Methoxylated 3,4-diaryl-5-methyl-1(H)-pyrazoles: discovery of a new anti-inflammatory scaffold

Inflammation participates in the development and progression of chronic diseases such as diabetes, cancer, and neurodegenerative disorders. Therefore, the search for novel anti-inflammatory agents is always required. Herein, we report a series of methoxylated 3,4-diarylpyrazoles with potent anti-inflammatory activity in the 12- O -tetradecanoylphorbol-13-acetate (TPA)-induced topical edema. Most derivatives reduced phorbol's toxicity by more than 50%. The anti-inflammatory activity of the trimethoxylated analog 3r reached 90% inhibition and surpassed that of celecoxib. 3r also reduced the secretion of myeloperoxidase (MPO) and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Micrographs of the ear's tissue clearly showed a decrease in thickness and infiltration of neutrophils, which correlates with the reduction of MPO and cytokines. Finally, molecular docking suggested that the series could inhibit cyclooxygenases and displayed a binding mode like that of celecoxib, though the enzymatic assay will be performed in future work. • 26 methoxylated pyrazoles were prepared through a [3 + 2] cycloaddition. • Most of the analogs reduced the TPA-induced edema by more than 50%. • Derivative 3r reduced the activity of myeloperoxidase and secretion of pro-inflammatory cytokines. • Molecular docking suggested cyclooxygenases as a plausible mechanism of action.