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To develop new anti-inflammatory agents with improved pharmaceutical profiles, a series of new phenyl-pyrazoline-coumarin derivatives ( 4a ∼ 4m ) were designed and synthesized. Compounds 4a and 4b were determined by X-ray crystallography. All of the compounds have been screened for their anti-inflammatory activity characterized by evaluating their inhibition against LPS-induced IL-6 release. Among them, compound 4m showed the highest anti-inflammatory activity with inhibiting IL-6, TNF-α and nitric oxide (NO) production lipopolysaccharide (LPS)-stimulated. The further study showed that title compound 4m could significantly suppress expressions of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the productions of IL-6, TNF-α, NO through NF-κB/MAPK signaling pathway. The anti-inflammatory activity of compound 4m was determined by carrageenan induced paw edema. Furthermore in vivo evaluation results indicated that compound 4m could inhibit AA-induced rat ankle joints. [ABSTRACT FROM AUTHOR]

Phthalide is a promising chemical scaffold and has been proved to show potent anti-inflammatory efficacy. In this study, three series, total of 31 novel phthalide derivatives were designed and synthesized, their anti-inflammatory activities were screened in vitro and in vivo. The anti-inflammatory activity of all the compounds were screened on LPS induced NO production to evaluating their inhibitory effects. Structure-activity relationship has been concluded, and finally 3-((4-((4-fluorobenzyl)oxy)phenyl)(hydroxy)methyl)-5,7-dimethoxyisobenzofuran-1 (3H)-one (compound 9o) was found to be the active one with low toxicity, which showed 95.23% inhibitory rate at 10 μM with IC 50 value of 0.76 μM against LPS-induced NO over expression. Preliminary mechanism studies indicated that compound 9o activated Nrf2/HO-1 signaling pathway via accumulation ROS and blocks the NF-κB/MAPK signaling pathway. The in vivo anti-inflammatory activity shown that compound 9o had obvious therapeutic effect against the adjuvant-induced rat arthritis model. Image 1 • Novel phthalide derivatives were designed and synthesized. • In vivo studies showed that title compound had good therapeutic effect. • Preliminary mechanisms of anti-inflammatory action were discovered. [ABSTRACT FROM AUTHOR]