Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines

Two sets of diaminopyrimidines, totalling 45 compounds, were synthesized and assayed against Plasmodium falciparum. The SAR was relatively shallow, with only the presence of a 2-(pyrrolidin-1-yl)ethyl group at R2 significantly affecting activity. A subsequent series addressed high Log D values by introducing more polar side groups, with the most active compounds possessing diazepine and N-benzyl-4-aminopiperidyl groups at R1/R2. A final series attempted to address high in vitro microsomal clearance by replacing the C6-Me group with CF3, however antiplasmodial activity decreased without any improvement in clearance. The C6-CF3 group decreased hERG inhibition, probably as a result of decreased amine basicity at C2/C4.

Graphical abstractThe synthesis, antiplasmodial activity and selected DMPK properties of novel 2,4-diaminopyrimidines is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide