Discovery and development of novel rhodanine derivatives targeting enoyl-acyl carrier protein reductase
Discovery and development of novel rhodanine derivatives targeting enoyl-acyl carrier protein reductase
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发现和开发靶向烯酰基载体蛋白还原酶的新型绕丹宁衍生物
DOI：
10.1016/j.bmc.2019.02.043
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发表时间：
2019
影响因子：
3.5
通讯作者：
Hai-Liang Zhu
中科院分区：
文献类型：
--
作者：
Jian-Fei Xu;Tian-Tian Wang;Qing Yuan;Yong-Tao Duan;Yun-Jie Xu;Peng-Cheng Lv;Xiao-Ming Wang;Yu-Shun Yang;Hai-Liang Zhu
通过两轮筛选合成了一系列罗丹宁衍生物RB 1-RB 23。评价了它们对结核分枝杆菌（Mtb）InhA的抑制活性和对Mtb生长的阻断能力。最有效的命中化合物RB 23表明InhA对映体（IC 50 = 2.55 μM）与阳性对照三氯生（IC 50 = 6.14 μM）和异烟肼（IC 50 = 8.29 μM）相当。其对结核分枝杆菌的生长阻断作用的改善和低毒性具有进一步开发的吸引力。对接模拟揭示了这一系列可能的结合模式，并挑选出关键的相互作用残基为Ser 20，Phe 149，Lys 165和Thr 196。3D-QSAR模型使SAR讨论可视化，并暗示了新的信息。修饰绕丹宁的周围环境可能是今后研究的一个有希望的尝试。
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 (IC50 = 2.55 μM) with the positive control Triclosan (IC50 = 6.14 μM) and Isoniazid (IC50 = 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.