Tests in mice showed the one-off treatment prevented infection for the full 30 days of the study.
The chemical compound fought early infection in the liver, as well as malaria parasites that were circulating in the blood.
The researchers hope their early work, published in the journal, Nature, could lead to new drugs for people.
"The advantage of a single dose antimalarial is that it potentially reduces costs and removes the issue of patients not completing the course of treatment.
Malaria is spread to humans by the bites of infected female mosquitoes and it is estimated that about half of the world's population is at risk of catching the disease.
In 2015, there were 214 million new cases of malaria and 438,000 malaria deaths, according to the World Health Organization.
Dr Nobutaka Kato and colleagues, from Massachusetts Institute of Technology and Harvard, searched a library of more than 100,000 compounds for a new treatment.
They were hunting for something that would work in an entirely new way to existing drugs.
The compound they found targets an enzyme called phenylalanyl-tRNA synthetase and appears to wipe out parasites before they can multiple in the liver and be released in bigger numbers into the bloodstream.
Lead researcher Prof Stuart Schreiber hopes the findings will lead to the discovery of better antimalarials in coming years.
Nature - Diversity-oriented synthesis yields novel multistage antimalarial inhibitors
Antimalarial drugs have thus far been derived mainly from two sources – natural products and synthetic ‘drug-like’ compounds. We hypothesized that antimalarial agents with novel mechanisms of action might be discovered using a diverse collection of synthetic compounds having three-dimensional features reminiscent of natural products and underrepresented in typical screening collections. We identified such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. The bicylic azetidines display single low-dose cure with activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to cure and prevent transmission of the disease as well as protect populations at risk, all in a single oral exposure, and highlight the strength of diversity-oriented synthesis to reveal promising therapeutic targets.
25 pages of supplemental information
SOURCES- Nature, BBC News