title: 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.
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.
authors.affiliation: Department of Chemistry, Capital Normal University, Beijing, 100048, China.
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: 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.forename: Jiamei
authors.initials: J
authors.lastname: Guo
authors.affiliation: 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.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Capital Normal University, Beijing, 100048, China.
authors.forename: Mengdi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 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.forename: Mingyu
authors.initials: M
authors.lastname: Ba
authors.affiliation: Department of Chemistry, Capital Normal University, Beijing, 100048, China.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: 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.forename: Yingli
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Chemistry, Capital Normal University, Beijing, 100048, China.
authors.forename: Ricai
authors.initials: R
authors.lastname: He
authors.affiliation: 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.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Chemistry, Capital Normal University, Beijing, 100048, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Chemistry, Capital Normal University, Beijing, 100048, China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Chemistry, Capital Normal University, Beijing, 100048, China.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Huang
authors.affiliation: 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.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Chemistry, Capital Normal University, Beijing, 100048, China. Electronic address: guocb@cnu.edu.cn.
authors.forename: Changbin
authors.initials: C
authors.lastname: Guo
mesh_terms: D015195:Drug Design; D057809:HEK293 Cells; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D062105:Molecular Docking Simulation; D009154:Mutation; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism / 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; Non-nucleoside reverse transcriptase inhibitors; Structure activity relationship; Structure optimization