Structure–Activity Relationship Studies of Pyrrolone Antimalarial Agents
Article first published online: 5 AUG 2013
© 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.
Volume 8, Issue 9, pages 1537–1544, September 2013
How to Cite
Murugesan, D., Kaiser, M., White, K. L., Norval, S., Riley, J., Wyatt, P. G., Charman, S. A., Read, K. D., Yeates, C. and Gilbert, I. H. (2013), Structure–Activity Relationship Studies of Pyrrolone Antimalarial Agents. ChemMedChem, 8: 1537–1544. doi: 10.1002/cmdc.201300177
- Issue published online: 27 AUG 2013
- Article first published online: 5 AUG 2013
- Manuscript Received: 21 APR 2013
- Funded Access
- UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)
- Wellcome Trust. Grant Number: 083481
- antiprotozoal agents;
- Plasmodium falciparum;
- structure–activity relationships
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.