2. Academic Validation
  3. Design, synthesis and preliminary SAR studies of novel N-arylmethyl substituted piperidine-linked aniline derivatives as potent HIV-1 NNRTIs

Design, synthesis and preliminary SAR studies of novel N-arylmethyl substituted piperidine-linked aniline derivatives as potent HIV-1 NNRTIs

  • Bioorg Med Chem. 2014 Jan 1;22(1):633-42. doi: 10.1016/j.bmc.2013.10.033.
Lingzi Zhang 1,  Peng Zhan 1,  Xuwang Chen 1,  Zhenyu Li 1,  Zhoumeng Xie 1,  Tong Zhao 1,  Huiqing Liu 2,  Erik De Clercq 3,  Christophe Pannecouque 3,  Jan Balzarini 3,  Xinyong Liu 4
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 Ji'nan, Shandong, PR China.
  • 2 Institute of Pharmacology, School of Medicine, Shandong University, 44, West Culture Road, 250012 Ji'nan, 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 Ji'nan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 24275349 DOI: 10.1016/j.bmc.2013.10.033
Abstract

A series of novel N-arylmethyl substituted piperidine-linked aniline derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. All the new compounds showed moderate to potent activities against wild-type (wt) HIV-1 with an EC₅₀ range from 0.022 to 2.1 μM. Among them, compound 5a6 (EC₅₀=0.022 ± 0.0091 μM, SI >10,770) was confirmed to be the most potent and selective inhibitor, which proved more potent than DDI and DLV in a cell-based assay against wt HIV-1, and more efficient than NVP in an RT (Reverse Transcriptase) assay. Besides, it is worth noting that compound 7a1 retained moderate inhibitory activity (EC₅₀=4.8 ± 0.95 μM) against the HIV-1 double RT mutant strain (K103N/Y181C). The preliminary structure-activity relationship was discussed and rationalized by molecular simulation.

Keywords

AIDS; Anti-HIV-1 activity; HIV-1; NNRTIs; Synthesis.

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