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

Mohamed Abdel-Aziz; Eman A Beshr; Islam M Abdel-Rahman; Keriman Ozadali; Oya Unsal Tan; Omar M Aly

doi:10.1016/j.ejmech.2014.03.001

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.

Authors

Mohamed Abdel-Aziz¹, Eman A Beshr¹, Islam M Abdel-Rahman¹, Keriman Ozadali², Oya Unsal Tan², Omar M Aly³

Affiliations

¹ Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sihhiye, Ankara, Turkey.
³ Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt. Electronic address: omarsokkar@yahoo.com.

PMID: 24631895
DOI: 10.1016/j.ejmech.2014.03.001

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