gem-Difluorobisarylic derivatives: design, synthesis and anti-inflammatory effect

Abeer J Ayoub; Layal Hariss; Nehme El-Hachem; Ghewa A El-Achkar; Sandra E Ghayad; Oula K Dagher; Nada Borghol; René Grée; Bassam Badran; Ali Hachem; Eva Hamade; Aida Habib

doi:10.1186/s13065-019-0640-5

gem-Difluorobisarylic derivatives: design, synthesis and anti-inflammatory effect

BMC Chem. 2019 Oct 31;13(1):124. doi: 10.1186/s13065-019-0640-5. eCollection 2019 Dec.

Authors

Abeer J Ayoub^#^{1

2}, Layal Hariss^#³, Nehme El-Hachem^#^{4

5}, Ghewa A El-Achkar¹, Sandra E Ghayad⁶, Oula K Dagher¹, Nada Borghol², René Grée⁷, Bassam Badran², Ali Hachem^#³, Eva Hamade^#², Aida Habib^#^{1

8}

Affiliations

¹ 1Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
² 2Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon.
³ 3Laboratory for Medicinal Chemistry and Natural Products, Faculty of Sciences I and PRASE-EDST Lebanese University, Beirut, Lebanon.
⁴ 4Integrative Systems Biology, Institut de Recherches Cliniques de Montréal, Montreal, QC Canada.
⁵ 8Present Address: Department of Electrical and Computer Engineering, American University of Beirut, Beirut, Lebanon.
⁶ 5Department of Biology, Faculty of Sciences II, EDST, Lebanese University, Fanar, Lebanon.
⁷ 6Université de Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) UMR 6226, 35000 Rennes, France.
⁸ Université de Paris, Centre de Recherche sur l'Inflammation (CRI), INSERM, UMR1149, CNRS, ERL 8252, 75018 Paris, France.

^# Contributed equally.

Abstract

Introduction: New fluorinated diaryl ethers and bisarylic ketones were designed and evaluated for their anti-inflammatory effects in primary macrophages.

Methods: The synthesis of the designed molecules started from easily accessible and versatile gem-difluoro propargylic derivatives. The desired aromatic systems were obtained using Diels-Alder/aromatization sequences and this was followed by Pd-catalyzed coupling reactions and, when required, final functionalization steps. Both direct inhibitory effects on cyclooxygenase-1 or -2 activities, protein expression of cyclooxygenase-2 and nitric oxide synthase-II and the production of prostaglandin E₂, the pro-inflammatory nitric oxide and interleukin-6 were evaluated in primary murine bone marrow-derived macrophages in response to lipopolysaccharide. Docking of the designed molecules in cyclooxygenase-1 or -2 was performed.

Results: Only fluorinated compounds exerted anti-inflammatory activities by lowering the secretion of interleukin-6, nitric oxide, and prostaglandin E₂, and decreasing the protein expression of inducible nitric oxide synthase and cyclooxygenase-2 in mouse primary macrophages exposed to lipopolysaccharide, as well as cyclooxygenase activity for some inhibitors with different efficiencies depending on the R-groups. Docking observation suggested an inhibitory role of cyclooxygenase-1 or -2 for compounds A3, A4 and A5 in addition to their capacity to inhibit nitrite, interleukin-6, and nitric oxide synthase-II and cyclooxygenase-2 expression.

Conclusion: The new fluorinated diaryl ethers and bisarylic ketones have anti-inflammatory effects in macrophages. These fluorinated compounds have improved potential anti-inflammatory properties due to the fluorine residues in the bioactive molecules.

Keywords: Cyclooxygenase; Diaryl ethers; Fluorine; Inflammation; Macrophages.