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

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Abstract

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.

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About the authors

Anton O. Kashirin

Institute of Experimental Medicine

Author for correspondence.
Email: kashirin.anton@mail.ru

Postgraduate student

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

Irina B. Krylova

Institute of Experimental Medicine

Email: irinakrylova@mail.ru
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

Email: selina.elena@mail.ru
ORCID iD: 0000-0003-4591-209X
SPIN-code: 5558-2731

Researcher

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

Valery A. Polukeev

Institute of Experimental Medicine

Email: cyclic@peterlink.ru
SPIN-code: 6843-8295

Junior Researcher

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

Irina V. Zarubina

Institute of Experimental Medicine

Email: I.V.Zarubina@inbox.ru

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

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

Evgenii R. Bychkov

Institute of Experimental Medicine

Email: bychkov@mail.ru
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

Email: pdshabanov@mail.ru
ORCID iD: 0000-0003-1464-1127
SPIN-code: 8974-7477

Dr. Sci. (Med.), Professor

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

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

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

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