Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines

Novel 3,3′-disubstituted-5,5′-bi­(1,2,4-triazine)
compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered.
To improve the pharmacokinetic properties of the triazine derivatives,
a new structure–activity relationship (SAR) investigation was
initiated with a focus on enhancing the metabolic stability of lead
compounds. These efforts led to the identification of second-generation
highly potent antimalarial bis-triazines, exemplified by triazine 23, which exhibited significantly improved in vitro metabolic stability (8 and 42 μL/min/mg protein in human and
mouse liver microsomes). The disubstituted triazine dimer 23 was also observed to suppress parasitemia in the Peters 4-day test
with a mean ED50 value of 1.85 mg/kg/day and exhibited
a fast-killing profile, revealing a new class of orally available
antimalarial compounds of considerable interest.