Structure–Activity Relationship Studies of
New Sinapic Acid Phenethyl Ester Analogues Targeting the Biosynthesis
of 5‑Lipoxygenase Products: The Role of Phenolic Moiety, Ester
Function, and Bioisosterism
posted on 2022-01-07, 18:05authored byMohamed Touaibia, Diene Codou Faye, Jérémie
A. Doiron, Audrey Isabel Chiasson, Sébastien Blanchard, Pierre-Philippe Roy, Marc E. Surette
Sinapic acid is found in many edible
plants and fruits, such as
rapeseed, where it is the predominant phenolic compound. New sinapic
acid phenethyl ester (SAPE) analogues were synthesized and screened
as inhibitors of the biosynthesis of 5-lipoxygenase (5-LO) in stimulated
HEK293 cells and polymorphonuclear leukocytes (PMNL). Inhibition of
leukotriene biosynthesis catalyzed by 5-LO is a validated therapeutic
strategy against certain inflammatory diseases and allergies. Unfortunately,
the only inhibitor approved to date has limited clinical use because
of its poor pharmacokinetic profile and liver toxicity. With the new
analogues synthesized in this study, the role of the phenolic moiety,
ester function, and bioisosterism was investigated. Several of the
34 compounds inhibited the biosynthesis of 5-LO products, and 20 compounds
were 2–11 times more potent than zileuton in PMNL, which are
important producers of 5-LO products. Compounds 5i (IC50: 0.20 μM), 5l (IC50: 0.20
μM), and 5o (IC50: 0.21 μM) bearing
4-trifluoromethyl, methyl, or methoxy substituent at meta-position of the phenethyl moiety were 1.5 and 11.5 times more potent
than SAPE (IC50: 0.30 μM) and zileuton (IC50: 2.31 μM), respectively. Additionally, compound 9 (IC50: 0.27 μM), which was obtained after acetylation
of the 4-hydroxyl of SAPE, was equivalent to SAPE and 8 times more
active than zileuton. Furthermore, compound 20b (IC50: 0.27 μM) obtained after the bioisosteric replacement
of the ester function of SAPE by the 1,2,4-oxadiazole heterocycle
was equivalent to SAPE and 8 times more active than zileuton. Thus,
this study provides a basis for the rational design of new molecules
that could be developed further as anti 5-LO therapeutics.