Startseite Design, synthesis and anti-mycobacterial evaluation of some new iV-phenylpyrazine-2-carboxamides
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Design, synthesis and anti-mycobacterial evaluation of some new iV-phenylpyrazine-2-carboxamides

  • Jan Zitko EMAIL logo , Servusová-Vanásková Barbora , Pavla Paterová , Lucie Navrátilová , František Trejtnar , Jiří Kuneš und Martin Doležal
Veröffentlicht/Copyright: 11. Februar 2016
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Chemical Papers
Aus der Zeitschrift Chemical Papers Band 70 Heft 5

Abstract

N-Phenylpyrazine-2-carboxamides (anilides of pyrazinoic acids with simple substituents in various positions) were previously shown to possess significant biological activities in vitro, markedly anti-mycobacterial and photosynthesis-inhibiting activity. Based on structure-activity relationships (SAR) extracted from previously published series, 25 new anilides of non-substituted pyrazinoic acid (POA), 5-CH3-POA, 6-Cl-POA, 5-tert-butyl-POA and 5-tert-butyl-6-Cl-POA were designed and synthesised. The phenyl part was substituted with simple hydrophobic substituents chosen from methyl and halogens. 5-tert-Butyl-N-(5-fluoro-2-methylphenyl)pyrazine-2- carboxamide (9), N-(3-chloro-4-methylphenyl)-5-methylpyrazine-2-carboxamide (12), 6-chloro-N- (3-chloro-4-methylphenyl)pyrazine-2-carboxamide (13) and 6-chloro-N-(5-iodo-2-methylphenyl)pyrazine-2-carboxamide (18) possessed whole cell anti-mycobacterial activity in vitro against Mycobacterium tuberculosisH37Rv with minimum inhibitory concentration (MIC) of around 10 μM. Importantly, no cytotoxicity in the HepG2 model was detected in vitro at the concentrations tested and the estimated IC50 values were in hundreds of μM, indicating promising selectivity. N-(3-Chloro-4-methylphenyl)pyrazine-2-carboxamide (11) and N-(4-chloro-2-iodophenyl)pyrazine- 2-carboxamide (21) exerted significant activity against Mycobacterium kansasiiwith MIC 12.6 μM and 8.7 μM, respectively. No activity was detected against Mycobacterium avium. SAR were in accordance with those observed for the derivatives previously published.

Keywords: anilide; anti-mycobacterial activity; cytotoxicity in vitro; lipophilicity; pyrazinoic acid

Acknowledgements.

This study was co-financed by the European Social Fund and the state budget of the Czech Republic, project no. CZ.1.07/2.3.00/20.0235, denoted as TEAB. This study was also supported by the Ministry of Health of the Czech Republic (IGA NZ 13346) and SVV 260 183.

Supplementary data

Supplementary data associated with this article can be found in the online version of this paper (DOI: 10.1515/chempap-2015-0246).

References

Abe, Y., Shigeta, Y., Uchimaru, F., Okada, S., & Ozasayama, E. (1969). JP Patent No. 44,012,898. Tokyo, Japan: Japan Patent Office.Suche in Google Scholar

Brennan, P. J. (2003). Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis. Tuberculosis, 83, 91-97. DOI: 10.1016/s1472-9792(02)00089-6.10.1016/s1472-9792(02)00089-6Suche in Google Scholar

Collins, L., & Franzblau, S. G. (1997). Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrobial Agents and Chemotherapy, 41, 1004-1009.10.1128/AAC.41.5.1004Suche in Google Scholar PubMed PubMed Central

Doležal, M., Hartl, J., Miletin, M., Machacek, M., & Kralova, K. (1999). Synthesis and photosynthesis-inhibiting activity of some anilides of substituted pyrazine-2-carboxylic acids. Chemical Papers, 53, 126-130.10.3390/ecsoc-4-01921Suche in Google Scholar

Dolezal, M., Miletin, M., Kunes, J., & Kralova, K. (2002). Substituted amides of pyrazine-2-carboxylic acids: Synthesis and biological activity. Molecules, 7, 363-373. DOI: 10.3390/70300363.10.3390/70300363Suche in Google Scholar

Dolezal, M., Palek, L., Vinsova, J., Buchta, V., Jampilek, J., & Kralova, K. (2006). Substituted pyrazinecarboxamides: Synthesis and biological evaluation. Molecules, 11, 242-256. DOI: 10.3390/11040242.10.3390/11040242Suche in Google Scholar PubMed PubMed Central

Dolezal, M., Cmedlova, P., Palek, L., Vinsova, J., Kunes, J., Buchta, V., Jampilek, J., & Kralova, K. (2008). Synthesis and antimycobacterial evaluation of substituted pyrazinecarboxamides. European Journal of Medicinal Chemistry, 43, 1105-1113. DOI: 10.1016/j.ejmech.2007.07.013.10.1016/j.ejmech.2007.07.013Suche in Google Scholar PubMed

Doležal, M., Zitko, J., Kesetovicova, D., Kunes, J., & Svobodova, M. (2009). Substituted N-phenylpyrazine-2-carboxamides: Synthesis and antimycobacterial evaluation. Molecules, 14, 4180-4189. DOI: 10.3390/molecules14104180.10.3390/molecules14104180Suche in Google Scholar PubMed PubMed Central

Dolezal, M., Zitko, J., Osicka, Z., Kunes, J., Vejsova, M., Buchta, V., Dohnal, J., Jampilek, J., & Kralova, K. (2010). Synthesis, antimycobacterial, antifungal and photosynthesis-inhibiting activity of chlorinated N-phenylpyrazine-2-carbox-amides. Molecules, 15, 8567-8581. DOI: 10.3390/molecules 15128567.10.3390/molecules15128567Suche in Google Scholar PubMed PubMed Central

Dolezal, M., & Kralova, K. (2011). Synthesis and evaluation of pyrazine derivatives with herbicidal activity. In P. M. Larramendy (Ed.), Herbicides, theory and applications (pp. 581610). Rijeka, Croatia: InTech.Suche in Google Scholar

Dolezal, M., Kesetovic, D., & Zitko, J. (2011). Antimy-cobacterial evaluation of pyrazinoic acid reversible derivatives. Current Pharmaceutical Design, 17, 3506-3514. DOI: 10.2174/138161211798194477.10.2174/138161211798194477Suche in Google Scholar PubMed

Dolezal, M., Zitko, J., & Jampilek, J. (2012). Pyrazinecarboxylic acid derivatives with antimycobacterial activity. In P. J. Cardona (Ed.), Understanding tuberculosis - New approaches to fighting against drug resistance. Rijeka, Croatia: InTech.Suche in Google Scholar

Gonec, T., Zadrazilova, I., Nevin, E., Kauerova, T., Pesko, M., Kos, J., Oravec, M., Kollar, P., Coffey, A., O’Mahony, J., Cizek, A., Kralova, K., & Jampilek, J. (2015). Synthesis and biological evaluation of N-alkoxyphenyl-3-hydroxynaphthal- ene-2-carboxanilides. Molecules, 20, 9767-9787. DOI: 10. 3390/molecules20069767.10. 3390/molecules20069767Suche in Google Scholar

Kos, J., Nevin, E., Soral, M., Kushkevych, I., Gonec, T., Bobal, P., Kollar, P., Coffey, A., O’Mahony, J., Liptaj, T., Kralova, K., & Jampilek, J. (2015a). Synthesis and antimycobacterial properties of ring-substituted 6-hydroxynaphthalene-2- carboxanilides. Bioorganic & Medicinal Chemistry, 23, 20352043. DOI: 10.1016/j.bmc.2015.03.018.10.1016/j.bmc.2015.03.018Suche in Google Scholar PubMed

Kos, J., Zadrazilova, I., Nevin, E., Soral, M., Gonec, T., Kollar, P., Oravec, M., Coffey, A., O’Mahony, J., Liptaj, T., Kralova, K., & Jampilek, J. (2015b). Ring-substituted 8- hydroxyquinoline-2-carboxanilides as potential antimycobacterial agents. Bioorganic & Medicinal Chemistry, 23, 41884196. DOI: 10.1016/j.bmc.2015.06.047.10.1016/j.bmc.2015.06.047Suche in Google Scholar PubMed

Kratky, M., & Vinsova, J. (2011). Salicylanilide ester prodrugs as potential antimicrobial agents - a Review. Current Pharmaceutical Design, 17, 3494-3505. DOI: 10.2174/13816121 1798194521.10.2174/13816121 1798194521Suche in Google Scholar

Krätky, M., Vinsova, J., Volkova, M., Buchta, V., Trejtnar, F., & Stolarikova, J. (2012). Antimicrobial activity of sulfonamides containing 5-chloro-2-hydroxybenzaldehyde and 5-chloro-2- hydroxybenzoic acid scaffold. European Journal of Medicinal Chemistry, 50, 433-440. DOI: 10.1016/j.ejmech.2012.01.060.10.1016/j.ejmech.2012.01.060Suche in Google Scholar PubMed

Krätky, M., Vinsova, J., Novotna, E., & Stolarikova, J. (2014). Salicylanilide pyrazinoates inhibit in vitro multidrug-resistant Mycobacterium tuberculosis strains, atypical mycobacteria and isocitrate lyase. European Journal of Pharmaceutical Sciences, 53, 1-9. DOI: 10.1016/j.ejps.2013.12. 001.10.1016/j.ejps.2013.12. 001Suche in Google Scholar

Krätký, M., Mandikova, J., Trejtnar, F., Buchta, V., Stolarikova, J., & Vinsova, J. (2015). Synthesis and antimicrobial activity of sulphamethoxazole-based ureas and imidazolidine-2,4,5-triones. Chemical Papers, 69, 1108-1117. DOI: 10.1515/chempap-2016-0109.10.1515/chempap-2016-0109Suche in Google Scholar

Merget, B., Zilian, D., Muller, T., & Sotriffer, C. A. (2013). MycPermCheck: the Mycobacterium tuberculosis permeability prediction tool for small molecules. Bioinformatics, 29, 62-68. DOI: 10.1093/bioinformatics/bts641.10.1093/bioinformatics/bts641Suche in Google Scholar PubMed

Nemeček, P., Mocak, J., Lehotay, J., & Waisser, K. (2013). Prediction of anti-tuberculosis activity of 3-phenyl-2H-1,3- benzoxazine-2,4(3H)-dione derivatives. Chemical Papers, 67, 305-312. DOI: 10.2478/s11696-012-0278-4.10.2478/s11696-012-0278-4Suche in Google Scholar

Ngo, S. C., Zimhony, O., Chung, W. J., Sayahi, H., Jacobs, W. R., Jr., & Welch, J. T. (2007). Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs. Antimicrobial Agents and Chemotherapy, 51, 24302435. DOI: 10.1128/aac.01458-06.10.1128/aac.01458-06Suche in Google Scholar

Owen, T. C. (1993). U.S. Patent No. 5,185,450. Washington, D.C., USA: U.S. Patent and Trademark Office.Suche in Google Scholar

Sayahi, H., Pugliese, K. M., Zimhony, O., Jacobs, W. R., Jr., Shekhtman, A., & Welch, J. T. (2012). Analogs of the antituberculous agent pyrazinamide are competitive inhibitors of NADPH binding to M. tuberculosis fatty acid synthase I. Chemistry & Biodiversity, 9, 2582-2596. DOI: 10.1002/cbdv.201200291.10.1002/cbdv.201200291Suche in Google Scholar PubMed

Servusova, B., Eibinova, D., Doležal, M., Kubicek, V., Paterova, P., Pesko, M., & Kralova, K. (2012). Substituted N-benzylpyrazine-2-carboxamides: Synthesis and biological evaluation. Molecules, 17, 13183-13198. DOI: 10.3390/ molecules171113183.10.3390/ molecules171113183Suche in Google Scholar

Servusova, B., Paterova, P., Mandikova, J., Kubicek, V., Kucera, R., Kunes, J., Doležal, M., & Zitko, J. (2014). Alkylamino derivatives of pyrazinamide: Synthesis and antimycobacterial evaluation. Bioorganic & Medicinal Chemistry Letters, 24, 450-453. DOI: 10.1016/j.bmcl.2013.12.054.10.1016/j.bmcl.2013.12.054Suche in Google Scholar PubMed

Servusova-Vanaskova, B., Jandourek, O., Paterova, P., Kordulakova, J., Plevakova, M., Kubicek, V., Kucera, R., Garaj, V., Naesens, L., Kunes, J., Doležal, M., & Zitko, J. (2015a). Alkylamino derivatives of N-benzylpyrazine-2- carboxamide: Synthesis and antimycobacterial evaluation. MedChemComm, 6, 1311-1317. DOI: 10.1039/c5md00178a.10.1039/c5md00178aSuche in Google Scholar

Servusova-Vanaskova, B., Paterova, P., Garaj, V., Mandikova, J., Kunes, J., Naesens, L., Jilek, P., Doležal, M., & Zitko, J. (2015b). Synthesis and antimicrobial evaluation of 6- alkylamino-N-phenylpyrazine-2-carboxamides. Chemical Biology & Drug Design, 4, 674-681. DOI: 10.1111/cbdd.12536.10.1016/j.bmc.2015.06.047Suche in Google Scholar PubMed

Shi, W. L., Zhang, X. L., Jiang, X., Yuan, H. M., Lee, J. S., Barry, C. E., Wang, H. H., Zhang, W. H., & Zhang, Y. (2011). Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science, 333, 1630-1632. DOI: 10.1126/science. 1208813.10.2174/13816121 1798194521Suche in Google Scholar

Singh, M., Sasi, P., Rai, G., Gupta, V. H., Amarapurkar, D., & Wangikar, P. P. (2011). Studies on toxicity of antituber- cular drugs namely isoniazid, rifampicin, and pyrazinamide in an in vitro model of HepG2 cell line. Medicinal Chemistry Research, 20, 1611-1615. DOI: 10.1007/s00044-010-9405-3.10.1016/j.ejmech.2012.01.060Suche in Google Scholar PubMed

Tostmann, A., Bchempape, M. J., Aarnoutse, R. E., De Lange, W. C. M., Van Der Ven, A., & Dekhuijzen, R. (2008a). Antituberculosis drug-induced hepatotoxicity: Concise up-to-date review. Journal of Gastroenterology and Hepatology, 23, 192-202. DOI: 10.1111/j.1440-1746.2007.05207.x.10.1016/j.ejps.2013.12. 001Suche in Google Scholar

Tostmann, A., Bchempape, M. J., Peters, W. H. M., Roelofs, H. M. J., Aarnoutse, R. E., van der Ven, A., & Dekhuijzen, P. N. R. (2008b). Isoniazid and its toxic metabolite hydrazine induce in vitro pyrazinamide toxicity. International Journal of Antimicrobial Agents, 31, 577-580. DOI: 10.1016/j.ijantimicag.2008.01.022.10.1515/chempap-2016-0109Suche in Google Scholar

Venturello, C., & D’Aloisio, R. (1986). European Patent No. 0,201,934. Munich, Germany: European Patent Office.Suche in Google Scholar

World Health Organisation (2014). WHO. Global tuberculosis report 2014Geneva, Switzerland: WHO Press. (WHO/ HTM/TB/2014.08)Suche in Google Scholar

Yang, J. J., Liu, Y. D., Bi, J., Cai, Q. X., Liao, X. L., Li, W. Q., Guo, C. Y., Zhang, Q., Lin, T. W., Zhao, Y. F., Wang, H. H., Liu, J., Zhang, X. L., & Lin, D. H. (2015). Structural basis for targeting the ribosomal protein S1 of Mycobacterium tuberculosis by pyrazinamide. Molecular Microbiology, 95, 791803. DOI: 10.1111/mmi.12892.10.1111/mmi.12892Suche in Google Scholar PubMed

Zitko, J., Servusova, B., Paterova, P., Mandikova, J., Kubicek, V., Kucera, R., Hrabcova, V., Kunes, J., Soukup, O., & Doležal, M. (2013). Synthesis, antimycobacterial activity and in vitro cytotoxicity of 5-chloro-N-phenylpyrazine-2- carboxamides. Molecules, 18, 14807-14825. DOI: 10.3390/ molecules181214807.10.3390/molecules181214807Suche in Google Scholar PubMed PubMed Central

Zitko, J., Servusova, B., Janoutova, A., Paterova, P., Mandikova, J., Garaj, V., Vejsova, M., Marek, J., & Doležal, M. (2015). Synthesis and antimycobacterial evaluation of 5- alkylamino-N-phenylpyrazine-2-carboxamides. Bioorganic & Medicinal Chemistry, 23, 174-183. DOI: 10.1016/j.bmc.2014. 11.014.10.1016/j.bmc.2014.11.014Suche in Google Scholar PubMed

Received: 2015-8-26
Received: 2015-9-30
Accepted: 2015-10-21
Published Online: 2016-2-11
Published in Print: 2016-5-1

© 2015 Institute of Chemistry, Slovak Academy of Sciences

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https://doi.org/10.1515/chempap-2015-0246
Schlagwörter für diesen Artikel
anilide; anti-mycobacterial activity; cytotoxicity in vitro; lipophilicity; pyrazinoic acid

Artikel in diesem Heft

  1. Original Paper
  2. Preparation and characterisation of gelatine hydrogels predisposed to use as matrices for effective immobilisation of biocatalystst‡
  3. Original Paper
  4. Photocatalytic reduction of nitro aromatic compounds to amines using a nanosized highly active CdS photocatalyst under sunlight and blue LED irradiation
  5. Original Paper
  6. Synthesis of butyrate using a heterogeneous catalyst based on polyvinylpolypyrrolidone
  7. Original Paper
  8. Behaviour of selected pesticide residues in blackcurrants (Ribes nigrum) during technological processing monitored by liquid-chromatography tandem mass spectrometry
  9. Original Paper
  10. Influence of solvents and novel extraction methods on bioactive compounds and antioxidant capacity of Phyllanthus amarus
  11. Original Paper
  12. Investigation of phytochemicals and antioxidant capacity of selected Eucalyptus species using conventional extraction
  13. Original Paper
  14. Innovative approach to treating waste waters by a membrane capacitive deionisation system
  15. Original Paper
  16. Liquid—liquid equilibria of ternary systems of 1-hexene/hexane and extraction solvents
  17. Original Paper
  18. Design of extractive distillation process with mixed entraineri‡
  19. Original Paper
  20. Kinetic study of non-reactive iron removal from iron-gall inks
  21. Original Paper
  22. Chemoenzymatic polycondensation of para-benzylamino phenol
  23. Original Paper
  24. Copper corrosion behaviour in acidic sulphate media in the presence of 5-methyl-lH-benzotriazole and 5-chloro-lH-benzotriazole
  25. Original Paper
  26. Synthesis of new 5-bromo derivatives of indole and spiroindole phytoalexins
  27. Original Paper
  28. Design, synthesis and anti-mycobacterial evaluation of some new iV-phenylpyrazine-2-carboxamides
  29. Short Communication
  30. Convenient amidation of carboxyl group of carboxyphenylboronic acids
  31. Short Communication
  32. A novel intramolecular reversible reaction between the hydroxyl group and isobutenylene chain in a cyclophane-type macrocycle
  33. Erratum
  34. Erratum to “Adriana Bakalova, Boryana Nikolova-Mladenova, Rossen Buyukliev, Emiliya Cherneva, Georgi Momekov, Darvin Ivanov: Synthesis, DFT calculations and characterisation of new mixed Pt(II) complexes with 3-thiolanespiro-5′-hydantoin and 4-thio-1H-tetrahydropyranspiro-5′-hydantoin”, Chemical Papers 70 (1) 93–100 (2016)*
  35. Erratum
  36. Erratum to “Martyna Rzelewska, Monika Baczyńska, Magdalena Regel-Rosocka, Maciej Wiśniewski: Trihexyl(tetradecyl)phosphonium bromide as extractant for Rh(III), Ru(III) and Pt(IV) from chloride solutions”, Chemical Papers 70 (4) 454–460 (2016)*
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