摘要 ：人类免疫缺陷病毒（Human immunodeficiency virus， HIV），是致使艾滋病的罪魁祸首。这一病毒传播性很广，它对人类的健康有着严重的伤害。自从1981年第一次报出了几例被HIV感染的患者以来，这种恶性疾病不仅造成了经济问题，而且还对社会和伦理问题造成了严重的影响。这种危急的情况刺激了人们发现针对HIV的新药物。79568

在这一论文中，一系列的DABOs类化合物被用来作为HIV逆转录酶抑制剂。通过CoMFA、CoMSIA以及Topomer CoMFA等一系列计算机辅助药物设计的研究方法，对所选取的35个DABOs系列衍生物进行三维定量构效关系研究，建立有效的模型，其显示的统计学参数（q2> 0。5，r2> 0。9）显示了良好的预测能力，所得到的各场的色块图能有助于我们清楚影响HIV逆转录酶抑制剂分子活性的结构特征。

对这些衍生物中的活性最佳的一个化合物进行合成设计研究。设计年产量为30吨的化合物6，即5-甲基-6-[(1-氯-5-氟)甲基苄基]-2-环戊基硫基嘧啶-4（3H）-酮的合成工艺流程。用β-酮酯类化合物与硫脲、卤代烃等化合物在催化剂醇钠和无水DMF等的作用下进行合成，经过两步反应、三次结晶、过滤干燥等操作来生产目标化合物。此项工艺设计主要包括方案选择及设计工艺过程中的物料衡算、能量衡算、主要的设备选型、三废及综合处理等内容。

毕业论文关键词:  3D-QDAR；逆转录酶抑制剂；CoMFA；CoMSIA；合成设计

Study on the Structure - activity Relationship and Synthetic Design of HIV Reverse Transcriptase Inhibitors

Abstract : Human immunodeficiency virus (HIV) is the culprit lead to AIDS。 The spread of the virus is very wide, it has serious harm to human health。 Since the first time in 1981, several cases of HIV-infected patients have reported that this malignancy has not only caused economic problems, but also has a serious impact on social and ethical issues。 This critical situation stimulates the discovery of new drugs for HIV。

In this paper, a series of DABOs are used as inhibitors of HIV reverse transcriptase。 A series of computer-aided drug design studies are conducted by CoMFA, CoMSIA and Topomer CoMFA。 Three effective quantitative models are selected for the 35 DABOs, and the statistical parameters (q2> 0。5, r2> 0。9) show good predictive power, and the resulting block diagram of each field can help us to clearly understand the structural characteristics of the HIV reverse transcriptase inhibitor。

A study of the best activity of these derivatives is carried out。 A solution of 30 tons of compound 6, 5-methyl-6 - [(1-chloro-5-fluoro) methylbenzyl] -2-cyclopentylthio pyrimidin-4 (3H) Synthetic process。 The compounds are produced by the reaction of β-ketoester compounds with thiourea, halogenated hydrocarbons under the action of sodium alkoxide and anhydrous DMF, and the reaction is carried out by two-step reaction, tertiary crystallization, filtration drying and so on。 The process design includes the program selection and design process of material accounting, energy accounting, the main equipment selection, waste and comprehensive treatment and so on。

Keywords:  3D-QDAR; Integrase strand transfer inhibitor; CoMFA; CoMSIA; Synthetic design

目录

1绪论 1

1。1 HIV的基本结构及复制过程 2

1。2 HIV逆转录酶抑制剂的简介 2

1。3 DABOs衍生物的研究现状 3

1。4 研究意义及内容 4

2研究原理和方法 5

2。1 计算机辅助药物设计