Design and synthesis of L- and D-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase
Design and synthesis of L- and D-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase
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DOI：
10.1016/j.bmc.2013.03.041
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发表时间：
2013-06-01
影响因子：
3.5
通讯作者：
Talele, Tanaji T.
中科院分区：
文献类型：
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作者：
Patel, Bhargav A.;Krishnan, Ramalingam;Talele, Tanaji T.
丙型肝炎病毒 (HCV) NS5B 聚合酶是抗 HCV 疗法开发的关键靶标。在此，我们报告了我们之前报道的先导化合物 1 (IC50 = 7.7 μM) 和 2 (IC50 = 10.6 μM) 的分子杂合体的合成和抗 NS5B 聚合酶活性的体外评估，如杂合化合物 27 (IC50 = 6.7 μM) 所示。我们通过生成一组六个类似物，探索了 27 中 3-苯氧基亚苄基部分末端苯环上的最佳取代基。这导致化合物 34 的鉴定，IC50 为 2.6 μM。为了探讨立体化学对观察到的生物活性的作用，我们合成并评估了 D-异构体 41 (IC50 = 19.3 μM) 和 45 (IC50 = 5.4 μM)，分别作为 L-异构体 27 和 34 的对映体。化合物 32 和 34 的结合位点被映射到 NS5B 的手掌口袋-I (PP-I)。研究了34和45在NS5B的PP-I内的对接模型以设想抑制的分子机制。 (C) 2013 Elsevier Ltd. 保留所有权利。
Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50 = 7.7 mu M) and 2 (IC50 = 10.6 mu M) as represented by hybrid compound 27 (IC50 = 6.7 mu M). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 mu M. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the D-isomers 41 (IC50 = 19.3 mu M) and 45 (IC50 = 5.4 mu M) as enantiomers of the L-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition. (C) 2013 Elsevier Ltd. All rights reserved.