3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity.
Xue L., Shi D-H., Harjani JR., Huang F., Beveridge JG., Dingjan T., Ban K., Diab S., Duffy S., Lucantoni L., Fletcher S., Chiu FCK., Blundell S., Ellis K., Ralph SA., Wirjanata G., Teguh S., Noviyanti R., Chavchich M., Creek D., Price RN., Marfurt J., Charman SA., Cuellar ME., Strasser JM., Dahlin JL., Walters MA., Edstein MD., Avery VM., Baell JB.
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 μM, had high in vitro potency against P. falciparum lines resistant to chloroquine (W2, IC50 = 0.0047 ± 0.0011 μM) and artemisinin (MRA1240, IC50 = 0.0086 ± 0.0010 μM). Excellent ex vivo potency of 6k was shown against clinical field isolates of both P. falciparum (IC50 = 0.022-0.034 μM) and Plasmodium vivax (IC50 = 0.0093-0.031 μM) 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.