新型六元芳杂环类抗耐药性HIV-1 NNRTI的设计、合成与活性研究

The discovery and development of novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved antiviral efficacy, pharmacokinetic and drug resistance mutation profiles is critical for a more successful application of NNRTIs in combination therapy, which has been a main goal for medicinal chemists. Diarylpyrimidine (DAPY) derivatives, one family of HIV-1 NNRTIs with excellent potency against wild-type and resistant mutant strains of HIV-1, have attracted considerable attention over the past few years. Encouraged by our promising research foundation in this field, in this project, through the analysis of several crystal structures of HIV-1 RT/DAPYs complexes, together with the general SAR of DAPY analogues, several series of novel diarylazine scaffold (such as diarylpyridazine, diarylpyrimidine, diaryltriazine, diarylpyridone, diarylamionpyridine) were designed as isosters of the existing DAPYs lead compounds to form extensive π-π interaction, main chain hydrogen bonding or to target highly conserved residues in HIV-1 RT according to the classical "bioisosterism" principle. Meanwhile, with aim to make an additional hydrogen bond with the K103 backbone and to improve pharmacokinetic profiles of DAPYs, based on the "scaffold hopping" strategy, a series of piperidine-linked arylazines were designed by replacing of benzene ring in the right wing with a more flexible piperidine group. By introducing the active substituents from the active DAPYs, diarylazines and piperidine-linked arylazine molecular library were constructed, respectively. By the hierarchical multiple-filter virtual database searching strategy to predict the favorable molecules with high binding affinity and multiple drug-like profiles, the top-ranking compounds will be selected to be synthesized, and evaluated their anti-HIV activities in vitro and vivo and their preliminary pharmacokinetics to obtain next generation of DAPY-based HIV-1 NNRTIs with improved potency against both wild and mutant HIV-1 strains.

研发新型高效抗耐药性的HIV-1 非核苷类逆转录酶抑制剂（NNRTI）是抗艾滋病药物领域的热点。本课题在对高效抗耐药性NNRTI药效团模型分析及药物设计策略充分理解的基础上，以DAPY类高效抗耐药性NNRTI为先导物，根据前期研究基础，通过分子模拟和构效关系分析，进行合理药物设计。以增加与RT 的亲和力（π-π堆积和氢键）及提高与保守性氨基酸结合力为目的，构建新型的二芳基哒嗪、嘧啶、三嗪、吡啶酮及氨基吡啶等多系列"U"型柔性骨架；同时，为增强DAPY类C环区域与蛋白/溶剂界面区残基的"附加"作用力，设计了多系列取代哌啶芳嗪类结构。通过计算机辅助对构建的结构多样的两个虚拟化合物库进行多层级虚拟筛选（HMFDSS），对虚拟评价各项预测指标俱佳的化合物进行定向合成，并进行体内外抗HIV-1活性实验，及初步的成药性评价，由此发现高效低毒、抗耐药性的新型NNRTI，为该类抗艾滋病药物的研发奠定基础。

HIV-1逆转录酶(RT)在该病毒的说明周期中发挥关键性的作用，使其成为抗HIV-1药物研发的重要靶标。RT抑制剂主要包括核苷类逆转录酶抑制剂和非核苷类逆转录酶抑制剂。其中，非核苷类抑制剂具有活性高、选择性强、毒性低等诸多优点，是目前治疗艾滋病高效抗逆转录病毒疗法(俗称“鸡尾酒疗法”)的重要组成部分。但是非核苷类抑制剂在临床治疗中易出现耐药性、具有一定的毒副作用及药代动力学性质差等缺点在很大程度上限制了其广泛应用。因此，研发高效、广谱抗耐药以及具有良好药代动力学性质的新型非核苷类抑制剂是目前抗艾滋病药物研究的重要领域之一。本课题在对高效抗耐药性NNRTI药效团模型分析及药物设计策略充分理解的基础上，以DAPY类高效抗耐药性NNRTI为先导物，根据前期研究基础，通过分子模拟和构效关系分析，进行合理药物设计。以增加与RT的亲和力（π-π堆积和K103N等氢键）及提高与保守性氨基酸结合力为目的，构建新型的六元杂环及稠合环等多系列“U”型柔性骨架；同时，为增强DAPY类化合物与蛋白/溶剂界面区残基的“附加”作用力，引入氨基哌啶等结构多样性的取代基，共设计、合成了二芳基杂环类和哌啶取代单芳基杂环类共计16个子系列、361个DAPY衍生物，通过抗HIV-1活性实验、酶学活性实验及初步的成药性评价，发现了一批新型、高效抗耐药的先导化合物，具有进一步研究的价值；其中有2个化合物进入临床前研究阶段，为该类抗艾滋病药物的研发奠定物质基础。此外，系统探讨了DAPY类NNRTI的构效关系及构毒关系，并运用计算机模拟研究了活性化合物与靶点的精准结合模式，为进一步的结构修饰奠定了理论基础。该科学发现共发表SCI论文37篇，获授权国家发明专利6项，申请国际专利2项；培养毕业博士研究生6名，毕业硕士研究生7名。

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