Synthesis and SAR studies of mono O-prenylated coumarins as potent 15-lipoxygenase inhibitors.

All of the mono isopentenyloxy, -geranyloxy and -farnesyloxy derivatives of coumarin were synthesized and their inhibitory potency against soybean 15-lipoxygenase (SLO) and human 15-lipoxygenase-1 (HLO-1) were determined. Amongst the synthetic analogs, 5-farnesyloxycoumarin showed the most potent inhibitory activity against SLO (IC(50) = 0.8 µM) while 6-farnesyloxycoumarin was the strongest HLO-1 inhibitor (IC(50) = 1.3 µM). The IC(50) variations of the farnesyl derivatives for HLO-1 (1.3 to ∼75 µM) were much higher than that observed for SLO (0.8-5.8 µM). SAR studies showed that hydrogen bonding, CH/π, anion-π and S-OC interactions with Fe(III)-OH, Leu408, Glu357 and Met419 were the distinct intermolecular interactions which can lead to important role of the coumarin substitution site in HLO-1 inhibitory potency, respectively.