Synthesis and SAR comparative studies of 2-allyl-4-methoxy-1-alkoxybenzenes as 15-lipoxygenase inhibitors

Figures & data

Figure 1.  Molecular structure of some of allylbenzene analogues as lipoxygenase inhibitors.

Scheme 1.  General procedures for the synthesis of compounds 4a–j.

Table I.  Enzyme inhibitory assessment and docking analysis data of consensus conformers of eugenol, methyl eugenol, methyl isoeugenol and compounds 4a–j. K_i (M): Estimate d Inhibition Constant. The IC₅₀ (µM) values are given as mean ± SD.

Compound	IC50 (μM)	Ki (μM)
Eugenol	34.1 ± 2.1	-
Methyleugenol	96.1 ± 3.3	-
Methylisoeugenol	138.9 ± 3.1	-
4a	93.1 ± 5.9	31.88
4b	91.1 ± 4.2	27.18
4c	34.3 ± 2.3	3.88
4d	5.9 ± 0.6	1.14
4e	58.6 ± 3.7	17.16
4f	20.8 ± 1.4	7.91
4g	35.8 ± 3.4	3.43
4h	11.4 ± 0.6	33.15
4i	40.2 ± 3.7	14.12
4j	44.1 ± 2.6	13.81

Figure 2.  Stick (right) and solvent surface (left) view of flexible residues, surrounding the consensus bonding conformations of compounds 4a–j in the SLO active site.

Figure 3.  Multiple alignment of SLO (1ik3_A). The residues which have lipophilic interactions with docked ligands are highlighted in green respectively.

Figure 4.  Diagram of IC₅₀ value versus K_i for consensus structure of compounds 4a–j.

Figure 5.  Stick view of the consensus bonding conformation of compound 4d which has lipophilic interaction through its isopropyl moiety with hydrophobic pockets (surface view) formed by Leu⁵¹⁵, Trp⁵¹⁹, Val⁵⁶⁶ and Ile⁵⁷² side chain. In this figure we can see the orientation of linoleic acid (green stick) bonded to Fe via proxy bridge.