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

Yuxiang Dong, Xiaofang Wang, Sriraghavan Kamaraj, Vivek J. Bulbule, Francis C.K. Chiu, Jacques Chollet, Manickam Dhanasekaran, 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. CharmanHugues Matile, Sergio Wittlin, Susan A. Charman, Jonathan L. Vennerstrom

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2654-2668
Number of pages15
JournalJournal of Medicinal Chemistry
Volume60
Issue number7
DOIs
StatePublished - Apr 13 2017

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Antimalarials
Structure-Activity Relationship
1,2,4-trioxane

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439). / Dong, Yuxiang; Wang, Xiaofang; Kamaraj, Sriraghavan; Bulbule, Vivek J.; Chiu, Francis C.K.; Chollet, Jacques; Dhanasekaran, Manickam; Hein, Christopher D.; Papastogiannidis, Petros; Morizzi, Julia; Shackleford, David M.; Barker, Helena; Ryan, Eileen; Scheurer, Christian; Tang, Yuanqing; Zhao, Qingjie; Zhou, Lin; White, Karen L.; Urwyler, Heinrich; Charman, William N.; Matile, Hugues; Wittlin, Sergio; Charman, Susan A.; Vennerstrom, Jonathan L.

In: Journal of Medicinal Chemistry, Vol. 60, No. 7, 13.04.2017, p. 2654-2668.

Research output: Contribution to journalArticle

Dong, Y, Wang, X, Kamaraj, S, Bulbule, VJ, Chiu, FCK, 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 & Vennerstrom, JL 2017, 'Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)', Journal of Medicinal Chemistry, vol. 60, no. 7, pp. 2654-2668. https://doi.org/10.1021/acs.jmedchem.6b01586
Dong, Yuxiang ; Wang, Xiaofang ; Kamaraj, Sriraghavan ; Bulbule, Vivek J. ; Chiu, Francis C.K. ; Chollet, Jacques ; Dhanasekaran, Manickam ; Hein, Christopher D. ; Papastogiannidis, Petros ; Morizzi, Julia ; Shackleford, David M. ; Barker, Helena ; Ryan, Eileen ; Scheurer, Christian ; Tang, Yuanqing ; Zhao, Qingjie ; Zhou, Lin ; White, Karen L. ; Urwyler, Heinrich ; Charman, William N. ; Matile, Hugues ; Wittlin, Sergio ; Charman, Susan A. ; Vennerstrom, Jonathan L. / Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439). In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 7. pp. 2654-2668.
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AU - Chiu, Francis C.K.

AU - Chollet, Jacques

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AU - Zhou, Lin

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AU - Charman, William N.

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AU - Charman, Susan A.

AU - Vennerstrom, Jonathan L.

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N2 - 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.

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