Synthesis of bioisosteres of caffeic acid phenethyl ester: 1,3,4-oxadiazole derivatives containing a catechol fragment with anti-inflammatory activities in vitro and in vivo

Aimed to enhance the anti-inflammatory activity of caffeic acid phenethyl ester (CAPE), the oxadiazole derivatives were synthesized by substituting its ester group. The structure-activity relationships revealed that the electron-withdrawing group in the phenethyl moiety enhanced anti-inflammatory activity. The order of activity potency was F ≥ CF₃ > Cl > NO₂ > CN. The most potent compound 2d suppressed the secretions of inflammatory cytokines (NO, IL-6, IL-1β and TNF-α), inhibited inducible nitric oxide synthase (iNOS) expression, upregulated the antioxidant gene HO-1 expression and antioxidant enzyme SOD level, together with decreasing reactive oxygen species (ROS) amount and oxidative stress marker MDA level. In vivo, 2d significantly attenuated the carrageenan-induced paw edema in rats more than CAPE. In liposaccharide (LPS)-induced acute lung injury model, 2d also exerted a therapeutic effect similar to dexamethasone. Moreover, 2d suppressed the NLRP3 inflammasome activation in THP-1 cells, as evidenced by decreasing the expressions of inflammasome signaling pathway-associated proteins (NLRP3, ASC, caspase-1, and pro-IL-1β), leading to down-regulation of IL-1β secretion. Molecular docking analysis also confirmed that 2d could bind to NLRP3, ASC and caspase-1protein. Therefore, this study suggested that synthesis of oxadiazole derivatives of CAPE could be a promising strategy to discover the anti-inflammation drugs.