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本文研究了N4-(杂)芳基磺酰基喹喔啉酮类化合物6-氯-3-甲基-4-(2-甲氧羧基噻吩-3-磺酰基)-3,4-二氢喹啉-2-(1H)-酮(XU07011)抗HIV-1作用机制及特点。采用细胞水平模型评价该化合物抗HIV-1活性;通过在不同时间点加入化合物检测化合物失效时间,确定化合物抑制病毒复制的具体环节;酶联免疫吸附法和荧光法测定化合物对逆转录酶的DNA聚合酶活性和核糖核酸酶H(RNase H)催化活性的影响;应用非核苷类逆转录酶抑制剂(non-nucleoside reverse-transcriptase inhibitors,NNRTIs)耐药逆转录酶和重组病毒模型分别在酶和细胞水平研究化合物的作用特点。结果显示,XU07011可剂量依赖性地抑制HIV-1复制,IC50为(0.057±0.01)μmol·L?1,活性与奈韦拉平相当;该化合物作用于HIV-1复制的逆转录环节,抑制了逆转录酶的RNA依赖DNA聚合酶活性,IC50为(1.1±0.3)μmol·L?1,而对逆转录酶RNase H活性无显著影响;该化合物对9种NNRTI耐药病毒的耐药倍数为33～2000倍,其中对K103N耐药病毒活性优于奈韦拉平。本研究为新型HIV-1抑制剂的研发提供了物质基础。
In this paper, the effects of N4- (hetero) arylsulfonylquinoxalinones on the synthesis of 6-chloro-3-methyl-4- (2-methoxycarboxythiophene-3-sulfonyl) The Mechanism and Characteristics of Anti-HIV-1 Action of XU07011. The cell-level model was used to evaluate the anti-HIV-1 activity of the compound. Compounds were tested for their ability to inhibit viral replication by adding compounds at different time points. Enzyme-linked immunosorbent assay (FACS) Polymerase (RNase) activity and RNase H activity. Using non-nucleoside reverse-transcriptase inhibitors (NNRTIs) and RT-PCR, Cell-level studies of the role of compounds. The results showed that XU07011 could inhibit HIV-1 replication in a dose-dependent manner with an IC50 of (0.057 ± 0.01) μmol·L -1, comparable to that of nevirapine. The compound acts on the reverse transcriptional part of HIV-1 replication and inhibits reverse transcription The RNA of the enzyme was dependent on the activity of DNA polymerase with IC50 of (1.1 ± 0.3) μmol·L -1, but had no significant effect on the activity of reverse transcriptase RNase H. The resistance of the compound to 9 NNRTI resistant viruses was 33 ~ 2000 times, of which K103N resistant virus activity is better than nevirapine. This study provides a material basis for the development of new HIV-1 inhibitors.