New pyrazolobenzothiazine derivatives as hepatitis C virus NS5B polymerase palm site I inhibitors.
New pyrazolobenzothiazine derivatives as hepatitis C virus NS5B polymerase palm site I inhibitors.
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DOI：
10.1021/jm401688h
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发表时间：
2014-04-24
影响因子：
7.3
通讯作者：
Cecchetti V
中科院分区：
文献类型：
--
作者：
Manfroni G;Manvar D;Barreca ML;Kaushik-Basu N;Leyssen P;Paeshuyse J;Cannalire R;Iraci N;Basu A;Chudaev M;Zamperini C;Dreassi E;Sabatini S;Tabarrini O;Neyts J;Cecchetti V
我们以前已经确定吡唑并苯并噻嗪支架作为一个有前途的化学型对丙型肝炎病毒（HCV）NS 5 B聚合酶，一个验证和有前途的抗HCV的目标。在这里，我们描述了新的抗HCV抑制剂吡唑并苯并噻嗪的设计，合成，酶，和细胞特性。采用突变体反筛选测定将代表性衍生物的结合位点映射到NS 5 B棕榈位点I，从而验证了我们先前的计算机预测。衍生物2b被证明是新系列中选择性最好的抗HCV衍生物，在基于细胞的HCV复制子系统测定中显示出对NS 5 B聚合酶的7.9 μM的IC 50和抗病毒作用（EC 50 = 8.1 μM; EC 90 = 23.3 μM），并且没有任何抗代谢作用（CC 50> 224 μM; SI > 28）。值得注意的是，显微镜分析显示，与母体化合物不同，衍生物2b没有显示出任何显著的细胞形态学改变。此外，由于测试的大多数吡唑并苯并噻嗪改变了细胞形态，因此通过探索化合物处理期间脂质代谢的可能扰动来进一步研究该不期望的方面。
We have previously identified the pyrazolobenzothiazine scaffold as a promising chemotype against hepatitis C virus (HCV) NS5B polymerase, a validated and promising anti-HCV target. Herein we describe the design, synthesis, enzymatic, and cellular characterization of new pyrazolobenzothiazines as anti-HCV inhibitors. The binding site for a representative derivative was mapped to NS5B palm site I employing a mutant counterscreen assay, thus validating our previous in silico predictions. Derivative 2b proved to be the best selective anti-HCV derivative within the new series, exhibiting a IC50 of 7.9 μM against NS5B polymerase and antiviral effect (EC50 = 8.1 μM; EC90 = 23.3 μM) coupled with the absence of any antimetabolic effect (CC50 > 224 μM; SI > 28) in a cell based HCV replicon system assay. Significantly, microscopic analysis showed that, unlike the parent compounds, derivative 2b did not show any significant cell morphological alterations. Furthermore, since most of the pyrazolobenzothiazines tested altered cell morphology, this undesired aspect was further investigated by exploring possible perturbation of lipid metabolism during compound treatment.
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影响因子：
7.6
作者：
Betzi, Stephane;Eydoux, Cecilia;Canard, Bruno
通讯作者：
Canard, Bruno
影响因子：
--
作者：
Chen, Ye;Bopda-Waffo, Alain;Kaushik-Basu, Neerja
通讯作者：
Kaushik-Basu, Neerja
影响因子：
5.6
作者：
Barreca, Maria Letizia;Iraci, Nunzio;Cecchetti, Violetta
通讯作者：
Cecchetti, Violetta
DOI：
10.1056/nejmra1213651
发表时间：
2013-05-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Liang TJ;Ghany MG
通讯作者：
Ghany MG
鉴定和表征香豆作为新型HCV NS5B聚合酶抑制剂。
影响因子：
14.9
作者：
Kaushik-Basu, Neerja;Bopda-Waffo, Alain;Talele, Tanaji T.;Basu, Amartya;Costa, Paulo R. R.;da Silva, Alcides J. M.;Sarafianos, Stefan G.;Noel, Francois
通讯作者：
Noel, Francois