Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 2 December 2021 / Approved: 6 December 2021 / Online: 6 December 2021 (15:47:49 CET)

A peer-reviewed article of this Preprint also exists.

Savateev, K.V.; Fedotov, V.V.; Rusinov, V.L.; Kotovskaya, S.K.; Spasov, A.A.; Kucheryavenko, A.F.; Vasiliev, P.M.; Kosolapov, V.A.; Sirotenko, V.S.; Gaidukova, K.A.; Uskov, G.M. Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity. Molecules 2022, 27, 274. Savateev, K.V.; Fedotov, V.V.; Rusinov, V.L.; Kotovskaya, S.K.; Spasov, A.A.; Kucheryavenko, A.F.; Vasiliev, P.M.; Kosolapov, V.A.; Sirotenko, V.S.; Gaidukova, K.A.; Uskov, G.M. Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity. Molecules 2022, 27, 274.

Journal reference: Molecules 2022, 27, 274
DOI: 10.3390/molecules27010274

Abstract

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. The 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 lead compounds was confirmed using lipopolysaccharide (LPS) treated blood to mimic 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.

Keywords

azolo[1,5-a]pyrimidines; benzo[4,5]imidazo[1,2-a][1,2,3]triazolo[4,5-e]pyrimidines; nitrocompounds; anticoagulant; cytokine storm.

Subject

CHEMISTRY, Medicinal Chemistry

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