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

J Enzyme Inhib Med Chem. 2012 Feb;27(1):101-9. doi: 10.3109/14756366.2011.578575. Epub 2011 May 25.

Abstract

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 µM) and collagen (IC(50) = 4.5 µM). 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 A(2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzodioxoles / chemical synthesis
  • Benzodioxoles / chemistry
  • Benzodioxoles / pharmacology*
  • Biological Products / chemical synthesis
  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Blood Platelets / drug effects
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Humans
  • Hydrazines / chemical synthesis
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Molecular Structure
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemical synthesis
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology*
  • Rabbits
  • Reference Values
  • Safrole / chemistry*

Substances

  • Benzodioxoles
  • Biological Products
  • Hydrazines
  • N-methyl-N'-((5-nitrofuran-2-yl)methylene)benzo(d)dioxole-5-carbohydrazide
  • Platelet Aggregation Inhibitors
  • Safrole