嘧啶类HIV-1逆转录酶抑制剂的设计、合成与生物活性研究

逆转录酶（RT）是抑制HIV-1复制过程中的关键靶点之一。本小组多年来一直以HIV-1 RT为药物分子设计靶标，采用分子模拟和三维定量构效关系研究等手段，设计合成了多个系列的HIV-1逆转录酶抑制剂。其中，二芳基嘧啶类化合物因表现优秀而备受关注，诸多化合物对野生型HIV-1病毒株的抑制活性达到纳摩尔水平，对多种临床耐药株（K103N，Y181C，K103N+Y181C）亦显示出高抑制活性，部分化合物还对HIV-2显示出良好的抑制活性。本研究基于前期的研究发现，结合分子杂交策略和计算机辅助药物设计手段，设计了三类新型嘧啶类HIV-1 RT抑制剂，拟合成活性更高、抗耐药性更好、细胞毒性更小且具有良好药代动力学性质的新型HIV-1抑制剂，以期得到具有良好前景的苗头化合物。

Reverse transcriptase (RT) is a key target for inhibiting HIV-1 replication. For years, our group have designed and synthesized several series of HIV-1 RT inhibitors based on molecular docking and three dimensional quantitative structure-activity relationship. Among them, diarylpyrimidines are noticeable for their excellence in potent activities against not only wild-type HIV-1 but also HIV-1 mutants such as K103N, Y181C, K103N+Y181C. Moreover, some compounds displayed excellent activites against HIV-2. In this study, we combine the strategy of molecular hybridization and computer-aided drug design (CADD) to design three series of novel pyrimidine analogues as HIV-1 inhibitors based on our previous discoveries, which is aimed to discover excellent hit compounds with fine prospect.