The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside

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dc.contributor.authorGibhard, Liezl
dc.contributor.authorCoertzen, Dina
dc.contributor.authorReader, Janette
dc.contributor.authorvan der Watt, Mariëtte E
dc.contributor.authorBirkholtz, Lyn-Marie
dc.contributor.authorWong, Ho Ning
dc.contributor.authorBatty, Kevin T
dc.contributor.authorHaynes, Richard K
dc.contributor.authorWiesner, Lubbe
dc.date.accessioned2022-04-03T19:07:00Z
dc.date.available2022-04-03T19:07:00Z
dc.date.issued2021-12-03
dc.date.updated2021-12-23T15:06:27Z
dc.description.abstractBecause of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5–2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.en_US
dc.identifierdoi: 10.3390/pharmaceutics13122066
dc.identifier.apacitationGibhard, L., Coertzen, D., Reader, J., van der Watt, M. E., Birkholtz, L., Wong, H. N., ... Wiesner, L. (2021). The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside. <i>Pharmaceutics</i>, 13(12), 2066. http://hdl.handle.net/11427/36251en_ZA
dc.identifier.chicagocitationGibhard, Liezl, Dina Coertzen, Janette Reader, Mariëtte E van der Watt, Lyn-Marie Birkholtz, Ho Ning Wong, Kevin T Batty, Richard K Haynes, and Lubbe Wiesner "The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside." <i>Pharmaceutics</i> 13, 12. (2021): 2066. http://hdl.handle.net/11427/36251en_ZA
dc.identifier.citationGibhard, L., Coertzen, D., Reader, J., van der Watt, M.E., Birkholtz, L., Wong, H.N., Batty, K.T. & Haynes, R.K. et al. 2021. The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside. <i>Pharmaceutics.</i> 13(12):2066. http://hdl.handle.net/11427/36251en_ZA
dc.identifier.ris TY - Journal Article AU - Gibhard, Liezl AU - Coertzen, Dina AU - Reader, Janette AU - van der Watt, Mariëtte E AU - Birkholtz, Lyn-Marie AU - Wong, Ho Ning AU - Batty, Kevin T AU - Haynes, Richard K AU - Wiesner, Lubbe AB - Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5–2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies. DA - 2021-12-03 DB - OpenUCT DP - University of Cape Town IS - 12 J1 - Pharmaceutics LK - https://open.uct.ac.za PY - 2021 T1 - The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside TI - The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside UR - http://hdl.handle.net/11427/36251 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/36251
dc.identifier.vancouvercitationGibhard L, Coertzen D, Reader J, van der Watt ME, Birkholtz L, Wong HN, et al. The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside. Pharmaceutics. 2021;13(12):2066. http://hdl.handle.net/11427/36251.en_ZA
dc.language.isoenen_US
dc.publisher.departmentDepartment of Chemistryen_US
dc.publisher.facultyFaculty of Scienceen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourcePharmaceuticsen_US
dc.source.journalissue12en_US
dc.source.journalvolume13en_US
dc.source.pagination2066en_US
dc.source.urihttps://www.mdpi.com/journal/pharmaceutics
dc.titleThe Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemisideen_US
dc.typeJournal Articleen_US
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