Abstract: Interleukin-6 (IL-6)/signal transducers and activators of transcription (STAT) signaling pathway is closely related to the development and progression of atherosclerosis (AS). Taking Chinese natural product berberine (BBR) as the leading compound, a series of novel BBR analogues defined on different types of substituents on position 3 or/and 9 were designed, synthesized and evaluated for their inhibitory activities on phosphorylation of STAT-1 and STAT-3 induced by IL-6. The structure-activity relationship indicated that introduction of rigid fragment on position 3 or 9 was beneficial for enhancing their activities. Among them, compounds 2b and 9 exhibited the most satisfactory potency. The study revealed that the compounds 2b and 9 exhibit anti-inflammatory potencies via activating AMPK, and down-regulation of phosphorylation of STAT1 and STAT3 induced by IL-6 in HUVEC cells. These results suggest that BBR derivatives may inhibit the inflammatory response mediated by the IL-6/STAT signaling pathway through regulation of AMPK, which provides useful insight into the development of BBR derivatives for treatment of atherosclerosis.