Novel furfurylidene N-acylhydrazones derived from natural safrole: Discovery of LASSBio-1215, a new potent antiplatelet prototype

摘要

We describe herein the discovery of (E)-N-methyl-N'-((5-nitrofuran-2-yl) methylene)benzo[d] 1,3 dioxole-5-carbohydrazide (9e), named LASSBio-1215, as a novel antiplatelet agent belonging to the N-methyl-N-acylhydrazone class, which exert their antiaggregating actions on human and rabbit platelets induced by different agonists, through cyclooxygenase-1 (COX-1) or thromboxane synthase inhibition. This compound was elected after screening of a series of functionalized furyl N-acylhydrazone derivatives, synthesized from natural safrole 10. In vitro assays showed that compound 9e presents platelet-aggregating activity in rabbit platelet-rich plasma (PRP) induced by arachidonic acid (IC 50=0.7 M) and collagen (IC 50=4.5 M). Moreover, LASSBio-1215 also inhibited almost completely the second wave of adenosine diphosphate-induced platelet aggregation in human PRP, and this effect was correlated with their ability to block the production of pro-aggregating autacoid thromboxane A2.