目的设计合成双二酮酸类化合物，并探讨此类化合物抑制 HIV-1整合酶活性的构效关系。 方法以甲基取代苯乙酮为起始原料，经溴代后与羟基取代苯乙酮反应生成乙酰基苄氧苯乙酮，然后在氢化钠作用下，脱去α氢后进攻草酸二乙酯生成双二酮酸酯，水解脱去酯基生成双二酮酸；经1H-NMR、IR和 MS验证化合物结构。ELISA法测定目标化合物对 HIV-1整合酶的抑制活性；采用高通量荧光法测定目标化合物对 HIV-1整合酶3'加工过程的抑制活性；测定目标化合物对 HIV假病毒的细胞活性。 结果合成了6个全新结构的二酮酸类化合物；体外整合酶活性评价结果表明，6个目标化合物对 HIV-1整合酶的活性 IC50≤20μg/ml，双二酮酸之间距离稍短的5a、5c、5d对3'加工过程有一定的活性，IC50约为40μg/ml。 结论6个新化合物对 HIV-1的活性主要表现在链转移过程。%Objective To explore the relationship of structure and activity of these compounds with anti HIV-1 integrase through designing and synthesizing a series of novel bis-diketo acid compounds. Methods Title compounds were synthesized through bromination, substitution and hydrolyzation. 6 target compounds were obtained. All structures were confirmed by1H-NMR, IR and MS. Anti HIV-1 integrase activitiesin vitro of the target compounds were tested by ELISA, high-throughput fluorescence method was used to anti HIV-1 integrase 3P activities, and HIV-1 pseudovirus was applied to determine the infection rate of cells inhibited by the compounds. Results 6 novel compounds were synthesized. The title compounds exhibited moderate anti-integrase activity with IC50≤ 20μg/ml. Three target compounds exhibited 3P activity with IC50≈ 40μg/ml. Conclusion 6 novel compounds exihibit mainly ST activity. The study will help to understand the relationship of structure and activity of compounds with anti HIV-1 activities.
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