Pyrazolylbenzyltriazoles as cyclooxygenase inhibitors: synthesis and biological evaluation as dual anti-inflammatory and antimicrobial agents

Abstract

A series of pyrazolylbenzyltriazoles as celecoxib analogues having a 1,5-diaryl relationship as potential leads for the development of molecular probes for imaging of COX-2 expression was prepared by the reaction of appropriate trifluoromethyl-β-diketones (12a–12i) with 1-[(4-hydrazinophen-1-yl)methyl]-1H-1,2,4-triazole hydrochloride in refluxing ethanol. All compounds were screened for in vitro cyclooxygenase (COX) assays to determine COX-1 and COX-2 inhibitory potency. Moreover, the anti-inflammatory activity of selected compounds, which are the most selective COX-2 inhibitors in the COX inhibition assay, was investigated in vivo using a carrageenan-induced rat paw edema model. Four compounds 13b, 13e, 13g and 13h were found to be the most potent selective COX-2 inhibitors of this study with 13h showing the best COX-2 profile. Compounds 13b, 13c and 13h also showed promising anti-inflammatory (AI) activity at 5 h after the carrageenan injection that was comparable to that of the standard drug celecoxib. In addition to that, compounds were also evaluated for in vitro antimicrobial activity against two Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), two Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and two fungal strains (Saccharomyces cerevisiae and Candida albicans). Most of the compounds exhibited moderate to excellent antibacterial activity against both Gram-positive pathogens and against one Gram negative species (Escherichia coli). The selective COX-2 inhibitory activity of compound 13h is significant and it could be employed as a dual anti-inflammatory and antibacterial drug. Therefore, these compounds would represent a fruitful matrix for the development of dual anti-inflammatory antimicrobial candidates with significant COX activity.