P. falciparum with resistance to pyrimidine-2,4-diamines mediated by the ABCI3 transporter
A screen of the Janssen Jumpstarter library against P. falciparum identified W482 with a pyrimidine-2,4-diamine scaffold. Structure-activity relationships revealed the importance of the pyrimidine core and its endocyclic nitrogen while alternative amines were well tolerated in the 4-position. Bulky and hydrophobic carboxamides or substituted phenyl ureas displayed the most potent anti-plasmodial activity. Resistance selection and whole genome sequencing revealed an amplification in the ABCI3 transporter protein. W482 was found to exhibit higher activity against parasites with reduced expression of the ABCI3 transporter, confirming that resistance is related to the transporter.