Scavenger receptor CD36 could bind and endocytose oxLDL into macrophages which were then differentiated into foam cells that constitute the atherosclerotic lesion core, and was considered to be a potential target to treat atherosclerosis.  In the establishment of the compound library of berberine (BBR, 1) analogues, we discovered that 13-hexylberberine (2) showed an antagonistic activity against CD36.  Taking 2 as the lead compound, 21 derivatives were synthesized and their antagonistic activities were evaluated via an ELISA-like high-throughput screening (HTS) model.  The primary structure-activity relationships were studied.  It was  indicated that the introduction of suitable groups at the 2- and 3-position of the aromatic ring A or at the 9-position of the aromatic ring D could enhance the activity.  Among the 21 studied compounds, 7g bearing  a benzyloxyl group at the 9-position provided a highest CD36 antagonistic activity with the IC₅₀ value of 7.7 μmol·L⁻¹.  Besides, its antagonistic activity was further verified with Sf9 insect cell HTS model.  So berberine analogues are a new family of CD36 receptor antagonists and worthy to be studied further.