Synthesis of N-(chlorophenyl ) -2 -hydroxynicotinanilides as potential anti-inflammatory agents

Chien-Ming Huang, Y. Hsieh, Wen‐Hsin Huang, A. Lee
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引用次数: 1

Abstract

Leflunomide 1 and its non-enzymically active metabolite, malononitrilamide (MNA, 2) are clinical use for treating rheumatoid arthritis (RA). Study indicated that the active pharmacophore, a β-keto amide with the enolic hydroxyl group, was fully responsible for the immunosuppressive effects of malononitrilamide 2 leading a salicylamide derivative 3 developed. Previously, we have conducted isosterically structural modification mainly based on salicylamide derivative 3, which β-hydroxy-enamide-containing portion remains untouched, to successfully synthesize a series of N-(4-substituted phenyl)-2-hydroxynicotinanilides. After pharmacological screenings, compounds bearing electron-withdrawing groups such as 4-Cl, 4-Br, and 4-NO2 significantly showed potent anti-inflammatory activity. Currently, a series of compounds 5-14, which are the chloro variants on phenyl moiety, mainly based on N-(substituted phenyl)-2-hydroxynicotin-anilide 4-14 were further synthesized in high yields. After systematic pharmacological screenings of compounds 4-14 and controls, compound 14 exhibited potent in-vivo anti-inflammatory activity comparable to that of compound 5 and Leflunomide 1, whereas the other compounds have comparable activity to compound 4 and malononitrilamide 2 by both in vitro suppressing nitric oxide (NO) production under the LPS-elicited macrophage Raw 264.7 cell and the in-vivo carrageenaninduced paw edema assay, except for compounds 8 and 11.
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作为潜在抗炎剂的N-(氯苯基)-2 -羟基烟酰苯胺的合成
来氟米特1及其非酶活性代谢物丙二硝基酰胺(MNA, 2)被临床用于治疗类风湿性关节炎(RA)。研究表明,丙二硝基酰胺2的免疫抑制作用完全由具有烯醛羟基的β-酮酰胺这一活性药效团导致水杨酰胺衍生物3的开发。在此之前,我们主要以水杨酰胺衍生物3为基础,对其β-羟基-酰胺部分进行了等构修饰,成功合成了一系列N-(4-取代苯基)-2-羟基烟酰苯胺。经过药理学筛选,含有4-Cl, 4-Br和4-NO2等吸电子基团的化合物显着显示出有效的抗炎活性。目前,以N-(取代苯基)-2-羟基烟碱-苯胺4-14为基础,进一步合成了一系列化合物5-14,它们是苯基部分的氯变体。在对化合物4-14和对照进行系统药理学筛选后,化合物14显示出与化合物5和来氟米特1相当的体内抗炎活性,而在lps诱导的巨噬细胞Raw 264.7细胞和体内角叉菜胶诱导的足跖水肿实验中,其他化合物的体外抑制一氧化氮(NO)产生的活性与化合物4和丙二腈酰胺2相当,但化合物8和11除外。
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