以HIV-1整合酶为靶标的杂环并吡啶类衍生物的设计、合成及其构效关系研究

发布时间：2018-02-09 14:07

本文关键词： 人类免疫缺陷病毒(HIV-1) 整合酶抑制剂 N-羟基-二氢萘胺酮衍生物吡啶并吡咯衍生物 6-取代基吡啶并吡咯类衍生物　出处：《北京工业大学》2016年博士论文　论文类型：学位论文

【摘要】：艾滋病是人类免疫缺陷病毒(HIV)感染引起的获得性免疫缺陷综合征(AIDS)的简称,是一种对人类健康有着严重威胁性的重大传染病。自从1981年6月在美国首次发现艾滋病患者到2015年底,这种疾病已导致三千多万人死亡。目前,高效抗逆转录病毒联合疗法(HAART)是艾滋病的最佳治疗方法,但由于HIV病毒的迅速变异能力,导致耐药性病毒株以及药物的毒副作用使得寻找新的治疗药物成为该研究领域亟待解决的问题。HIV的pol基因编码病毒复制过程中所需要的三个关键酶:逆转录酶,蛋白酶和整合酶。整合酶是一个32kd的蛋白,作用是催化病毒DNA整合到宿主DNA上。由于人体内不存在这样功能或者与其同源性较高的酶,因而HIV整合酶是一个理想的抗HIV药物设计靶标。从2007年起已有三个整合酶抑制剂陆续上市:雷特格韦、埃替格韦和德罗格韦。但是由于HIV的高突变性,对这些已上市药物有着耐药性的毒株也相继出现,这使得寻找新的治疗药物变得更为迫切。本研究通过药效团研究和生物电子等排等原理,在已报道化合物的基础上设计了三种全新的先导化合物母核。通过在所设计的母核上连接不同的取代基团而设计并成功合成了三个系列衍生物,且分别在分子水平和细胞水平对所设计合成的化合物进行活性测定。最后利用分子对接方法研究这些化合物结构与HIV整合酶相互作用的模式以及抑制活性之间的关系,并分析得到了这些化合物活性差异的原因,期望以此为基础设计和合成出活性更好的整合酶抑制剂。本论文内容主要包括以下几个方面:(1)结合已上市的三种整合酶抑制剂和三种N-羟基类整合酶抑制剂的结构特点,而设计出咪唑并哌啶类(J1-10a~J1-10s)和噻唑并哌啶类化合物(J2-12a~J2-12s),并通过在C-12位引入各种疏水芳香基团来探讨活性与结构之间的关系,为避免化合物设计不合理的问题,用分子对接程序对这两类化合物中的代表物进行了结合模式、对接能量和抑制活性的分析和预测。(2)基于前人报导的N-羟基-二氢萘胺酮衍生物,以及已经上市的雷特格韦,我们设计了一种全新的N-羟基-二氢萘胺酮的母核,并在该母核的C-2位上引入各种疏水性芳基以探讨活性与结构之间的关系,合成了一系列N-羟基-二氢萘胺酮类衍生化合物(J3-a~J3-l)。这些化合物的结构都通过1H NMR和ESI-HRMS确定,同时测定了这些合成化合物对HIV-1整合酶的3'端加工抑制活性、链转移抑制活性和细胞水平上的抗HIV增殖的活性。最后借助分子对接的方法,对代表化合物进行结合模式分析和对接能量预测,并通过理论计算的结果对这类化合物进行了构效关系的分析,为这类化合物的继续改进指明了方向。(3)二酮酸类HIV整合酶抑制剂是一类非常具有应用前景的化合物。为了探索新的整合酶抑制剂结构,我们以已上市药物雷特格韦为模板化合物,利用生物电子等排原理,设计了一种吡啶并吡咯的母核,并在该母核的C-10位上引入各种疏水性芳基以探讨活性与结构之间的关系,合成了一系列吡啶并吡咯衍生物(J4-6a~J4-6t),同时测定了这些合成化合物对HIV-1整合酶的3'端加工抑制活性和细胞水平上的抗HIV增殖的活性。最后借助分子对接的方法对这类化合物进行了构效关系的分析,为这类化合物的继续改进指明了方向。(4)在吡啶并吡咯类衍生物的结构基础上,通过分子对接的方法分析其代表化合物J4-6i的结合模式和雷特格韦结合模式之间的差异,而设计了6-取代吡啶并吡咯类母核。在该母核的C-6位上引入一些疏水性芳基探讨活性与结构之间的关系,而合成了6-取代吡啶并吡咯类衍生物(J5-7a~J5-7i),同时测定了这些合成化合物对HIV-1整合酶的3'端加工抑制活性和细胞水平上的抗HIV增殖的活性。最后借助分子对接方法对这类化合物进行了构效关系分析,为这类化合物的继续优化奠定了基础。
[Abstract]:AIDS is human immunodeficiency virus (HIV) infection caused by acquired immunodeficiency syndrome (AIDS) for short, is a kind of human health has a severe infectious disease threat. Since June 1981 in the United States for the first time found in AIDS patients by the end of 2015, the disease has killed about thirty million people. At present, highly active antiretroviral virus combination therapy (HAART) is the best treatment for AIDS, but due to the rapid mutation of the HIV virus, leading to drug resistance strains and drug side effects that find new drugs become three key enzymes required for pol gene encoding the viral replication process to solve the problems on.HIV: reverse transcriptase the enzyme, protease and integrase. Integrase is a 32KD protein catalytic role is the integration of viral DNA into host DNA. Due to the lack of this kind of function or body With its homologous enzymes, thus HIV integrase is an ideal target for anti HIV drug design. Since 2007 there have been three integrase inhibitors listed: Rett Kawet, Egypt and Germany for Kawet Luogewei. But due to the high mutation of HIV, a resistance strain appeared on these listed the drug, which makes the search for new therapeutic drugs has become more urgent. This study through pharmacophore research and bio isostere principle, based on the reported compounds on the design of the three new lead compound nucleus. The design of nucleus with different substituents designed and synthesized successfully the three series of derivatives, and at the molecular level and cell level on the design of the synthesized compounds were detected. Finally using molecular docking method to study the structures of these compounds and HIV integrase interactions The relationship between the model and the inhibitory activity, and analysis of the causes of differences in the activity of these compounds, expectations based design and synthesis of integrated enzyme inhibitor activity better. Main contents of this paper include the following aspects: (1) a combination of three integrase inhibitors have been listed and three kinds of N- hydroxyl integration the structure characteristics of enzyme inhibitors, designed imidazo piperidine (J1-10a~J1-10s) and thiazole and piperidine compounds (J2-12a~J2-12s), and through a variety of hydrophobic aromatic groups are introduced at the C-12 position to explore the relationship between activity and structure, in order to avoid the unreasonable design of the compound, the binding mode by using molecular docking procedures on behalf of on the two kinds of compounds, and inhibit the activity of the docking energy analysis and prediction. (2) reported before two N- hydroxy - naphthylamine derivatives based on hydrogen, and has been listed on the thunder Tegewei, we design a new N- two - hydroxy ketone naphthylamine hydrogen nucleus, and the introduction of a variety of hydrophobic aromatic groups in the nucleus C-2 to explore the relationship between activity and structure, a series of N- hydroxy - two hydrogen naphthylamine ketones derivatizing compounds were synthesized. The structure of (J3-a~J3-l) compound by 1H NMR and ESI-HRMS are determined, these synthetic compounds of HIV-1 integrase 3'end processing inhibition activity was also determined, chain transfer inhibitory activity and the cellular level of anti HIV proliferation activity. Finally using molecular docking method to represent compounds with mode analysis and docking energy prediction, and through the theoretical calculation results were analyzed the structure-activity relationship of these compounds, as these compounds continue to indicate the direction of improvement. (3) two ketone acids HIV integrase inhibitor is a kind of very promising compounds. In order to explore the structure of the new integrase inhibitors, we have listed Rett as the template Kawet drug compounds, using the principle of bioisosterism, designed a pyridine and pyrrole nucleus, and the introduction of a variety of hydrophobic aromatic groups in the nucleus C-10 to explore the relationship between activity and structure, a a series of pyridine and pyrrole derivatives were synthesized (J4-6a~J4-6t), these synthetic compounds of HIV-1 integrase 3'end processing inhibitory activity and the cellular level of anti HIV proliferation activity was also determined. Finally using molecular docking method analysis of structure-activity relationship of these compounds, as these compounds continue to indicate the direction of improvement. (4) the structural basis of pyridine and pyrrole derivatives, through molecular docking method to analysis the representative compounds combining J4-6i model and Rett Kawet binding mode between the difference and design The 6- substituted pyridine and pyrrole nucleus. Probe into some hydrophobic aryl relationship between activity and structure in the nucleus of C-6, and the synthesis of 6- substituted pyridine and pyrrole derivatives (J5-7a~J5-7i), these synthetic compounds of HIV-1 integrase 3'end processing inhibitory activity and the cell level HIV anti proliferation activity was also determined. Finally using the molecular docking method of this kind of compounds of structure-activity relationship analysis, which laid the foundation for the continued optimization of this kind of compounds.

【学位授予单位】：北京工业大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914;R91

【相似文献】