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.
Highlights
TAPs being efficacious in vivo provide a novel therapeutic approach to treat malaria by targeting this essential proton pump
A very low rate of spontaneous resistance to TAPs coupled with the lack of point mutations in the V-type H þ -ATPase gene from a diverse collection of global isolates confirm the lack of pre-existing mutations to this important gene in Pf
To test whether the identified mutation in the V-type H þ -ATPase subunit D protein affects the ionic homeostasis of the parasite’s vacuole, we determined the size of vacuoles relative to overall parasite size from microscopic Giemsa-stained images
Summary
Synthetic scheme for representative TAPs (compounds 7, 8, 9 and 12). All reagents, starting materials and solvents described in the procedure were commercially available and used without further purification. Analytical thin-layer chromatography was performed on SiO2 plates on alumina and the purity of all final derivatives for biological testing was confirmed to be 495% using the following conditions: a Shimadzu HPLC (high-performance liquid chromatography) instrument with a Hamilton reverse-phase column (HxSil, C18, 3 mm, 2.1 mm  50 mm (H2)). The structure of the intermediates and end products was confirmed by proton (1H), carbon (13C) nuclear magnetic resonance (NMR) and mass spectroscopy. Liquid Chromatography-Mass Spectrometer (LC-MS) data was acquired using Agilent LCMS VL series. High-resolution mass spectrometry (HRMS) data was acquired using an Agilent 6520, Quadrupole-Time of flight tandem mass spectrometry (MS/MS) coupled with an Agilent 1200 series HPLC system
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