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 Pharmaceutical Botany Faculty of Pharmacy in Hradec Králové Charles University Hradec Králové Czech Republic

Department of Pharmaceutical Chemistry Aristotle University of Thessaloniki School of Pharmacy Thessaloniki Greece

Department of Pharmacognosy Faculty of Pharmacy Charles University Hradec Králové Czech Republic

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Králové Charles University Hradec Králové Czech Republic

Dipartimento di Chimica G Ciamician Alma Mater Studiorum Università di BolognaBologna Italy

InterBioScreen Moscow Russia

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

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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 Synthesis of 3,3-dimethyl-6-oxopyrano[3,4-c]pyridines and their antiplatelet and vasodilatory activity / $c 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

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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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$a Spinelli, Domenico $u Dipartimento di Chimica G. Ciamician, Alma Mater Studiorum-Università di BolognaBologna, Italy

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$a Dias, Patrícia $u Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic $1 https://orcid.org/0000000241691667

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$a Kartsev, Victor $u InterBioScreen, Moscow, Russia

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$a Carazo, Alejandro $u Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic $1 https://orcid.org/0000000236047981

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$a Hovakimyan, Anush A $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

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$a Karlíčková, Jana $u Department of Pharmaceutical Botany, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic

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$a Geronikaki, Athina $u Department of Pharmaceutical Chemistry, Aristotle University of Thessaloniki, School of Pharmacy, Thessaloniki, Greece $1 https://orcid.org/0000000198947777

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