New class of potent antinociceptive and antiplatelet 10H-phenothiazine-1-acylhydrazone derivatives

Bioorg Med Chem. 2004 Jun 15;12(12):3149-58. doi: 10.1016/j.bmc.2004.04.009.

Abstract

In this work, we reported the synthesis and evaluation of the analgesic, antiinflammatory, and antiplatelet properties of new phenothiazine-attached acylhydrazone derivatives (6), designed exploring the molecular hybridization approach between antipsychotic chlorpromazine (4) and other heterocyclic derivatives (3) and (5) developed at LASSBio. Target compounds were synthesized in very good yields exploiting diphenylamine (7) as starting material, through regioselective functionalization of the C-1 position of 10H-phenothiazine ring. The evaluation of platelet antiaggregating profile lead us to identify a new potent prototype of antiplatelet derivative, that is (6a) (IC(50)=2.3 microM), which acts in arachidonic acid pathway probably by inhibition of platelet COX-1 enzyme. Additionally, the change of para-substituent group of acylhydrazone framework permitted us to identify hydrophilic carboxylate derivative (6g) and hydrophobic bromo derivative (6b) as two new leads of analgesics more active than dipyrone used as standard and with selective peripheral or central mechanism of action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / administration & dosage
  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Drug Design*
  • Humans
  • Hydrazones / administration & dosage
  • Hydrazones / chemical synthesis*
  • Hydrazones / chemistry
  • Hydrazones / pharmacology*
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / administration & dosage
  • Platelet Aggregation Inhibitors / chemical synthesis*
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology*
  • Rabbits
  • Rats
  • Thiazines / administration & dosage
  • Thiazines / chemical synthesis*
  • Thiazines / chemistry
  • Thiazines / pharmacology*

Substances

  • 10H-phenothiazine-1-acylhydrazone
  • Analgesics
  • Anti-Inflammatory Agents
  • Hydrazones
  • Platelet Aggregation Inhibitors
  • Thiazines