手性二芳基嘧啶逆转录酶抑制剂的合理设计、不对称合成及抗HIV病毒活性研究

开发高效、低毒、特别是对耐药有效的HIV治疗候选药物是当务之急。我们已设计了一系列新型联苯二芳基嘧啶类逆转录酶抑制剂，从中筛选出了活性好、具有良好抗耐药性衍生物，但对Y188L突变病毒株效果不佳。分子模拟预测，引入手性羟基连接臂时该分子与Y188L形成新的氢键可能弥补其结合力减弱，保持其活性。本申请拟开展（R）-或（S）-构型CH(X)-biph-DAPYs若干系列的合理分子设计、催化不对称合成及其抗HIV病毒活性的研究，进一步确认最佳构型的CH(X)-biph-DAPYs化合物，以期获得高活性、低毒、生物利用度好的手性抗HIV候选药物先导物。

It is in an urgent need to develop novel anti-HIV drug candidates with high potency, low toxicity and efficacy toward wild-type (WT) and especially drug resistant viral strains. A novel series of biphenyl diarylpyrimidines as reverse transcriptase inhibitors have been designed using molecular docking. They exhibited highly potent activity especially toward drug resistant mutants. However, they were inactive toward Y188L mutant virus strain. Molecular modeling predicted that introducing a chiral OH linker could form a new hydrogen bonding interaction with Y188L to compensate the π-π stacking interaction and keep the activity. In this proposal, rational design of (R)-, (S)- CH(X)-biph-DAPYs will be performed and catalysis asymmetric synthesized. Their antiviral activity will be investigated to confirm the best configuration of CH(X)-biph-DAPYs. Hopefully, highly potent, low toxic and good bioavailable anti-HIV drug candidates could be obtained, providing scientific foundation for the development of HIV therapeutic agents.