Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Bioorg Med Chem. 2013 Jun 1;21(11):3262-71. doi: 10.1016/j.bmc.2013.03.041. Epub 2013 Mar 31.
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 μM) and 2 (IC50=10.6 μM) as represented by hybrid compound 27 (IC50=6.7 μM). 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 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the D-isomers 41 (IC50=19.3 μM) and 45 (IC50=5.4 μM) 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.
丙型肝炎病毒 (HCV) NS5B 聚合酶是抗 HCV 治疗药物开发的关键靶点。本文报道了我们之前报道的先导化合物 1（IC50=7.7 μM）和 2（IC50=10.6 μM）的分子杂交体 27（IC50=6.7 μM）的抗 NS5B 聚合酶活性的体外评价。我们通过生成一组六个类似物，探索了 27 中末端苯环上的最佳取代基。这导致了化合物 34 的鉴定，其 IC50 为 2.6 μM。为了探究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），它们分别是 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 palm 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。
