Structure–Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)

Building
on insights gained from the discovery of the antimalarial ozonide
arterolane (OZ277), we now describe the structure–activity
relationship (SAR) of the antimalarial ozonide artefenomel (OZ439).
Primary and secondary amino ozonides had higher metabolic stabilities
than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional
groups decreased in vivo antimalarial efficacy. For secondary amino
ozonides, additional functional groups had variable effects on metabolic
stability and efficacy, but the most effective members of this series
also had the highest log D7.4 values.
For tertiary amino ozonides, addition of polar functional groups with
H-bond donors increased metabolic stability but decreased in vivo
antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl
and heterocycle substructures were superior to their acyclic counterparts.
The high curative efficacy of these ozonides was most often associated
with high and prolonged plasma exposure, but exposure on its own did
not explain the presence or absence of either curative efficacy or
in vivo toxicity.