3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) derivatives with Potent in vitro and in vivo Antimalarial Activity.

A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC50 (50% inhibitory concentration) of 0.008 mu M, had high in vitro potency against P. falciparum lines resistant to chloroquine (W2, IC50 = 0.0047 +/- 0.0011 mu M) and artemisinin (MRA1240, IC50 = 0.0086 +/- 0.0010 mu M). Excellent ex vivo potency of 6k was shown against clinical field isolates of both P. falciparum (IC50 = 0.022-0.034 mu M) and Plasmodium vivax (IC50 = 0.0093-0.031 mu M) from the blood of outpatients with uncomplicated malaria. Despite 6k being cleared relatively rapidly in mice, it suppressed parasitemia in the Peters 4-day test, with a mean ED50 value (50% effective dose) of 1.47 mg kg(-1) day(-1) following oral administration. The disubstituted triazine dimer 6k represents a new class of orally available antimalarial compounds of considerable interest for further development.