• Open Access

Structure–Activity Relationship Studies of Pyrrolone Antimalarial Agents

Authors

  • Dr. Dinakaran Murugesan,

    1. Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dow St, Dundee, DD1 5EH (UK)
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  • Dr. Marcel Kaiser,

    1. Swiss Tropical & Public Health Institute, Postfach, Socinstrasse 57, 4002 Basel (Switzerland)
    2. University Basel, Petersplatz 1, 4003 Basel (Switzerland)
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  • Dr. Karen L. White,

    1. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052 (Australia)
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  • Suzanne Norval,

    1. Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dow St, Dundee, DD1 5EH (UK)
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  • Jennifer Riley,

    1. Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dow St, Dundee, DD1 5EH (UK)
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  • Prof. Paul G. Wyatt,

    1. Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dow St, Dundee, DD1 5EH (UK)
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  • Prof. Susan A. Charman,

    1. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052 (Australia)
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  • Dr. Kevin D. Read,

    1. Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dow St, Dundee, DD1 5EH (UK)
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  • Dr. Clive Yeates,

    1. InPharma Consultancy, Hertfordshire (UK)
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  • Prof. Ian H. Gilbert

    Corresponding author
    1. Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dow St, Dundee, DD1 5EH (UK)
    • Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dow St, Dundee, DD1 5EH (UK)

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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.

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