靶向细菌膜的苯基噻唑和苯基噻吩嘧啶二胺衍生物的设计，合成和评估。,European Journal of Medicinal Chemistry

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靶向细菌膜的苯基噻唑和苯基噻吩嘧啶二胺衍生物的设计，合成和评估。
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-11 , DOI: 10.1016/j.ejmech.2020.112141
Tingting Fan ₁ , Weikai Guo ₂ , Ting Shao ₂ , Wenbo Zhou ₂ , Pan Hu ₂ , Mingyao Liu ₂ , Yihua Chen ₂ , Zhengfang Yi ₂

Affiliation

随着抗生素耐药性发生率的不断提高，迫切需要开发出具有抗菌活性的新型化学支架，以控制对常规抗生素耐药性的传播。在这项研究中，通过改性命中化合物（N2-异丁基-N4-（（4-甲基-2-苯基噻唑-5-基）甲基）嘧啶-2,4-合成并设计了一系列苯基噻唑和苯基噻吩嘧啶二胺衍生物在体外和体内均对二胺及其抗菌活性进行了评估。在测试的化合物中，化合物14g（N4-（（5-（3-溴苯基）噻吩-2-基）甲基）-N2-异丁基嘧啶-2,4-二胺）表现出最佳的抗菌活性，不仅具有在体外以低至2和3μg/ mL的浓度抑制大肠杆菌和金黄色葡萄球菌的生长，而且对体内菌血症小鼠模型也有效。与常规抗生素不同，已阐明化合物14g主要破坏细菌细胞膜，从而耗散膜电位和内容物泄漏，最终导致细胞死亡。细胞结构的破坏对于诱导细菌耐药性具有挑战性，这表明化合物14g可能是一种有前途的抗生素替代细菌。

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Design, synthesis and evaluation of phenylthiazole and phenylthiophene pyrimidindiamine derivatives targeting the bacterial membrane.

As the continuous rise in the incidence of antibiotic resistance, it is urgent to develop novel chemical scaffolds with antibacterial activities to control the spread of resistance to conventional antibiotics. In this study, a series of phenylthiazole and phenylthiophene pyrimidindiamine derivatives were designed and synthesized by modifying the hit compound (N2-isobutyl-N4-((4-methyl-2-phenylthiazol-5-yl)methyl) pyrimidine-2,4-diamine) and their antibacterial activities were evaluated both in vitro and in vivo. Among the tested compounds, compound 14g (N4-((5-(3-bromophenyl)thiophen-2-yl)methyl)-N2-isobutylpyrimidine-2,4-diamine) displayed the best antibacterial activities, which was not only capable of inhibiting E. coli and S. aureus growth at concentrations as low as 2 and 3 μg/mL in vitro, but also efficacious in a mice model of bacteremia in vivo. Unlike conventional antibiotics, compound 14g was elucidated to mainly destroy the bacterial cell membrane, with the dissipation of membrane potential and leakage of contents, ultimately leading to cell death. The destruction of cell structure is challenging to induce bacterial resistance, which suggested that compound 14g may be a kind of promising alternatives to antibiotics against bacteria.

更新日期：2020-02-12

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