新型哌啶类衍生物作为CCR5小分子拮抗剂的设计、合成及活性研究

发布时间：2018-04-28 23:25

  本文选题：HIV-1 + CCR5拮抗剂　； 参考：《浙江大学》2014年硕士论文

【摘要】：AIDS是由感染人类免疫缺陷病毒(HIV)所引起的免疫缺陷综合症,是威胁人类健康的致命疾病之一。目前临床上广泛采用的治疗方式是高活性抗逆转录病毒疗法(HAART),虽然HAART可以降低HW-1°病毒感染后的发病率和致死率,但是长期使用这种治疗方案会产生治疗毒性和病毒耐药性,因此开发新的HIV的治疗方法仍然是当前研究的热点。病毒进入抑制剂可以有效地预防HIV感染,研究者发现趋化因子受体5(CCR5)是病毒与宿主细胞结合的主要位点之一。这一发现促使许多研究人员开发CCR5拮抗剂,同时也避免了HAART的缺陷。 本论文中,我们以TAK-220为先导化合物,设计了哌啶-4-甲酰胺衍生物及1-环己基哌啶衍生物两大系列共44个全新结构的化合物。对所合成的所有化合物进行了基于基于钙流模型的CCR5拮抗活性的测试,发现化合物2-89、2-96、2-97及2-98具有很强的CCR5拮抗活性(IC50分别为4.78,5.67,2.04及1.35nM),比阳性药naraviroc(IC50=11.38rnM)更优。另外,对6个哌啶-4-甲酰胺衍生物进行了体外抗HIV-1病毒测试,部分化合物显示出一定的抗HIV-1病毒活性。上述研究,为进一步设计新型的CCR5拮抗剂提供了实验依据。
[Abstract]:AIDS is a kind of immunodeficiency syndrome caused by human immunodeficiency virus (HIV) infection, and it is one of the fatal diseases threatening human health. At present, highly active antiretroviral therapy is widely used in clinic. Although HAART can reduce the morbidity and mortality of HW-1 掳virus infection, long-term use of this treatment can produce therapeutic toxicity and virus resistance. Therefore, the development of a new treatment for HIV is still the focus of current research. Virus entry inhibitors can effectively prevent HIV infection, and the chemokine receptor 5 CCR5 is one of the major sites for virus binding to host cells. The discovery prompted many researchers to develop CCR5 antagonists while avoiding the HAART flaw. In this thesis, we designed four novel compounds of piperidine-4-formamide derivative and 1-cyclohexyl-piperidine derivative with TAK-220 as the leading compound. All the synthesized compounds were tested for CCR5 antagonistic activity based on calcium current model. It was found that the IC50 of compounds 2-89O2-96O2-97 and 2-98 with strong CCR5 antagonistic activity were 4.785.6c2.04 and 1.35nMN, respectively, which were superior to the positive drug Naraviroca IC5011.38rnM. In addition, six piperidine-4-formamide derivatives were tested for anti-HIV-1 virus in vitro. Some of the compounds showed certain anti-HIV-1 activity. These studies provide experimental basis for the further design of new CCR5 antagonists.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R96
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本文编号：1817380