Xu Zhongliang, Guo Jiamei, Yang Ying, Zhang Mengdi, Ba Mingyu, Li Zhenzhong, Cao Yingli, He Ricai, Yu Miao, Zhou Hua, Li Xiaoxi, Huang Xiaoshan, Guo Ying, Guo Changbin
Department of Chemistry, Capital Normal University, Beijing, 100048, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Eur J Med Chem. 2016 Nov 10;123:309-316. doi: 10.1016/j.ejmech.2016.07.047. Epub 2016 Jul 22.
In our previous work, novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were synthesized, and their activities were evaluated against HIV-1 reverse transcriptase. Some interesting results were obtained, which led us to a new discovery regarding these TSTs. In the present study, 21 new 2,4,5-trisubstituted thiazole derivatives were rationally designed and synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) in accordance with our previous study. Among the synthesized target compounds, compounds 14, 16, 17, and 19 showed more potent inhibitory activities against HIV-1 with an IC50 value of 0.010 μM. Compounds 4, 9, 10, 11, 13 and 16 were further tested on nine NNRTI-resistant HIV-1 strains, and all of these compounds exhibited inhibitory effects. A molecular docking study was conducted, and the results showed a consistent and stable binding mode for the typical compounds. These results have provided deeper insights and SAR of these types of NNRTIs.
在我们之前的工作中，合成了新型的2,4,5-三取代噻唑衍生物（TSTs），并评估了它们对HIV-1逆转录酶的活性。获得了一些有趣的结果，这使我们对这些TSTs有了新的发现。在本研究中，根据我们之前的研究，合理设计并合成了21种新型的2,4,5-三取代噻唑衍生物作为HIV-1非核苷类逆转录酶抑制剂（NNRTIs）。在合成的目标化合物中，化合物14、16、17和19对HIV-1表现出更强的抑制活性，IC50值为0.010 μM。化合物4、9、10、11、13和16在9种对NNRTI耐药的HIV-1毒株上进一步进行了测试，所有这些化合物均表现出抑制作用。进行了分子对接研究，结果显示典型化合物具有一致且稳定的结合模式。这些结果为这类NNRTIs提供了更深入的见解和构效关系。
