基于CCR5靶标的哌啶衍生物设计、合成及抗HIV-1活性研究

发布时间：2019-06-19 22:08

【摘要】：获得性免疫缺陷综合征(Acquired Immune Deficiency Syndrome)，简称艾滋病(AIDS)，其在全球范围内的广泛传播已对人类健康和生命造成了严重的威胁。CCR5是HIV-1进入细胞的关键辅助受体，以CCR5为靶标的HIV-1小分子拮抗剂研究是抗艾滋病领域研究的热点之一。本文的工作主要围绕CCR5这一靶标做了三方面工作，即药物设计、化学合成、生物学活性测定。药物设计方面，应用Discovery Studio2.5程序中的Hypogen模块建立了一个可靠的药效团模型Hypothesis1，然后以该药效团模型来对自建的小分子化合物库进行筛选，结合本实验室的先前所取得的工作成果，设计了以1-哌啶丙胺为分子骨架的两个系列共14个分子,并应用药效团模型Hypothesis1对这14个分子进行了活性预测。化学合成方面，以新方法合成了中间体4-(3-苄基-1H-吡唑-5-基)哌啶，系列1中目标化合物的合成经历了11步反应，系列2中目标化合物的合成经历了7步反应，所经历的反应类型有亲核取代反应、酰化反应、Grignard反应、Claisen缩合反应等，最终两个系列共合成14个化合物，所合成的中间体及目标化合物经过1H NMR、13C NMR及ESI-MS确认。生物学活性测定方面，，应用MAGI方法，测定了目标化合物的生物学活性，证实了Hypothesis1模型的可靠性，发现化合物吡唑哌啶甲酰胺19g的活性相较于系列2中化合物有显著提高，IC50为750nmol·L-1，治疗指数达到了203，将其作为先导化合物进一步结构优化有望获得活性更好毒性更低的以CCR5为靶标的药物分子。
[Abstract]:The wide spread of acquired immunodeficiency syndrome (Acquired Immune Deficiency Syndrome),) (AIDS), in the world has caused a serious threat to human health and life. CCR5 is the key auxiliary receptor for HIV-1 to enter cells. The study of HIV-1 small molecule antagonists targeting CCR5 is one of the hotspots in the field of anti-AIDS. In this paper, three aspects of work have been done around the target of CCR5, namely, drug design, chemical synthesis and biological activity determination. In the aspect of drug design, a reliable pharmacophore model Hypothesis1, was established by using the Hypogen module of Discovery Studio2.5 program, and then the self-built small molecular compound library was screened by using the pharmacophore model. Combined with the previous work results in our laboratory, two series of 14 molecules with 1-piperidine propylamine as molecular skeleton were designed, and the activity of the 14 molecules was predicted by using the pharmacophore model Hypothesis1. In the aspect of chemical synthesis, the intermediate 4-(3-benzyl-1H-pyrazole-5-yl) piperidine was synthesized by a new method. The synthesis of the target compound in series 1 went through 11 steps, and the synthesis of the target compound in series 2 underwent 7 steps. The reaction types were nucleophilic substitution reaction, acylation reaction, Grignard reaction, Claisen condensation reaction and so on. Finally, 14 compounds were synthesized in the two series. The synthesized intermediates and target compounds were confirmed by 1H NMR,13C NMR and ESI-MS. In the aspect of biological activity determination, the biological activity of the target compound was determined by MAGI method, and the reliability of the Hypothesis1 model was confirmed. It was found that the activity of the compound pyrazole piperidine formamide 19g was significantly higher than that of the compound in series 2, the IC50 was 750nmol 路L-1, and the treatment index reached 203. It is expected that the drug molecule with lower activity and lower toxicity can be obtained by further structural optimization of the target compound.
【学位授予单位】：北京工业大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R512.91;TQ463

【相似文献】