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

    21 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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