Pleyotropic antiaggregant effects of an innovative antiarrhythmic of class III SS-68, an indole derivative

A new indole derivative with the lab code-number SS-68 demonstrates a significant antiarrhythmic (anti-fibrillation) activity associated with the predominant influence on potassium and calcium conductivity of cardiomyocytes plasmalemmas. The preliminary data give evidence of SS-68 possessing an antiaggregant activity. The influence of SS-68 on the platelet formation stage of hemostasis was determined by assessment of the anti-platelet effect (measuring platelet aggregation with Born/ O’Brien method), the dynamics of intracellular concentration of calcium ions in platelets was studied with FURA-2/АМ fluorescent prob

Antiplatelet activity of new derivatives of benzimidazole containing sterically hindered phenolic group in their structure

The chemical class of benzimidazole derivatives with a hindered phenolic substituent in their structure is promising for the search for new antiaggregant and antioxidant drug

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 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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Funding: This research was funded within the framework of the grant agreement as government subsidies from the federal budget in accordance with paragraph 4 of article 78.1 of the Budget Code of the Russian Federation (Moscow, 1 October 2020, No. 075-15-2020-777)

Pleyotropic antiaggregant effects of an innovative antiarrhythmic of class III SS-68, an indole derivative

A new indole derivative with the lab code-number SS-68 demonstrates a significant antiarrhythmic (anti-fibrillation) activity associated with the predominant influence on potassium and calcium conductivity of cardiomyocytes plasmalemmas. The preliminary data give evidence of SS-68 possessing an antiaggregant activity. The influence of SS-68 on the platelet formation stage of hemostasis was determined by assessment of the anti-platelet effect (measuring platelet aggregation with Born/ O’Brien method), the dynamics of intracellular concentration of calcium ions in platelets was studied with FURA-2/АМ fluorescent prob

ANTITROMBOTIC ACTIVITY OF A NEW BENZIMIDAZOLE DERIVATIVE WITH A SPATIALLY DIFFICULT PHENOLIC SUBSTITUTE IN ITS STRUCTURE

The aim of the study was to investigate antithrombogenic properties of compound RU-1144 with previously identified pronounced antiplatelet and antioxidant activities. The thrombosis induced by Ferric chloride (FeCl3) was carried out in rats’ carotid artery, in comparison with the known antiaggregant drugs - acetylsalicylic acid (ASA) and clopidogrel, as well as with the antioxidant preparation - ethylmethylhydroxypyridine succinate (EMHPS).Materials and methods. The antithrombotic activity of compound RU-1144 was studied on the model of the rats with carotid artery thrombosis, induced by the application of 50% ferric chloride (FeCl3), and the Global Thrombosis Test model (the Görög Thrombosis Test). The evaluation of this type of activity was carried out by prolonging the time of a blood clot formation. The studies of the compound RU-1144 effect on the bleeding time parameter were performed in mice. Acetylsalicylic acid, clopidogrel and EMHPS were used as reference drugs.Results. The antithrombotic effect of the RU-1144 substance revealed in the model of arterial thrombosis induced by the application of ferric chloride (FeCl3), exceeded that of both acetylsalicylic acid and clopidogrel by 3.5 times and that of EMHPS by 2.9 times. In the model of the in vitro Global Thrombosis Test (the Görög Thrombosis Test), compound RU-1144 reduced the thrombogenic potential of the blood equally with acetylsalicylic acid and clopidogrel. The assessment of “the bleeding time”, caused by the RU-1144 substance, showed that the prolongation of bleeding was twice as less pronounced than that caused by ASA and clopidogrel.Conclusion. The performed studies demonstrated a pronounced antithrombotic activity of compound RU-1144, which exceeded that of acetylsalicylic acid, clopidogrel and EMHPS, while the ability to prolong the bleeding time was reliably lower than that of reference drugs.Abbreviations: EMHPS-ethylmethylhydroxypyridine succinate; ASA - acetylsalicylic acid

Azolo[1,5-<i>a</i>]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 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

Dimethyl 7-Methyl-2-N-Tolyl-4-Phenylpyrrolo[2,1-F] [2,1,4]Triazine-5,6-Dicarboxylate with Anticoagulant Effect

Изобретение относится к новому диметил 7-метил-2-(n-толил)-4-фенилпирроло[2,1-ƒ][1,2,4]триазин-5,6-дикарбоксилату . Технический результат: получено новое соединение, обладающее антикоагулянтным действием, которое может быть использовано для предотвращения тромботических состояний при тяжелых формах вирусной инфекции. 5 ил., 3 пр.FIELD: chemistry. SUBSTANCE: invention relates to a new dimethyl 7-methyl-2-(n-tolyl)-4-phenylpyrrolo[2,1-ƒ][1,2,4]triazine-5,6-dicarboxylate . EFFECT: new compound with anticoagulant activity was obtained, which can be used to prevent thrombotic conditions in severe forms of viral infection. 1 cl, 5 dwg, 3 ex