Etodolac Thiosemicarbazides: A novel class of hepatitis C virus NS5B polymerase inhibitors
Etodolac Thiosemicarbazides: A novel class of hepatitis C virus NS5B polymerase inhibitors
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DOI：
10.12991/201317382
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发表时间：
2013-01-01
期刊：
影响因子：
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通讯作者：
Kucukguzel, S. Guniz
中科院分区：
文献类型：
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作者：
Cikla, Pelin;Arora, Payal;Kucukguzel, S. Guniz
本研究合成了一系列新的依托度酸酰肼衍生物，1-[2-(1,8-二乙基-1,3,4,9四氢吡喃[3,4-b]吲哚-1-基)乙酰基]-4-烷基/芳基氨基硫脲[3a-h]。新化合物的结构通过光谱（FT-IR、H-1-NMR、C-13-NMR 和 LC-MS）方法确定。通过引物依赖性延伸测定在体外评价依托度酸氨基硫脲对丙型肝炎病毒NS5B RNA依赖性RNA聚合酶活性的抑制。该系列中最活跃的化合物是3a (SGK 224)、3d (SGK 227) 和3e (SGK 229)，IC50 值分别为18.7 μM、29.2 μM 和16.8 μM。对最活跃的化合物1-[2-(1,8-二乙基1,3,4,9-四氢吡喃并[3,4-b]吲哚-1-基)乙酰基]-4-烯丙基氨基硫脲(3e)的结合模式研究表明HCV NS5B聚合酶的TP-II可能是依托度酸氨基硫脲的潜在结合位点，并为修饰以提高依托度酸的效力提供了线索衍生物。
A novel series of new etodolac hydrazide derivatives, 1-[2-(1,8-diethyl-1,3,4,9tetrahydropyrano[ 3,4-b] indole-1-yl) acetyl]-4-alkyl/aryl thiosemicarbazides [3a-h] have been synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, H-1-NMR, C-13-NMR and LC-MS) methods. Inhibition of hepatitis C virus NS5B RNA dependent RNA polymerase activity by etodolac thiosemicarbazides was evaluated in vitro by primer dependent elongation assays. The most active compounds of this series were3a (SGK 224), 3d (SGK 227) and 3e (SGK 229) with IC50 values of 18.7 mu M, 29.2 mu M and 16.8 mu M, respectively. Binding mode investigations of the most active compound 1-[2-(1,8-diethyl1,3,4,9- tetrahydropyrano[3,4-b] indole-1-yl) acetyl]-4-allyl thiosemicarbazide (3e) suggested that TP-II of HCV NS5B polymerase may be the potential binding site for etodolac thiosemicarbazides and provided clues for modifications to improve the potency of etodolac derivatives.