1. Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).
- Author
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Dong Y, Wang X, Kamaraj S, Bulbule VJ, Chiu FC, Chollet J, Dhanasekaran M, Hein CD, Papastogiannidis P, Morizzi J, Shackleford DM, Barker H, Ryan E, Scheurer C, Tang Y, Zhao Q, Zhou L, White KL, Urwyler H, Charman WN, Matile H, Wittlin S, Charman SA, and Vennerstrom JL
- Subjects
- Adamantane administration & dosage, Adamantane blood, Adamantane pharmacology, Adamantane therapeutic use, Animals, Antimalarials administration & dosage, Antimalarials blood, Antimalarials pharmacology, Female, Male, Mice, Peroxides administration & dosage, Peroxides blood, Peroxides pharmacology, Rats, Structure-Activity Relationship, Adamantane analogs & derivatives, Antimalarials therapeutic use, Malaria drug therapy, Peroxides therapeutic use, Plasmodium berghei drug effects, Plasmodium falciparum drug effects
- Abstract
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 pK
a 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.- Published
- 2017
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