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
  • 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: [email protected].
  • 4. Department of Chemistry, Capital Normal University, Beijing, 100048, China. Electronic address: [email protected].
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.