Design, synthesis, and SAR study of isopropoxy allylbenzene derivatives as 15-lipoxygenase inhibitors

Allylbenzenes have been recently developed as inhibitors of lipoxygenases. They decrease peroxidation activity via mimicking 1,4-unsaturated bonds of fatty acids by their allyl portion. We designed and synthesized new derivatives of allyl benzenes (6a-f) with isopropoxy and amide substituents at ortho and meta positions towards allyl group, respectively. The inhibitory potency of the synthetized allylbenzenes against soybean 15-lipoxygenase (SLO) and subsequently structure-activity relationships was assessed.

3-allyl-4-isopropoxybenzenamine (5) as starting material was synthesized by coupling of 4-nitropheol with allyl bromide, performing Claisen rearrangement and finally reduction of the nitro moiety. Final products 6a-f were prepared via amidation of 5 with the desired acyl chloride.

Among the compounds, N-(3-allyl-4-isopropoxyphenyl)adamantan carboxamide (6f) potentially showed best inhibition (IC₅₀ = 1.35 µM) while 6a with cyclopropyl carboxamide moiety was the weakest inhibitor and 6e with phenyl carboxamide moiety showed no effect. Energy minimized 3D structures of the compounds were docked into the active site pocket of SLO. For the aliphatic amides, docking results showed compatibility between inhibitory potency and average Ki of the cluster conformers, in which their allyl moiety oriented towards SLO iron core. For the aliphatic analogs, by enlargement of the amide moiety size the inhibitory potency was increased.

Docking results showed that orientation of the amide and allyl moieties of the inhibitors in the active site pocket is the major factor in inhibitory potency variation. Based on the mentioned orientation, for cycloaliphatic amides, by enlargement of the amide moiety both inhibition potency and calculated binding energy increases.