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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity.
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Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity.

机译：吡啶酮衍生物：具有抗病毒活性的特定人类免疫缺陷病毒1型逆转录酶抑制剂。

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Derivatives of pyridinones were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevent the spread of HIV-1 infection in cell culture without an appreciable effect on other retroviral or cellular polymerases. 3-[( (4,7-Dimethyl-1,3-benzoxazol-2-yl) methyl]amino ]-5-ethyl-6-methylpyridin-2(1H)-one (L-697,639) and 3-[[ (4,7-dichloro-1,3-benzoxazol-2-yl) methyl]amino]-5-ethyl-6-methylpyridin-2(1H)-one (L-697,661), two compounds within this series, had HIV-1 RT IC50 values in the range of 20-800 nM, depending upon the template-primer used. The most potent inhibition was obtained with rC.dG and dA.dT as template--primers. With rC.dG, reversible slow-binding non-competitive inhibition was observed. [3H]L-697,639 bound preferentially to enzyme-template-primer complexes. This binding was magnesium-dependent and saturable with a stoichiometry of 1 mol of [3H]L-697,639 per mol of RT heterodimer. Displacement of [3H]L-697,639 was seen with phosphonoformate. In human T-lymphoid-cell culture, L-697,639 and L-697,661 inhibited the spread of HIV-1 infection by at least 95% at concentrations of 12-200 nM. Synergism between 3'-azido-3'-deoxythymidine or dideoxyinosine and either of these compounds was also demonstrated in cell culture. Based upon their specificity for HIV-1 RT activity, template-primer dependence on potency and ability to displace [3H]L-697,639; a tetrahydroimidazo [4,5,1-jk] [1,4]-benzodiazepin-2(1H)-thione derivative R82150 and the dipyridodiazepinone BI-RG-587 appear to inhibit RT activity by the same mechanism as the pyridinones.
机译：发现吡啶酮类衍生物可以抑制人类1型免疫缺陷病毒（HIV-1）逆转录酶（RT）活性，并防止HIV-1感染在细胞培养中传播，而对其他逆转录病毒或细胞聚合酶没有明显影响。 3-[（（（4,7-二甲基-1,3-苯并恶唑-2-基）甲基]氨基] -5-乙基-6-甲基吡啶-2（1H）-一（L-697,639）和3-[[ （4,7-二氯-1,3-苯并恶唑-2-基）甲基]氨基] -5-乙基-6-甲基吡啶-2（1H）-一（L-697,661），该系列中的两种化合物均患有艾滋病毒-1 RT IC50值在20-800 nM范围内，具体取决于所使用的模板引物。使用rC.dG和dA.dT作为模板引物可获得最有效的抑制作用。观察到结合性[3H] L-697,639优先结合到酶-模板-引物复合物中，这种结合是镁依赖性的，并且以每摩尔RT异二聚体1摩尔[3H] L-697,639的化学计量饱和。在膦酸酯中观察到[3H] L-697,639的置换在人类T淋巴细胞培养物中，当浓度为12-200 nM时，L-697,639和L-697,661抑制了HIV-1感染的传播至少95％。 3'-叠氮基-3'-脱氧胸苷或双脱氧肌苷与这两种化合物的协同作用也是在细胞培养中证明。根据它们对HIV-1 RT活性的特异性，模板引物对效价的依赖性和置换[3H] L-697,639的能力；四氢咪唑并[4,5,1-jk] [1,4]-苯并二氮杂-2-2（1H）-硫酮衍生物R82150和二吡啶二氮杂酮BI-RG-587似乎通过与吡啶酮相同的机理抑制RT活性。

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