The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage <i>P. falciparum</i> Parasites, DMPK Properties, and the Case for Artemiside
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 th...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/12/2066 |
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| author | Liezl Gibhard Dina Coertzen Janette Reader Mariëtte E. van der Watt Lyn-Marie Birkholtz Ho Ning Wong Kevin T. Batty Richard K. Haynes Lubbe Wiesner |
| author_facet | Liezl Gibhard Dina Coertzen Janette Reader Mariëtte E. van der Watt Lyn-Marie Birkholtz Ho Ning Wong Kevin T. Batty Richard K. Haynes Lubbe Wiesner |
| author_sort | Liezl Gibhard |
| collection | DOAJ |
| description | 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 <i>P. falciparum</i> (<i>Pf</i>) blood stage parasites (IC<sub>50</sub> 1.5–2.6 nM). Against <i>Pf</i> NF54 blood stage gametocytes, artemisox is potently active (IC<sub>50</sub> 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 <i>po</i> and <i>iv</i> administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite C<sub>max</sub> 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 C<sub>max</sub>, 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. |
| first_indexed | 2024-03-10T03:19:37Z |
| format | Article |
| id | doaj.art-961b961512034a18beeab2e2a9be0ff9 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T03:19:37Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-961b961512034a18beeab2e2a9be0ff92023-11-23T10:05:26ZengMDPI AGPharmaceutics1999-49232021-12-011312206610.3390/pharmaceutics13122066The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage <i>P. falciparum</i> Parasites, DMPK Properties, and the Case for ArtemisideLiezl Gibhard0Dina Coertzen1Janette Reader2Mariëtte E. van der Watt3Lyn-Marie Birkholtz4Ho Ning Wong5Kevin T. Batty6Richard K. Haynes7Lubbe Wiesner8H3D, Department of Chemistry, University of Cape Town, Observatory, Cape Town 7925, South AfricaMalaria Parasite Molecular Laboratory, Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Pretoria 0028, South AfricaMalaria Parasite Molecular Laboratory, Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Pretoria 0028, South AfricaMalaria Parasite Molecular Laboratory, Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Pretoria 0028, South AfricaMalaria Parasite Molecular Laboratory, Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Pretoria 0028, South AfricaCentre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom 2520, South AfricaCurtin Medical School, Curtin University, Bentley 6102, AustraliaCentre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom 2520, South AfricaDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, Cape Town 7925, South AfricaBecause 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 <i>P. falciparum</i> (<i>Pf</i>) blood stage parasites (IC<sub>50</sub> 1.5–2.6 nM). Against <i>Pf</i> NF54 blood stage gametocytes, artemisox is potently active (IC<sub>50</sub> 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 <i>po</i> and <i>iv</i> administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite C<sub>max</sub> 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 C<sub>max</sub>, 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.https://www.mdpi.com/1999-4923/13/12/2066antimalarial drugsartemisininsACTsresistanceamino-artemisininspharmacokinetics |
| spellingShingle | Liezl Gibhard Dina Coertzen Janette Reader Mariëtte E. van der Watt Lyn-Marie Birkholtz Ho Ning Wong Kevin T. Batty Richard K. Haynes Lubbe Wiesner The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage <i>P. falciparum</i> Parasites, DMPK Properties, and the Case for Artemiside Pharmaceutics antimalarial drugs artemisinins ACTs resistance amino-artemisinins pharmacokinetics |
| title | The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage <i>P. falciparum</i> Parasites, DMPK Properties, and the Case for Artemiside |
| title_full | The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage <i>P. falciparum</i> Parasites, DMPK Properties, and the Case for Artemiside |
| title_fullStr | The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage <i>P. falciparum</i> Parasites, DMPK Properties, and the Case for Artemiside |
| title_full_unstemmed | The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage <i>P. falciparum</i> Parasites, DMPK Properties, and the Case for Artemiside |
| title_short | The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage <i>P. falciparum</i> Parasites, DMPK Properties, and the Case for Artemiside |
| title_sort | artemiside artemisox artemisone m1 tetrad efficacies against blood stage i p falciparum i parasites dmpk properties and the case for artemiside |
| topic | antimalarial drugs artemisinins ACTs resistance amino-artemisinins pharmacokinetics |
| url | https://www.mdpi.com/1999-4923/13/12/2066 |
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