Chemical transformations of new mono- and bis-derivatives of spiroindol-3,3’-pyrrolo[3,4-c]pyrrole based on bis-maleiminides and the study of the microbiological activity of the compounds synthesized

Authors

  • Ye. I. Siumka National University of Pharmacy, Ukraine
  • K. M. Sytnik National University of Pharmacy, Ukraine
  • D. V. Levashov National University of Pharmacy, Ukraine
  • T. V. Spychak National University of Pharmacy, Ukraine
  • V. D. Horiachyi National University of Pharmacy, Ukraine
  • L. A. Shemchuk National University of Pharmacy, Ukraine

DOI:

https://doi.org/10.24959/ophcj.19.181138

Keywords:

bis-spirocyclic systems, 2-oxindole, alkylation, acylation, nitrosation, antimicrobial activity

Abstract

Aim. To synthesize new derivatives based on hexamethylene(ethylene)-N,N’-bis(spiroindole-3,3’-pyrrolo-[3,4-c]pyrrole-2a,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trions) and 1’-(m-phenylene-N-maleimidido)-2a’,5a’-dihydro-1’H- spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-2,2’,6’(1H,1’H,5’H)-trions by modifying the NH-group of the pyrrole moiety in position 4’ (alkylation, acylation, nitrosation) and study their microbiological activity.
Results and discussion. The possibility of further chemical modification of the derivatives of hexamethylene(ethylene)-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trion) has been developed on the example of ethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrol-5’-methyl-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trion), ethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-5’-isopropyl-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trione), hexamethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-5’-benzyl-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trion) and 1’-(m-phenylene-N-maleimidido)-2a’,5a’-dihydro-1’H-spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-5’-methyl-2,2’,6’(1H,1’H,5’H)-trione by modification of the NH-group of the pyrrole fragment in position 4’ (nitrosation) or the NH-group of the indole fragment in position 1 (alkylation), or acylation at once in two positions. The structure of the compounds obtained has been reliably confirmed by instrumental methods. Data from the microbiological screening show a high biological effect of the compounds synthesized in relation to gram-positive (Staphylococcus aureus, Bacillus subtilis), gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris) and fungi (Candida albicans).
Experimental part. The synthesis of the initial and target compounds in classical preparative conditions was performed; instrumental methods for determining the structure of organic compounds, the agar diffusion method in the modification of wells were used.
Conclusions. The chemical modification of mono- and bis-derivatives of spiro-2-oxindole[3,3’]pyrrole has been performed: new functionalized nitroso derivatives have been synthesized, the alkylation reaction has been performed, and the reaction of acylation has been studied. It has been shown that the acylation occurs immediately in two positions – by the secondary amino group of the pyrrole and indole fragments, while the alkylation proceeds by the indole fragment. The structure of the compounds obtained has been proven. The antimicrobial effect of the compounds synthesized has been studied.

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References

  1. Ball-Jones, N. R., Badillo, J. J., & Franz, A. K. (2012). Strategies for the enantioselective synthesis of spirooxindoles. Organic & Biomolecular Chemistry, 10 (27), 5165–5181. https://doi.org/10.1039/c2ob25184a
  2. Jossang, A., Jossang, P., Hadi, H. A., Sevenet, T., Bodo, B. (1991). Horsfiline, an oxindole alkaloid from Horsfieldia superba. The Journal of Organic Chemistry, 56 (23), 6527–6530. https://doi.org/10.1021/jo00023a016
  3. Zhang, Z., Wang, P., Yuan, W., & Li, S. (2008). Steroids, alkaloids, and coumarins from Gelsemium sempervirens. Planta Medica, 74 (15), 1818–1822. https://doi.org/10.1055/s-0028-1088327
  4. Kang, T.-H., Matsumoto, K., Tohda, M., Murakami, Y., Takayama, H., Kitajima, M., Aimi, N., Watanabe, H. (2002). Pteropodine and isopteropodine positively modulate the function of rat muscarinic M1 and 5-HT2 receptors expressed in Xenopus oocyte. European Journal of Pharmacology, 444 (1–2), 39–45. https://doi.org/10.1016/s0014-2999(02)01608-4
  5. Cui, C.-B., Kakeya, H., Osada, H. (1996). Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron, 52 (39), 12651–12666. https://doi.org/10.1016/0040-4020(96)00737-5
  6. Zhang, W., Huang, X.-J., Zhang, S.-Y., Zhang, D.-M., Jiang, R.-W., Hu, J.-Y., Zhang, X.-Q., Ye, W.-C. (2015). Geleganidines A–C, unusual monoterpenoid indole alkaloids from Gelsemium elegans. Journal of Natural Products, 78 (8), 2036–2044. https://doi.org/10.1021/acs.jnatprod.5b00351
  7. Kim, S. Y., Roh, H. J., Seo, D. Y., Ryu, J. Y., Lee, J., Kim, J. N. (2017). Base-catalyzed one-pot synthesis of dispiro-1,3-dioxolane bisoxindoles from N-methylisatin and methyl propiolate. Tetrahedron Letters, 58 (10), 914–918. https://doi.org/10.1016/j.tetlet.2017.01.055
  8. Qu, J., Fang, L., Ren, X.-D., Liu, Y., Yu, S.-S., Li, L., Bao, X.-Q., Zhang, D., Li, Y., Ma, S.-G. (2013). Bisindole alkaloids with neural anti-inflammatory activity from Gelsemium elegans. Journal of Natural Products, 76 (12), 2203–2209. https://doi.org/10.1021/np4005536
  9. Ramu, P., Arul, T. A. P., Vithiyac, S. M., Arul, S. A. (2014). Synthesis, characterization and biological activity of novel spiroheterocycles from isatin derivatives. Der Pharma Chemica, 6 (4), 30–36.
  10. Kato, S., Yoshino, T., Shibasaki, M., Kanai, M., Matsunaga, S. (2012). Catalytic asymmetric synthesis of spirooxindoles by a Mannich-type reaction of isothiocyanato oxindoles. Angewandte Chemie, 124 (28), 7113–7116. https://doi.org/10.1002/ange.201203005
  11. Kim, S. Y., Roh, H. J., Seo, D. Y., Ryu, J. Y., Lee, J., Kim, J. N. (2017). Base-catalyzed one-pot synthesis of dispiro-1,3-dioxolane bisoxindoles from N-methylisatin and methyl propiolate. Tetrahedron Letters, 58 (10), 914–918. https://doi.org/10.1016/j.tetlet.2017.01.055
  12. Redkin, R. G., Syumka, E. I., Shemchuk, L. A., Chernykh, V. P. (2017). Synthesis and antimicrobial activity of bis-derivatives of 3a’,6a’-dihydro-2’Hspiro[indole-3,1’-pyrrolo[3,4-c]pyrrole]-2,4’,6’(1H,3’H,5’H)-trione. Journal of Applied Pharmaceutical Science, 7 (6), 069–078. https://doi.org/10.7324/japs.2017.70610
  13. Syumka, Y. I., Shemchuk, L. A., Chernykh, V. P., Redkin, R. G. (2018). The study of the three-component interaction between isatin, α-amino acids and N,N’-di(3-carboxypropenoyl)-1,2-ethylenediamine and determination of the structure of the compounds obtained. Journal of Organic and Pharmaceutical Chemistry, 16 (61), 34–41. https://doi.org/10.24959/ophcj.18.932
  14. Syumka, Ye. I., Sytnik, K. M., Levashov, D. V., Shemchuk, L. A. (2018). Synthesis and chemical transformations of m-phenylene-N-maleimide derivatives of spiroindole-3,3’-pyrrolo[3,4-с]pyrrole. Chemistry of Nitrogen Containing Heterocycles in Memoriam of Prof. Valeriy Orlov: book of abstracts of 8th International Conference, 12–16 November, 2018. Kharkiv: Ekskluziv, 2018, 145.
  15. Syumka, Y. I., Osolodchenko, T. P., Chernykh, V. P., Shemchuk, L. A. (2018). The study of the antimicrobial activity of ethylene-N,N’- bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trione) derivatives. News of Pharmacy, 2 (94), 57–62. https://doi.org/10.24959/nphj.18.2202
  16. Balouiri, M., Sadiki, M., Ibnsouda, S. K. (2016). Methods for in vitro evaluating antimicrobial activity: a review. Journal of Pharmaceutical Analysis, 6 (2), 71–79. https://doi.org/10.1016/j.jpha.2015.11.005
  17. Volianskyi, Yu. L., Hrytsenko, I. S., Shyrobokov V. P. (2004). Vyvchennia spetsyfichnoi aktyvnosti protymikrobnykh likarskykh zasobiv. Kyiv, 38.
  18. Coyle, M. B. (2005). Manual of Antimicrobial Susceptibility Testing. Washington: American Society for Microbiology, 236.

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Published

2019-11-25

How to Cite

(1)
Siumka, Y. I.; Sytnik, K. M.; Levashov, D. V.; Spychak, T. V.; Horiachyi, V. D.; Shemchuk, L. A. Chemical Transformations of New Mono- and Bis-Derivatives of Spiroindol-3,3’-pyrrolo[3,4-c]pyrrole Based on Bis-Maleiminides and the Study of the Microbiological Activity of the Compounds Synthesized. J. Org. Pharm. Chem. 2019, 17, 44-52.

Issue

Vol. 17 No. 4(68) (2019)

Section

Original Researches

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