Mansorins and mansonones have been isolated from Mansonia gagei heartwoods, a traditional herbal medicine used to treat heart failure, and characterized to have anti-oxidant, anti-bacterial, anti-tumor, and anti-estrogenic activities. However, there is as yet no information on their effects on adipogenesis and lipid storage associated with heart disease. In this study, we investigated the effects of naturally occurring compounds on adipogenic differentiation and sought to develop more potent anti-adipogenic compound. We found that mansonone G (MG) suppressed adipocyte differentiation of 3T3-L1 cells, with a 40% decrease in lipid accumulation at 10 μM. MG derivatives including ether and ester analogues were then synthesized and assayed for their ability to suppress adipogenesis. A novel MG derivative, chlorobenzoyl MG (CBMG) most potently suppressed adipocyte differentiation with the decreased level of aP2 and adiponectin. Interestingly, CBMG treatment decreased the expression of CCAAT enhancer binding protein-α (C/EBPα) and peroxisome proliferator-activated receptor-γ (PPARγ). Further analysis confirmed that CBMG suppressed both the expression and activity of PPARγ, a master regulator of adipogenesis, and subsequently led to decreases in transcription of C/EBPα, aP2, and adiponectin in adipogenesis, thereby attenuating adipocyte differentiation. Our results suggest that a novel MG derivative, CBMG may have beneficial applications in the control of obesity through the suppression of PPARγ-induced adipocyte differentiation and lipid accumulation.