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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.
Original language | English |
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Journal | ChemMedChem |
Early online date | 5 Aug 2013 |
DOIs | |
Publication status | Published - 2013 |
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Dive into the research topics of 'Structure-Activity Relationship Studies of Pyrrolone Antimalarial Agents'. Together they form a unique fingerprint.Projects
- 1 Finished
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Aref#d: 19815. Wellcome Trust Centre for Drug Discovery (Strategic Award)
Fairlamb, A. (Investigator), Ferguson, M. (Investigator) & Frearson, J. (Investigator)
1/01/08 → 31/12/12
Project: Research