Artefenomel Mesylate

Plasmodium falciparum artemisinin‐resistance boosted the quest for novel plasmodial “fast killers,” uncovering antimalarial candidates OZ439 and E209, whose peroxide precursors are 1,2,4‐trioxolane (1) and 1,2,4,5‐tetraoxane (2), differing solely in the pharmacophore (trioxolane or tetraoxane). Combining X‐ray crystallography and vibrational spectroscopy, along with Hirshfeld surface analysis and calculations (CE‐B3LYP/6‐31G(d,p)) of pairwise interaction energies of intermolecular contacts existing in the crystal structure, may deepen the understanding of relative reactivity and properties of these endoperoxides classes. In the crystal, the tetraoxane ring in 2 and the trioxolane‐adamantyl fragment in 1 are disordered, with molecules 1 and 2 existing as two distinct, stable conformations. Whereas the dominant C−H⋅⋅⋅O H‐bonds in 1 connect an adamantyl C−H and O1 or O2 of the trioxolane ring, in 2 they involve the carbonyl oxygen, acting as a double acceptor from phenyl ring C−H groups. C−H⋅⋅⋅O and C−H⋅⋅⋅π H‐bonds define the molecular packing of 2, while C−H⋅⋅⋅H−C van der Waals interactions determine the packing of 1. The dispersive component dominates the interaction energies calculated for the most representative molecular pairs.

Interventions that effectively target Plasmodium vivax are critical for the future control and elimination of malaria. We conducted a P. vivax volunteer infection study to characterize the antimalarial activity of artefenomel, a new drug candidate.

Eight healthy, malaria-naive participants were intravenously inoculated with blood-stage P. vivax and subsequently received a single oral 200-mg dose of artefenomel. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma artefenomel concentration. Mosquito feeding assays were conducted before artefenomel dosing to investigate parasite transmissibility.

Initial parasite clearance occurred in all participants after artefenomel administration (log10 parasite reduction ratio over 48 hours, 1.67; parasite clearance half-life, 8.67 hours). Recrudescence occurred in 7 participants 11–14 days after dosing. A minimum inhibitory concentration of 0.62 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 0.83 ng/mL were estimated, and a single 300-mg dose was predicted to clear 109 parasites per milliliter with 95% certainty. Gametocytemia developed in all participants and was cleared 4–8 days after dosing. At peak gametocytemia, 75% of participants were infectious to mosquitoes.

The in vivo antimalarial activity of artefenomel supports its further clinical development as a treatment for P. vivax malaria.

NCT02573857.