Structure-activity relationship studies of pyrrolone antimalarial agents

Dinakaran Murugesan, Marcel Kaiser, Karen Louise White, Suzanne Norval, Jennifer Riley, Paul G Wyatt, Susan Ann Charman, Kevin D Read, Clive Yeates, Ian Hugh Gilbert

Research output: Contribution to journalArticleResearchpeer-review

35 Citations (Scopus)


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
Pages (from-to)1537 - 1544
Number of pages8
Issue number9
Publication statusPublished - 2013

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