Synthesis, inhibitory activity and in silico docking of dual COX/5-LOX inhibitors with quinone and resorcinol core

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F20%3A00531731" target="_blank" >RIV/61389030:_____/20:00531731 - isvavai.cz</a>

Alternative codes found

RIV/60460709:41210/20:84400

Result on the web

<a href="http://doi.org/10.1016/j.ejmech.2020.112620" target="_blank" >http://doi.org/10.1016/j.ejmech.2020.112620</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2020.112620" target="_blank" >10.1016/j.ejmech.2020.112620</a>

Result language

angličtina

Original language name

Synthesis, inhibitory activity and in silico docking of dual COX/5-LOX inhibitors with quinone and resorcinol core

Original language description

Based on the significant anti-inflammatory activity of natural quinone primin (5a), series of 1,4-benzoquinones, hydroquinones, and related resorcinols were designed, synthesized, characterized and tested for their ability to inhibit the activity of cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) enzymes. Structural modifications resulted in the identification of two compounds 5b (2-methoxy-6-undecyl-1,4-benzoquinone) and 6b (2-methoxy-6-undecyl-1,4-hydroquinone) as potent dual COX/5-LOX inhibitors. The IC50 values evaluated in vitro using enzymatic assay were for compound 5b IC50 = 1.07, 0.57, and 0.34 μM and for compound 6b IC50 = 1.07, 0.55, and 0.28 μM for COX-1, COX-2, and 5-LOX enzyme, respectively. In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC50 = 0.14 μM, reference inhibitor zileuton IC50 = 0.66 μM) from the tested compounds while its inhibitory potential against COX enzymes (IC50 = 2.65 and 2.71 μM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC50 = 4.50 and 2.46 μM, respectively). The most important structural modification leading to increased inhibitory activity towards both COXs and 5-LOX was the elongation of alkyl chain in position 6 from 5 to 11 carbons. Moreover, the monoacetylation in ortho position of bromo-hydroquinone 13 led to the discovery of potent (IC50 = 0.17 μM) 5-LOX inhibitor 17 (2-bromo-6-methoxy-1,4-benzoquinone) while bromination stabilized the hydroquinone form. Docking analysis revealed the interaction of compounds with Tyr355 and Arg120 in the catalytic site of COX enzymes, while the hydrophobic parts of the molecules filled the hydrophobic substrate channel leading up to Tyr385. In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10401 - Organic chemistry

Project

<a href="/en/project/LTC18065" target="_blank" >LTC18065: Selective COX-1 inhibition as cardioprotective therapeutical target</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

—

Volume of the periodical

204

Issue of the periodical within the volume

15 October

Country of publishing house

FR - FRANCE

Number of pages

11

Pages from-to

112620

UT code for WoS article

000573916100027

EID of the result in the Scopus database

2-s2.0-85088652307