中文摘要
HIV-1逆转录酶为抗艾滋病药物研究的重要靶点。本项目通过对逆转录酶抑制剂的作用机理、构象关系及耐药性的详尽研究，结合计算机辅助设计，以TNK-651为模板设计合成出了一类新型HIV-1 RT抑制剂－环庚骈嘧啶化合物，即在嘧啶环5，6位上骈一个七元脂环来限定苯环的构象，产生一个与TNK-651构象非常相似的构型化合物，对活性产生影响。此设计思想至今尚未见研究报道，在寻找新一代抗HIV 药物领域里具有重要的科学意义。申请者在前期工作的基础上（国家自然科学基金20172007)，对前期的合成路线进行完善，合成了一系列新型的9-芳烃环庚骈嘧啶类化合物约30多个，并对其进行初步活性评估，发现其中有些目标化合物对HIV-1 RT的抑制活性好于临床应用的药物Nevirapine，针对一些活性较好的目标化合物进行了抗HIV-1病毒的活性检测及临床变异病毒株的活性测定。与此同时，我们对有些目标化合物进行了SIV活性测定，实验结果显示化合物对HIV-1和SIV具有特异的选择性，这与目前的文献报道一致。继续深入此项研究，探讨结构与活性关系及其作用机理，有可能发展出一类新型抗艾滋病药物。
英文摘要
Reverse transcriptase (RT) is one of the most attractive targets for the development of new antiretroviral agents. In recent years NNRTIs have gained an increasingly important role in the therapy of HIV infections. Among the NNRTIs, MKC-442 has been considered as an interesting lead compound with activity against HIV..In our report new novel cyclohepta[d]pyrimidine derivatives targeting the non-nucleoside inhibitor (NNI) binding site of HIV reverse transcriptase (RT) have been rationally designed based on the structure of the NNI binding pocket. The seven-member annelated compounds with relatively rigid structures can lock the orientation of the aromatic ring. Docking results indicate that these analogues share the same binding mode as the crystal inhibitor in the pocket geometries of TNK-651. Therefore, we developed a facile synthetic route in reaching C5 and C6 annelated structure of uracil with a seven-member ring and obtained about 30 analogue derivatives, and evaluated the influence of these compounds on the anti-HIV-1 activity. The biological activity results obtained with our compounds are in accordance with the docking's in that some compounds showed high inhibitory activity against HIV-1 replication with respect to Nevirapine. At the same time, we also evaluated the activity against SIV with some compounds, and the results are in line with the reference's report.. Encouraged by this result, more detailed SAR studies on the annelated compounds are underway with a focus on exploring the important role of this unique structure feature. The final result of the program may find effective anti-HIV agents.
结题摘要
HIV-1逆转录酶为抗艾滋病药物研究的重要靶点。本项目通过对逆转录酶抑制剂的作用机理、构象关系及耐药性的详尽研究，结合计算机辅助设计，以TNK-651为模板设计合成出了一类新型HIV-1 RT抑制剂－环庚骈嘧啶化合物，即在嘧啶环5，6位上骈一个七元脂环来限定苯环的构象，产生一个与TNK-651构象非常相似的构型化合物，对活性产生影响。此设计思想至今尚未见研究报道，在寻找新一代抗HIV 药物领域里具有重要的科学意义。申请者在前期工作的基础上（国家自然科学基金20172007)，对前期的合成路线进行完善，合成了一系列新型的9-芳烃环庚骈嘧啶类化合物约30多个，并对其进行初步活性评估，发现其中有些目标化合物对HIV-1 RT的抑制活性好于临床应用的药物Nevirapine，针对一些活性较好的目标化合物进行了抗HIV-1病毒的活性检测及临床变异病毒株的活性测定。与此同时，我们对有些目标化合物进行了SIV活性测定，实验结果显示化合物对HIV-1和SIV具有特异的选择性，这与目前的文献报道一致。继续深入此项研究，探讨结构与活性关系及其作用机理，有可能发展出一类新型抗艾滋病药物。