N-substituted indole carbohydrazide derivatives: synthesis and evaluation of their antiplatelet aggregation activity

Daru. 2014 Sep 20;22(1):65. doi: 10.1186/s40199-014-0065-6.

Abstract

Background: Platelet aggregation is one of the most important factors in the development of thrombotic disorders which plays a central role in thrombosis (clot formation). Prophylaxis and treatment of arterial thrombosis are achieved using anti-platelet drugs. In this study, a series of novel substituted indole carbohydrazide was synthesized and evaluated for anti-platelet aggregation activity induced by adenosine diphosphate (ADP), arachidonic acid (AA) and collagen.

Methods: Our synthetic route started from methyl 1H-indole-3-carboxylate (1) and ethyl 1H-indole-2-carboxylate (4) which were reacted with hydrazine monohydrate 99%. The aldol condensation of the later compound with aromatic aldehydes led to the formation of the title compounds. Sixteen indole acylhydrazone derivatives, 3d-m and 6d-i were tested for anti-platelet aggregation activity induced by adenosine diphosphate (ADP), arachidonic acid (AA) and collagen.

Results: Among the synthesized compounds, 6g and 6h with 100% inhibition, proved to be the most potent derivatives of the 2-substituted indole on platelet aggregation induced by AA and collagen, respectively. In 3-substituted indole 3m with 100% inhibition and 3f and 3i caused 97% inhibition on platelet aggregation induced by collagen and AA, respectively.

Conclusion: In this study, compounds 6g, 6h, 3m, 3f and 3i showed better inhibition on platelet aggregation induced by AA and collagen among the title compounds. Quantitative structure-activity relationship (QSAR) analysis between the structural parameters of the investigated derivatives and their antiplatelet aggregation activity was performed with various molecular descriptors but, analysis of the physicochemical parameters doesn't show a significant correlation between the observed activities and general molecular parameters of the synthesized derivatives. Although, due to the existence of several receptors on the platelets surface which are responsible for controlling the platelet aggregation, the investigated compounds in the present study may exert their activities through binding to more than one of these receptors and therefore no straight forward SAR could be obtained for them.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / pharmacology
  • Arachidonic Acid / pharmacology
  • Blood Platelets / drug effects*
  • Collagen / pharmacology
  • Humans
  • Hydrazines / chemical synthesis*
  • Hydrazines / pharmacology*
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemical synthesis*
  • Platelet Aggregation Inhibitors / pharmacology*
  • Platelet Function Tests
  • Quantitative Structure-Activity Relationship

Substances

  • Hydrazines
  • Platelet Aggregation Inhibitors
  • Arachidonic Acid
  • Adenosine Diphosphate
  • Collagen
  • carbohydrazide