gem-Difluorobisarylic derivatives: design, synthesis and anti-inflammatory effect - Université de Rennes Access content directly
Journal Articles BMC Chemistry Year : 2019

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

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 E-2, 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 E-2, 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.
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Dates and versions

hal-02391905 , version 1 (27-04-2020)
hal-02391905 , version 2 (20-12-2023)

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Abeer J. Ayoub, Layal Hariss, Nehme El-Hachem, Ghewa A. El-Achkar, Sandra E Ghayad, et al.. gem-Difluorobisarylic derivatives: design, synthesis and anti-inflammatory effect. BMC Chemistry, 2019, 13 (1), ⟨10.1186/s13065-019-0640-5⟩. ⟨hal-02391905v2⟩
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