2,4,5-Trisubstituted thiazole derivatives as HIV-1 NNRTIs effective on both wild-type and mutant HIV-1 reverse transcriptase: Optimization of the substitution of positions 4 and 5

• DOI: 10.1016/j.ejmech.2016.07.047
• Publication Date: 2016-07-23T05:15:10Z
• Authors: Zhongliang Xu; Jiamei Guo; Ying Yang; Mengdi Zhang; Mingyu Ba; Zhenzhong Li; Yingli Cao; Ricai He; Miao Yu; Hua Zhou; Xiaoxi Li; Xiaoshan Huang; Ying Guo; Changbin Guo
• Keywords: 0303 health sciences; Protein Conformation; HIV Reverse Transcriptase; Molecular Docking Simulation; Structure-Activity Relationship; Thiazoles; 03 medical and health sciences; HEK293 Cells; Drug Design; Mutation; HIV-1; Humans; Reverse Transcriptase Inhibitors

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.