Efficacies and ADME properties of redox active methylene blue and phenoxazine analogues for use in new antimalarial triple drug combinations with amino-artemisinins Article Swipe
Daniel J. Watson
,
Lizahn Laing
,
Jacobus P. Petzer
,
Ho Ning Wong
,
Christopher J. Parkinson
,
Lubbe Wiesner
,
Richard K. Haynes
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.3389/fphar.2023.1308400
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.3389/fphar.2023.1308400
Efforts to develop new artemisinin triple combination therapies effective against artemisinin-tolerant strains of Plasmodium falciparum based on rational combinations comprising artemisone or other amino-artemisinins, a redox active drug and a third drug with a different mode of action have now been extended to evaluation of three potential redox partners. These are the diethyl analogue AD01 of methylene blue (MB), the benzo [α]phenoxazine PhX6, and the thiosemicarbazone DpNEt. IC 50 values in vitro against CQ-sensitive and resistant P. falciparum strains ranged from 11.9 nM for AD01–41.8 nM for PhX6. PhX6 possessed the most favourable pharmacokinetic (PK) profile: intrinsic clearance rate CL int was 21.47 ± 1.76 mL/min/kg, bioavailability was 60% and half-life was 7.96 h. AD01 presented weaker, but manageable pharmacokinetic properties with a rapid CL int of 74.41 ± 6.68 mL/min/kg leading to a half-life of 2.51 ± 0.07 h and bioavailability of 15%. DpNEt exhibited a half-life of 1.12 h and bioavailability of 8%, data which discourage its further examination, despite a low CL int of 10.20 mL/min/kg and a high C max of 6.32 µM. Efficacies of AD01 and PhX6 were enhanced synergistically when each was paired with artemisone against asexual blood stages of P. falciparum NF54 in vitro . The favourable pharmacokinetics of PhX6 indicate this is the best partner among the compounds examined thus far for artemisone. Future work will focus on extending the drug combination studies to artemiside in vitro , and conducting efficacy studies in vivo for artemisone with each of PhX6 and the related benzo[α]phenoxazine SSJ-183.
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- Type
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- Language
- en
- Landing Page
- https://doi.org/10.3389/fphar.2023.1308400
- https://www.frontiersin.org/articles/10.3389/fphar.2023.1308400/pdf?isPublishedV2=False
- OA Status
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- Cited By
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- References
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- Related Works
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- OpenAlex ID
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Raw OpenAlex JSON
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- DOI
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https://doi.org/10.3389/fphar.2023.1308400Digital Object Identifier
- Title
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Efficacies and ADME properties of redox active methylene blue and phenoxazine analogues for use in new antimalarial triple drug combinations with amino-artemisininsWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2024Year of publication
- Publication date
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2024-01-08Full publication date if available
- Authors
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Daniel J. Watson, Lizahn Laing, Jacobus P. Petzer, Ho Ning Wong, Christopher J. Parkinson, Lubbe Wiesner, Richard K. HaynesList of authors in order
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https://doi.org/10.3389/fphar.2023.1308400Publisher landing page
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https://www.frontiersin.org/articles/10.3389/fphar.2023.1308400/pdf?isPublishedV2=FalseDirect link to full text PDF
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://www.frontiersin.org/articles/10.3389/fphar.2023.1308400/pdf?isPublishedV2=FalseDirect OA link when available
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Pharmacology, Chemistry, Phenoxazine, ADME, Drug, Redox, Medicine, Organic chemistry, PhenothiazineTop concepts (fields/topics) attached by OpenAlex
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1Total citation count in OpenAlex
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2025: 1Per-year citation counts (last 5 years)
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10Other works algorithmically related by OpenAlex
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