Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
Bioorg Med Chem. 2021 Jul 15;42:116239. doi: 10.1016/j.bmc.2021.116239. Epub 2021 May 28.
To further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), a new series of diarylpyrimidines (DAPYs) were designed and synthesized as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs). The target compounds were evaluated for anti-HIV potency in MT-4 cells. Most of the synthesized DAPYs exhibited moderate to excellent activity against the HIV-1 wild-type (WT) strain with EC values ranging from 16 nM to 0.722 µM. Interestingly, few compounds displayed remarkable activity in inhibiting K103N mutant virus with EC values ranging from 39 nM to 1.708 µM. Notably, FS2 (EC = 16 nM, EC = 39 nM, SI = 294) was identified as the most significant compound, which was considerably more potent than nevirapine, lamivudine, and comparable to zidovudine. Additionally, the HIV-1 RT inhibition assay confirmed their binding target. Preliminary structure-activity relationships (SARs) and molecular modeling studies were also performed, providing significant suggestions for further optimization.
为了进一步探索 NNRTI 结合口袋（NNIBP）“疏水通道”周围的化学空间，设计并合成了一系列新的二芳基嘧啶（DAPY）作为有效的 HIV-1 非核苷 RT 抑制剂（NNRTIs）。评估了目标化合物在 MT-4 细胞中的抗 HIV 效力。大多数合成的 DAPY 对 HIV-1 野生型（WT）株表现出中等至优异的活性，EC 值范围为 16 nM 至 0.722 μM。有趣的是，少数化合物对 K103N 突变病毒表现出显著的抑制活性，EC 值范围为 39 nM 至 1.708 μM。值得注意的是，FS2（EC=16 nM，EC=39 nM，SI=294）被鉴定为最显著的化合物，其效力明显优于奈韦拉平、拉米夫定，与齐多夫定相当。此外，HIV-1 RT 抑制测定法证实了它们的结合靶标。还进行了初步的构效关系（SAR）和分子建模研究，为进一步优化提供了重要建议。
