Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity

Malaria kills nearly
0.5 million people yearly and impacts the
lives of those living in over 90 countries where it is endemic. The
current treatment programs are threatened by increasing drug resistance.
Dihydroorotate dehydrogenase (DHODH) is now clinically validated as
a target for antimalarial drug discovery as a triazolopyrimidine class
inhibitor (DSM265) is currently undergoing clinical development.
We discovered a related isoxazolopyrimidine series in a phenotypic
screen, later determining that it targeted DHODH. To determine if
the isoxazolopyrimidines could yield a drug candidate, we initiated
hit-to-lead medicinal chemistry. Several potent analogues were identified,
including a compound that showed in vivo antimalarial activity. The
isoxazolopyrimidines were more rapidly metabolized than their triazolopyrimidine
counterparts, and the pharmacokinetic data were not consistent with
the goal of a single-dose treatment for malaria.