Chemical Papers

, Volume 65, Issue 3, pp 352–366 | Cite as

Antimycobacterial 3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones substituted on phenyl and benzoxazine moiety in position 6

  • Eva PetrlíkováEmail author
  • Karel Waisser
  • Rafael Doležal
  • Pavel Holý
  • Jiří Gregor
  • Jiři Kuneš
  • Jarmila Kaustová
Original Paper


A series of forty-five derivatives of 3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and forty-five derivatives of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones was synthesised. The compounds exhibited in-vitro activity against Mycobacterium tuberculosis, M. kansasii (two strains), and M. avium. The most active derivatives were more active than isonicotinhydrazide (INH). The quantitative relationships between the structure and antimycobacterial activity were calculated. The activity against M. tuberculosis increased with the lipophilicity of the substituents.


benzoxazine thioxo group tuberculostatics QSAR antimycobacterial activity 


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  1. Aaron, L., Saadoun, D., Calatroni, I., Launay, O., Mémain, N., Vincent, V., Marchal, G., Dupont, B., Bouchaud, O., Valeyre, D., & Lortholary, O. (2004). Tuberculosis in HIV-infected patients: a comprehensive review. Clinical Microbiology and Infection, 10, 388–398. DOI: 10.1111/j.1469-0691.2004.00758.x.CrossRefGoogle Scholar
  2. Dye, C. (2009). Doomsday postponed? Preventing and reversing epidemics of drug-resistant tuberculosis. Nature Reviews Microbiology, 7, 81–87. DOI: 10.1038/nrmicro2048.CrossRefGoogle Scholar
  3. Free, S. M., & Wilson, J. W. (1964). A mathematical contribution to structure-activity studies. Journal of Medicinal Chemistry, 7, 395–399. DOI: 10.1021/jm00334a001.CrossRefGoogle Scholar
  4. Fujita, T., & Ban, T. (1971). Structure-activity relation. 3. Structure-activity study of phenethylamines as substrates of biosynthetic enzymes of sympathetic transmitters. Journal of Medicinal Chemistry, 14, 148–152. DOI: 10.1021/jm00284a016.CrossRefGoogle Scholar
  5. Golbraikh, A., & Tropsha, A. (2002). Beware of q2! Journal of Molecular Graphics and Modelling, 20, 269–276. DOI: 10.1016/S1093-3263(01)00123-1.CrossRefGoogle Scholar
  6. Gupta, R. A., Gupta, A. K., Soni, L. K., & Kaskhedikar, S. G. (2009). Study of physicochemical properties-antitubercular activity relationship of naphtalene-1,4-dione analogs: A QSAR approach. Chemical Papers, 63, 723–730. DOI: 10.2478/s11696-009-0080-0.CrossRefGoogle Scholar
  7. Hansch, C., & Leo, A. J. (1979). Substituent constants for correlation analysis in chemistry and biology. New York, NY, USA: Wiley.Google Scholar
  8. Hlasta, D. J., Demers, J. P, Foleno, B. D, Frago-Spano, S. A., Guan, J., Hilliar, J. J., Macielag, M. J., Ohemeng, K. A., Sheppard, C. M., Sui, Z., Webb, G. C., Weidner-Wells, M. A., Werblood, H., & Barrett, J. F. (1998). Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity: Pharmacofore identification based on the screening hit closantel. Bioorganic & Medicinal Chemistry Letters, 8, 1923–1928. DOI: 10.1016/S0960-894X(98)00326-6.CrossRefGoogle Scholar
  9. Li, X., Liu, N., Zhang, H., Knudson, S. E., Slayden, R. A., & Tonge, P. J. (2010). Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: Novel antibacterial agents against Mycobacterium tuberculosis. Bioorganic & Medicinal Chemistry Letters, 20, 6306–6309. DOI: 10.1016/j.bmcl.2010.08.076.CrossRefGoogle Scholar
  10. Macielag, M. J., Demers, J. P., Fraga-Spano, S. A., Hlasta, D. J., Johnson, S. G., Kanojia, R. M., Russell, R. K., Sui, Z., Weidner-Wells, M. A., Werblood, H., Foleno, B. D., Goldschmidt, R. M., Loeloff, M. J., Webb, G. C., & Barrett, J. F. (1998). Substituted salicylanilides as inhibitors of two-component regulatory systems in bacteria. Journal of Medicinal Chemistry, 41, 2939–2943. DOI: 10.1021/jm9803572.CrossRefGoogle Scholar
  11. Matyk, J., Waisser, K., Dražková, K., Kuneš, J., Klimešová, V., Palát, K., Jr., Kaustová, J. (2005). Heterocyclic isosters of antibacterial salicylanilides. II Farmaco, 60, 399–408. DOI: 10.1016/j.farmac.2005.02.002.CrossRefGoogle Scholar
  12. Naidoo, K., Naidoo, K., Padayatchi, N., & Karim, Q. A. (2011). HIV-associated tuberculosis. Clinical and Developmental Immunology, 2011, Article ID 585919, 8 pages. DOI: 10.1155/2011/585919.Google Scholar
  13. Nemeček, P., Ďurčeková, T., Mocák, J., & Waisser, K. (2009). Chemometrical analysis of computed QSAR parameters and their use in biological activity prediction. Chemical Papers, 63, 84–91. DOI: 10.2478/s11696-008-0089-9.CrossRefGoogle Scholar
  14. O’Brien, R. J., & Nunn, P. P. (2001). The need for new drugs against tuberculosis. American Journal of Respiratory and Critical Care Medicine, 163, 1055–1058.Google Scholar
  15. Petrlíková, E., Waisser, K., Jílek, P., & Dufková, I. (2010). Antibacterial activity of N-nenzylsalicylthioamides, Folia Microbiologica, 55, 418–421. DOI: 10.1007/s12223-010-0070-1.CrossRefGoogle Scholar
  16. Petrlíková E., Waisser K., Palát, K., Kuneš, J., Kaustová J. (2011). A new group of potential antituberculotics: N-(2-pyridylmethyl)salicylamides and N-(3-pyridylmethyl)salicylamides, Chemical Papers, 65, 52–59. DOI: 10.2478/s11696-010-0084-9.CrossRefGoogle Scholar
  17. Saeed, A., & Ashraf, Z. (2008). Synthesis of some 3-aryl-1H-isochromene-1-thiones. Journal of Heterocyclic Chemistry, 45, 679–682. DOI: 10.1002/jhet.5570450307.CrossRefGoogle Scholar
  18. Schroeder, E. K., de Souza, O. N., Santos, D. S., Blanchard, J. S., & Basso, L. A. (2002). Drugs that inhibit mycolic acid biosynthesis in mycobacterium tuberculosis. Current Pharmaceutical Biotechnology, 3, 197–225. DOI: 10.2174/1389201023378328.CrossRefGoogle Scholar
  19. Tortoli, E. (2009). Clinical manifestations of nontuberculous mycobacteria infections. Clinical Microbiology and Infection, 15, 906–910. DOI: 10.1111/j.1469-0691.2009.03014.x.CrossRefGoogle Scholar
  20. van den Boogaard, J., Kibiki, G. S., Kisanga, E. R., Boeree, M. J., & Aarnoutse, R. E. (2009). New drugs against tuberculosis: Problems, progress, and evaluation of agents in clinical development. Antimicrobial Agents and Chemotherapy, 53, 849–862. DOI: 10.1128/AAC.00749-08.CrossRefGoogle Scholar
  21. Wagner, G., Singer, D., & Weuffen, W. (1966). Studies on 2-hydroxythiobenzamide and 2-hydroxythiobenzanilide. 1. Synthesis of the compounds. Pharmazie, 21, 161–166.Google Scholar
  22. Waisser, K., Čižmárik, J., Holý, P., Petrlíková, E., Kuneš, J., & Kaustová, J. (2009). Antimycobacterial 3-(4-ethoxythiocarbonylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-(4-ethoxythiocarbonylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones. Acta Facultatis Pharmaceuticae Universitatis Comenianae, 56, 171–179.Google Scholar
  23. Waisser, K., Gregor, J., Kubicová, L., Klimešová, V., Kuneš, J., Macháček, M., & Kaustová, J. (2000). New groups of antimycobacterial agents: 6-chloro-3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 6-chloro-3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones. European Journal of Medicinal Chemistry, 35, 733–741. DOI: 10.1016/S0223-5234(00)00 174-4.CrossRefGoogle Scholar
  24. Waisser, K., Hladůvková, J., Holý, P., Macháček, M., Karajannis, P., Kubicová, L., Klimešová, V., Kuneš, J., & Kaustová, J. (2001a). 2H-1,3-benzoxazine-2,4(3H)-diones substituted in position 6 as antimycobacterial agents. Chemical Papers, 55, 323–334.Google Scholar
  25. Waisser, K, Hladůvková, J, Kuneš, J, Kubicová, L, Klimešová, V, Karajannis, P, & Kaustová, J. (2001b). Synthesis and antimycobacterial activity of salicylanilides substituted in position 5. Chemical Papers, 55, 121–129.Google Scholar
  26. Waisser, K., Matyk, J., Divišová, H., Husáková, P., Kuneš, J., Klimešová, V., Kaustová, J., Möllmann, U., Dahse, H.-M., & Miko, M. (2006). The oriented development of antituberculotics: Salicylanilides. Archiv der Pharmazie, 339, 616–620. DOI: 10.1002/ardp.200600093.CrossRefGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2011

Authors and Affiliations

  • Eva Petrlíková
    • 1
    Email author
  • Karel Waisser
    • 1
  • Rafael Doležal
    • 2
  • Pavel Holý
    • 1
  • Jiří Gregor
    • 1
  • Jiři Kuneš
    • 1
  • Jarmila Kaustová
    • 3
  1. 1.Department of Inorganic and Organic ChemistryCharles University in Prague, Faculty of Pharmacy in Hradec KrálovéHradec KrálovéCzech Republic
  2. 2.Faculty of ScienceUniversity of Hradec KrálovéHradec KrálovéCzech Republic
  3. 3.Regional Institute of Public HealthOstravaCzech Republic

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