Efficacies and ADME properties of redox active methylene blue and phenoxazine analogues for use in new antimalarial triple drug combinations with amino-artemisinins

Daniel J Watson; Lizahn Laing; Jacobus P Petzer; Ho Ning Wong; Christopher J Parkinson; Lubbe Wiesner; Richard K Haynes

doi:10.3389/fphar.2023.1308400

Efficacies and ADME properties of redox active methylene blue and phenoxazine analogues for use in new antimalarial triple drug combinations with amino-artemisinins

Front Pharmacol. 2024 Jan 8:14:1308400. doi: 10.3389/fphar.2023.1308400. eCollection 2023.

Authors

Daniel J Watson¹, Lizahn Laing¹, Jacobus P Petzer², Ho Ning Wong³, Christopher J Parkinson⁴, Lubbe Wiesner¹, Richard K Haynes^{2

3}

Affiliations

¹ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
² Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa.
³ Rural Health Research Institute, Charles Sturt University, Orange, NSW, Australia.
⁴ School of Dentistry and Medical Sciences, Charles Sturt University, Orange, NSW, Australia.

Abstract

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. IC₅₀ 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.

Keywords: artemisone; benzo[a]phenoxazine; combinations; malaria; synergism.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded by the South African Medical Research Council (MRC) Flagship Project MALTB-Redox with funds from the National Treasury under its Economic Competitiveness and Support Package (MRC-RFA-UFSP-01-2013) and the South African National Research Foundation (NRF) grant UID129135 to RKH.