title: Discovery of novel piperidine-substituted indolylarylsulfones as potent HIV NNRTIs via structure-guided scaffold morphing and fragment rearrangement.
abstract: To further explore the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing N-substituted piperidine at indole-2-carboxamide were identified as potent HIV NNRTIs by structure-guided scaffold morphing and fragment rearrangement. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC50values ranging from 0.62 μM to 0.006 μM 8 (EC50= 6 nM) and 18 (EC50= 9 nM) were identified as the most potent compounds, which were more active than NVP and DLV, and reached the same order of EFV and ETV. Furthermore, most compounds maintained high activity agaist various single HIV-1 mutants (L100I, K103N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC50values in low-micromolar to double-digit nanomolar concentration ranges. Especially, 8 displayed outstanding potency against L100I (EC50= 17 nM with a 2.8-fold resistance ratio) and 18 was relatively more potent to E138K mutant (EC50= 43 nM with a 4.7-fold resistance ratio). Preliminary SARs and molecular modeling studies were also discussed in detail, 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: Xiao
authors.initials: X
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: Ping
authors.initials: P
authors.lastname: Gao
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: Zhongxia
authors.initials: Z
authors.lastname: Zhou
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: Zhao
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Liu
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
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: 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: zhanpeng1982@sdu.edu.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
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: D002460:Cell Line; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D010880:Piperidines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Antiviral activity; Chemical space; Drug design; HIV; Indolylarylsulfones; Molecular modeling; NNRTIs; SAR