title: Design, synthesis and evaluation of novel HIV-1 NNRTIs with dual structural conformations targeting the entrance channel of the NNRTI binding pocket.
abstract: On the basis of structure-based bioisosteric replacement and molecular hybridization strategy, a series of novel dual structural-conformation inhibitors targeting the "entrance channel" of HIV-1 NNRTIs binding pocket (NNIBP) were designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells using the MTT method. Five compounds exhibited moderate to excellent potencies inhibiting wild-type (wt) HIV-1 replication with EC50 values ranging from 31.36 μM to 0.11 μM. Among them, compound 15b was identified as the most potent inhibitor with EC50 values of 0.11 μM and 2.18 μM against wt and K103N/Y181C double mutant HIV-1 strain (RES056), respectively. In addition, preliminary structure-activity relationships (SARs) and molecular simulation studies were discussed, which may provide valuable insights for further optimization.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Xuwang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Kang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Boshi
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Daelemans
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Electronic address: Christophe.Pannecouque@rega.kuleuven.be.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase
keywords: DAPY derivatives; Dual structural conformations; Entrance channel; HIV-1 NNRTIs; SARs