Click Chemistry-Facilitated Structural Diversification of Nitrothiazoles, Nitrofurans, and Nitropyrroles Enhances Antimicrobial Activity against Giardia lamblia.
Click Chemistry-Facilitated Structural Diversification of Nitrothiazoles, Nitrofurans, and Nitropyrroles Enhances Antimicrobial Activity against Giardia lamblia.
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点击化学促进硝基噻唑、硝基呋喃和硝基吡咯的结构多样化增强对贾第鞭毛虫的抗菌活性。
DOI：
10.1128/aac.02397-16
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发表时间：
2017
影响因子：
4.9
通讯作者：
Eckmann,Lars
中科院分区：
文献类型：
--
作者：
Kim,WanJung;Korthals,KeithA;Li,Suhua;Le,Christine;Kalisiak,Jarosław;Sharpless,KBarry;Fokin,ValeryV;Miyamoto,Yukiko;Eckmann,Lars
蓝氏贾第鞭毛虫是引起腹泻疾病的一种重要且普遍存在的原因。治疗贾第鞭毛虫病的主要药物是硝基杂环类药物，特别是咪唑类甲硝唑和替硝唑以及噻唑类硝唑尼特。虽然这些药物通常是有效的，但治疗失败的病例高达20%，并且在体内和体外都显示出耐药性。先前的工作表明，对咪唑核心的侧链进行修饰可以产生新的有效的5-硝基-咪唑类药物，从而对抗硝基耐药性，但咪唑以外的硝基杂环化合物产生有效的新抗心包药物的全部潜力还没有被探索。在这里，我们生成了两个临床上使用的硝基杂环的衍生物，硝基噻唑和硝基呋喃，以及第三个杂环，硝基吡咯，它与硝基咪唑有关，但尚未被系统地作为抗菌药物支架进行研究。采用点击化学方法合成了442个具有广泛侧链修饰的新型硝基杂环化合物。该文库对典型的革兰氏杆菌菌株的筛选显示了广泛的体外活性，其中许多化合物显示出比参比药物更好的活性，其中几种化合物的效力和克服现有形式的甲硝唑耐药性的能力提高了100倍。大多数新化合物对人体细胞没有细胞毒性，有几个化合物在体内对小鼠贾第虫有口服活性。这些发现为以非咪唑为核心的硝基杂环化合物的系统开发提供了额外的动力，作为治疗贾第虫病和潜在的其他感染性病原体的替代和改进药物。
Giardia lamblia is an important and ubiquitous cause of diarrheal disease. The primary agents in the treatment of giardiasis are nitroheterocyclic drugs, particularly the imidazoles metronidazole and tinidazole and the thiazole nitazoxanide. Although these drugs are generally effective, treatment failures occur in up to 20% of cases, and resistance has been demonstratedin vivoandin vitro. Prior work had suggested that side chain modifications of the imidazole core can lead to new effective 5-nitroimidazole drugs that can combat nitro drug resistance, but the full potential of nitroheterocycles other than imidazole to yield effective new antigiardial agents has not been explored. Here, we generated derivatives of two clinically utilized nitroheterocycles, nitrothiazole and nitrofuran, as well as a third heterocycle, nitropyrrole, which is related to nitroimidazole but has not been systematically investigated as an antimicrobial drug scaffold. Click chemistry was employed to synthesize 442 novel nitroheterocyclic compounds with extensive side chain modifications. Screening of this library against representative G. lamblia strains showed a wide spectrum ofin vitroactivities, with many of the compounds exhibiting superior activity relative to reference drugs and several showing >100-fold increase in potency and the ability to overcome existing forms of metronidazole resistance. The majority of new compounds displayed no cytotoxicity against human cells, and several compounds were orally active against murine giardiasisin vivo. These findings provide additional impetus for the systematic development of nitroheterocyclic compounds with nonimidazole cores as alternative and improved agents for the treatment of giardiasis and potentially other infectious agents.