TY - JOUR
T1 - Structure-activity relationship studies of pyrrolone antimalarial agents
AU - Murugesan, Dinakaran
AU - Kaiser, Marcel
AU - White, Karen Louise
AU - Norval, Suzanne
AU - Riley, Jennifer
AU - Wyatt, Paul G
AU - Charman, Susan Ann
AU - Read, Kevin D
AU - Yeates, Clive
AU - Gilbert, Ian Hugh
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201300177/abstract;jsessionid=61E81C83816DF94C9A4126385B124BC5.f03t01
U2 - 10.1002/cmdc.201300177
DO - 10.1002/cmdc.201300177
M3 - Article
SN - 1860-7179
VL - 8
SP - 1537
EP - 1544
JO - ChemMedChem
JF - ChemMedChem
IS - 9
ER -