Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors
Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors
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DOI：
10.1016/j.cclet.2020.09.035
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发表时间：
2021-04-21
影响因子：
9.1
通讯作者：
Chen, Fener
中科院分区：
文献类型：
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作者：
Li, Daxiong;Zhang, Chunsheng;Chen, Fener
为了继续寻找具有不同结构的强效HIV-1 nnrti，我们设计、合成了一系列新的6-（2-环己基-1-烷基）-2-（2-氧-2-苯基-乙基磺胺基）嘧啶-4(3H)-的S-DACO类似物，并评估了它们在MT-4细胞中的抗病毒活性。这些新化合物对野生型HIV-1的IC50值在7.55 μ mol/L ~ 0.018 μ mol/L之间，显示出中等到良好的抗活性。其中，化合物5c的IC50值为0.018 mu mol/L， CC50值为194 mu mol/L， SI值为12791，其抑制HIV-1复制的效果远高于对照药物NVP和DLV，与AZT和EFV相当。此外，与对照药物NVP/DLV和DB02相比，5c对双突变HIV-1株RES056的活性也有所提高。并对初步的构效关系（SAR）和分子模型研究进行了讨论，为指导新型S-DACO类似物的进一步合理设计提供了有益的指示。(C) 2020中国化学学会、中国医学科学院药物研究所。Elsevier B.V.版权所有。
In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures, a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3H)-ones were designed, synthesized and evaluated for their antiviral activities in MT-4 cells. Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC50 values ranging from 7.55 mu mol/L to 0.018 mu mol/L. Among them, compound 5c was identified as the most promising inhibitor against HIV-1 replication with an IC50 = 0.018 mu mol/L, CC50 = 194 mu mol/L, and SI = 12791, which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV. In addition, 5c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02. The preliminary structure-activity relationship (SAR) and molecular modeling studies were also discussed, which provides some useful indications for guiding the further rational design of new S-DACO analogues. (C) 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.