Investigation of the acute toxicity of new xanthine xenobiotics with noticeable antioxidant activity


D Vasylyev, B. Priimenko, K. Aleksandrova, Y. Mykhalchenko, B. Gutyj, I. Mazur, N. Magrelo, H. Sus, O. Dashkovskyy, U. Vus, O. Kamratska

Over the last few decades, there was significant interest in applying various xanthine derivatives to treat several diseases as highly potent antioxidant agents. Our study introduced several pharmacophore groups in the xanthine core to improve its antioxidant activity and increase biological fluids' solubility. We synthesized a set of new low-toxic 3-methylxanthine derivatives. Such compounds bear challenging scaffolds for finding effective antioxidant agents with broad application in medicine and pharmacy.

Keywords: reactive oxygen species; 3-methylxanthine derivatives; antioxidant activity



Ames, B.N., Shigenaga, M.K., & Hagen, T.M. (1993). Oxidants, antioxidants and the degenerative diseases of aging. Proc. Natl. Acad. Sci. USA., 90, 7915-7922.

Bandyopudya, U., Das, D., & Banerjee, R.K. (1999). ROS: oxidative damage and pathogenesis. Curr. Sci., 77, 658-666.

Dastmalchi, N., Baradaran, B., Latifi-Navid, S., Safaralizadeh, R., Khojasteh, S.M.B., Amini, M., Roshani, E., & Lotfinejad, P. (2020). Antioxidants with two faces toward cancer. Life Sciences, 258, 118186. doi: 10.1016/j.lfs.2020.118186.

Delesderrier, E., Curioni, C., Omena, J., Macedo, C.R., Cople-Rodrigues, C., & Citelli, M. (2020). Antioxidant nutrients and hemolysis in sickle cell disease. Clinica Chimica Acta, 510, 381-390. doi: 10.1016/j.cca.2020.07.020.

Gerard-Monnier, D, Erdelmeir, I, Chaudiere, J, & Yadan, J. (1998). Pat. 5726063 USA, G01N 33/52. Method of colorimetric analysis of malonic dialdehydes and 4-hydroxy-2-enaldehydes as indexes of lipid peroxidation, kits for use in said mathod and their preparation. ??? 08/702197; Pub. date.10.03.98.

Grymak, Y., Skoromna, O., Stadnytska, O., Sobolev, O., Gutyj, B., Shalovylo, S., Hachak, Y., Grabovska, O., Bushueva, I., Denys, G., Hudyma, V., Pakholkiv, N., Jarochovich, I., Nahirniak, T., Pavliv, O., Farionik, ?., Bratyuk, V. (2020). Influence of "Thireomagnile" and "Thyrioton" preparations on the antioxidant status of pregnant cows. Ukrainian Journal of Ecology, 10(1), 122-126.  doi: 10.15421/2020_19

Gutyj, B., Stybel, V., Darmohray, L., Lavryshyn, Y., Turko, I., Hachak, Y., Shcherbatyy, A., Bushueva, I., Parchenko, V., Kaplaushenko, A., Krushelnytska, O. (2017). Prooxidant-antioxidant balance in the organism of bulls (young cattle) after using cadmium load. Ukrainian Journal of Ecology, 7(4), 589–596

Harris, I.S., & DeNicola, G.M. (2020). The Complex Interplay between Antioxidants and ROS in Cancer. Trends in Cell Biology, 30(6), 440-451. doi: 10.1016/j.tcb.2020.03.002.

Khariv, M., Gutyj, B., Ohorodnyk, N., Vishchur, O., Khariv, I., Solovodzinska, I., Mudrak, D., Grymak, C., & Bodnar, P. (2017). Activity of the T- and B-system of the cell immunity of animals under conditions of oxidation stress and effects of the liposomal drug. Ukrainian Journal of Ecology, 7(4), 536–541.

Krishnamurthy, P., & Wadhwani, A (2012). Antioxidant enzymes and human health. Antioxidant Enzyme. InTech.

Leonarduzzi, G., Sottero, B., & Poli, G. (2010). Targeting tissue oxidative damage by means of cell signaling modulators: The antioxidant concept revisited. Pharmacology & Therapeutics, 128(2), 336-374. doi: 10.1016/j.pharmthera.2010.08.003.

Mao, X.Y., Jin, M.Z., Chen, J.F., Zhou, H.H., & Jin, W.L. (2018). Live or let die: Neuroprotective and anti-cancer effects of nutraceutical antioxidants. Pharmacology & Therapeutics, 183, 137-151. doi: 10.1016/j.pharmthera.2017.10.012.

Martyshuk, T.V., & Gutyj, B.V. (2019). Influence of feed additive "Butaselmevit-Plus" on antioxidant status of rats in conditions of oxidative stress. Scientific Messenger of Lviv National University of Veterinary Medicine and Biotechnologies. Series: Agricultural sciences, 21(90), 76–81. doi: 10.32718/nvlvet-a9013

Martyshuk, T.V., Gutyj, B.V., Zhelavskyi, M.M., Midyk. S.V., Fedorchenko, A.M., Todoriuk, V.B., Nahirniak, T.B., Kisera, Ya.V., Sus, H.V., Chemerys, V.A. , Levkivska, N.D., Iglitskej, I.I. (2020). Effect of Butaselmevit-Plus on the immune system of piglets during and after weaning. Ukrainian Journal of Ecology, 10(2), 347-352. doi: 10.15421/2020_106

Mikhalchenko, ??.K., Aleksandrova, ??.V., Levich, S.V., & Sinchenko, D.M. (2017). Synthesis and physical-chemical properties of 3-benzyl-8-propylxanthinyl-7-acetic acid and its derivatives. Actual questions of pharmaceutical and medical science and practice, 1(23), 14-19.

Pisoschi, A.M., Pop, A., Iordache, F., Stanca, L., Predoi, G., & Serban, A.I. (2021). Oxidative stress mitigation by antioxidants - An overview on their chemistry and influences on health status. European Journal of Medicinal Chemistry, 209, 112891. doi: 10.1016/j.ejmech.2020.112891.

Prozorovsky, V.B., & Prozorovskaya, V.M. (1978) Express-method for determining mean effective dose and its error. Farmakol i toksikol, 4, 497–502 (in Russian).

Ramis-Ramos, G. (2003). Synthetic antioxidants. In: Caballero B (ed.). Encyclopaedia of food sciences and nutrition. 2nd edition, Springer, Dordrecht, Netherlands, 265–275.

Reyes-Fermín, L.M., Aparicio-Trejo, O.E., Avila-Rojas, S.H., Gómez-Sierra, T., Martínez-Klimova, E., & Pedraza-Chaverri, J. (2020). Natural antioxidants' effects on endoplasmic reticulum stress-related diseases. Food and Chemical Toxicology, 138, 111229. doi: 10.1016/j.fct.2020.111229.

Scotti, L., & Scotti, M.T. (2015). Computer aided drug design studies in the discovery of secondary metabolites targeted against age-related neurodegenerative diseases. Curr. Top. Med. Chem., 15(21), 2239-2252. doi: 10.2174/1568026615666150610143510.

Sidorov, K.K (1973). On the classification of toxicity of poisons in parenteral methods of administration. Toxicology of new industrial chemicals. Moscow, 13, 47-57.

Son, J.M., & Lee, C. (2019). Mitochondria: multifaceted regulators of aging. BMB Rep., 52(1), 13-23. doi: 10.5483/BMBRep.2019.52.1.300.

Vasylyev, D.A., Kazunin, M.S., Priimenko, A.O., Achkasova, E.N., & Priimenko, B.O. (2012). Synthesis and antimicrobial estimation of some new substituted purine derivatives. Actual questions of experimental, clinical medicine and pharmacy, 1, 53.

Warraich, U.E.A., Hussain, F., & Kayani, H.U.R. (2020). Aging - Oxidative stress, antioxidants and computational modeling. Heliyon, 6(5), e04107. doi: 10.1016/j.heliyon.2020.e04107.

Zaycev, V.M., Liflyandskiy, V.G., & Marinkin, V.I. (2006). Applied medical statistics: textbook. Foliant, Saint Petersburg.

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