3-5-bis(2-fluorobenzylidene)piperidin-4-one and Sepsis

We previously reported the design and discovery of three series of 5-carbon linker-containing mono-carbonyl analogs of curcumin (MCACs) as excellent anti-inflammatory agents. In continuation of our ongoing research, we designed and synthesized the fourth series of MCACs, whose central linker is a piperid-4-one. Their inhibitory effects against IL-6 production were evaluated in lipopolysaccharide (LPS)-stimulated macrophages. Among them, compounds F8, F29, F33, F35, and F36 exhibited the IC50 values under 5 μM. The structure-activity relationship was discussed. Mechanistically, F35 and F36 dose-dependently prevented LPS-induced NF-κB and ERK activation. Finally, pretreatment with F35 and F36 significantly protected the C57B/L6 mice from LPS-induced septic death. Together, these data present a series of new analogs of curcumin as promising anti-inflammatory agents.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Curcumin; Dose-Response Relationship, Drug; Drug Discovery; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Inflammation; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Piperidones; Sepsis; Signal Transduction; Structure-Activity Relationship; Survival Analysis