The synthesis of 2-amino-4-aryl-4H-pyrano[3,2-c][1,2] benzoxathiine-3-carbonitrile 5,5-dioxides and the study of their effect on the blood coagulation process
Keywords:1, 2-benzoxathiin-4(3H)-one 2, 2-dioxide, aromatic aldehydes, malononitrile, 4H-pyran, anticoagulant activity, hemostatic activity
To date, coumaric oral anticoagulants are the worldwide standard for thrombosis treatment. However, representatives of this group also possess a number of undesirable side effects; therefore, the search for novel anticoagulants are still in progress.
Aim. To synthesize 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carbonitrile 5,5-dioxides and study their effect on the blood coagulation process.
Results and discussion. Reflux of equimolar quantities of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with malononitrile and arenecarbaldehydes for 1 h in ethanol with the catalytic amount of triethylamine led to formation of 2-amino4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carbonitrile 5,5-dioxides. A wide range of substituted aromatic aldehydes was used for further study of the “structure – biological activity” relationship. Among the compounds synthesized substances with anticoagulant and hemostatic properties were found.
Experimental part. A series of 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carbonitrile 5,5-dioxides was synthesized. The effect of the compounds obtained on the blood coagulation process was studied in vitro by the Burker method.
Conclusions. The target 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carbonitrile 5,5-dioxides can be easily obtained with moderate to high yields in the three-component interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide, malononitrile and arenecarbaldehydes. According to the in vitro studies both anticoagulant and hemostatic substances with relatively high levels of the activities were found among this novel heterocyclic group of compounds. Thus, the effect of 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carbonitrile 5,5-dioxides on the blood coagulation process requires further detailed study.
Ali, G., Subhan, F., Khan, I., Islam, N. (2014). Input of Isosteric and Bioisosteric Approach in Drug design. Journal of the Chemical Society of Pakistan, 36 (1), 150–169.
Langmuir, I. (1919). Isomorphism, isosterism and covalence. Journal of the American Chemical Society, 41 (10), 1543–1559. https://doi.org/10.1021/ja02231a009
Erlenmeyer, H., Leo, M. (1932). On pseudoatoms. Helv. Chim. Acta, 15, 1171.
Friedman, H. L. (1951). Influence of Bioisosteric Replacements upon Biological Activity. National Academy of Sciences-National Research Council, Washington, 206, 295.
Hansch, C. (1974). Bioisosterism. Intrascience Chem. Rep., 8, 17–25.
Fujita, T., Iwasa, J., & Hansch, C. (1964). A New Substituent Constant, π, Derived from Partition Coefficients. Journal of the American Chemical Society, 86 (23), 5175–5180. https://doi.org/10.1021/ja01077a028
Harter, K., Levine, M., & Henderson, S. (2015). Anticoagulation Drug Therapy: A Review. Western Journal of Emergency Medicine, 16 (1), 11–17. https://doi.org/10.5811/westjem.2014.12.22933
Vardanyan, R., Hruby, V. (2016). Synthesis of Best-Seller Drugs. Academic Press, 868. https://doi.org/10.1016/c2012-0-07004-4
Grygoriv, G.V., Lega, D.A., Chernykh, V.P., Zaprutko, L., Gzella, A.K., Pawełczyk, A. & Shemchuk, L.A. (2018). 1,2-Benzoxathiin4(3H)-one 2,2-dioxide – new enol nucleophile in three-component interaction with benzaldehydes and active methylene nitriles. RSC Adv., 8, 37295 - 37302. https://doi.org/10.1039/c8ra06801a
Grygoriv, G., Lega, D., Chernykh, V., Osolodchenko, T., & Shemchuk, L. (2017). Synthesis of 1,2-benzoxathiine 2,2-dioxide derivatives using aliphatic aldehydes and assessment of their antimicrobial activity. Žurnal organìčnoï ta farmacevtičnoï hìmìï, 15 (4 (60)), 33–40. https://doi.org/10.24959/ophcj.17.927
Stefanov, O. V. (2001). Doklinichni doslidzhennya likarskih zasobiv. Kyiv: «Avitsenna», 528.
Medvedev, V. V., Volchek, Yu. Z. (2006). Klinicheskaia laboratornaia diagnostika: spravochnik dlia vrachei. St. Petersburg: Gippokrat, 360.
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