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  • Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

    Author(s)
    Norcross, Neil R
    Baragana, Beatriz
    Wilson, Caroline
    Hallyburton, Irene
    Osuna-Cabello, Maria
    Norval, Suzanne
    Riley, Jennifer
    Stojanovski, Laste
    Simeons, Frederick RC
    Porzelle, Achim
    Grimaldi, Raffaella
    Wittlin, Sergio
    Duffy, Sandra
    Avery, Vicky M
    Meister, Stephan
    Sanz, Laura
    Jimenez-Diaz, Belen
    Angulo-Barturen, Inigo
    Ferrer, Santiago
    Santos Martinez, Maria
    Javier Gamo, Francisco
    Frearson, Julie A
    Gray, David W
    Fairlamb, Alan H
    Winzeler, Elizabeth A
    Waterson, David
    Campbell, Simon F
    Willis, Paul
    Read, Kevin D
    Gilbert, Ian H
    Griffith University Author(s)
    Duffy, Sandra
    Avery, Vicky M.
    Year published
    2016
    Metadata
    Show full item record
    Abstract
    In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of ...
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    In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.
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    Journal Title
    Journal of Medicinal Chemistry
    Volume
    59
    DOI
    https://doi.org/10.1021/acs.jmedchem.6b00028
    Subject
    Medicinal and Biomolecular Chemistry not elsewhere classified
    Medicinal and Biomolecular Chemistry
    Organic Chemistry
    Pharmacology and Pharmaceutical Sciences
    Publication URI
    http://hdl.handle.net/10072/100442
    Collection
    • Journal articles

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