A novel series of diarylpyrimidine derivatives, which could simultaneously occupy the classical NNRTIs binding pocket (NNIBP) and the newly reported “NNRTI Adjacent” binding site, were designed, synthesized, and evaluated for their antiviral activities in MT-4 cell cultures. The results demonstrated that six compounds (20, 27 and 31–34) showed excellent activities against wild-type (WT) HIV-1 strain (EC₅₀ = 2.4–3.8 nM), which were more potent than that of ETV (EC₅₀ = 4.0 nM). Furthermore, 20, 27, 33, and 34 showed more potent or equipotent activity against single mutant HIV-1 strains compared to that of ETV. Especially, 20 showed marked antiviral activity, which was 1.5-fold greater against WT and 1.5- to 3-fold greater against L100I, K103N, Y181C, Y188L, and E138K when compared with ETV. In addition, all compounds showed lower toxicity (CC₅₀ = 5.1–149.2 μM) than ETV (CC₅₀ = 2.2 μM). The HIV-1 RT inhibitory assay was further conducted to confirm their binding target. Preliminary structure–activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed comprehensively.

中文翻译：

---

发现新型二芳基嘧啶衍生物作为靶向“ NNRTI相邻”结合位点的有效HIV-1 NNRTIs

设计，合成并评估了一系列新的二芳基嘧啶衍生物，它们可以同时占据经典的NNRTIs结合口袋（NNIBP）和新报道的“ NNRTI Adjacent”结合位点，并评估其在MT-4细胞培养物中的抗病毒活性。结果表明，六种化合物（20，27和31 - 34）显示针对野生型极好的活性（WT）HIV-1毒株（EC ₅₀ = 2.4-3.8纳米），其明显低于ETV的更有效（EC ₅₀ = 4.0 nM）。此外，20，27，33，和34与ETV相比，对单一突变HIV-1菌株显示出更高的效价或等价活性。特别是，20个具有显着的抗病毒活性，与ETV相比，抗WT的活性高1.5倍，对L100I，K103N，Y181C，Y188L和E138K的抗病毒活性高1.5到3倍。此外，所有化合物均显示出比ETV（CC ₅₀ = 2.2μM）更低的毒性（CC ₅₀ = 5.1–149.2μM ）。进一步进行HIV-1 RT抑制测定以确认其结合靶标。初步讨论了所选化合物的初步构效关系（SARs），分子模型和计算出的理化性质。