Anti-inflammatory activity of novel hdac8 inhibitory 2,5-disubstituted-1,3,4-oxadiazoles with glycine/alanine hybrids

Histone deacetylases (HDACs) are the regulators of inflammation and HDAC inhibitors are shown to be anti-inflammatory agents. Previously, we designed and synthesized a series of novel glycine and alanine hybrids of 2,5-disubstituted 1, 3, 4-oxadiazoles as class I HDAC inhibitors. All the compounds synthesized (10a-j) showed moderate HDAC8 selectivity and anti-tumor activity. Here we evaluated the anti-inflammatory potency of the compounds on E. coli-infected mouse macrophage, RAW 264.7, cells. Among the 10 compounds (10a-j), compounds 10f and 10h alone did not inhibit the macrophage proliferation. Further studies using 10f and 10h showed reduced colony-forming units (CFU) of bacteria isolated from the infected macrophage and inhibition of the COX-2 inflammatory protein levels along with inhibition of the pro-inflammatory cytokines (IL-12, TNF-, IFN-γ). Further in vivo studies using carrageenan-induced paw edema in rat model demonstrated a significant reduction in the paw edema at 20 mg/kg body weight when compared to untreated control. The study results thus signify that compounds 10f and 10h with moderate HDAC8 inhibitory activity also possess potent anti-inflammatory activity.