逆转录酶（RT）和整合酶（IN）是HIV-1复制过程中必不可少的两种酶。本研究基于多靶点药物的设计思路，将IN抑制剂二酮酸类化合物（DKAs）的二酮酸药效团引入到RT抑制剂二芳基嘧啶类化合物（DAPYs）的嘧啶环C-6位，设计得到一类新的衍生物DKA-DAPYs，并测试它们的HIV-1 RT和IN抑制活性，以及它们对HIV-1野生株、常见变异株和HIV-2的抑制活性。DKA-DAPYs既保留了RT抑制剂DAPYs的药效结构，又引入了可与镁离子形成较强配位作用而抑制IN的二酮酸药效团，可起到RT/IN双重抑制作用，连续阻断HIV复制周期中的逆转录和整合两个关键阶段，显著减小HIV-1变异株幸存的机会，有望解决目前RT抑制剂和IN抑制剂普遍存在的耐药性问题。

Reverse transcriptase (RT) and integrase (IN) are two indispensable enzymes in the replication cycle of HIV-1. In this work, the diketoacid pharmacophore of IN inhibitors diketoacid analogues (DKAs) was fused into the C-6 position of the pyrimidine ring of RT inhibitors diarylpyrimidines (DAPYs) to get a novel series of diketoacid-substituted diarylpyrimidines (DKA-DAPYs) based on the design philosophy of multi-target drugs. The target molecules were evaluated for their HIV-1 RT and IN inhibitory activities, as well as their activities against wild-type HIV-1, its common mutants and HIV-2. DKA-DAPYs retain the pharmacophoric structure of DAPYs which target HIV-1 RT, and introduce the diketoacid pharmacophore which chelates Mg2+ to target HIV-1 IN, therefore, could dually inhibit HIV-1 RT and IN. DKA-DAPYs, which block both the reverse transcriptation and integration to reduce the surviving chances of HIV-1 mutants, are promising to overcome the widespread drug resistance of the approved anti-HIV drugs.