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

Abstract

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.

Comparison of Antiplatelet Effects of Phenol Derivatives in Humans

“…These experiments were analogous to our previous experiments with lysis of erythrocytes [ 19 ]. Human erythrocyte suspension was obtained by firstly centrifuging whole blood at 2700× g for 10 min and discarding the supernatant.…”

New Bicyclic Pyridine-Based Hybrids Linked to the 1,2,3-Triazole Unit: Synthesis via Click Reaction and Evaluation of Neurotropic Activity and Molecular Docking

“…We synthesized terminal alkines from the 3(6)-hydroxy derivatives of cyclopenta[ c ]pyridine 1a [ 25 ], 5,6,7,8-tetrahydroisoquinolines 1b – d [ 25 ], pyrano [3,4- c ]pyridines 1e – g [ 14 , 26 ], and 2,7-naphtyridines 1h , i [ 27 ] to obtain the aimed hybrids, the 1,2,3-triazoles. It should be mentioned that tautomerism is possible in compound 1 lactam-lactim (NH/OH) via proton-migration of a hydrogen atom between the two basic centers.…”

“…In our previous work we demonstrated that the terminal triple bond was obtained based on the 3(6)-hydroxy derivatives of bicyclic pyridines 1 , and the compound was found to have strong antiplatelet and vasodilatory potential, as well as an IC 50 twice as low as that of the clinically used acetylsalicylic acid [ 14 ]. The azido group was synthesized based on the 6-piperazino derivatives of pyrano [3,4- c ]pyridines, which show pronounced neurotropic [ 15 , 16 ] and antimicrobial [ 17 ] activities.…”

Can Isoquinoline Alkaloids Affect Platelet Aggregation in Whole Human Blood?

“…The most potent compound, papaverine, had an IC 50 of 26.9 ± 12.2 μM followed by bulbocapnine with an IC 50 of 30.7 ± 5.4 μM. The IC 50 of the clinical standard ASA was 23.8 ± 10.4 μM [ 19 ]. Other alkaloids were clearly less active with IC 50 values > 50 μM.…”

“…An initial screening of the antiplatelet effects was performed with whole human blood using an impedance aggregometer Multiplate ® (Roche, Switzerland) [ 34 ]. The detailed measurement procedure has been previously described [ 19 ]. In brief, 300 μL of whole blood was diluted with an equivalent amount of preheated 0.9% sodium chloride and incubated for 3 min at 37 °C with 5 μL of the appropriate tested compound (dissolved in DMSO, final concentration < 1%) or DMSO (blank sample).…”