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.
Highlights
Leukotrienes (LTs) are a class of lipid mediators implicated in inflammatory responses [1]
We describe the design and synthesis of new caffeic acid phenylethyl ester analogs bearing substituted triazole derived from compound (Figure 2)
All analogs were synthesized by an efficient sequential procedure that directly links the azides, which can be potentially explosive, obtained from the commercially available organic halides to the alkyne moiety of the caffeic propargylic ester
Summary
Leukotrienes (LTs) are a class of lipid mediators implicated in inflammatory responses [1]. Many studies have developed new pharmacological agent that influence the biosynthesis or action of LTs [2]. Despite their implication in inflammatory and allergic responses, LTs are involved in many inflammatory diseases like asthma, arthritis, irritable bowel syndrome, and even cancer [3, 4]. Caffeic acid phenethyl ester (CAPE, ) (Figure 1) was found to be a potent 5-LO inhibitor [10,11,12] by our research group. Many studies reported by our laboratory have shown the potential of CAPE and its analogs as potential anti-inflammatory compounds
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