1-(4-Methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamides: synthesis, molecular modeling, evaluation of their anti-inflammatory activity and ulcerogenicity

Eur J Med Chem. 2014 Apr 22:77:155-65. doi: 10.1016/j.ejmech.2014.03.001. Epub 2014 Mar 3.

Abstract

A series of novel 1-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamides were synthesized and confirmed with different spectroscopic techniques. The prepared compounds exhibited remarkable anti-inflammatory activity that represents 38%-100% of indomethacin activity and 44%-115% of celecoxib activity after 3 h. The anilides 5a-l and hydrazide 6 exhibit low incidence of gastric ulceration compared to indomethacin which was confirmed with histopathological investigation. In vitro COX-1/COX-2 inhibition studies showed compounds 4b (COX-1 IC50 = 45.9 μM; COX-2 IC50 = 68.2 μM) and 6 (COX-1 IC50 = 39.8 μM; COX-2 IC50 = 46.3 μM) are the most potent COX inhibitors in the tested compounds. The binding mode for some of the tested compounds to the enzymes was predicted using docking studies.

Keywords: 1,2,4-Triazole; Anti-inflammatory; Cyclooxygenase activity; Docking study; Histopathological investigation; Ulcerogenicity.

MeSH terms

  • Animals
  • Anisoles / chemical synthesis
  • Anisoles / chemistry
  • Anisoles / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Carrageenan
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase Inhibitors / administration & dosage
  • Cyclooxygenase Inhibitors / adverse effects*
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Edema / chemically induced
  • Edema / drug therapy
  • Hydrazines / chemical synthesis
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Male
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Stomach Ulcer / chemically induced*
  • Stomach Ulcer / pathology
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • 1-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-(1,2,4)triazole-3-carboxylic acid hydrazide
  • 1-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-(1,2,4)triazole-3-carboxylic acid methylamide
  • Anisoles
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase Inhibitors
  • Hydrazines
  • Triazoles
  • Carrageenan
  • Cyclooxygenase 1
  • Cyclooxygenase 2