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Synthesis of 3,3-dimethyl-6-oxopyrano[3,4-c]pyridines and their antiplatelet and vasodilatory activity
SN. Sirakanyan, M. Hrubša, D. Spinelli, P. Dias, V. Kartsev, A. Carazo, AA. Hovakimyan, J. Pourová, EK. Hakobyan, J. Karlíčková, S. Parvin, J. Fadraersada, K. Macáková, A. Geronikaki, P. Mladěnka
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články
Grantová podpora
CZ.02.1.01/0.0/0.0/16_019/0000841
EFSA-CDN project
SVV 260 549
ERDF
Charles University
Odkazy
PubMed
34106261
DOI
10.1093/jpp/rgab075
Knihovny.cz E-zdroje
- MeSH
- agregace trombocytů * MeSH
- antikoagulancia farmakologie MeSH
- inhibitory agregace trombocytů * chemie farmakologie MeSH
- pyridiny farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: Both pyridine and pyrano derivatives have been previously shown to possess biologically relevant activity. In this study, we report the incorporation of these two scaffolds into one molecule. METHODS: The designed 3,3-dimethyl-6-oxopyrano[3,4-c]pyridines were synthesized by the acylation of enamine under Stork conditions followed by condensation of formed β-diketones with 2-cyanoacetamide. The structures of these compounds were confirmed by using a wide spectrum of physico-chemical methods. Their antiplatelet, anticoagulant and vasodilatory activity together with toxicity were evaluated. KEY FINDINGS: A series of 6-oxopyrano[3,4-c]pyridines 3a-j was obtained. Four of these compounds were reported for the first time. None of the tested compounds demonstrated anticoagulant effect but 8-methyl derivative (3a) was a potent antiplatelet compound with IC50 numerically twice as low as the clinically used acetylsalicylic acid. A series of further mechanistic tests showed that 3a interferes with calcium signaling. The compound is also not toxic and in addition possesses vasodilatory activity as well. CONCLUSIONS: Compound 3a is a promising inhibitor of platelet aggregation, whose mechanism of action should be studied in detail.
Department of Pharmacognosy Faculty of Pharmacy Charles University Hradec Králové Czech Republic
Dipartimento di Chimica G Ciamician Alma Mater Studiorum Università di BolognaBologna Italy
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- $a Sirakanyan, Samvel N $u Scientific Technological Center of Organic and Pharmaceutical Chemistry of National Academy of Science of Republic of Armenia, Institute of Fine Organic Chemistry of A.L.Mnjoyan, Yerevan, Armenia $1 https://orcid.org/0000000260561446
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- $a OBJECTIVES: Both pyridine and pyrano derivatives have been previously shown to possess biologically relevant activity. In this study, we report the incorporation of these two scaffolds into one molecule. METHODS: The designed 3,3-dimethyl-6-oxopyrano[3,4-c]pyridines were synthesized by the acylation of enamine under Stork conditions followed by condensation of formed β-diketones with 2-cyanoacetamide. The structures of these compounds were confirmed by using a wide spectrum of physico-chemical methods. Their antiplatelet, anticoagulant and vasodilatory activity together with toxicity were evaluated. KEY FINDINGS: A series of 6-oxopyrano[3,4-c]pyridines 3a-j was obtained. Four of these compounds were reported for the first time. None of the tested compounds demonstrated anticoagulant effect but 8-methyl derivative (3a) was a potent antiplatelet compound with IC50 numerically twice as low as the clinically used acetylsalicylic acid. A series of further mechanistic tests showed that 3a interferes with calcium signaling. The compound is also not toxic and in addition possesses vasodilatory activity as well. CONCLUSIONS: Compound 3a is a promising inhibitor of platelet aggregation, whose mechanism of action should be studied in detail.
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