1108147-59-6Relevant articles and documents
Structure-activity relationship studies of pyrrolone antimalarial agents
Murugesan, Dinakaran,Kaiser, Marcel,White, Karen L.,Norval, Suzanne,Riley, Jennifer,Wyatt, Paul G.,Charman, Susan A.,Read, Kevin D.,Yeates, Clive,Gilbert, Ian H.
, p. 1537 - 1544 (2013)
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.
