформаційний лист [Текст] / МОЗ України № 05. 4. 1 / 1670. – Київ, 2000. – 4 с.

14. Волянський, Ю. Л. Вивчення специфічної активності протимікробних лікарських засобів [Текст]: метод. рек. МОЗ України / Ю. Л. Волянський, І. С. Гриценко, В. П. Широбоков та ін.; ДФЦ МОЗ України. – К., 2004. – 38 с.

15. Наказ «Про затвердження методичних вказівок "Визначення чутливості мікроорганізмів до антибактеріальних препаратів"» [Текст]. – МОЗ України, 2007. – № 167.







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