New selective cyclooxygenase-2 inhibitors from cyclocoumarol: Synthesis, characterization, biological evaluation and molecular modeling

Anita Marie Rayar; Nathalie Lagarde; Frederique Martin; Florent Blanchard; Bertrand Liagre; Clotilde Ferroud; Jean-François Zagury; Matthieu Montes; Maité Sylla-Iyarreta Veitía

doi:10.1016/j.ejmech.2018.01.054

New selective cyclooxygenase-2 inhibitors from cyclocoumarol: Synthesis, characterization, biological evaluation and molecular modeling

Eur J Med Chem. 2018 Feb 25:146:577-587. doi: 10.1016/j.ejmech.2018.01.054. Epub 2018 Jan 31.

Authors

Anita Marie Rayar¹, Nathalie Lagarde², Frederique Martin³, Florent Blanchard⁴, Bertrand Liagre³, Clotilde Ferroud⁵, Jean-François Zagury², Matthieu Montes², Maité Sylla-Iyarreta Veitía⁶

Affiliations

¹ Equipe de Chimie Moléculaire du Laboratoire CMGPCE, EA 7341, Conservatoire National des Arts et métiers, 2 rue Conté, 75003, Paris, France; Laboratoire Génétique Bioinformatique et Applications, EA 4627, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.
² Laboratoire Génétique Bioinformatique et Applications, EA 4627, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.
³ Université de Limoges, Laboratoire PEIRENE, Faculté de Pharmacie, 2 rue du Dr Marcland, 87025 Limoges, France.
⁴ Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université. Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
⁵ Equipe de Chimie Moléculaire du Laboratoire CMGPCE, EA 7341, Conservatoire National des Arts et métiers, 2 rue Conté, 75003, Paris, France.
⁶ Equipe de Chimie Moléculaire du Laboratoire CMGPCE, EA 7341, Conservatoire National des Arts et métiers, 2 rue Conté, 75003, Paris, France. Electronic address: [email protected].

PMID: 29407982
DOI: 10.1016/j.ejmech.2018.01.054

Abstract

In this work, a serie of cyclocoumarol derivatives was designed, synthesized, characterized and studied for their potentialities as selective inhibitors of COX-2. All target compounds have been screened for their anti-inflammatory activity by the assay of PGE₂ production. Among them, compound 5d exhibited the most potent inhibitory activity with a PGE₂ inhibition compared to NS-398 (79% and 88% respectively) and showed non-inhibitory activity towards the COX-1 enzyme. Docking studies revealed the capacity of this compound to occupy the selective COX-2 cavity establishing additional hydrogen bonds between the oxygen of the methoxy group and the His90 and Arg513 of the binding site of the enzyme.

Keywords: Anti-inflammatory; COX-1/COX-2 inhibition; COX-2 inhibitors; Cyclocoumarol; Cyclooxygenase; Docking study.

MeSH terms

4-Hydroxycoumarins / chemical synthesis
4-Hydroxycoumarins / chemistry
4-Hydroxycoumarins / pharmacology*
Cyclooxygenase 2 / metabolism*
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / chemistry
Cyclooxygenase 2 Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Models, Molecular
Molecular Structure
Structure-Activity Relationship

Substances

4-Hydroxycoumarins
Cyclooxygenase 2 Inhibitors
cyclocumarol
Cyclooxygenase 2