1428183-45-2

Upstream product

• 626-34-6 ethyl aminocrotonate 
• 571-66-4 2,5-dimethyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrrole 
• 78120-39-5 (E)-ethyl 3-amino-2-(2-chloroacetyl)but-2-enoate 
• 88-17-5 2-(trifluoromethyl)benzenamine 
• 110-13-4 2,5-hexanedione 
• 65713-63-5 ethyl 5-methyl-3-oxo-1,2-dihydropyrrole-4-carboxylate 
• 932226-24-9 2,5-dimethyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbaldehyde 

Downstream Products

• 1428184-13-7 C₂₂H₂₃F₃N₂O₃ 
• 1428184-12-6 C₂₃H₂₃F₃N₂O₃ 

Relevant academic research and scientific papers

Discovery and structure-activity relationships of pyrrolone antimalarials

In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC50 ～ 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.

Structure-activity relationship studies of pyrrolone antimalarial agents

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.