Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate.

ABSTRACT: The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30?mg?kg(-1) and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36?h in humans, a single dose of 260?mg might be sufficient to maintain therapeutic blood concentration for 4-5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.

SUBMITTER: Hameed P S 

PROVIDER: S-EPMC4389225 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature