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
  • 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: 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.