State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Children's Hospital, Zhengzhou 450018, China.
Bioorg Med Chem. 2019 Apr 15;27(8):1509-1516. doi: 10.1016/j.bmc.2019.02.043. Epub 2019 Feb 21.
A series of rhodanine derivatives RB1-RB23 were synthesized through a two-round screening. Their Mycobacterial tuberculosis (Mtb) InhA inhibitory activity and Mtb growth blocking capability were evaluated. The most potent hit compound RB23 indicated comparable InhA inhibiton (IC = 2.55 μM) with the positive control Triclosan (IC = 6.14 μM) and Isoniazid (IC = 8.29 μM). Its improved growth-blocking effect on Mtb and low toxicity were attractive for further development. The docking simulation revealed the possible binding pattern of this series and picked the key interacted residues as Ser20, Phe149, Lys165 and Thr196. The 3D-QSAR model visualized the SAR discussion and hinted new information. Modifying the surroundings near rhodanine moiety might be promising attempts in later investigations.
通过两轮筛选，合成了一系列硫代罗丹宁衍生物 RB1-RB23。评估了它们对分枝杆菌结核（Mtb）InhA 的抑制活性和 Mtb 生长阻断能力。最有效的化合物 RB23 对 InhA 的抑制作用与阳性对照三氯生（IC=6.14μM）和异烟肼（IC=8.29μM）相当。它对 Mtb 的生长阻断作用得到改善，且毒性较低，具有进一步开发的潜力。对接模拟揭示了该系列可能的结合模式，并挑选出关键的相互作用残基，包括 Ser20、Phe149、Lys165 和 Thr196。3D-QSAR 模型可视化了 SAR 讨论，并提示了新的信息。修饰硫代罗丹宁部分附近的环境可能是后期研究中很有前途的尝试。
