A Parallel Synthesis Approach to the Identification of Novel Diheteroarylamide-Based Compounds Blocking HIV Replication: Potential Inhibitors of HIV-1 Pre-mRNA Alternative Splicing
A Parallel Synthesis Approach to the Identification of Novel Diheteroarylamide-Based Compounds Blocking HIV Replication: Potential Inhibitors of HIV-1 Pre-mRNA Alternative Splicing
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DOI：
10.1021/acs.jmedchem.5b01357
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发表时间：
2016-03-10
影响因子：
7.3
通讯作者：
Grierson, David S.
中科院分区：
文献类型：
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作者：
Cheung, Peter K.;Horhant, David;Grierson, David S.
在抗hiv筛选中，对256个化合物文库进行了评估，以确定融合四环吲哚化合物1 （IDC16）的结构“模拟物”，该化合物保留其抗hiv活性而没有相关的细胞毒性。四种二异芳酰胺型化合物，均含有一个共同的5-硝基异苯并噻唑基序，被鉴定为活性化合物。在随后的筛选中，最有效的化合物9 （1C8）对野生型HIV-1(IIIB) （B亚型，X4-tropic）和hiv - 197ussn54 （A亚型，R5-tropic）具有活性，EC50分别为0.6 μ M和0.9 μ M。化合物9还能抑制针对HIV逆转录酶、蛋白酶、整合酶和辅助受体CCRS的药物耐药的HIV毒株，EC50值在0.9 ~ 1.5 μ M之间。在细胞毒性实验中，化合物9的CC50值为100 μ M，对应的治疗指数（CC50/EC50）约为100。进一步的比较研究表明，虽然化合物9的抗hiv活性与母体分子1相似，但化合物9的细胞毒作用如预期的那样被明显抑制。
A 256-compound library was evaluated in an anti-HIV screen to identify structural "mimics" of the fused tetracyclic indole compound 1 (IDC16) that conserve its anti-HIV activity without associated cytotoxicity. Four diheteroarylamide-type compounds, containing a common 5-nitroisobenzothiazole motif, were identified as active. In subsequent screens, the most potent compound 9 (1C8) was active against wild-type HIV-1(IIIB) (subtype B, X4-tropic) and HIV-1 97USSN54 (subtype A, R5-tropic) with EC50's of 0.6 and 0.9 mu M, respectively. Compound 9 also inhibited HIV strains resistant to drugs targeting HIV reverse transcriptase, protease, integrase, and coreceptor CCRS with EC50's ranging from 0.9 to 1.5 mu M. The CC50 value obtained in a cytotoxicity assay for compound 9 was >100 mu M, corresponding to a therapeutic index (CC50/EC50) of approximately 100. Further comparison studies revealed that, whereas the anti-HIV activity for compound 9 and the parent molecule 1 are similar, the cytotoxic effect for compound 9 was, as planned, markedly suppressed.