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

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Virology
• Hematology

Background:

• Hypercytokinemia (cytokine storm) is a severe complication of infections, increasing mortality in COVID-19 and sepsis.
• Cytokine storms cause epithelial dysfunction and coagulopathy, leading to thromboembolism and organ failure.
• Existing anticoagulants and antivirals have compatibility issues, necessitating dual-action drug development.

Purpose of the Study:

• To synthesize novel azolo[1,5-a]pyrimidines and their analogs with potential dual antiviral and anticoagulant properties.
• To evaluate the anticoagulant activity of these novel compounds.

Main Methods:

• Synthesis of azolo[1,5-a]pyrimidines and condensed polycyclic analogs via cyclocondensation and CH-functionalization.
• Assessment of anticoagulant properties, comparing against dabigatran etexilate.
• Confirmation of antithrombin activity using lipopolysaccharide (LPS)-treated blood to simulate cytokine release syndrome.

Main Results:

• Five novel compounds, including 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones, exhibited superior anticoagulant activity to dabigatran etexilate.
• The most active compounds significantly increased thrombin time (6.5-15.2 times) in LPS-treated blood.
• This suggests potent antithrombin activity relevant to cytokine storm conditions.

Conclusions:

• Novel azolo[1,5-a]pyrimidine derivatives show promising dual anticoagulant and potential antiviral properties.
• These compounds represent a potential therapeutic strategy for managing thromboembolic complications in severe infections like COVID-19 and sepsis.
• Further research into their antiviral efficacy and safety is warranted.