Synthesis, in vitro antiplatelet activity and molecular modelling studies of 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones

The multistep preparation of the new 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones 6a–o, and of the two isomers 10-ethyl-2-(diethylamino)pyrimido[1,2-a]benzimidazol-4(10H)-one 6p and 10-ethyl-4-(diethylamino)pyrimido[1,2-a]benzimidazol-2(10H)-one 13, as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca2+ ionophore A23187 were here described. Nine out of fifteen 2-(1-piperazinyl)derivatives (6g–o) showed good inhibitory properties towards all the platelet aggregation agonists used. Moreover, a molecular modelling study has been performed on two of the best compounds of this series (6i and 6o) to confirm in silico their interactions with the catalytic site of human platelet PDE3, using the X-ray data of the PDE3B isoform in complex with an inhibitor.

Graphical abstractBest IC50 values against platelet aggregation: 12 ± 5 μM (ADP), 8 ± 1 μM (collagen), 11 ± 6 μM (A23187).Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Synthesis of 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones. ► In vitro inhibitory activity on platelet aggregation induced in human PRP by ADP, collagen and A23187. ► Molecular modelling study on two of the most active compounds of the series. ► Their in silico interactions with human platelet PDE3 catalytic site.