ABSTRACT
p38mitogen activated protein kinase (MAPK) inhibitors provide a novel approach for the treatment of inflammatory disorders. A series of fifteen pyrazolyl urea derivatives (-) were synthesized and evaluated for their p38MAPK inhibition and antioxidant potential. Compounds-andshowed low micromolar range potency (ICvalues ranging from 0.037 ± 1.56 to 0.069 ± 0.07 µmol/L) compared to the standard inhibitor SB 203580 (IC= 0.043 ± 3.62 µmol/L) when evaluated for p38MAPK 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,, showed better percentage antioxidant activity (75.06%) compared to butylated hydroxy anisole (71.53%) at 1 mmol/L concentration. Compounds-andshowed promisinganti-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-release in mice (IDof-= 19.98, 11.32 and 9.67 mg/kg, respectively). Among the screened compounds, derivativewas found to be the most potent and its binding mode within the p38MAPK is also reported.
ABSTRACT
Inspired from occurrence of anti-inflammatory activity of 3-substituted coumarins and antiulcer activity of various 2-substituted benzimidazoles, novel compounds have been designed by coupling coumarin derivatives at 3-position directly or through amide linkage with benzimidazole nucleus at 2-position. The resultant compounds are expected to exhibit both anti-inflammatory and antioxidant activities along with less gastric toxicity profile. Two series of coumarin-benzimidazole derivatives (4a-e and 5a-e) were synthesized and evaluated for anti-inflammatory activity and antioxidant activity. Compounds 4c, 4d and 5a displayed good anti-inflammatory (45.45%, 46.75% and 42.85% inhibition, respectively, versus 54.54% inhibition by indomethacin) and antioxidant (IC50 of 19.7, 13.9 and 1.2 µmol/L, respectively, versus 23.4 µmol/L for butylatedhydroxytoluene) activities. Evaluation of ulcer index and in vivo biochemical estimations for oxidative stress revealed that compounds 4d and 5a remain safe on gastric mucosa and did not induce oxidative stress in tissues. Calculation of various molecular properties suggests the compounds to be sufficiently bioavailable.