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

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.

Keywords

coumarin derivatives / acute hypobaric hypoxia / lifespan / high-altitude threshold

References

[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] Venugopala K.N., Rashmi V., Odhav B. Review on natural coumarin lead compounds for their pharmacological activity // Biomed Res Int. 2013. Vol. 2013. ID963248. DOI: 10.1155/2013/963248

[3] 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

[4] Pereira T.M., Franco D.P., Vitorio F., Kummerle A.E. Coumarin сompounds in medicinal chemistry: some important examples from the last years // Curr Top Med Chem. 2018. Vol. 18. No. 2. P. 124–148. DOI: 10.2174/1568026618666180329115523

[5] 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

[6] 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. Vol. 8. No. 1. P. 1–10. DOI: 10.4314/ajtcam.v8i1.60483

[7] 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

[8] Lončarić M., Gašo-Sokač D., Jokić S., et al. Recent advances in the synthesis of coumarin derivatives from different starting materials // Biomolecules. 2020. Vol. 10. No. 1. P. 151. DOI: 10.3390/biom10010151

[9] 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

[10] Carneiro A., Matos M.J., Uriarte E., et al. Trending topics on coumarin and its derivatives in 2020 // Molecules. 2021. Vol. 26. No. 2. P. 501. DOI: 10.3390/molecules26020501

[11] 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

[12] Al-Majedy Y.K., Kadhum A.A.H., Al-Amiery A.A., et al. Coumarins: The Antimicrobial agents // Syst Rev Pharm. 2017. Vol. 8. P. 62–70. DOI: 10.5530/srp.2017.1.11

[13] 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

[14] Chen L.Z., Sun W.W., Bo L., et al. New arylpyrazoline-coumarins: synthesis and anti-inflammatory activity // Eur J Med Chem. 2017. Vol. 138. P. 170–181. DOI: 10.1016/j.ejmech.2017.06.044

[15] 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

[16] Emami S., Dadashpour S. Current developments of coumarin-based anti-cancer agents in medicinal chemistry // Eur J Med Chem. 2015. Vol. 102. P. 611–630. DOI: 10.1016/j.ejmech.2015.08.033

[17] 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

[18] Keri R.S., Sasidhar B.S., Nagaraja B.M., et al. Recent progress in the drug development of coumarin derivatives as potent antituberculosis agents // Eur J Med Chem. 2015. Vol. 100. P. 257–269. DOI: 10.1016/j.ejmech.2015.06.017

[19] 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

[20] Anand P., Singh B., Singh N. A review on coumarins as acetylcholinesterase inhibitors for Alzheimer’s disease // Bioorg Med Chem. 2012. Vol. 20. No. 3. P. 1175–1180. DOI: 10.1016/j.bmc.2011.12.042

[21] Mashkovskii MD. Lekarstvennye sredstva. In 2 vol. Vol. 1. Moscow: Novaya volna, 2002. 540 p. (In Russ.)

[22] Машковский М.Д. Лекарственные средства. В 2 томах. Т. 1. Москва: Новая волна, 2002. 540 c.

[23] 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

[24] 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. Vol. 18. No. 3. P. 1102–1105. DOI: 10.1016/j.bmcl.2007.12.004

[25] 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

[26] Salar U., Khan K.M., Jabeen A., et al. ROS inhibitory activity and cytotoxicity evaluation of benzoyl, acetyl, alkyl ester, and sulfonate ester substituted coumarin derivative // Med Chem. 2020. Vol. 16. No. 8. P. 1099–1111. DOI: 10.2174/1573406415666190826153001

[27] Ivkin DYu. Antiaritmicheskie, antikoagulyatsionnye i tsentral’nye ehffekty kombinirovannykh geterotsiklicheskikh soedinenii 2Н-1-benzopiran-2-onovogo ryada [dissertation abstract]. Saint Petersburg, 2011. (In Russ.)

[28] Ивкин Д.Ю. Антиаритмические, антикоагуляционные и центральные эффекты комбинированных гетероциклических соединений 2Н-1-бензопиран-2-онового ряда: автореф. дис. … канд. биол. наук. Санкт-Петербург, 2011.

[29] Levchenkova OS, Novikov VE, Parfenov EhA. Antigipoksicheskaya aktivnost’ novykh proizvodnykh kumarina. Medical newsletter of Vyatka. 2004;(2–4):40–43. (In Russ.)

[30] Левченкова О.С., Новиков В.Е., Парфенов Э.А. Антигипоксическая активность новых производных кумарина // Вятский медицинский вестник. 2004. № 2–4. С. 40–43.

[31] 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

[32] Родионова О.М., Сафонова А.Ф., Каширин А.О., и др. Влияние новых производных кумарина на выживаемость мышей в модельных условиях острой гипоксии // Медицинский академический журнал. 2019. Т. 19, № 4. С. 103–108. DOI: 10.17816/MAJ19258

[33] Andreeva NN. Ehksperimental’nye i klinicheskie aspekty primeneniya meksidola pri gipoksii. Medical almanac. 2009;(4):193–197. (In Russ.)

[34] Андреева Н.Н. Экспериментальные и клинические аспекты применения Мексидола при гипоксии // Медицинский альманах. 2009. № 4. С. 193–197.

[35] FMBA Rossii. Biomeditsinskoe (doklinicheskoe) izuchenie antigipoksicheskoi aktivnosti lekarstvennykh sredstv. Metodicheskie rekomendatsii. FMBA Rossii MR.21.44-2017. Moscow, 2017. (In Russ.)

[36] ФМБА России. Биомедицинское (доклиническое) изучение антигипоксической активности лекарственных средств: Методические рекомендации. ФМБА России МР.21.44–2017. Москва, 2017.

[37] Halliwell B. How to Characterize a Biological Antioxidant. Free Rad Res. 1990;9(1):1–32. DOI: 10.3109/10715769009148569

[38] Halliwell B. How to Characterize a Biological Antioxidant // Free Rad Res. 1990. Vol. 9. No. 1. P. 1–32. DOI: 10.3109/10715769009148569

[39] 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

[40] 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. Vol. 33. No. 1. P. 5–15. DOI: 10.1007/s12272-010-2220-z 5

[41] 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

[42] Зайцев В.Г., Островский О.В., Закревский В.И. Связь между химическим строением и мишенью действия как основа классификации антиоксидантов прямого действия // Экспериментальная и клиническая фармакология. 2003. Т. 66, № 4. С. 66–70. DOI: 10.30906/0869-2092-2003-66-4-66-70

[43] 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.)

[44] Левченкова О.С., Новиков В.Е. Антигипоксанты: возможные механизмы действия и клиническое применение // Вестник Смоленской государственной медицинской академии. 2011. Т. 10, № 4. С. 43–57.

[45] 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

[46] Bubols G.B., Vianna D.R., Medina-Remon A., et al. The antioxidant activity of coumarins and flavonoids // Mini Rev Med Chem. 2013. Vol. 13. No. 3. P. 318–334. DOI: 10.2174/138955713804999775

[47] 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

[48] Jagadeesh G.S., Meeran M.F., 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. Vol. 777. P. 70–77. DOI: 10.1016/j.ejphar.2016.02.063

[49] 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

[50] Каширин А.О., Полукеев В.А., Пшеничная А.Г., и др. Поведенческие эффекты новых соединений на основе кумарина у крыс // Обзоры по клинической фармакологии и лекарственной терапии. 2020. Т. 18, № 1. С. 37–42. DOI: 10.17816/RCF18137-42

RIGHTS & PERMISSIONS

Kashirin A.O., Krylova I.B., Selina E.N., Polukeev V.A., Zarubina I.V., Bychkov E.R., Shabanov P.D.