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Structure-activity relationship of the antimalarial ozonide artefenomel (OZ439)

Dong, Yuxiang and Wang, Xiaofang and Kamaraj, Sriraghavan and Bulbule, Vivek J. and Chiu, Francis C. K. and Chollet, Jacques and Dhanasekaran, Manickam and Hein, Christopher D. and Papastogiannidis, Petros and Morizzi, Julia and Shackleford, David M. and Barker, Helena and Ryan, Eileen and Scheurer, Christian and Tang, Yuanqing and Zhao, Qingjie and Zhou, Lin and White, Karen L. and Urwyler, Heinrich and Charman, William N. and Matile, Hugues and Wittlin, Sergio and Charman, Susan A. and Vennerstrom, Jonathan L.. (2017) Structure-activity relationship of the antimalarial ozonide artefenomel (OZ439). Journal of medicinal chemistry, 60 (7). pp. 2654-2668.

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Official URL: http://edoc.unibas.ch/55095/

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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 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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Scheurer, Christian and Wittlin, Sergio
Item Type:Article, refereed
Publisher:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Oct 2017 05:56
Deposited On:06 Jun 2017 12:07

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