2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2016 Nov 10:123:309-316. doi: 10.1016/j.ejmech.2016.07.047.
Zhongliang Xu 1,  Jiamei Guo 2,  Ying Yang 2,  Mengdi Zhang 1,  Mingyu Ba 2,  Zhenzhong Li 1,  Yingli Cao 2,  Ricai He 1,  Miao Yu 2,  Hua Zhou 1,  Xiaoxi Li 1,  Xiaoshan Huang 1,  Ying Guo 3,  Changbin Guo 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Capital Normal University, Beijing, 100048, China.
  • 2 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.
  • 3 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. Electronic address: yingguo6@imm.ac.cn.
  • 4 Department of Chemistry, Capital Normal University, Beijing, 100048, China. Electronic address: guocb@cnu.edu.cn.
PMID: 27484516 DOI: 10.1016/j.ejmech.2016.07.047
Abstract

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.

Keywords

2,4,5-Trisubstituted thiazole derivatives; HIV-1; Non-nucleoside reverse transcriptase inhibitors; Structure activity relationship; Structure optimization.

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