Design, synthesis and evaluation of phenylthiazole and phenylthiophene pyrimidindiamine derivatives targeting the bacterial membrane
Design, synthesis and evaluation of phenylthiazole and phenylthiophene pyrimidindiamine derivatives targeting the bacterial membrane
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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、合成和评价
DOI：
10.1016/j.ejmech.2020.112141
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发表时间：
2020
影响因子：
6.7
通讯作者：
Yi Zhengfang
中科院分区：
文献类型：
--
作者：
Fan Tingting;Guo Weikai;Shao Ting;Zhou Wenbo;Hu Pan;Liu Mingyao;Chen Yihua;Yi Zhengfang
随着抗生素耐药发生率的不断上升，迫切需要开发具有抗菌活性的新型化学支架来控制常规抗生素耐药的蔓延。本研究通过对hit化合物（n2 -异丁基- n4 -（（4-甲基-2-苯基噻唑-5-基）甲基）嘧啶-2,4-二胺）进行修饰，设计合成了一系列苯基噻唑和苯基噻吩嘧啶衍生物，并对其体外和体内抗菌活性进行了评价。在所测试的化合物中，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）表现出最好的抗菌活性，不仅具有抑制作用。coliandS。在低至2和3 μg/ min的浓度下，金黄色葡萄球菌在体外生长，但在体内细菌血症小鼠模型中也有效。与常规抗生素不同，化合物14g主要破坏细菌细胞膜，使膜电位耗散，内容物渗漏，最终导致细胞死亡。通过破坏细胞结构来诱导细菌产生耐药性具有挑战性，这表明化合物14g可能是一种很有前景的抗细菌抗生素替代品。
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 bothin vitroandin vivo. Among the tested compounds, compound14g(N4-((5-(3-bromophenyl)thiophen-2-yl)methyl)-N2-isobutylpyrimidine-2,4-diamine) displayed the best antibacterial activities, which was not only capable of inhibitingE. coliandS. aureusgrowth at concentrations as low as 2 and 3 μg/mLin vitro, but also efficacious in a mice model of bacteremiain vivo. Unlike conventional antibiotics, compound14gwas 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 compound14gmay be a kind of promising alternatives to antibiotics against bacteria.