2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel double-winged galloyl derivatives as HIV-1 RNase H inhibitors

Design, synthesis, and biological evaluation of novel double-winged galloyl derivatives as HIV-1 RNase H inhibitors

  • Eur J Med Chem. 2022 Oct 5;240:114563. doi: 10.1016/j.ejmech.2022.114563.
Lina Zhang 1,  Fenju Wei 1,  David Borrego 2,  Fabao Zhao 1,  Javier Martínez Del Río 2,  Estrella Frutos-Beltrán 2,  Jiwei Zhang 1,  Shujing Xu 1,  Nerea López-Carrobles 2,  Shenghua Gao 1,  Dongwei Kang 1,  Christophe Pannecouque 3,  Erik De Clercq 3,  Xinyong Liu 4,  Luis Menéndez-Arias 5,  Peng Zhan 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China.
  • 2 Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Aut?onoma de Madrid), Madrid, Spain.
  • 3 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China. Electronic address: xinyongl@sdu.edu.cn.
  • 5 Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Aut?onoma de Madrid), Madrid, Spain. Electronic address: lmenendez@cbm.csic.es.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan, 250012, China. Electronic address: zhanpeng1982@sdu.edu.cn.
PMID: 35780636 DOI: 10.1016/j.ejmech.2022.114563
Abstract

Human immunodeficiency virus (HIV) Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) remains as the only Enzyme encoded within the viral genome not clinically validated as an Antiviral target. We have previously reported that the galloyl derivative II-25 had RNase H inhibitory activity in enzymatic assays but showed weak Antiviral activity in phenotypic assays due its large polarity and poor membrane permeability. In this report, we report on a series of II-25 derivatives, obtained by addition of different hydrophobic moieties ("the wings") at the C-2 and C-3 positions of the piperazine ring that showed improved RNase H inhibitory activity. Six compounds showed strong inhibitory activity and were found to be more potent than β-thujaplicinol in enzymatic assays. The most potent compound was IA-6 and exhibited the best inhibitory activity (IC50 = 0.067 ± 0.02 μM). IA-6 was around 11 and 30 times more potent than II-25 and β-thujaplicinol, respectively. Molecular modeling studies predict a strong hydrophobic interaction between the furylmethylaminyl group of IA-6 and the side chain of His539, explaining the potent HIV-1 RNase H inhibition. Unfortunately, none of the derivatives showed significant Antiviral activity in Cell Culture. It is worth emphasizing that most of the obtained compounds show low cytotoxicity (CC50 > 20 μM), which confirms the significance of identifying galloyl derivatives as valuable leads for further optimization.

Keywords

Chelating agents; Galloyl derivatives; Human immunodeficiency virus (HIV); RNase H Inhibitors.

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