A SAR study on a series of synthetic lipophilic chalcones as Inhibitor of transcription factor NF-κB

To define the structural features responsible for the activity of 2,4-dihydroxy-6-isopentyloxychalcone, a newly established inhibitor of LPS induced NF-κB activation (IC50 = 10 μM), a series of its analogues was prepared and studied for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells. Among the synthesized derivatives, (E)-1-(2-(decyloxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (IC50 = 2.7 μM) and (E)-1-(2-hydroxy-6-(tetradecyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (IC50 = 4.2 μM) showed the most potent inhibition. The SAR studies confirmed that the length (C8–C14) and C-6 position of linear alkyl chain of ring A is an important factor for the inhibitory activity. Hydroxyl group and its location at 4-position on ring B is also important for the inhibition. The α,β-unsaturated ketone moiety appears as a crucial motif of chalcones for the activity. [Display omitted] ► SAR of novel 2,4-dihydroxy-6-isopentyloxychalcone as NF-κB inhibitor was explored. ► Replacement of isopentyl chain with C8–C14 linear alkyls increases the activity. ► Hydroxyl group and its location at 4-position on ring B are important. ► The α,β-unsaturated ketone moiety appears as a crucial motif.