SAR of the Antimalarial Ozonide Artefenomel (OZ439)

04 Jan 2017

Yuxiang Dong, Xiaofang Wang, Sriraghavan Kamaraj, Vivek J. Bulbule, Francis C. K. Chiu, Jacques Chollet, Dhanasekaran Manickam, Christopher D. Hein, Petros Papastogiannidis, Julia Morizzi, David M. Shackleford, Helena Barker, Eileen Ryan, Christian Scheurer, Yuanqing Tang, Qingjie Zhao, Lin Zhou, Karen L. White, Heinrich Urwyler, William N. Charman, Hugues Matile, Sergio Wittlin, Susan A. Charman, and Jonathan L. Vennerstrom

Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.6b01586


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.

Read the full article on ACS Pulications' website.