AIM: To evaluate the safety, tolerability and pharmacokinetics in healthy participants of orally administered MMV367 (GSK3772701), a novel antimalarial interfering with Plasmodium falciparum acyl coenzyme A synthetase 10/11 function. METHODS: This first-in-human study enrolled 47 healthy male and female participants. Part 1 was a randomised, double-blind, placebo-controlled study in which four sequential fasted cohorts received MMV367 single ascending doses (100, 300, 750 and 1500 mg) or placebo (six active, two placebo per cohort). Part 2 was a randomised, open-label crossover (fed-fasted) pilot food-effect study of MMV367 440 mg (n = 8). In Part 3 MMV367 400 mg was administered once daily for 3 days in a single cohort (six active, two placebo). RESULTS: Treatment-emergent adverse events (TEAEs) occurred in 36.8% (14/38) of participants receiving MMV367 vs 44.4% (4/9) with placebo. There were two MMV367-related TEAEs, and no serious or severe TEAEs or clinically relevant changes in electrocardiograms, vital signs or laboratory tests. In Part 1 (fasted), maximum plasma concentrations occurred between 2.0 and 5.0 h post dose, with a geometric mean half-life of 16.5-18.4 h. Approximate dose proportionality was demonstrated across the dose range (100-1500 mg). In Part 2, MMV367 relative bioavailability (fed vs fasted) was 161.4% (90% confidence interval 148.3, 175.6) for maximum observed concentration (C CONCLUSIONS: MMV367 demonstrated acceptable safety, tolerability and pharmacokinetic profiles supporting further development as an antimalarial drug.