Structure–Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines

Based
on the initial optimization of orally active antimalarial
2,4-diamino-thienopyrimidines and with the help of metabolite identification
studies, a second generation of derivatives involving changes at the
2- and 4-positions of the thienopyrimidine core were synthesized.
Improvements in the physiochemical properties resulted in the identification
of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg
once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously
reported compounds, and with a slightly improved hERG profile.