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

Abstract

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. Compound10e, an analog bearingp-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 with12g, clearly increased 5-LO inhibition which confirms the importance of hydrophobic interactions. Molecular docking revealed new hydrogen bonds andπ-πinteractions between the enzyme and some of the investigated compounds. Overall, this work highlights the relevance of exploring polyphenolic compounds as leukotrienes biosynthesis inhibitors.