Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition.
Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition.
复制标题
用于 HCV NS5B 聚合酶抑制的二酮酸药效团的合成和 SAR 优化。
DOI：
10.1016/j.ejmech.2011.08.028
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发表时间：
2011
影响因子：
6.7
通讯作者：
Talele,TanajiT
中科院分区：
文献类型：
--
作者：
Bhatt,Aaditya;Gurukumar,KR;Basu,Amartya;Patel,MaulikR;Kaushik-Basu,Neerja;Talele,TanajiT
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。本文报道了一系列新的α，γ-二酮酸（DKAs）作为NS5B聚合酶抑制剂的合成和生物学评价。我们围绕化合物1a [IC50= 21.8 μM]的呋喃部分进行了构效关系（SAR）优化，以获得更有效的NS5B抑制剂。该化合物3a [IC50= 8.2 μM]含有5-溴苯并呋喃-2-基片段，是该系列中第一个有前景的先导化合物。将呋喃部分与噻吩、噻唑和茚唑部分改变，得到含有3-甲基噻吩-2-基部分的化合物11a [IC50= 7.5 μM]。最后用生物等构苯环取代噻吩环进一步提高了化合物21a [IC50= 5.2 μM]和24a [IC50= 2.4 μM]的抑制活性。化合物24a在NS5B聚合酶活性位点内采用滑翔对接的结合方式，将成为未来SAR优化的基础。
Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of α,γ-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure–activity relationship (SAR) optimization around the furan moiety of compound 1a [IC50= 21.8 μM] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50= 8.2 μM] bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a [IC50= 7.5 μM] bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a [IC50= 5.2 μM] and 24a [IC50= 2.4 μM]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization.