Synthesis of Bioactive Complex Small Molecule-Ciprofloxacin Conjugates and Evaluation of Their Antibacterial Activity.,ACS Combinatorial Science

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Synthesis of Bioactive Complex Small Molecule-Ciprofloxacin Conjugates and Evaluation of Their Antibacterial Activity.
ACS Combinatorial Science Pub Date : 2020-07-21 , DOI: 10.1021/acscombsci.0c00060
Rahul Upadhyay _{1,

2} , Rahul Kumar _{1,

2} , Manoj Jangra ₃ , Rohit Rana _{1,

2} , Onkar S Nayal _{1,

2} , Hemraj Nandanwar _{2,

3} , Sushil K Maurya _{1,

2}

Affiliation

Conjugates between pharmaceuticals and small molecules enable access to a vast chemical space required for the discovery of new lead molecules with modified therapeutic potential. However, the dearth of specific chemical reactions that are capable of functionalizing drugs and bioactive natural products presents a formidable challenge for preparing their conjugates. Here, we report a support-free CuI-nanoparticle-catalyzed strategy for conjugating electron-deficient and electron-rich terminal alkynes with a ciprofloxacin methyl ester. Our conjugation technique exploits the late-stage functionalization of bioactive natural products such as tocopherol, vasicinone, amino acids, and pharmaceuticals such as aspirin and paracetamol to provide conjugates in excellent yields under mild and green conditions. This protocol also enabled the synthesis of (hetero)arene-ciprofloxacin 1,4-disubstituted 1,2,3-triazoles in good yields and high regioselectivities. These synthesized ciprofloxacin conjugates were evaluated in vitro for their antibacterial activity against a panel of relevant bacteria. A significant number of conjugates showed comparable activity against Gram-positive and Gram-negative bacteria. Moreover, some conjugates exhibited less toxicity than ciprofloxacin against two mammalian cell lines, suggesting the utility for the future investigation of these compounds for in vivo efficacy and pharmacokinetic studies.

中文翻译：

生物活性复合小分子环丙沙星缀合物的合成及其抗菌活性评价。

药物和小分子之间的结合物能够进入发现具有改良治疗潜力的新先导分子所需的广阔化学空间。然而，能够使药物和生物活性天然产物功能化的特定化学反应的缺乏对制备它们的缀合物提出了艰巨的挑战。在这里，我们报告了一种无支持的 CuI 纳米颗粒催化策略，用于将缺电子和富电子的末端炔烃与环丙沙星甲酯结合。我们的缀合技术利用生物活性天然产物（如生育酚、vasicinone、氨基酸和阿司匹林和扑热息痛等药物）的后期功能化，在温和和绿色条件下以优异的产量提供缀合物。该协议还能够以良好的产率和高区域选择性合成（杂）芳烃-环丙沙星 1,4-二取代 1,2,3-三唑。评估了这些合成的环丙沙星偶联物体外对一组相关细菌的抗菌活性。大量缀合物对革兰氏阳性菌和革兰氏阴性菌显示出相当的活性。此外，一些缀合物对两种哺乳动物细胞系的毒性低于环丙沙星，这表明这些化合物在未来研究中用于体内功效和药代动力学研究的实用性。

更新日期：2020-09-14

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