title: Synthesis, characterization and pharmacological evaluation of pyrazolyl urea derivatives as potential anti-inflammatory agents.
abstract: p38αmitogen 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 p38αMAPK inhibition and antioxidant potential. Compounds3a-e, 3gand3hshowed low micromolar range potency (IC50values ranging from 0.037 ± 1.56 to 0.069 ± 0.07 µmol/L) compared to the standard inhibitor SB 203580 (IC50= 0.043 ± 3.62 µmol/L) when evaluated for p38αMAPK 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. Compounds3a-e, 3gand3hshowed promisingin vivoanti-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-αrelease in mice (ID50of3a-c= 19.98, 11.32 and 9.67 mg/kg, respectively). Among the screened compounds, derivative3cwas found to be the most potent and its binding mode within the p38αMAPK is also reported.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi 110062, India.
authors.forename: Kanagasabai
authors.initials: K
authors.lastname: Somakala
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi 110062, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Amir
keywords: Anti-inflammatory; DPPH; Gastric toxicity; Lipid peroxidation; MAPK; Pyrazolyl urea; p38