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  • Identification of novel quinazoline derivatives as potent antiplasmodial agents

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    Skinner-Adams158586.pdf (594.8Kb)
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    Accepted Manuscript (AM)
    Author(s)
    Bouchut, Anne
    Rotili, Dante
    Pierrot, Christine
    Valente, Sergio
    Lafitte, Sophia
    Schultz, Johan
    Hoglund, Urban
    Mazzone, Roberta
    Lucidi, Alessia
    Fabrizi, Giancarlo
    Pechalrieu, Dany
    Arimondo, Paola B
    Skinner-Adams, Tina S
    Chua, Ming Jang
    Andrews, Kathy T
    Mai, Antonello
    Khalife, Jamal
    Griffith University Author(s)
    Skinner-Adams, Tina
    Andrews, Katherine T.
    Year published
    2019
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    Abstract
    Despite the recent reductions in the global burden of malaria, this disease remains a devastating cause of death in tropical and subtropical regions. As there is no broadly effective vaccine for malaria, prevention and treatment still rely on chemotherapy. Unfortunately, emerging resistance to the gold standard artemisinin combination therapies means that new drugs with novel modes of action are urgently needed. In this context, Plasmodium histone modifying enzymes have emerged as potential drug targets, prompting us to develop and optimize compounds directed against such epigenetic targets. A panel of 51 compounds designed ...
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    Despite the recent reductions in the global burden of malaria, this disease remains a devastating cause of death in tropical and subtropical regions. As there is no broadly effective vaccine for malaria, prevention and treatment still rely on chemotherapy. Unfortunately, emerging resistance to the gold standard artemisinin combination therapies means that new drugs with novel modes of action are urgently needed. In this context, Plasmodium histone modifying enzymes have emerged as potential drug targets, prompting us to develop and optimize compounds directed against such epigenetic targets. A panel of 51 compounds designed to target different epigenetic enzymes were screened for activity against Plasmodium falciparum parasites. Based on in vitro activity against drug susceptible and drug-resistant P. falciparum lines, selectivity index criterion and favorable pharmacokinetic properties, four compounds, one HDAC inhibitor (1) and three DNMT inhibitors (37, 43 and 45), were selected for preclinical studies in a mouse model of malaria. In vivo data showed that 37, 43 and 45 exhibited oral efficacy in the mouse model of Plasmodium berghei infection. These compounds represent promising starting points for the development of novel antimalarial drugs.
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    Journal Title
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
    Volume
    161
    DOI
    https://doi.org/10.1016/j.ejmech.2018.10.041
    Copyright Statement
    © 2019 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
    Subject
    Medicinal and biomolecular chemistry
    Organic chemistry
    Pharmacology and pharmaceutical sciences
    Publication URI
    http://hdl.handle.net/10072/382916
    Collection
    • Journal articles

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