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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides bearing heteroaromatic rings as novel antibacterial agents: Design, synthesis, biological evaluation and target identification
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N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides bearing heteroaromatic rings as novel antibacterial agents: Design, synthesis, biological evaluation and target identification

机译：N-噻二唑-4-羟基-2-喹啉-3-甲酰胺含有杂芳烃作为新型抗菌剂：设计，合成，生物评估和目标鉴定

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摘要

Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 mu g/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25-1 mu g/mL vs. 1-64 14/ mu L) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6-155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：由于抗生素耐药性的发生，细菌感染性疾病已成为公众健康构成严重威胁。为了克服抗生素抗性，迫切需要新的抗生素。的N- thiadiazole4羟基-2-喹诺酮-3-甲酰胺是潜在的新类抗菌剂，作为其衍生物的一个被确定为针对金黄色葡萄球菌的抗菌剂。然而，没有效力定向结构优化已经完成。在这项研究中，我们设计并合成了37个衍生物，和评价了它们对金黄色葡萄球菌ATCC29213，而导致的识别10有效的抗菌剂的具有最小抑制浓度（MIC）值低于1个微克/毫升的抗菌活性。接下来，我们针对耐药临床分离株，包括耐甲氧西林金黄色葡萄球菌，以及与HepG2和HUVEC细胞的细胞毒性测定法的一个面板进行细菌生长抑制测定法。一种测试化合物的命名为1-乙基-4-羟基-2-氧代-N-（5-（噻唑-2-基）-1,3,4-噻二唑-2-基）-1,2-二氢喹啉-3-甲酰胺（G37）显示2至128倍的改善与针对所测试的菌株的抗菌效力的术语万古霉素相比（MICS：0.25-1亩克/ mL相对1-64 14 /亩L）和最佳选择毒性（HepG2细胞/ MRSA，110.6至221.2; HUVEC / MRSA，77.6-155.2）。此外，综合评价表明，G37并没有引起MRSA的抗性发展了20代，它已被证实是杀菌，代谢稳定，口服有效的抗菌剂。更重要的是，我们已经确定了金黄色葡萄球菌DNA促旋酶B中其潜在的目标，并提出了由潜在分子对接结合模式。总之，目前的工作报告该化学系列的最有效的衍生物（G37）和揭示其潜在的目标，其中规定用于通过基于结构的药物设计技术进一步促进先导物优化了坚实的基础。 （c）2019年Elsevier Masson SAS。版权所有。

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  • 来源
  • 作者

    Xue Wenjie; Li Xueyao; Ma Guixing; Zhang Hongmin; Chen Ya; Kirchmair Johannes; Xia Jie; Wu Song;

  • 作者单位

    Chinese Acad Med Sci Inst Mat Med Dept New Drug Res &

    Dev State Key Lab Bioact Subst &

    Funct Nat;

    Chinese Acad Med Sci Inst Mat Med Dept New Drug Res &

    Dev State Key Lab Bioact Subst &

    Funct Nat;

    Southern Univ Sci &

    Technol Dept Biol Guangdong Prov Key Lab Cell Microenvironm &

    Dis R Shenzhen;

    Southern Univ Sci &

    Technol Dept Biol Guangdong Prov Key Lab Cell Microenvironm &

    Dis R Shenzhen;

    Univ Hamburg Fac Math Informat &

    Nat Sci Ctr Bioinformat ZBH Dept Comp Sci Hamburg Germany;

    Univ Hamburg Fac Math Informat &

    Nat Sci Ctr Bioinformat ZBH Dept Comp Sci Hamburg Germany;

    Chinese Acad Med Sci Inst Mat Med Dept New Drug Res &

    Dev State Key Lab Bioact Subst &

    Funct Nat;

    Chinese Acad Med Sci Inst Mat Med Dept New Drug Res &

    Dev State Key Lab Bioact Subst &

    Funct Nat;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    Antibiotic resistance; Antibacterial agent; MRSA; DNA gyrase B; Molecular docking;

    机译：抗生素抗性;抗菌剂;MRSA;DNA庚酶B;分子对接;

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