New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition

Molecules

MarcE. Surette¹  Samuel Robichaud¹  Mohamed Touaibia¹  AudreyIsabel Chiasson¹  Maroua Mbarik¹  FantaJ. Ndongou Moutombi¹  MathieuP. A. Hébert¹ 

[1] Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A3E9, Canada;

关键词: 5-Lipoxygenase inhibitors;    anti-leukotrienes;    zileuton;    sinapic acid;    hydroxyurea;    inflammation;   

DOI  :  10.3390/molecules25204686

来源: DOAJ

【 摘 要 】

A novel series of zileuton-hydroxycinnamic acid hybrids were synthesized and screened as 5-lipoxygenase (5-LO) inhibitors in stimulated HEK293 cells and polymorphonuclear leukocytes (PMNL). Zileuton’s (1) benzo[b]thiophene and hydroxyurea subunits combined with hydroxycinnamic acid esters’ ester linkage and phenolic acid moieties were investigated. Compound 28, bearing zileuton’s (1) benzo[b]thiophene and sinapic acid phenethyl ester’s (2) α,β-unsaturated phenolic acid moiety 28, was shown to be equipotent to zileuton (1), the only clinically approved 5-LO inhibitor, in stimulated HEK293 cells. Compound 28 was three times as active as zileuton (1) for the inhibition of 5-LO in PMNL. Compound 37, bearing the same sinapic acid (3,5-dimethoxy-4-hydroxy substitution) moiety as 28, combined with zileuton’s (1) hydroxyurea subunit was inactive. This result shows that the zileuton’s (1) benzo[b]thiophene moiety is essential for the inhibition of 5-LO product biosynthesis with our hydrids. Unlike zileuton (1), Compound 28 formed two π–π interactions with Phe177 and Phe421 as predicted when docked into 5-LO. Compound 28 was the only docked ligand that showed a π–π interaction with Phe177 which may play a part in product specificity as reported.

【 授权许可】

Unknown