Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials

Clinical development of the antimalarial artefenomel was recently halted due to formulation challenges stemming from the drug's lipophilicity and low aqueous solubility. The symmetry of organic molecules is known to influence crystal packing energies and by extension solubility and dissolution rates. Here we evaluate RLA-3107, a desymmetrized, regioisomeric form of artefenomel in vitro and in vivo, finding that the regioisomer retains potent antiplasmodial activity while offering improved human microsome stability and aqueous solubility as compared to artefenomel. We also report in vivo efficacy data for artefenomel and its regioisomer across 12 different dosing regimens.

Automated summary

The development of the antimalarial drug artefenomel was halted due to formulation challenges caused by its lipophilicity and low aqueous solubility. The symmetry of organic molecules influences their solubility and dissolution rates. In this study, we evaluated RLA-3107, a desymmetrized regioisomer of artefenomel, and found that it retains potent antiplasmodial activity and has improved human microsome stability and aqueous solubility compared to artefenomel. We also present in vivo efficacy data for artefenomel and its regioisomer with 12 different dosing regimens.