Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

In this paper we describe the optimization
of a phenotypic hit
against Plasmodium falciparum, based on a trisubstituted
pyrimidine scaffold. This led to compounds with good pharmacokinetics
and oral activity in a P. berghei mouse model of
malaria. The most promising compound (13) showed a reduction
in parasitemia of 96% when dosed at 30 mg/kg orally once a day for
4 days in the P. berghei mouse model of malaria.
It also demonstrated a rapid rate of clearance of the erythrocytic
stage of P. falciparum in the SCID mouse model with
an ED90 of 11.7 mg/kg when dosed orally. Unfortunately,
the compound is a potent inhibitor of cytochrome P450 enzymes, probably
due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule
with a potentially useful antimalarial profile, which could either
be further optimized or be used for target hunting.