Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2017-12-24 , DOI: 10.1016/j.bmc.2017.12.033 Anna Maria Monforte , Laura De Luca , Maria Rosa Buemi , Fatima E. Agharbaoui , Christophe Pannecouque , Stefania Ferro
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of human immunodeficiency virus (HIV) infection. These regimens are extremely effective in suppressing virus replication. Recently, our research group identified some N1-aryl-2-arylthioacetamido-benzimidazoles as a novel class of NNRTIs. In this research work we report the design, the synthesis and the structure–activity relationship studies of new compounds (20–34) in which some structural modifications have been introduced in order to investigate their effects on reverse transcriptase (RT) inhibition and to better define the features needed to increase the antiviral activity. Most of the new compounds proved to be highly effective in inhibiting both RT enzyme at nanomolar concentrations and HIV-1 replication in MT4 cells with minimal cytotoxicity. Among them, the most promising N1-aryl-2-arylthioacetamido-benzimidazoles and N1-aryl-2-aryloxyacetamido-benzimidazoles were also tested toward a panel of single- and double-mutants strain responsible for resistance to NNRTIs, showing in vitro antiviral activity toward single mutants L100I, K103N, Y181C, Y188L and E138K. The best results were observed for derivatives 29 and 33 active also against the double mutants F227L and V106A. Computational approaches were applied in order to rationalize the potency of the new synthesized inhibitors.
中文翻译:
N 1-芳基-苯并咪唑类化合物的结构优化,用于发现对野生型和突变型HIV-1菌株具有活性的新型非核苷类逆转录酶抑制剂
非核苷逆转录酶抑制剂(NNRTIs)是推荐的抗逆转录病毒联合疗法的成分,可用于治疗人类免疫缺陷病毒(HIV)感染。这些方案在抑制病毒复制方面极为有效。最近,我们的研究小组确定了一些N 1-芳基-2-芳基硫代乙酰氨基-苯并咪唑类作为一类新的NNRTIs。在这项研究工作中,我们报告了新化合物的设计,合成以及结构与活性之间的关系(20 – 34),其中已引入一些结构修饰,以研究其对逆转录酶(RT)抑制的影响并更好地定义增加抗病毒活性所需的功能。事实证明,大多数新化合物都能以最小的细胞毒性抑制纳摩尔浓度的RT酶和MT4细胞中HIV-1的复制。其中,最有前途的N 1-芳基-2-芳硫基乙酰乙酰氨基-苯并咪唑和N 1-芳基-2-芳氧基乙酰胺基-苯并咪唑也针对一组对NNRTIs具有抗性的单突变体和双突变体菌株进行了测试,显示了体外对单个突变体L100I,K103N,Y181C,Y188L和E138K的抗病毒活性。对于衍生物,观察到最佳结果29和33对双突变体F227L和V106A也有活性。为了使新型合成抑制剂的效力合理化,应用了计算方法。