Structure-Activity Relationship Studies of Pyrrolone Antimalarial Agents

Dinakaran Murugesan, Marcel Kaiser, Karen L. White, Suzanne Norval, Jennifer Riley, Paul G. Wyatt, Susan A. Charman, Kevin D. Read, Clive Yeates, Ian H. Gilbert (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    18 Citations (Scopus)

    Abstract

    Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure-activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine- and pyrimethamine-resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival.
    Original languageEnglish
    JournalChemMedChem
    Early online date5 Aug 2013
    DOIs
    Publication statusPublished - 2013

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    Antimalarials
    Structure-Activity Relationship
    Parasites
    Derivatives
    Humulus
    Pyrimethamine
    Parasitemia
    Chloroquine
    Plasmodium falciparum
    Scaffolds
    Solubility
    Malaria
    Rodentia
    Esters
    Infection

    Cite this

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    title = "Structure-Activity Relationship Studies of Pyrrolone Antimalarial Agents",
    abstract = "Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure-activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine- and pyrimethamine-resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival.",
    author = "Dinakaran Murugesan and Marcel Kaiser and White, {Karen L.} and Suzanne Norval and Jennifer Riley and Wyatt, {Paul G.} and Charman, {Susan A.} and Read, {Kevin D.} and Clive Yeates and Gilbert, {Ian H.}",
    note = "{\circledC} 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.",
    year = "2013",
    doi = "10.1002/cmdc.201300177",
    language = "English",
    journal = "ChemMedChem",
    issn = "1860-7179",
    publisher = "Wiley-VCH",

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    Structure-Activity Relationship Studies of Pyrrolone Antimalarial Agents. / Murugesan, Dinakaran; Kaiser, Marcel; White, Karen L.; Norval, Suzanne; Riley, Jennifer; Wyatt, Paul G.; Charman, Susan A.; Read, Kevin D.; Yeates, Clive; Gilbert, Ian H. (Lead / Corresponding author).

    In: ChemMedChem, 2013.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Structure-Activity Relationship Studies of Pyrrolone Antimalarial Agents

    AU - Murugesan, Dinakaran

    AU - Kaiser, Marcel

    AU - White, Karen L.

    AU - Norval, Suzanne

    AU - Riley, Jennifer

    AU - Wyatt, Paul G.

    AU - Charman, Susan A.

    AU - Read, Kevin D.

    AU - Yeates, Clive

    AU - Gilbert, Ian H.

    N1 - © 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    PY - 2013

    Y1 - 2013

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    AB - Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure-activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine- and pyrimethamine-resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival.

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