Myrrhanone A (5S,8R,9R,10R)-3-oxo-8,30-dihydroxypolypoda-13E,17E,21E-triene), a bicyclic triterpene isolated from guggul (Commiphora mukul Hook) gum resin, was found to be a very useful bioactive natural scaffold. The aim of this work is to carry out chemical transformations on myrrhanone A to synthesize some novel pyrimidine hybrids and investigate their anti-inflammatory activity. In vitro PMA/LPS activated human monocyte U937 cells were used to screen the anti-inflammatory activity of the compounds. Interestingly, most of the synthesized hybrids have shown higher anti-inflammatory activity than the parent molecule. Especially, methyl-, nitro-, bromo-, and difluoro-substituted analogues have shown promising inhibitory activity on TNF-α and IL-1β expression at 10 µM concentrations. Most significantly, the difluoro-substituted analogue (IC50: 3.22 ± 0.44 μM for TNF-α, 9.04 ± 1.92 μM for IL-1β) exhibited potent anti-inflammatory activity when compared to the parent myrrhanone A (IC50: 20.87 ± 3.01 μM for TNF-α, 14.10 ± 1.69 μM for IL-1β). © 2017, Springer-Verlag GmbH Austria.