Abstract
IntroductionNew fluorinated diaryl ethers and bisarylic ketones were designed and evaluated for their anti-inflammatory effects in primary macrophages.MethodsThe 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.ResultsOnly 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.ConclusionThe 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.
Highlights
New fluorinated diaryl ethers and bisarylic ketones were designed and evaluated for their anti-inflam‐ matory effects in primary macrophages
We synthesized new gem-difluorobisarylic derivatives and evaluated their anti-inflammatory effects. We first investigated their effects on P GE2 production in mouse primary macrophages in response to lipopolysaccharide (LPS) and their anti-cyclooxygenase (COX)-1 and -2 activities. We studied their effects on the production of the pro-inflammatory nitric oxide (NO) and interleukin (IL)-6 and the expression of NO synthase-II (NOS-II) and COX-2
Synthesis of bisarylic derivatives Based on our previous study [12], five bisarylic compounds A1 to A5 were designed as indicated in Scheme 1
Summary
New fluorinated diaryl ethers and bisarylic ketones were designed and evaluated for their anti-inflam‐ matory effects in primary macrophages. Diaryl ethers are key scaffolds present in many natural or synthetic organic molecules, which are often used in medicinal chemistry [1]. Fenoprofen for instance is one of the synthetic diarylethers [2] with nonsteroidal. Benzophenone analogues, such as ketoprofen, recently have been reported as potent antiinflammatory agents by inhibiting prostaglandin (PG) production [4, 5]. The introduction of fluorine into organic molecules may cause profound pharmacological. Ayoub et al BMC Chemistry (2019) 13:124 effects by improving the activity and selectivity of the bioactive molecules [7]. The CF2 unit for instance is generally considered as a bioisostere of the oxygen atom or of a carbonyl group [11]
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