2. Academic Validation
  3. Discovery of novel piperidine-substituted indolylarylsulfones as potent HIV NNRTIs via structure-guided scaffold morphing and fragment rearrangement

Discovery of novel piperidine-substituted indolylarylsulfones as potent HIV NNRTIs via structure-guided scaffold morphing and fragment rearrangement

  • Eur J Med Chem. 2017 Jan 27:126:190-201. doi: 10.1016/j.ejmech.2016.10.009.
Xiao Li 1,  Ping Gao 1,  Boshi Huang 1,  Zhongxia Zhou 1,  Zhao Yu 1,  Zheng Yuan 2,  Huiqing Liu 2,  Christophe Pannecouque 3,  Dirk Daelemans 3,  Erik De Clercq 3,  Peng Zhan 4,  Xinyong Liu 5
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Pharmacology, Shandong University School of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
  • 3 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
  • 4 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.
  • 5 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.
PMID: 27750153 DOI: 10.1016/j.ejmech.2016.10.009
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 EC50 values 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 EC50 values 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.

Keywords

Antiviral activity; Chemical space; Drug design; HIV; Indolylarylsulfones; Molecular modeling; NNRTIs; SAR.

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