Novel 1-[4-(Aminosulfonyl)phenyl]-1H-1,2,4-triazole derivatives with remarkable selective COX-2 inhibition: design, synthesis, molecular docking, anti-inflammatory and ulcerogenicity studies

Gamal El-Din A A Abuo-Rahma; Mohamed Abdel-Aziz; Nahla A Farag; Tamer S Kaoud

doi:10.1016/j.ejmech.2014.06.049

Novel 1-[4-(Aminosulfonyl)phenyl]-1H-1,2,4-triazole derivatives with remarkable selective COX-2 inhibition: design, synthesis, molecular docking, anti-inflammatory and ulcerogenicity studies

Eur J Med Chem. 2014 Aug 18:83:398-408. doi: 10.1016/j.ejmech.2014.06.049. Epub 2014 Jun 24.

Authors

Gamal El-Din A A Abuo-Rahma¹, Mohamed Abdel-Aziz², Nahla A Farag³, Tamer S Kaoud⁴

Affiliations

¹ Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
² Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt. Electronic address: abulnil@hotmail.com.
³ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Misr International University, Abbassia, 11566 Cairo, Egypt.
⁴ Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.

PMID: 24983538
DOI: 10.1016/j.ejmech.2014.06.049

Abstract

A novel series of 1,2,4-triazole derivatives were synthesized and confirmed with different spectroscopic techniques. The prepared compounds exhibited remarkable anti-inflammatory activity comparable to that of indomethacin and celecoxib after 3 h. The tested compounds exhibited very low incidence of gastric ulceration compared to indomethacin. Most of the newly developed compounds showed excellent selectivity towards human COX-2 with selectivity indices (COX-1 IC50/COX-2 IC50) ranged from 62.5 to 2127. Docking studies results revealed that the highly selective tested compounds 6h and 6j showed lower CDOCKER energies, which means that they require less energy for proper interaction with the enzyme. The additional H-bonds with the oxygen of the amide and/or H of NH of the amide with the amino acid residues may be responsible for the higher binding affinity of this group of compounds towards COX-2.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / adverse effects
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / metabolism
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Chemistry Techniques, Synthetic
Cyclooxygenase 2 / chemistry
Cyclooxygenase 2 / metabolism*
Cyclooxygenase 2 Inhibitors / adverse effects
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / metabolism
Cyclooxygenase 2 Inhibitors / pharmacology
Drug Design*
Humans
Male
Molecular Docking Simulation*
Protein Conformation
Quantitative Structure-Activity Relationship
Rats
Stomach Ulcer / chemically induced*
Substrate Specificity
Triazoles / chemical synthesis*
Triazoles / metabolism
Triazoles / pharmacology*

Substances

1-(4-(aminosulfonyl)phenyl)-1H-1,2,4-triazole
Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase 2 Inhibitors
Triazoles
1,2,4-triazole
Cyclooxygenase 2