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Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity

Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epi...

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Autores principales: Savateev, Konstantin V., Fedotov, Victor V., Rusinov, Vladimir L., Kotovskaya, Svetlana K., Spasov, Alexandr A., Kucheryavenko, Aida F., Vasiliev, Pavel M., Kosolapov, Vadim A., Sirotenko, Victor S., Gaidukova, Kseniya A., Uskov, Georgiy M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8746358/
https://www.ncbi.nlm.nih.gov/pubmed/35011506
http://dx.doi.org/10.3390/molecules27010274
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author Savateev, Konstantin V.
Fedotov, Victor V.
Rusinov, Vladimir L.
Kotovskaya, Svetlana K.
Spasov, Alexandr A.
Kucheryavenko, Aida F.
Vasiliev, Pavel M.
Kosolapov, Vadim A.
Sirotenko, Victor S.
Gaidukova, Kseniya A.
Uskov, Georgiy M.
author_facet Savateev, Konstantin V.
Fedotov, Victor V.
Rusinov, Vladimir L.
Kotovskaya, Svetlana K.
Spasov, Alexandr A.
Kucheryavenko, Aida F.
Vasiliev, Pavel M.
Kosolapov, Vadim A.
Sirotenko, Victor S.
Gaidukova, Kseniya A.
Uskov, Georgiy M.
author_sort Savateev, Konstantin V.
collection PubMed
description Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. Anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time, it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of most active compounds was confirmed using lipopolysaccharide (LPS)-treated blood to mimic the conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5–15.2 times as compared to LPS-treated blood.
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spelling pubmed-87463582022-01-11 Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity Savateev, Konstantin V. Fedotov, Victor V. Rusinov, Vladimir L. Kotovskaya, Svetlana K. Spasov, Alexandr A. Kucheryavenko, Aida F. Vasiliev, Pavel M. Kosolapov, Vadim A. Sirotenko, Victor S. Gaidukova, Kseniya A. Uskov, Georgiy M. Molecules Article Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. Anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time, it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of most active compounds was confirmed using lipopolysaccharide (LPS)-treated blood to mimic the conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5–15.2 times as compared to LPS-treated blood. MDPI 2022-01-02 /pmc/articles/PMC8746358/ /pubmed/35011506 http://dx.doi.org/10.3390/molecules27010274 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Savateev, Konstantin V.
Fedotov, Victor V.
Rusinov, Vladimir L.
Kotovskaya, Svetlana K.
Spasov, Alexandr A.
Kucheryavenko, Aida F.
Vasiliev, Pavel M.
Kosolapov, Vadim A.
Sirotenko, Victor S.
Gaidukova, Kseniya A.
Uskov, Georgiy M.
Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity
title Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity
title_full Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity
title_fullStr Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity
title_full_unstemmed Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity
title_short Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity
title_sort azolo[1,5-a]pyrimidines and their condensed analogs with anticoagulant activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8746358/
https://www.ncbi.nlm.nih.gov/pubmed/35011506
http://dx.doi.org/10.3390/molecules27010274
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