Abstract
Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antimalarials / chemistry
-
Antimalarials / pharmacokinetics
-
Antimalarials / pharmacology*
-
Antimalarials / therapeutic use
-
Cell Line, Tumor
-
Drug Discovery*
-
Drug Evaluation, Preclinical
-
Drug Resistance
-
Erythrocytes / parasitology
-
Humans
-
Imidazoles / chemistry
-
Imidazoles / pharmacokinetics
-
Imidazoles / pharmacology*
-
Imidazoles / therapeutic use
-
Liver / parasitology*
-
Malaria / drug therapy*
-
Malaria / parasitology
-
Malaria / prevention & control
-
Mice
-
Mice, Inbred BALB C
-
Molecular Structure
-
Piperazines / chemistry
-
Piperazines / pharmacokinetics
-
Piperazines / pharmacology*
-
Piperazines / therapeutic use
-
Plasmodium / cytology
-
Plasmodium / drug effects*
-
Plasmodium / growth & development
-
Plasmodium / physiology
-
Plasmodium berghei / cytology
-
Plasmodium berghei / drug effects
-
Plasmodium berghei / growth & development
-
Plasmodium berghei / physiology
-
Plasmodium falciparum / cytology
-
Plasmodium falciparum / drug effects
-
Plasmodium falciparum / growth & development
-
Plasmodium falciparum / physiology
-
Plasmodium yoelii / cytology
-
Plasmodium yoelii / drug effects
-
Plasmodium yoelii / growth & development
-
Plasmodium yoelii / physiology
-
Polymorphism, Single Nucleotide
-
Protozoan Proteins / chemistry
-
Protozoan Proteins / genetics
-
Protozoan Proteins / metabolism
-
Random Allocation
-
Small Molecule Libraries
-
Sporozoites / drug effects
-
Sporozoites / growth & development
Substances
-
Antimalarials
-
GNF 179
-
Imidazoles
-
Piperazines
-
Protozoan Proteins
-
Small Molecule Libraries