新型1，2，6-噻二嗪二酮类非核苷类逆转录酶抑制剂的设计、合成及活性研究

发布时间：2018-03-27 14:02

本文选题：HIV-1　切入点：非核苷类逆转录酶抑制剂　出处：《山东大学》2014年硕士论文

【摘要】：获得性免疫缺陷综合征(俗称艾滋病,acquired immunodeficiency syndrome, AIDS)主要是由人免疫缺陷病毒1型(HIV-1)引起的,以攻击人体免疫系统为主的一类严重的传染性疾病。逆转录酶在HIV-1的生命周期中扮演着重要的角色,负责将HIV-1的遗传物质RNA逆转录成DNA,是病毒完成复制所必需的。非核苷类逆转录酶抑制剂(NNRTIs)作为高效抗逆转录疗法(HAART)的关键组成成分,具有高效、低毒、高选择性、抗耐药性等优点。尽管抗艾药物治疗有效地控制了艾滋病发病率、降低了死亡率,但由于病毒基因突变导致的耐药性很大程度上限制了临床药物的使用,因此开发新型的抗耐药艾滋病治疗药物显得尤为迫切。新型“杂环-NH-取代苯”类、DABO和DAPY类NNRTIs是目前抗艾滋药物研究的热点和重点,他们对多种变异型毒株都有效,而且具有选择性高、药代动力学性质良好的优势。尤其是新一代DAPY类衍生物中已有2种药物分别在2008年和2011年由FDA批准上市。本课题在基于以上先导化合物的结构特点、结合模式和构效关系分析的基础上,对先导化合物的结构进行优化,设计合成了新型1,1-二氧-1,2,6-噻二嗪芳基胺类衍生物(A系列化合物)和新型1,1-二氧-1,2,6-噻二嗪类DABO-DAPY杂化体(B系列化合物)两个系列的噻二嗪衍生物。基于生物电子等排体原理,两个系列的化合物中都引入能与逆转录酶结合口袋(NNIBP)中关键氨基酸形成更多氢键的1,1-二氧-1,2,6-噻二嗪杂环体系,增强与NNIBP的结合能力从而提高抗病毒活性。考虑到NNRTIs分子的柔性需求,在1,1-二氧-1,2,6-噻二嗪芳基胺类衍生物(A系列化合物)中B部分与苯氧基之间引入亚甲基,增强B部分的柔性以使该类化合物能够更好地与NNIBP中的疏水性氨基酸Try181、Tyr188、Trp229及Phe227形成的疏水口袋形成π-π相互作用或其他范德华相互作用。而利用分子杂合的概念设计了一类1,1-二氧-1,2,6-噻二嗪类DAB0-DAPY杂化体(B系列化合物),一方面保留DABO类化合物C-6位的优势基团,该部分可与Tyr181、 Tyr188、Trp229及Phe227等疏水性氨基酸形成π-π堆积作用；另一方面采用DAPY右翼的优势取代基,该部分伸向NNIBP的溶剂开口区,增强与氨基酸的相互作用。由此共设计了A、B两个系列共计45个新型的1,1-二氧-1,2,6-噻二嗪杂环衍生物。利用Syby1-X1.1对所设计的目标化合物进行对接分析,结果显示两个系列的化合物与先导化合物的结合模式相似,保持了与NNIBP中关键氨基酸的相互作用,并且新引入的噻二嗪环能与Lys101和Glu138形成更多的氢键,有可能增强化合物与RT的结合能力。 A、B两个系列的化合物以不同的羧酸为原料,与麦氏酸反应后生成5位取代的麦氏酸衍生物,然后与硫酰胺环合生成噻二嗪母环,再与TsCl反应生成母环羰基被活化的关键中间体。关键中间体再与合成的取代基反应生成目标产物。所合成的45个化合物经过光谱分析验证。对所合成的噻二嗪衍生物进行活性评价,体外细胞水平抗HIV活性测定结果显示,A系列化合物未表现出显著的抗病毒活性,原因可能与化合物性质、细胞吸收代谢等机制有关。B系列化合物的细胞水平抗HIV活性正在测定中。但初步的逆转录酶抑制活性结果表明,B系列化合物大部分具有抑制RT的活性,某些化合物的活性甚至优于阳性对照药NVP(IC50=2.38μM),其中最好的两个化合物为Ba9(IC50=0.270μM)和Bb7(IC50=0.397μM). 综上,本课题在结合先导化合物的结构特点、结合模式和构效关系研究的基础上,利用生物电子等排体、分子杂合等药物设计原理,设计并合成了共计45个结构全新的1,1-二氧-1,2,6-噻二嗪衍生物,其结构经光谱分析确证。尽管A系列化合物未能表现出显著的抗病毒活性,但为今后的抗HIV药物研究和进一步的结构优化提供了有价值的信息。
[Abstract]:Acquired immunodeficiency syndrome ( AIDS ) is a serious infectious disease caused by human immunodeficiency virus type 1 ( HIV - 1 ) . It plays an important role in the life cycle of HIV - 1 . It is necessary to reverse transcription of HIV - 1 genetic material into DNA .

The non - nucleoside reverse transcriptase inhibitor ( NNRTI ) is a key component of high - efficiency antiretroviral therapy ( HAART ) , and has the advantages of high efficiency , low toxicity , high selectivity , resistance to drug resistance , etc . Although the anti - AIDS drug treatment effectively controls the incidence of AIDS and reduces the mortality rate , the drug resistance caused by the mutation of the virus greatly limits the use of clinical drugs , so the development of a novel anti - drug - resistant AIDS treatment drug is particularly urgent .

The novel " heterocyclic - NH - substituted benzene " , DABO and DAPY class NNRtis are the hot spots and emphasis of the current anti - AIDS drugs research . They are effective for various types of mutated strains , and have the advantages of high selectivity and good pharmacokinetic properties . Especially in the new generation of DAPY derivatives , two kinds of drugs are approved by the FDA in 2008 and 2011 , respectively .

A novel 1,1 - dioxo - 1,2,6 - thiadiazine - type DAPY hybrid ( A - series compound ) and a novel 1,1 - dioxo - 1,2,6 - thiadiazine - type DABO - DAPY hybrid ( B - series compound ) have been designed and synthesized .
On the other hand , using the dominant substituent on the right flank of DAPY , this part extends to the solvent open area of NNBP to enhance the interaction with amino acids . A total of 45 new 1,1 - dioxo - 1 , 2,6 - thiadiazine heterocyclic derivatives are designed .

By using Syby1 - X1.1 for the docking analysis of the designed target compound , the results show that the two series of compounds are similar to the binding pattern of the lead compound , and the interaction of the key amino acids with NNis maintained , and the newly introduced thidiazoxide ring can form more hydrogen bonds with the Lys 101 and Glu138 , and it is possible to enhance the binding ability of the compound and RT .

A , B series of compounds are used as raw materials with different carboxylic acid as raw materials , 5 - position substituted mycophenolic acid derivatives are generated after reaction with wheat acid , then thiadiazine master ring is generated by cyclization with thiamide , and then the key intermediate of the parent ring carbonyl group is generated by reaction with TsCl . The key intermediate is then reacted with the synthesized substituent to generate the target product . The synthesized 45 compounds are verified by spectral analysis .

Activity evaluation of the synthesized thiadiazine derivatives showed that the level of anti - HIV activity in vitro cells showed no significant antiviral activity , which may be related to the properties of compounds , cell absorption metabolism and so on . However , the activity of anti - HIV activity of B - series compounds was in the assay . However , the preliminary reverse transcriptase inhibitory activity showed that most of the compounds were Ba9 ( IC50 = 0.270 渭M ) and Brech ( IC50 = 0.397 渭M ) .

A total of 45 new 1,1 - dioxo - 1 , 2,6 - thiadiazine derivatives were designed and synthesized on the basis of the structure characteristics , the combination mode and the structure - effect relationship of the pilot compounds , and the structures of the novel 1,1 - dioxo - 1,2,3 - thiadiazole derivatives were designed and synthesized .

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

【相似文献】