Carta Davide, Brun Paola, Dal Pra Matteo, Bernabè Giulia, Castagliuolo Ignazio, Ferlin Maria Grazia
Department of Pharmaceutical and , Pharmacological Sciences , University of Padova , 35131 Padova , Italy . Email:
Department of Molecular Medicine , University of Padova , 35131 Padova , Italy.
Medchemcomm. 2018 Apr 24;9(6):1017-1032. doi: 10.1039/c8md00139a. eCollection 2018 Jun 1.
Our aim was to identify new multi-target compounds endowed with both anti-inflammatory and anti-bacterial activities for treatment of human infections. Diflunisal, a nonsteroidal anti-inflammatory agent, has recently been repurposed for its anti-virulence properties against methicillin-resistant . Effective synthesis of some aza-analogs of the anti-inflammatory drug diflunisal was carried out following the route involving key oxazole intermediates to obtain - and -hydroxypyridinecarboxylic acid derivatives. The newly synthesized diflunisal aza-analogs did not exhibit cytotoxic activity up to 80 μM and some of them exhibited anti-inflammatory activities, decreasing the levels of pro-inflammatory cytokines and prostaglandins induced by bacterial lipopolysaccharide in human primary macrophages. Ten of the diflunisal aza-analogs were found to have interesting antibacterial activity, sensitizing , , , and to the antibacterial effects of beta-lactam antibiotics and protein synthesis inhibitors.
我们的目标是鉴定出具有抗炎和抗菌活性的新型多靶点化合物，用于治疗人类感染。双氟尼酸是一种非甾体抗炎药，最近因其对耐甲氧西林菌的抗毒力特性而被重新利用。通过涉及关键恶唑中间体的路线，有效地合成了一些抗炎药物双氟尼酸的氮杂类似物，以获得 - 和 - 羟基吡啶羧酸衍生物。新合成的双氟尼酸氮杂类似物在高达80 μM的浓度下未表现出细胞毒性活性，其中一些表现出抗炎活性，可降低人原代巨噬细胞中细菌脂多糖诱导的促炎细胞因子和前列腺素水平。发现十种双氟尼酸氮杂类似物具有有趣的抗菌活性，可使 、 、 和 对β-内酰胺抗生素和蛋白质合成抑制剂的抗菌作用敏感。
