New Caffeic Acid Phenylethyl Ester Analogs Bearing Substituted Triazole: Synthesis and Structure-Activity Relationship Study towards 5-Lipoxygenase Inhibition

Leukotrienes are biosynthesized by the conversion of arachidonic acid by 5-lipoxygenase and play a key role in many inflammatory disorders. inspired by caffeic acid phenylethyl ester (cape) (2) and an analog carrying a triazole substituted by cinnamoyl and 5-lo inhibitors recently reported by our team,sixteen new cape analogs bearing substituted triazole were synthesized by copper catalyzed huisgen 1,3-dipolar cycloaddition. compound 10e,an analog bearing p-cf3 phenethyl substituted triazole,was equivalent to cape (2) but clearly surpassed zileuton (2),the only approved 5-lo inhibitor. substitution of the phenethyl moiety by cyclohexylethyl,as with 12g,clearly increased 5-lo inhibition which confirms the importance of hydrophobic interactions. molecular docking revealed new hydrogen bonds and π-π interactions between the enzyme and some of the investigated compounds. overall,this work highlights the relevance of exploring polyphenolic compounds as leukotrienes biosynthesis inhibitors. © 2017 pierre-philipe roy et al.