Anticancer and antituberculosis effects of 5-fluoro- 1H-indole-2,3-dione 3-thiosemicarbazones

Abstract

Background and Aims: The aim of this study was to screen the in vitro anticancer/antituberculosis activities of 5-fluoro- 1-methyl/ethyl-1H-indole-2,3-dione 3-thiosemicarbazones. Methods: A549/U-87MG cell lines were used for the anticancer activity of the compounds, while CCD-19Lu cell line was used to determine their cytotoxic effects. In antituberculosis activity studies using MTB H37Rv cell line, BJ cell line was used to determine the cytotoxic effects. MTT assay was used to obtain IC50 values. Results: 6a, 6b, 6g, 6h, 6l, 6n, 7c, 7k and 7l were found to be highly effective against A549 cell line compared to cisplatin whereas 6d, 6h, 6l, 6n, 7d and 7f were found to be effective against U-87MG cell line compared to cisplatin. It was also determined that 6a, 6b and 7l did not show cytotoxic effects on CCD-19Lu cell line. The antituberculosis effects of the compounds were investigated against MTB H37Rv cell groups using rifampicin as standard. It was determined that 6b, 6c, 6g-k, 6n, 7b, 7j and 7l have near-standard activity and 6b, 7b and 7l were not cytotoxic on BJ cell line. Conclusion: While determining effective compounds in anticancer studies, it was concluded that active compounds can be reached by modifications in compounds in antituberculosis studies.

Keywords

• Anticancer activity
• antituberculosis activity
• 5-fluoro-1H-indole-2
• 3-diones

References

1. • Atioğlu, Z., Sevinçli, Z. Ş., Karalı, N., Akkurt, M., & Ersanlı C. C. (2017a). 2-(5-Fluoro-1-methyl-2-oxoindolin-3-ylidene)-N-[4- (methylsulfanyl)phenyl]hydrazine-1-carbothioamide. IUCrData, 2(5), x170671.
2. • Atioğlu, Z., Sevinçli, Z. Ş., Karalı, N., Akkurt, M., & Ersanlı C. C. (2017b). (2Z)-2-(5-Fluoro-1-methyl-2-oxoindolin-3-ylidene)- N-(3-fluorophenyl)hydrazine-1-carbothioamide. IUCrData, 2(6), x170900.
3. • Banerjee, D., Yogeeswari, P., Bhat, P., Thomas, A., Srividya, M., & Sriram, D. (2011). Novel isatinyl thiosemicarbazones derivatives as potential molecule to combat HIV-TB co-infection. European Journal of Medicinal Chemistry, 46(1), 106−121.
4. • Brimacombe K., Fales H. M., Gottesman M. M., Hall, M. D., & Handley, M. (2012). W.O. Patent No. 2012033601 A1.
5. • Dikmen, M., Özturk, N., & Özturk, Y. The antioxidant potency of Punica granatum L. Fruit peel reduces cell proliferation and induces apoptosis on breast cancer. Journal of Medicinal Food, 14(12), 1638−1646.
6. • Feng, L. S., Liu, M. L., Wang, B., Chai, Y., Hao, X. Q., Meng, S., & Guo, H. Y. (2010). Synthesis and in vitro antimycobacterial activity of balofloxacin ethylene isatin derivatives. European Journal of Medicinal Chemistry, 45, 3407−3412.
7. • Foongladda, S., Roengsanthia, D., Arjrattanakool, W., Chuchottaworn, C., Chaiprasert, A., & Franzblau, S. G. (2002). Rapid and simple MTT method for rifampicin and isoniazid susceptibility testing of Mycobacterium tuberculosis. The International Journal of Tuberculosis and Lung Disease, 6(12), 1118−1122.
8. • Güzel, Ö., Karalı, N., & Salman, A. (2008). Synthesis and antituberculosis activity of 5-methyl/ trifluoromethoxy-1H-indole-2,3- dione 3-thiosemicarbazone derivatives. Bioorganic & Medicinal Chemistry, 16(19), 8976−8987.

9. • Hall, M. D., Salam, N. K., Hellawell, J. L., Fales, H. M., Kensler, C. B., Ludwig, J. A. … Gottesman, M. M. (2009). Synthesis, activity, and pharmacophore development for isatin-β-thiosemicarbazones with selective activity toward multidrug-resistant cells. Journal of Medicinal Chemistry, 52(10), 3191−3204.
10. • Hall, M. D., Gottesman, M. M., Hellawell, J. L., Ludwig, J. A., Fales, H. M., Salam, N. K., & Szakács, G. (2010). U.S. Patent Application No. 12/867,206.
11. • Hall, M. D., Brimacombe, K. R., Varonka, M. S., Pluchino, K. M., Monda, J. K., Li, J. … Gottesman, M. M. (2011). Synthesis and structureactivity evaluation of isatin-β-thiosemicarbazones with improved selective activity toward multidrug-resistant cells expressing Pglycoprotein. Journal of Medicinal Chemistry, 54, 5878−5889.
12. • Karalı, N. (2002). Synthesis and primary cytotoxicity evaluation of new 5-nitroindole-2,3-dione derivatives. European Journal of Medicinal Chemistry, 37(11), 909−918.
13. • Karalı, N., Gürsoy, A., Kandemirli, F., Shvets, N., Kaynak, F. B.,Özbey, S. … Dimoglo, A. (2007). Synthesis and structure–antituberculosis activity relationship of 1H-indole-2,3-dione derivatives. Bioorganic & Medicinal Chemistry, 15(17), 5888−5904.
14. • Karalı, N., Akdemir, A., Göktaş, F., Eraslan-Elma, P., Angeli, A., Kızılırmak, M. & Supuran, C. T. (2017). Novel sulfonamide-containing 2-indolinones that selectively inhibit tumor-associated alpha carbonic anhydrases. Bioorganic & Medicinal Chemistry, 25(14), 3714−3718.
15. • Lin, H. H., Wu, W. Y., Cao, S. L., Liao, J., Ma, L., Gao, M. ... Xu, X. (2013). Synthesis and antiproliferative evaluation of piperazine-1-carbothiohydrazide derivatives of indolin-2-one. Bioorganic & Medicinal Chemistry Letters, 23(11), 3304−3307.
16. • Matesic, L., Locke, J. M., Bremner, J. B., Pyne, S. G., Skropeta, D., & Ranson, M. (2008). N-phenethyl and N-naphthylmethyl isatins and analogues as in vitro cytotoxic agents. Bioorganic & Medicinal Chemistry, 16, 3118−3124.
17. • Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65, 55−63.
18. • Pape, V. F. S., Tóth, S., Füredi, A., Szebényi, K., Lovrics, A., Szabó, P. … Szakács, G. (2016). Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance. European Journal of Medicinal Chemistry, 117, 335−354.
19. • Pervez, H., Saira, N., Iqbal, M. S., Yaqub, M., & Khan, K. M. (2011). Synthesis and toxicity evaluation of some N4-aryl substituted 5-trifluoromethoxyisatin-3-thiosemicarbazones. Molecules, 16(8), 6408−6421.
20. • Pervez, H., Saira, N., Iqbal, M. S., Yaqub, M., & Khan, K. M. (2013). Synthesis and biological evaluation of some N 4-aryl-substituted 5-fluoroisatin-3-thiosemicarbazones. Medicinal Chemistry Research, 22(12), 5878−5889.
21. • Priyanka, K. B., Manasa, C., & Sammaiah, G. (2014). Synthesis and evaluation of new isatin derivatives for cytotoxic activity. World Journal of Pharmacy and Pharmaceutical Sciences, 3, 2393−2402. •
22. Raut, U., Narang, P., Mendiratta, D. K., Narang, R., & Deotale, V. (2008). Evaluation of rapid MTT tube method for detection of drug susceptibility of Mycobacterium tuberculosis to rifampicin and isoniazid. Indian Journal of Medical Microbiology, 26, 222−227.
23. • Sabet, R., Mohammadpour, M., Sadeghi, A. & Fassihi, A. (2010). QSAR study of isatin analogues as in vitro anti-cancer agents, European Journal of Medicinal Chemistry, 45, 1113−1118.
24. • Sevinçli, Z. Ş., Duran, G., Özbil, M., & Karalı, N. (2020). Synthesis, molecular modeling and antiviral activity of novel 5-fluoro-1Hindole- 2,3-dione 3-thiosemicarbazones. Bioorganic Chemistry, In press, https://doi.org/10.1016/j.bioorg.2020.104202
25. • Vine, K. L., Locke, J. M., Ranson, M., Pyne, S. G., & Bremner, J. B. (2007). An investigation into the cytotoxicity and mode of action of some novel N-alkyl-substituted isatins. Journal of Medicinal Chemistry, 50, 5109−5117.