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) 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.

Active Compounds in Zingiber officinale as Possible Redox Inhibitors of 5-Lipoxygenase Using an In Silico Approach

“…Directed coupling was performed with the crystal structure of the 5-LOX/NDGA complex (pdb code: 6N2W) [ 2 , 11 , 12 ], the active site of which is composed of a tetrad of catalytic residues (His-367, His-372, His-550, and Leu-673) that coordinate with the iron atom, allowing for its catalysis [ 1 , 13 ]. Conformational analysis was performed to test molecular docking in 10 conformations of 6-gingerol and 6-shogaol.…”

“…Molecular docking showed that both 6-gingerol and 6-shogaol had a high affinity for the 5-LOX catalytic pocket as they had significant interactions with two (His-367 and His-372) out of the three histidines involved in the inhibition of 5-LOX [ 1 , 2 , 13 ]. 6-Shogaol demonstrated a lower binding energy because it showed a more significant interaction with the catalytic histidines for inhibition, and demonstrated higher degrees of interaction with the residues that were involved in this catalytic pocket [ 8 , 19 ].…”

Thiophene-Based Compounds with Potential Anti-Inflammatory Activity

“…Years later, Chiasson et al [ 44 ], searching for new molecules that inhibit the 5-LOX enzyme, evaluated a series of hybrid compounds containing benzothiophene moieties and a phenolic acid fraction, which were synthesized and tested in vitro against HEK293 cells and polymorphonuclear leukocytes. The compounds with the best activity were compounds 2 and 3 ( Figure 3 ), which respectively presented IC 50 values of 6.0 µM and 6.6 µM.…”

Synthesis and structure–activity relationships for some novel diflapolin derivatives with benzimidazole subunit

“…To prevent the leukotriene biosynthesis and therefore significantly intervene with the inflammatory process, there are two possibilities up to the current scientific level, (i) direct inhibition of 5-LOX for example by zileuton 11 , 12 or (ii) prevention of the 5-LOX/FLAP complex formation by FLAP inhibitors as MK-886. 9 Research has shown that direct 5-LOX inhibition can be achieved using three different methods (redox active compounds, non-redox types, and iron-ligands), 13 but to date only zileuton has received approval.…”

“…According to the latest information, it has been possible to synthesise zileuton-hydroxycinnamic acid hybrids, of which one candidate shows very promising inhibitory properties, being up to three times as active as its precursor, zileuton. 12 However the hope are on FLAP inhibitors, some of them are currently undergoing clinical trials (i.e. GSK-2190915 by Amira Pharmaceuticals and GlaxoSmithKline completed clinical phase II studies for treatment of asthma patients; licofelone by Merkle, Alfa Wassermann, and Lacer reached clinical phase III for the treatment of knee osteoarthritis [ClinicalTrials.gov]).…”