title: 2,4,5-Trisubstituted thiazole derivatives: a novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase.
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.
authors: Department of Chemistry, Capital Normal University, Beijing 100048, China.
authors: Zhongliang
authors: Z
authors: Xu
authors: 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.
authors: Mingyu
authors: M
authors: Ba
authors: Department of Chemistry, Capital Normal University, Beijing 100048, China.
authors: Hua
authors: H
authors: Zhou
authors: 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.
authors: Yingli
authors: Y
authors: Cao
authors: Department of Chemistry, Capital Normal University, Beijing 100048, China.
authors: Chaojun
authors: C
authors: Tang
authors: 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.
authors: Ying
authors: Y
authors: Yang
authors: Department of Chemistry, Capital Normal University, Beijing 100048, China.
authors: Ricai
authors: R
authors: He
authors: Department of Chemistry, Capital Normal University, Beijing 100048, China.
authors: Yu
authors: Y
authors: Liang
authors: 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.
authors: Xuemei
authors: X
authors: Zhang
authors: Department of Chemistry, Capital Normal University, Beijing 100048, China.
authors: Zhenzhong
authors: Z
authors: Li
authors: Department of Chemistry, Capital Normal University, Beijing 100048, China.
authors: Lihong
authors: L
authors: Zhu
authors: 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.
authors: Ying
authors: Y
authors: Guo
authors: Department of Chemistry, Capital Normal University, Beijing 100048, China. Electronic address: guocb@cnu.edu.cn.
authors: Changbin
authors: C
authors: Guo
mesh_terms: D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects; D057809:HEK293 Cells; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: 2,4,5-Trisubstituted thiazole derivatives; HIV-1; Molecular modeling; Non-nucleoside reverse transcriptase inhibitors; Three-dimensional quantitative structure activity relationship