Inhibition of the differentiation of adipocytes and reduced lipid synthesis are efficacious approaches for treating obesity-related metabolic disorders. Bouchardatine (Bou) is a natural alkaloid that has been reported to moderately inhibit the differentiation of 3T3-L1 cells without inducing toxicity. To explore the importance of aldehyde group at 8a-position of Bou and optimize the activity, we synthesized 35 (31 novel) compounds by discarding or replacing aldehyde group with halogen and introducing different amine chains at 5-position of Bou. The lipid-lowering activity was evaluated using a cell-based screening system. The substitution of the group at the 8a-position of compounds was important for its lipid-lowering activity, and the SAR was discussed. The selective compound 6e showed a 93-fold increase in its lipid-lowering effect (EC50 = 0.24 μM) compared with Bou (EC50 ≈ 25 μM). Further mechanistic studies revealed that compound 6e activated AMP-activated protein kinase (AMPK) pathway and inhibited MCE activity to block cell proliferation and induce cell cycle arrest at the early stage of differentiation, thus decreasing the expression of adipogenic factors and fatty acid synthesis-related proteins.