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

中文翻译：

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gem-Difluorobisarylic 衍生物：设计、合成和抗炎作用

设计并评估了新的氟化二芳基醚和双芳基酮在原代巨噬细胞中的抗炎作用。设计分子的合成始于易于获得且用途广泛的偕二氟炔丙基衍生物。使用 Diels-Alder/芳构化序列获得所需的芳烃体系，然后进行 Pd 催化的偶联反应，并在需要时进行最终的官能化步骤。在小鼠原代骨髓中评估了对环氧合酶 1 或 -2 活性、环氧合酶 2 和一氧化氮合酶 II 的蛋白质表达以及前列腺素 E2、促炎一氧化氮和白细胞介素 6 的产生的直接抑制作用。衍生巨噬细胞对脂多糖的反应。将设计的分子与环氧合酶-1 或-2 对接。只有含氟化合物通过降低白介素 6、一氧化氮和前列腺素 E2 的分泌，并降低暴露于脂多糖的小鼠原代巨噬细胞中诱导型一氧化氮合酶和环氧合酶 2 的蛋白质表达，以及环氧合酶来发挥抗炎活性某些抑制剂的活性取决于 R 基团，具有不同的效率。对接观察表明，除了化合物 A3、A4 和 A5 抑制亚硝酸盐、白细胞介素 6 和一氧化氮合酶 II 和环氧合酶 2 表达的能力外，环氧合酶 1 或 -2 还具有抑制作用。新的氟化二芳基醚和双芳基酮在巨噬细胞中具有抗炎作用。