Anti-Inflammatory and Analgesic Activities of 7-Chloro-4-(Piperazin-1-yl) Quinoline Derivative Mediated by Suppression of Inflammatory Mediators Expression in Both RAW 264.7 and Mouse Models

Abstract

Background: 4-Aminoquinoline derivatives possess various potential biological properties. The introduction of additional piperazine heterocyclic pharmacophoric moiety tends to have profound impact in increasing the activity. The present work was undertaken to investigate the in-vitro and in-vivo anti-inflammatory activity as well as the peripheral and central analgesic activities of compound 1-(4-(7-chloroquinoline-4-yl)piperazin-1-yl)-2-(4-phenylpiperazin-1-yl) ethanone (5) in experimental models. Methods: The percentage inhibition of the lipopolysaccharide induced NO release of 7-chloro-4-(piperazin-1-yl)quinoline derivatives 1-9 was determined in RAW 264.7 murine macrophage model. Western blot analysis was performed to evaluate the effect of compound 5 on protein expression of inducible nitric oxide synthase (iNOS). Gene expression of inflammatory markers was evaluated using real-time polymerase chain reaction. The peripheral and central analgesic activities of compound 5 were evaluated in mice using writhing and hot-plate tests, respectively. Anti-inflammatory activity was assessed using carrageenan-induced paw edema assay in mice and serum NO and COX-2 levels were measured. Results: Compound 5 demonstrated the highest NO inhibitory activity that was accompanied by inhibition of iNOS protein expression and decreased gene expression levels of inflammatory markers. It revealed a potential peripheral analgesic effect through inhibition of abdominal writhing in mice treated with doses of 15 and 30 mg/kg and its effect was comparable to diclofenac sodium. Compound 5 possessed an analgesic activity starting from 15 min post administration and reached its peak at 45 min which was significantly higher than that of tramadol hydrochloride suggesting its potential as central analgesic agent. It also showed percentage of inhibition of edema of 34, 50 and 64% at 1, 2, and 3 h respectively, post carrageenan challenge together with a significant decrease in serum NO and COX-2 levels. Conclusion: The remarkable anti-inflammatory and analgesic activities of compound 5 could be attributed to the advantageous introduction of the heterocyclic 7-chloro-4-(piperazin1-yl) quinoline scaffold incorporated with N-phenylpiperzine functional groups linked together with the ethanone pharmacophoric chain.