Spiro[benzo[е]pyrano[3,2-c][1,2]oxathiin-4,3’-indolil]-3-carbonitrile 5,5-dioxides: synthesis and the biological activity study

G. V. Grygoriv, D. A. Lega, I. A. Zupanets, S. K. Shebeko, S. M. Zimin, I. L. Starchikova, L. A. Shemchuk


The development of medicines with several pharmacological activities, including the analgesic, anti-inflammatory and antimicrobial properties, is one of the challenging tasks of modern medicinal chemistry.
Aim. To expand the range of novel spiro-condensed derivatives of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, and study the biological activity of the substances obtained.
Results and discussions. The target compounds were synthesized as a result of the interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, malononitrile and isatins. When using ethyl cyanoacetate the interaction appeared to be much more complicated and requires further research. The study of the biological activity has revealed the compounds with the analgesic properties and the antimicrobial effect against gram-positive strains.
Experimental part. Two new 2-amino-2’-oxospiro[4H-pyrano[3,2-c][1,2]benzoxathiine-4,3’-indoline]-3-carbonitrile 5,5-dioxides were synthesized by the three-component reaction based on 1,2-benzoxathiin-4(3H)-one 2,2-dioxide. The anti-inflammatory activity was studied on the model of the carrageenan induced paw edema, and the analgesic activity was assessed on the model of the local inflammatory hyperalgesia. The study of the antimicrobial activity of the compounds obtained was performed by the agar well diffusion method.
Conclusions. New spiro[benzo[е]pyrano[3,2-c][1,2]oxathiin-4,3’-indolil]-3-carbonitrile 5,5-dioxides have been synthesized. The compounds obtained have revealed high levels of the analgesic properties and the antimicrobial activity. The latter exceeds the activity of the reference drugs, and has appeared to be higher against grampositive bacteria.


1,2-benzoxathiin-4(3H)-one 2,2-dioxide; isatins; spiro compounds; analgesic activity; anti-inflammatory activity; antimicrobial activity

Full Text:



Kean, W. F., Buchanan, W. W. (2005). The use of NSAIDs in rheumatic disorders 2005: a global perspective. Inflammopharmacology, 13 (4), 343–370.

Green, G. A. (2001). Understanding NSAIDs: from aspirin to COX-2. Clinical Cornerstone, 3 (5), 50–59.

Nasonov, E. L. (2000). Nesteroidnye protivospalitelnye preparaty (Perspektivy primeneniia v meditcine. Moscow: Anko, 142.

Karateev, A. E., Iakhno, N. N., Lazebnik, L. B. (2009). Primenenie nesteroidny`kh protivovospalitel`ny`kh preparatov. Klinicheskie rekomendaczii. Moscow: IMA–PRESS, 167.

Karateev, A. E. (2010). Primenenie paraczetamola pri lechenii ostroj i khronicheskoj boli: sravnitel`naya e`ffektivnost` i bezopasnost`. Russkij mediczinskij zhurnal, 25, 1477–1488.

Lega, D. O., Filimonova, N. I., Zupanets, I. A., Shebeko, S. K., Chernykh, V. P., Shemchuk, L. A. (2016). Antimicrobial, anti-inflammatory and analgesic activities of 2-amino-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]benzothiazine 5,5-dioxides and triethylammonium 3-[1-(4-hydroxy-1-ethyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)-3-(het)arylmethyl]-1-ethyl-1H-2,1-benzo. News of Pharmacy, 3 (87), 61–69.

Grygoriv, G. V., Lega, D. A., Zaprutko, L., Gzella, A. K., Wieczorek-Dziurla, E., Chernykh, V. P., Shemchuk, L. A. (2019). Synthesis of novel spiro-condensed 2-amino-4H-pyrans based on 1,2-benzoxathiin-4(3H)-one 2,2-dioxide. Chemistry of Heterocyclic Compounds, 55 (3), 254–260.

Grygoriv, G. V., Lega, D. A., Chernykh, V. P., Zaprutko, L., Gzella, A. K., Pawełczyk, A., Shemchuk, L. A. (2018). 1,2-Benzoxathiin-4(3H)-one 2,2-dioxide – new enol nucleophile in three-component interaction with benzaldehydes and active methylene nitriles. RSC Advances, 8 (65), 37295–37302.

Grygoriv, G. V., Lega, D. A., Chernykh, V. P., Osolodchenko, T. P., Shemchuk, L. A. (2018). Domino-reactions of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, hetarenecarbaldehydes and active methylene nitriles in the construction of new 2-amino-4H-pyrans and the study of their antimicrobial properties. Journal of Organic and Pharmaceutical Chemistry, 16 (61), 3–10.

Coyle, M. B. (2005). Manual of Antimicrobial Susceptibility Testing. Washington: American Society for Microbiology, 236.

Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Second Informational Supplement. CLSI document M100-S22. (2012). Wayne: Clinical and Laboratory Standards Institute, 188.

Stefanov, A. V. (Ed.). (2002). Doklinicheskie issledovaniia lekarstvennykh sredstv. Kyiv: Avitcena, 528.

Rukovodstvo po provedeniiu doklinicheskikh issledovanii lekarstvennykh sredstv. Vol. 1. (2012). Moscow: Grif i K, 944.

Nkeh-Chungag, N. B., Mxolisi Bekwa, P. C., Ndebia, J. E., Kayo, M., Mbafor, T. J., Iputo, J. E. (2010). Analgesic and anti-inflammatory properties of Oxyanthus unilocularis. Journal of Medicinal Plants Research, 4 (10), 932–939.

Gunda, S., Chaitanya, I., Kutty, G. (2012). Evaluation of two 2,5-disubstitued-2,3-dihydro-1,3,4-oxadiazoles for anti-inflammatory and analgesic activities. Research Journal of Pharmaceutical, Biological and Chemical Sciences, 3 (1), 930–944.

Lapach, S. N., Chubenko, A. V., Babich, P. N. (2000). Statisticheskie metody v mediko-biologicheskikh issledovaniiakh s ispolzovaniem Excel. Kyiv: Morion, 320.

Rebrova, O. Iu. (2006). Statisticheskii analiz meditcinskikh dannykh. Primenenie paketa prikladnykh programm STATISTICA. 3d ed. Moscow: MediaSfera, 312.

Sergienko, V. I., Bondareva, I. B. (2006). Matematicheskaia statistika v klinicheskikh issledovaniiakh. 2nd ed. Moscow: GEOTAR-Media, 304.

Council of Europe. (1986). European convention for the protection of vertebrate animals used for experimental and other scientific purpose. Strasbourg, 52.

Good Laboratory Practice. (2005). OECD principles and guidance for compliance monitoring, 140.

McFarland, J. (1907). The nephelometer: an instrument for estimating the number of bacteria in suspensions used for calculating the opsonic index and for vaccines. The Journal of the American Medical Association, 49 (14), 1176–1178.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Abbreviated key title: J. Org. Pharm. Chem.

ISSN 2518-1548 (Online), ISSN 2308-8303 (Print)