Synthesis, characterization and pharmacological evaluation of pyrazolyl urea derivatives as potential anti-inflammatory agents

• 来源期刊: 药学学报（英文版）
• 关键词: Pyrazolyl urea p38 MAPK DPPH Anti-inflammatory Gastric toxicity Lipid peroxidation
• 年，卷（期）: 2017,（2）
• 页码范围: 230-240
• 页数: 11页
• 语种: 英文

摘要

p38α mitogen activated protein kinase (MAPK) inhibitors provide a novel approach for the treatment of inflammatory disorders.A series of fifteen pyrazolyl urea derivatives (3a-o) were synthesized and evaluated for their p38α MAPK inhibition and antioxidant potential.Compounds 3a--e,3g and 3h showed low micromolar range potency (IC5o values ranging from 0.037 ± 1.56 to 0.069 ± 0.07 μmol/L)compared to the standard inhibitor SB 203580 (IC5o =0.043 ± 3.62 μmol/L) when evaluated for p38α MAPK inhibition by an immunosorbent-based assay.Antioxidant activity was measured by a 2,2'-diphenyl-1-picryl hydrazyl radical (DPPH) free radical scavenging method and one of the compounds,3c,showed better percentage antioxidant activity (75.06％) compared to butylated hydroxy anisole (71.53％)at 1 mmol/L concentration.Compounds 3a-e,3g and 3h showed promising in vivo anti-inflammatory activity (ranging from 62.25％ to 80.93％) in comparison to diclofenac sodium (81.62％).The ulcerogenic liability and lipid peroxidation activity of these compounds were observed to be less in comparison to diclofenac sodium.These compounds also potently inhibited the lipopolysaccharide (LPS)-induced TNF-α release in mice (ID5o of 3a-c =19.98,11.32 and 9.67 mg/kg,respectively).Among the screened compounds,derivative 3c was found to be the most potent and its binding mode within the p38α MAPK is also reported.