2. Academic Validation
  3. 2,4,5-Trisubstituted thiazole derivatives: a novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase

2,4,5-Trisubstituted thiazole derivatives: a novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase

  • Eur J Med Chem. 2014 Oct 6:85:27-42. doi: 10.1016/j.ejmech.2014.07.072.
Zhongliang Xu 1,  Mingyu Ba 2,  Hua Zhou 1,  Yingli Cao 2,  Chaojun Tang 1,  Ying Yang 2,  Ricai He 1,  Yu Liang 1,  Xuemei Zhang 2,  Zhenzhong Li 1,  Lihong Zhu 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: 25072874 DOI: 10.1016/j.ejmech.2014.07.072
Abstract

Novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were designed and synthesized as HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTIs). Among the thirty-eight synthesized target compounds, thirty TSTs showed potent inhibition against HIV-1 replication in wild type HIV-1 at submicromolar concentrations (from 0.046 to 9.59 μM). Compounds 21, 23 and 24 were also tested on seven NNRTI-resistant HIV-1 strains, and all exhibited inhibitory effects with fold changes in IC50 ranging from 2.6 to 111, which were better than those of nevirapine (15.6-fold-371-fold). Docking simulations of compound 24 revealed a reasonable mechanism for the binding mode, and three-dimensional quantitative structure activity relationship (3-DQSAR) studies on this novel series of TST further elucidated the structure-activity relationship (SAR). The results suggested the great potential of TSTs as a novel class of NNRTIs with Antiviral efficacy and a good resistance profile.

Keywords

2,4,5-Trisubstituted thiazole derivatives; HIV-1; Molecular modeling; Non-nucleoside reverse transcriptase inhibitors; Three-dimensional quantitative structure activity relationship.

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