Synthesis and Preliminary Evaluation of N-Oxide Derivatives for the Prevention of Atherothrombotic Events.

Abstract

Thrombosis is the main outcome of many cardiovascular diseases. Current treatments to prevent thrombotic events involve the long-term use of antiplatelet drugs. However, this therapy has several limitations, thereby justifying the development of new drugs. A series of N-oxide derivatives (furoxan and benzofuroxan) were synthesized and characterized as potential antiplatelet/antithrombotic compounds. All compounds (3a,b, 4a,b, 8a,b, 9a,b, 13a,b and 14a,b) inhibited platelet aggregation induced by adenosine-5-diphosphate, collagen, and arachidonic acid. All compounds protected mice from pulmonary thromboembolism induced by a mixture of collagen and epinephrine; however, benzofuroxan derivatives (13a,b and 14a,b) were the most active compounds, reducing thromboembolic events by up to 80%. N-oxide derivative 14a did not induce genotoxicity in vivo. In conclusion, 14a has emerged as a new antiplatelet/antithrombotic prototype useful for the prevention of atherothrombotic events.

• Authors: Leandro Augusto Rosseto, Maria Elisa Lopes Pires, Aylime Castanho Bolognesi Melchior, Priscila Longhin Bosquesi, Aline Renata Pavan, Sisi Marcondes, Man Chin Chung, Jean Leandro Dos Santos
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 20 Issue 10 Pg. 18185-200 (Oct 07 2015) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 26457696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1,2,5-oxadiazole 2-oxide
• Benzoxazoles
• Oxadiazoles
• Platelet Aggregation Inhibitors
• benzofuroxan
• Collagen
• Epinephrine

Topics

• Animals
• Benzoxazoles (chemical synthesis, chemistry, pharmacology)
• Collagen (adverse effects)
• Disease Models, Animal
• Epinephrine (adverse effects)
• Humans
• Mice
• Molecular Docking Simulation
• Molecular Structure
• Oxadiazoles (chemical synthesis, chemistry, pharmacology)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (chemical synthesis, chemistry, pharmacology)
• Pulmonary Embolism (chemically induced, prevention & control)