Antihypoxic effect of new synthetic derivatives of 7-alkoxycoumarin and 4-aminocoumarin in acute hypobaric hypoxia in rats

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access


BACKGROUND: Coumarins are naturally occurring molecules with a wide range of pharmacological activities. Their use is limited by difficulties in isolation from plant material, toxicity, and low solubility. The chemical structure of these compounds makes coumarins promising for the synthesis of a large number of derivatives that may have biological activity and be of interest as potential drugs. We had synthesized coumarin derivatives, two of which – IEM-2266 (7-alkoxycoumarin derivative) and IEM-2267 (4-aminocoumarin derivative) – have shown antihypoxic effect in mice in models of hypoxic hypoxia with hypercapnia, histotoxic and hemic hypoxia.

AIM: The aim of this work was to study the antihypoxic effect of new coumarin derivatives IEM-2266 and IEM-2267 under conditions of acute hypobaric hypoxia in rats.

METHODS: The experimental work was performed on male Wistar rats weighing 200–220 g. Acute hypobaric hypoxia was induced in rats by placing them in a flow pressure chamber. Compounds IEM-2266 and IEM-2267 were administered intraperitoneally at the dose 25 mg/kg once 50 minutes before hypoxia. Mexidol® at the dose of 100 mg/kg was used as a reference drug. The antihypoxic activity of the substances was assessed according to the following indicators: 1) lifespan at the critical height 11,000 m; 2) the value of the individual high-altitude threshold; 3) individual resistance to hypoxia calculated from high-altitude threshold, expressed in points; 4) survival at consistently presented heights; 5) determination of the structure of population resistance according to the ratio of animals with low, medium and high resistance to hypoxia.

RESULTS: New coumarin derivatives IEM-2266 and IEM-2267 exhibited antihypoxic activity under acute hypobaric hypoxia conditions. With the use of IEM-2266, IEM-2267, and Mexidol, the lifespan of animals at a critical altitude of 11,000 m increased by 2.4, 5.4, and 4.9 times, respectively, compared with the control, the point based assessment of individual resistance to hypoxia increased by 36, 66 and 67%, the absolute value of high-altitude threshold increased significantly (p < 0.05). Coumarin derivatives changed the structure of population resistance, increasing the proportion of highly resistant animals.

CONCLUSIONS: Thus, the effect of IEM-2267 is comparable, and even exceeds the effect of Mexidol. The 7-alkoxycoumarin derivative IEM-2266 has a moderate, and the 4-aminocoumarin derivative IEM-2267 has high antihypoxic activity in rat AHbH conditions.

Full Text

Restricted Access

About the authors

Anton O. Kashirin

Institute of Experimental Medicine

Author for correspondence.

Postgraduate student

Russian Federation, 12, Academika Pavlova st., Saint Petersburg, 197376

Irina B. Krylova

Institute of Experimental Medicine

SPIN-code: 7478-0420

Cand. Sci. (Biol.), Senior Researcher

Russian Federation, 12, Academika Pavlova st., Saint Petersburg, 197376

Elena N. Selina

Institute of Experimental Medicine

ORCID iD: 0000-0003-4591-209X
SPIN-code: 5558-2731


Russian Federation, 12, Academika Pavlova st., Saint Petersburg, 197376

Valery A. Polukeev

Institute of Experimental Medicine

SPIN-code: 6843-8295

Junior Researcher

Russian Federation, 12, Academika Pavlova st., Saint Petersburg, 197376

Irina V. Zarubina

Institute of Experimental Medicine


Dr. Sci. Biol. (Pharmacology), Professor, Senior Researcher

Russian Federation, 12, Academika Pavlova st., Saint Petersburg, 197376

Evgenii R. Bychkov

Institute of Experimental Medicine

ORCID iD: 0000-0002-8911-6805
SPIN-code: 9408-0799

Cand. Sci. (Med.)

Russian Federation, 12, Academika Pavlova st., Saint Petersburg, 197376

Petr D. Shabanov

Institute of Experimental Medicine

ORCID iD: 0000-0003-1464-1127
SPIN-code: 8974-7477

Dr. Sci. (Med.), Professor

Russian Federation, 12, Academika Pavlova st., Saint Petersburg, 197376


  1. Venugopala KN, Rashmi V, Odhav B. Review on natural coumarin lead compounds for their pharmacological activity. Biomed Res Int. 2013;2013:963248. doi: 10.1155/2013/963248
  2. Pereira TM, Franco DP, Vitorio F, Kummerle AE. Coumarin сompounds in medicinal chemistry: some important examples from the last years. Curr Top Med Chem. 2018;18(2):124–148. doi: 10.2174/1568026618666180329115523
  3. Sasidharan S, Chen Y, Saravanan D, et al. Extraction, isolation and characterization of bioactive compounds from plants’ extracts. Afr J Tradit Complement Altern Med. 2011;8(1):1–10. doi: 10.4314/ajtcam.v8i1.60483
  4. Lončarić M, Gašo-Sokač D, Jokić S, et al. Recent advances in the synthesis of coumarin derivatives from different starting materials. Biomolecules. 2020;10(1):151. doi: 10.3390/biom10010151
  5. Carneiro A, Matos MJ, Uriarte E, et al. Trending topics on coumarin and its derivatives in 2020. Molecules. 2021;26(2):501. doi: 10.3390/molecules26020501
  6. Al-Majedy YK, Kadhum AAH, Al-Amiery AA, et al. Coumarins: The Antimicrobial agents. Syst Rev Pharm. 2017;8:62–70. doi: 10.5530/srp.2017.1.11
  7. Chen LZ, Sun WW, Bo L, et al. New arylpyrazoline-coumarins: synthesis and anti-inflammatory activity. Eur J Med Chem. 2017;138:170–181. doi: 10.1016/j.ejmech.2017.06.044
  8. Emami S, Dadashpour S. Current developments of coumarin-based anti-cancer agents in medicinal chemistry. Eur J Med Chem. 2015;102:611–630. doi: 10.1016/j.ejmech.2015.08.033
  9. Keri RS, Sasidhar BS, Nagaraja BM, et al. Recent progress in the drug development of coumarin derivatives as potent antituberculosis agents. Eur J Med Chem. 2015;100:257–269. doi: 10.1016/j.ejmech.2015.06.017
  10. Anand P, Singh B, Singh N. A review on coumarins as acetylcholinesterase inhibitors for Alzheimer’s disease. Bioorg Med Chem. 2012;20(3):1175–1180. doi: 10.1016/j.bmc.2011.12.042
  11. Mashkovskii MD. Lekarstvennye sredstva. In 2 vol. Vol. 1. Moscow: Novaya volna, 2002. 540 p. (In Russ.)
  12. Beillerot A, Domínguez J-C R, Kirsch G, et al. Synthesis and protective effects of coumarin derivatives against oxidative stress induced by doxorubicin. Bioorg Med Chem Lett. 2008;18(3):1102–1105. doi: 10.1016/j.bmcl.2007.12.004
  13. Salar U, Khan KM, Jabeen A, et al. ROS inhibitory activity and cytotoxicity evaluation of benzoyl, acetyl, alkyl ester, and sulfonate ester substituted coumarin derivative. Med Chem. 2020;16(8): 1099–1111. doi: 10.2174/1573406415666190826153001
  14. Ivkin DYu. Antiaritmicheskie, antikoagulyatsionnye i tsentral’nye ehffekty kombinirovannykh geterotsiklicheskikh soedinenii 2Н-1-benzopiran-2-onovogo ryada [dissertation abstract]. Saint Petersburg, 2011. (In Russ.)
  15. Levchenkova OS, Novikov VE, Parfenov EhA. Antigipoksicheskaya aktivnost’ novykh proizvodnykh kumarina. Medical newsletter of Vyatka. 2004;(2–4):40–43. (In Russ.)
  16. Rodionova OM, Safonova AF, Kashirin AO, et al. The influence of new coumarin derivatives on survival rate of mice in model conditions of acute hypoxia. Medical Academic Journal. 2019;19(4):103–108. (In Russ.) doi: 10.17816/MAJ19258
  17. Andreeva NN. Ehksperimental’nye i klinicheskie aspekty primeneniya meksidola pri gipoksii. Medical almanac. 2009;(4):193–197. (In Russ.)
  18. FMBA Rossii. Biomeditsinskoe (doklinicheskoe) izuchenie antigipoksicheskoi aktivnosti lekarstvennykh sredstv. Metodicheskie rekomendatsii. FMBA Rossii MR.21.44-2017. Moscow, 2017. (In Russ.)
  19. Halliwell B. How to Characterize a Biological Antioxidant. Free Rad Res. 1990;9(1):1–32. doi: 10.3109/10715769009148569
  20. Vukovic N, Sukdolak S, Solujic S, et al. An Efficient Synthesis and Antioxidant Properties of Novel Imino and Amino Derivatives of 4-Hydroxy Coumarins. Arch Pharm Res. 2010;33(1):5–15. doi: 10.1007/s12272-010-2220-z 5
  21. Zaitsev VG, Ostrovskii OV, Zakrevskii VI. Classification of the direct-acting antioxidants based on a relationship between chemical structure and target. Experimental and clinical pharmacology. 2003;66(4):66–70. (In Russ.) doi: 10.30906/0869-2092-2003-66-4-66-70
  22. Levchenkova OS, Novikov VE. Antihypoxants: possible mechanisms of action and their clinical uses. Vestnik of the Smolensk State Medical Academy. 2011;10(4):43–57. (In Russ.)
  23. Bubols GB, Vianna DR, Medina-Remon A, et al. The antioxidant activity of coumarins and flavonoids. Mini Rev Med Chem. 2013;13(3):318–334. doi: 10.2174/138955713804999775
  24. Jagadeesh GS, Meeran MF, Selvaraj P. Activation of ß1-adrenoceptor triggers oxidative stress mediated myocardial membrane destabilization in isoproterenol induced myocardial infarcted rats: 7-hydroxycoumarin and its counter action. Eur J Pharmacol. 2016;777:70–77. doi: 10.1016/j.ejphar.2016.02.063
  25. Kashirin AO, Polukeev VA, Pshenichnaya AG, et al. Behavioral effects of new compounds based on coumarin in rats. Reviews on Clinical Pharmacology and Drug Terapy. 2020;18(1):37–42. (In Russ.) doi: 10.17816/RCF18137-42

Copyright (c) 2021 Kashirin A.O., Krylova I.B., Selina E.N., Polukeev V.A., Zarubina I.V., Bychkov E.R., Shabanov P.D.

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

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies