To address the intractable issues of drug resistance and poor solubility, a novel series of morpholine-substituted diarylpyrimidines targeting the tolerant region I and tolerant region II of NNIBP were rationally designed by utilizing the available crystallography studies. The biological evaluation results showed that four most promising compounds (14e1, 14g1, 14g2 and 14j2) displayed excellent potency against WT HIV-1 strain with EC₅₀ values ranging from 58 to 87 nM, being far more potent than NVP and comparable to ETV. Besides, some derivatives exhibited moderate activity in inhibiting the mutant HIV-1 strains. More encouragingly, 14d2 (RF = 0.4) possessed higher antiresistance profile than ETV (RF = 6.3) and K-5a2 (RF = 3.0) toward the double mutant strain F227L + V106A. The HIV-1 RT inhibition assay confirmed their binding target. The molecular docking studies were conducted and discussed in detail to rationalize the preliminary SARs. Further test indicated that morpholine could indeed promote the improvement of water solubility. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features.

为解决耐药性和溶解性差的棘手问题，通过利用现有的晶体学研究合理地设计了靶向NNIBP耐受区域I和耐受区域II的一系列吗啉取代的二芳基嘧啶。生物学评价结果表明，四个最有希望的化合物（部14e1，14G1，14G2和14j2）显示优异的效力对抗WT HIV-1毒株具有EC _50个值范围从58至87纳米，是远比NVP更有效并且与ETV。此外，一些衍生物在抑制突变的HIV-1毒株中表现出中等活性。更令人鼓舞的是14d2（RF = 0.4）具有比ETV（RF = 6.3）和K-5a2（RF = 3.0）更高的抗双突变株F227L + V106A的抗性谱。HIV-1 RT抑制测定证实了它们的结合靶标。进行了分子对接研究并进行了详细讨论，以合理化初步合成孔径雷达。进一步的试验表明吗啉确实可以促进水溶性的改善。此外，研究了计算机化学预测的理化性质和CYP酶抑制能力，以评估其类似药物的功能。