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

ABSTRACT: 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) ?,?-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 ?-? interactions with Phe177 and Phe421 as predicted when docked into 5-LO. Compound 28 was the only docked ligand that showed a ?-? interaction with Phe177 which may play a part in product specificity as reported.

SUBMITTER: Chiasson AI 

PROVIDER: S-EPMC7587396 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature