A new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antibacterial agents: Design, synthesis and evaluation acting on microbes, DNA, HSA and topoisomerase IV
A new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antibacterial agents: Design, synthesis and evaluation acting on microbes, DNA, HSA and topoisomerase IV
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氨基噻唑喹诺酮肟作为潜在多靶点抗菌剂的新探索：作用于微生物、DNA、HSA 和拓扑异构酶 IV 的设计、合成和评价
DOI：
10.1016/j.ejmech.2019.06.046
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发表时间：
2019
影响因子：
6.7
通讯作者：
Zhou Cheng He
中科院分区：
文献类型：
--
作者：
Wang Liang Liang;Battini Narsaiah;Bheemanaboina Rammohan R Yadav;Ansari Mohammad Fawad;Chen Jin Ping;Xie Yun Peng;Cai Gui Xin;Zhang Shao Lin;Zhou Cheng He
该工作对氨基噻唑喹诺酮肟作为潜在的多靶点抗菌药物进行了新的探索。首次设计了一类喹诺酮、氨基噻唑、哌嗪和肟片段的新型杂化物，方便地合成并通过1H NMR、13C NMR和HRMS图谱进行了表征。生物活性表明，与参比药物相比，一些合成的化合物表现出良好的抗菌活性。尤其是O-甲基肟衍生物10b对MRSA和S表现出优异的抑制效果。 aureus25923 的 MIC 值分别为 0.009 和 0.017mM。进一步的研究表明，高活性化合物10b对BEAS-2B和A549细胞系表现出低毒性，并且没有明显引发细菌耐药性发展的倾向。还进行了量子化学研究并合理解释了活性所必需的结构特征。初步的机理探索表明，化合物10b不仅可以通过干扰细胞的完整性发挥高效的膜通透性，通过氢键和π-π堆积与拓扑异构酶IV-DNA复合物结合，还可以通过嵌入DNA形成稳定的生物超分子复合物，发挥高效的抗菌活性。化合物10b与人血清白蛋白(HSA)之间的超分子相互作用是静态猝灭的，结合过程是自发的，其中氢键和范德华力在活性化合物10b与HSA的超分子运输中发挥着重要作用。
This work did a new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antimicrobial agents. A class of novel hybrids of quinolone, aminothiazole, piperazine and oxime fragments were designed for the first time, conveniently synthesized as well as characterized by1H NMR,13C NMR and HRMS spectra. Biological activity showed that some of the synthesized compounds exhibited good antimicrobial activities in comparison with the reference drugs. Especially,O-methyl oxime derivative10bdisplayed excellent inhibitory efficacy against MRSA andS. aureus25923 with MIC values of 0.009 and 0.017 mM, respectively. Further studies indicated that the highly active compound10bshowed low toxicity toward BEAS-2B and A549 cell lines and no obvious propensity to trigger the development of bacterial resistance. Quantum chemical studies have also been conducted and rationally explained the structural features essential for activity. The preliminarily mechanism exploration revealed that compound10bcould not only exert efficient membrane permeability by interfering with the integrity of cells, bind with topoisomerase IV–DNA complex through hydrogen bonds and π-π stacking, but also form a steady biosupramolecular complex by intercalating into DNA to exert the efficient antibacterial activity. The supramolecular interaction between compound10band human serum albumin (HSA) was a static quenching, and the binding process was spontaneous, where hydrogen bonds and van der Waals force played vital roles in the supramolecular transportation of the active compound10bby HSA.