Synthesis and in vitro anti-HIV-1 evaluation of some N-arylsulfonyl-3-formylindoles

As our ongoing work on research of anti-HIV-1 inhibitors, fifteen N-arylsulfonyl-3-formylindoles (3a-o) were designed and prepared through two step synthetic route. Firstly, 3-formylindoles (2a-c) were synthesized via the Vilsmeier-Haack reaction. Subsequently, treatment of 2a-c with the appropriate arylsulfonyl chlorides led to the corresponding target compounds in excellent yields. All analogues were also preliminary evaluated in vitro for their inhibitory activity against HIV-1 replication. Among of all the reported analogues, three compounds 3c, 3g and 3i displayed significant anti-HIV-1 activity, with EC50 values of 9.57, 11.04 and 5.02 μM, and TI values of 31.89, 13.79 and 81.69, respectively. N-m-nitrophenylsulfonyl-3-formylindole (3c) and N-m-nitrophenylsulfonyl-6-methyl-3-formylindole (3i) especially exhibited the best promising anti-HIV-1 activity. In addition, it demonstrated that insertion of a methyl group at the C-6 position of the indolyl ring and a nitro group at the meta position of the arylsulfonyl ring, as in compound 3i, resulted in both low cytotoxicity (CC50= 410.41 μM) and good antiviral activity.

本研究围绕抗HIV-1抑制剂的研究展开，通过两步合成路线设计并制备了15个N-芳磺酰基-3-甲酰基吲哚（N-arylsulfonyl-3-formylindoles）类化合物（3a~3o）。首先，通过维尔斯迈尔-哈克（Vilsmeier-Haack）反应合成了3-甲酰基吲哚类中间体（2a~2c）。随后，将中间体2a~2c与相应的芳磺酰氯进行反应，以优异的收率得到目标化合物。所有上述类似物均通过体外实验初步评价了其抗HIV-1复制的抑制活性。在所有受试类似物中，化合物3c、3g和3i表现出显著的抗HIV-1活性，其半数有效浓度（EC50）分别为9.57、11.04和5.02 μM，治疗指数（TI）分别为31.89、13.79和81.69。其中，N-间硝基苯磺酰基-3-甲酰基吲哚（3c）与N-间硝基苯磺酰基-6-甲基-3-甲酰基吲哚（3i）展现出最为优异的抗HIV-1潜力。此外，研究表明，如化合物3i所示，在吲哚环的C-6位引入甲基、在芳磺酰基苯环的间位引入硝基，可同时实现较低的细胞毒性（半数细胞毒性浓度CC50=410.41 μM）与良好的抗病毒活性。