Comparative evaluation of the inhibitory activities of a series of pyrimidinedione congeners that inhibit human immunodeficiency virus types 1 and 2
Comparative evaluation of the inhibitory activities of a series of pyrimidinedione congeners that inhibit human immunodeficiency virus types 1 and 2
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DOI：
10.1128/aac.00972-07
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发表时间：
2008-01-01
影响因子：
4.9
通讯作者：
Cho, Eui-Hwan
中科院分区：
文献类型：
--
作者：
Buckheit, Robert W., Jr.;Hartman, Tracy L.;Cho, Eui-Hwan
合成了73种SJ-3366类似物（1-(3-环戊烯-1-基甲基)-5-乙基-6-(3,5-二甲基苯甲酰基)-2,4(1H,3H)-嘧啶二酮），并比较评价了它们抑制人类免疫缺陷病毒1型（HIV-1）和HIV-2复制的能力以及抑制病毒进入和逆转录的能力。进行这些研究的目的是鉴定活性高于当前先导分子 (SJ-3366) 的抑制剂，并利用构效关系 (SAR) 来定义嘧啶二酮同系物的化学特征，这些特征决定了其功效、毒性和抗 HIV 的双重作用机制。我们的 SAR 评估结果表明，在嘧啶二酮的 N-1 位添加同环部分可以获得抑制病毒进入的能力，并扩展了化合物的作用范围，包括 HIV-2。此外，结果表明，在同环取代基和嘧啶二酮的N-1之间具有甲基连接基的类似物比具有乙基连接基的类似物具有更多数量的高活性分子。鉴定出 6 个分子的活性等于或大于 SJ-3366，另外鉴定出 5 个分子，它们对逆转录酶和病毒进入具有高效抑制作用，并且对 HIV-1 和 HIV-2 均具有高效能。六种分子表现出对病毒的显着抑制作用，具有高度问题的非核苷逆转录酶抑制剂（NNRTI）抗性，导致逆转录酶中的氨基酸变化 K103N。这些评估表明，已经鉴定出一类新的 NNRTI，并且这些 NNRTI 对 HIV-1 具有高效抑制作用，作用范围更广，目前包括 HIV-2。
Seventy-three analogs of SJ-3366 (1-(3-cyclopenten-1-ylmethyl)-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4(1H,3H)-pyrimidinedione) were synthesized and comparatively evaluated for their ability to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) and HIV-2 and for their ability to suppress virus entry and reverse transcription. These studies were performed to identify inhibitors with activity greater than that of the current lead molecule (SJ-3366) and to utilize structure-activity relationships (SAR) to define the chemical features of the pyrimidinedione congeners responsible for their efficacy, toxicity, and dual mechanism of action against HIV. The results of our SAR evaluations have demonstrated that the addition of the homocyclic moiety at the N-1 of the pyrimidinedione results in acquisition of the ability to inhibit virus entry and extends the range of action of the compounds to include HIV-2. In addition, the results demonstrate that analogs with a methyl linker between the homocyclic substitution and the N-1 of the pyrimidinedione had a greater number of highly active molecules than those analogs possessing ethyl linkers. Six molecules were identified with activity equivalent to or greater than that of SJ-3366, and five additional molecules with highly potent inhibition of reverse transcriptase and virus entry and possessing high efficacy against both HIV-1 and HIV-2 were identified. Six molecules exhibited significant inhibition of viruses with the highly problematic nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance engendering amino acid change K103N in the reverse transcriptase. These evaluations indicate that a new class of NNRTIs has been identified and that these NNRTIs possess highly potent inhibition of HIV-1 with an extended range of action, which now includes HIV-2.