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

Abstract

A group of 2-alkoxy-5-methoxyallylbenzene were designed, synthesised and evaluated as potential inhibitors of the soybean 15-lipoxygenase (SLO) on the basis of the eugenol and esteragol structures. Compound 4d showed the best half maximal inhibitory concentration (IC₅₀) for SLO inhibition (IC₅₀ = 5.9 ± 0.6 µM). All the compounds were docked in the SLO active site retrieved from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB entry: 1IK3) and showed that the allyl group of the synthetic compounds similar to the linoleic acid double bond, were oriented toward the Fe³⁺-OH moiety in the active site of the enzyme and this conformation was especially fixed by the hydrophobic interaction of the 2-alkoxy group with Leu⁵¹⁵, Trp⁵¹⁹, Val⁵⁶⁶ and Ile⁵⁷². It was concluded that the molecular volume and shape of the alkoxy moiety was a major factor in the inhibitory potency variation of the synthetic compounds.

Keywords::

• Eugenol
• SLO
• docking
• linoleic acid

Notes

† Substrate (100 μM) was reacted with soybean LO enzyme (167 U/mL) in 3 mL borate buffer solution (0.1 M, pH 9) at 20°C for 15 min. The mixture was then analysed by UV at 230–270 nm and no absorption of vinyl benzene formation was appeared over the blank solution.