Novel isoflavones were found to be potent inhibitors of interleukin-5 (Il-5). 5-Benzyloxy-3-(4-hydroxyphenyl)-4H-chromen-4-one (2a, 87.8% inhibition at 50 microM, IC50 = 15.3 microM) was initially identified as a potent inhibitor of IL-5. Its activity was comparable to that of budesonide or sophoricoside (1a). The benzyloxy group appeared to be critical for the enhancement of the IL-5 inhibitory activity. To identify the role of this hydrophobic moiety, 5-cyclohexylmethoxy (2d), 7-cyclohexylmethoxy (2e), 5-cyclohexylethoxy (2f), 5-cyclohexylpropoxy (2g), 5-(2-methylpropoxy) (2h), 5-(3-methylbutoxy) (2i), 5-(4-methylpentoxy) (2j) and 5-(2-ethylbutoxy) (2k) analogs were prepared and tested for their effects on the bioactivity of IL-5. Compounds 2d (IC50 = 5.8 microM), 2e (IC50 = 4.0 microM) and 2j (IC50 = 7.2 microM) exhibited the most potent activities. Considering the cLog P values of compounds 2 and the different three dimensional structures of 2d and 2e, the alkoxy group on ring A contributed to their cell permeability for the enhancement of activity, rather than playing a role in the ligand motif binding to the receptor. The optimum alkoxy group should be one that provides cLog P values of compounds 2 in the range of 4.13 to 4.39.