Drug design of medicinal products on the basis of natural cardiosteroids

Authors

DOI:

https://doi.org/10.15587/2519-4852.2020.201107

Keywords:

cardio steroids, cardenolide, drug-design, aldimines, virtual screening, bis-cardenolides, cardiac glycosides, pharmaceutical development

Abstract

The aim. The article describes works about designing a structure, predicting of biological activity and the chemical transformation of natural cardiosteroids to obtain promising drugs with specified properties.

Materials and methods. An effective modified method for the synthesis of aldimines of cardenolides, based on the interaction of natural cardenolides with organic amines, is proposed. The abnormal physical and chemical properties of bis-ketoimines, which consist in their resistance to hydrolysis and increased polarity, are revealed.

Results. It is revealed that electrostatic fields play a decisive role in cardiotonic activity, which should be located in the form of a "sandwich" – in the α-plane there is a positive charge and in the β-plane is negative. The presence of a negative field at C3 is mandatory and the activity is higher if this negative field is extended further (the sugar component of the conditioned configuration, which does not violate the charges of the α- and β-planes). It is shown why the molar activity (biological activity expressed in moles of substance per kg of animal mass) of cardenolide glycosides is higher than their aglycones, that is, the sugar component contributes to the activity through electron fields, and not only due to changes in the hydrophilic-lipophilic properties of the substance.

Conclusions. The hypothesis of the existence of a phenomenon of non-inducing binding to Na +, K + -AT Phase, in which the substance acts as an antidote for active cardiosteroids is formulated.

A detailed analysis of this relatively exceptional case involves the simultaneous occurrence of two isomerism – conformational (conformers) and geometric in the synthesis of aldimines of cardenolides

Author Biographies

Iurii Gubin, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

PhD, Senior Researcher

Department of Quality Management

Olena Romelashvili, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

PhD, Associate Professor

Department of Quality Management

Tatiana Zborovska, National University of Pharmacy Pushkinska str., 53, Kharkiv, Ukraine, 61002

PhD, Associate Professor

Department of Quality Management

References

  1. Makarevych, I. F., Kovhanko, N. V., Chekman, I. S. et. al. (2009). Kardiotonichni steroidy. Kharkiv: Oryhinal, 688.
  2. Gubin, Y. I., Makarevich, I. F. (2010). bis-Cardenolides. Chemistry of Natural Compounds, 46 (5), 756–759. doi: http://doi.org/10.1007/s10600-010-9733-z
  3. Makarevich, I. F., Gubin, Y. I., Megges, R. (2005). Aldimines of Cardenolides and Cardenolide-Glycosides. Chemistry of Natural Compounds, 41 (3), 332–335. doi: http://doi.org/10.1007/s10600-005-0142-7
  4. Makarevich, I. F., Gubin, Y. I., Megges, R. (2005). Ketoimines of Cardenolides. Chemistry of Natural Compounds, 41 (1), 52–55. doi: http://doi.org/10.1007/s10600-005-0073-3
  5. Sarma, K., Roychoudhury, S., Bora, S., Dehury, B., Parida, P., Das, S. et. al. (2017). Molecular Modeling and Dynamics Simulation Analysis of KATNAL1 for Identification of Novel Inhibitor of Sperm Maturation. Combinatorial Chemistry & High Throughput Screening, 20 (1), 82–92. doi: http://doi.org/10.2174/1386207320666170116120104
  6. Shinozaki, H., Imaizumi, M., Tajima, M. (1983). A convenient conversion of aldoximes to nitriles under phase-transfer conditions. Chemistry Letters, 12 (6), 929–932. doi: http://doi.org/10.1246/cl.1983.929
  7. Makarevich, I. F., Georgievsky, V. P. (1991). New natural and Transformed cardenolides and prospects for their practical use. UNESCO Regional Seminar on Chemistry of Bioactive Natural Products. Shanghai, 1–4.
  8. Makarevich, I. F., Maslennikov, A. I., Pavlii, A. I., Kulagina, V. S., Ol’khovik, D. V., Kislichenko, S. G., Chernyaev, Y. A. (1987). Thermal transformations of cardiac glycosides and aglycons. Chemistry of Natural Compounds, 23 (3), 388–389. doi: http://doi.org/10.1007/bf00600862
  9. Makarevych, I. F., Kemertelidze, Ye. P., Kislichenko, S. H. et. al. (1975). Kardenolidy i bufadiienolidy. Tbilisi: Metsniereba, 227.
  10. Koh, C. H., Wu, J., Chung, Y. Y., Liu, Z., Zhang, R.-R., Chong, K. et. al. (2017). Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides. Scientific Reports, 7 (1). doi: http://doi.org/10.1038/s41598-017-02496-4
  11. Akimova, O. A., Kapilevich, L. V., Orlov, S. N., Lopina, O. D. (2016). Identification of proteins whose interaction with Na+,K+-ATPase is triggered by ouabain. Biochemistry, 81 (9), 1013–1022. doi: http://doi.org/10.1134/s0006297916090108
  12. Fіzer, L., Fіzer, M. (1971). Reagenti dlya organіchnogo sintezu. Vol. 4. Moscow: «Mir», 180.

Downloads

Published

2020-04-28

How to Cite

Gubin, I., Romelashvili, O., & Zborovska, T. (2020). Drug design of medicinal products on the basis of natural cardiosteroids. ScienceRise: Pharmaceutical Science, (2 (24), 26–32. https://doi.org/10.15587/2519-4852.2020.201107

Issue

No. 2 (24) (2020)

Section

Pharmaceutical Science

License

Copyright (c) 2020 Iurii Gubin, Olena Romelashvili, Tatiana Zborovska

Creative Commons License

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

Our journal abides by the Creative Commons CC BY copyright rights and permissions for open access journals.