Design, synthesis, anti-inflammatory activity, and molecular docking studies of perimidine derivatives containing triazole.

Abstract

We report here the design, synthesis, and anti-inflammatory activities of a series of perimidine derivatives containing triazole (5a-s). The chemical structures of the synthesized compounds have been assigned on the basis of IR, 1H NMR, 13C NMR, and HRMS spectral analyses. The anti-inflammatory properties of the synthesized perimidine derivatives were evaluated in a lipopolysaccharide (LPS)-stimulated inflammation model. Among the tested compounds, compound 7-(3-methylbenzyl)-7H-[1,2,4]triazolo[4,3-a]perimidine (hereafter referred to as 5h) and compound 7-(2-fluorobenzyl)-7H-[1,2,4]triazolo[4,3-a]perimidine (hereafter referred to as 5n) caused a reduction in the levels of the pro-inflammatory cytokines-tumor necrosis factor (TNF)-α and interleukin (IL)-6-in RAW264.7 cells. The anti-inflammatory potential of compounds 5h and 5n was also evaluated in vivo in a xylene-induced ear inflammation model. Compound 5n showed the most potent anti-inflammatory activity with an inhibition of 49.26% at a dose of 50mg/kg. This activity is more potent than that of the reference drug ibuprofen (28.13%), and slightly less than that of indometacin (49.36%). To further elucidate the mechanisms underlying these inhibitory effects, LPS-induced nuclear factor-κB (NF-κB) activation and mitogen-activated protein kinase (MAPK) phosphorylation were studied. The results of western blotting showed that the extract obtained from compound 5n inhibited NF-κB (p65) activation and MAPK (extracellular signal-regulated kinase (ERK) and p38) phosphorylation in a dose-dependent manner. Moreover, the results of a docking study of compound 5n into the COX-2 binding site revealed that its mechanism was possibly similar to that of naproxen, a COX-2 inhibitor. The effect of compound 5n on COX-2 antibody was showed it could significantly inhibit COX-2 activity.

• Authors: Hong-Jian Zhang, Xiu-Zhi Wang, Qi Cao, Guo-Hua Gong, Zhe-Shan Quan
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 27 Issue 18 Pg. 4409-4414 (09 15 2017) ISSN: 1464-3405 [Electronic] England
• PMID: 28823493 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cyclooxygenase 2 Inhibitors
• Cytokines
• Quinazolines
• Triazoles
• perimidine
• Cyclooxygenase 2

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Cell Survival (drug effects)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (chemical synthesis, chemistry, pharmacology)
• Cytokines (biosynthesis)
• Dose-Response Relationship, Drug
• Drug Design
• Mice
• Molecular Docking Simulation
• Molecular Structure
• Quinazolines (chemical synthesis, chemistry, pharmacology)
• RAW 264.7 Cells
• Structure-Activity Relationship
• Triazoles (chemistry, pharmacology)