Synthesis, antiinflammatory and antimicrobial activity of 6-(1H-benzimidazol-2-yl)-5-methyl-4-(alkylthio)thieno[2,3-d]pyrimidines

S. V. Vlasov, V. P. Chernykh

Abstract


An effective method for synthesis of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidine-4(3H)-thione starting from the corresponding 4-oxo analog has been developed. For the chemical diversity enlargement the alkylation of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidine-4(3H)-thione with benzyl chloroides, chloroacetamides and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazoles, which resulted in the series of 6-(1H-benzimidazol-2-yl)-5-methyl-4-(alkylthio)thieno[2,3-d]pyrimidines has been carried out. For the compounds obtained the screening of antimicrobial activity by the "agar well" diffusion method and antiinflammatory activity using the carrageenan rat paw edema model were performed. The results of the tests showed that alkylation of the sulphur atom at position 4 of thieno[2,3-d]pyrimidine improves the antimicrobial properties. Most of the 6-(1H-benzimidazol-2-yl)-5-methyl-4-(alkylthio)thieno[2,3-d]pyrimidines were active against the Candida albicans fungi strain. The compound containing the chlorine atom in the phenyl radical of thioacetamide fragment at position 4 of thieno[2,3-d]pyrimidine were found to be active against Staphylococcus aureus, Escherichia coli and Bacillus subtilis. After the treatment of rats with 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidine-4(3H)-one, 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidine-4(3H)-thione and 2-{[6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4-yl]thio}-N-phenylacetamide (dosages 1, 10 and 50 mg/kg) no statistically significant and dose-dependent reduction of the edema was observed versus the control pathology. The anti-inflammatory activity of the tested compounds was about 20%, which was 2-2,5 times less than the activity of the reference drug (diclofenac sodium).

Keywords


thiophene; pyrimidine; mercaptans; antiinflammatory; antibcterials

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References


Власов С. В., Заремба О. В., Коваленко С. М. та ін. // Журнал орг. фарм. хім. – 2011. –Т. 9, №4. – С. 24 – 30.

Власов С. В., Коваленко С. М., Федосов А. І. та ін. // Журнал орг. фарм. хім. – 2011. – Т. 9, №3. С. 51 – 55.

Власов С. В., Коваленко С. М., Черних В. П. // Журнал орг. фарм. хім. – 2013. – Т.11, №2. – С. 41 – 46.

Доклінічні дослідження лікарських засобів. Методичні рекомендації// За ред. О.В. Стефанова. – Київ. – 2001. – 528 с.

Некрасова Л.С., Свита В.М., Глушкевич Т.Г. та ін. Методичні вказівки "Визначення чутливості мікроорганізмів до антибактеріальних препаратів "— Київ, 2007. — 79 с.

American Society for Microbiology. Manual of Antimicrobial Susceptibility Testing. American Society for Microbiology: Washington. 2005. – P. 236.

Ansari K.F., Lal C. // Eur. J.Med. Chem. – 2009. – Vol. 44, No. 5. – P. 2294-2299.

Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement. Document M100-S22, Vol. 32, No. 3, CLSI, Wayne, PA, January, 2012.

Di Rosa M., Giround J.P., Williughby D.A. // J. Pathol. – 1971. – Vol. 104. - № 1. – P. 15-29.

Evans D., Hicks T. A., Williamson W. R. N. et al. // Eur. J. Med. Chem. – 1996. – Vol. 31, № 7-8. – P. 635-642.

Grinev A.N, Kaplina N.V. // Chem. of Heterocycl. Compnd. — 1985. — Vol. 21, № 7. – P. 767 - 770.

Achar K.C.S., Hosamani K.M., Seetharamareddy H.R.// Eur. J. Med. Chem. – 2010. – Vol. 45, №5. – P. 2048-2054.

Kotaiah Y., Harikrishna N., Nagaraju K., Venkata Rao C. // Eur. J. Med. Chem. – 2012. – Vol. 58. – P. 340- 345.

Kumar B.V.S., Vaidya S.D., Kumar R.V. et al. // Eur. J. Med. Chem., 2006. – Vol. 41, №5. – P. 599–604.

Leonard J.T., Jeyaseeli L., Kumar M., Sivakumar R. // Asian J. Chem. – 2006. – Vol. 18, №2. – P. 1104-1108.

Mariappan G., Bhuyan N. R., Kumar P. // Indian Journal of Chemistry -Section B. – 2011. – Vol.50B, №9. – P. 1216-1219.

Mavrova A.T., Anichina K.K., Vuchev D.I. et al. // Eur. J. Med. Chem. – 2006. –Vol.41, №12. – P. 1412-1420.

Pat. US 20070208040 (2007); Chem. Abstr., 147, 344106 (2007).

Pat. US 20130102601 (2013); Chem. Abstr., 158, 620878 (2013).

Pat. US 20130123231 (2013); Chem. Abstr., 158, 711376 (2013).

Sravanthi M., Nagaraju N., Manikanta K., Mogalabi Sk. et al. // J. Chem. Pharm. Res. – 2012. – Vol. 4, №8. P. 3832-3836.

Vlasov S. V., Kovalenko S. M., Chernykh V. P., Krolenko K.Yu. // J. Chem. Pharm. Res. –2014. – Vol. 6, № 6. – P. 22 – 27.

Vlasov S.V., Kovalenko S.M., Chernykh V.P., Krolenko K.Yu. // J. Org. Pharm. Chem.– 2015. – Vol. 13, №2. – P. 30-34.

Yadav S., Kumar P., Clercq E.D. et al. // Eur. J. Med. Chem. – 2010. – Vol. 45, № 12. – P. 5985-5997.


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DOI: https://doi.org/10.24959/88712

Abbreviated key title: Vìsn. farm.

ISSN 2415-8844 (Online), ISSN 1562-7241 (Print)