In Vitro Efficacies, ADME, and Pharmacokinetic Properties of Phenoxazine Derivatives Active against Mycobacterium tuberculosis

Lloyd Tanner; Joanna C Evans; Ronnett Seldon; Audrey Jordaan; Digby F Warner; Richard K Haynes; Christopher J Parkinson; Lubbe Wiesner

doi:10.1128/AAC.01010-19

In Vitro Efficacies, ADME, and Pharmacokinetic Properties of Phenoxazine Derivatives Active against Mycobacterium tuberculosis

Antimicrob Agents Chemother. 2019 Oct 22;63(11):e01010-19. doi: 10.1128/AAC.01010-19. Print 2019 Nov.

Authors

Lloyd Tanner¹, Joanna C Evans^{2

3}, Ronnett Seldon^{2

3

4}, Audrey Jordaan^{2

3}, Digby F Warner^{2

3

5}, Richard K Haynes⁶, Christopher J Parkinson⁷, Lubbe Wiesner⁸

Affiliations

¹ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa tnnllo001@myuct.ac.za.
² SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical TB Research, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
³ Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
⁴ H3D Drug Discovery and Development Centre, Department of Chemistry, University of Cape Town, Cape Town, South Africa.
⁵ Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa.
⁶ Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa.
⁷ School of Biomedical Sciences, Charles Sturt University, Orange, New South Wales, Australia.
⁸ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis, remains a leading infectious killer globally, demanding the urgent development of faster-acting drugs with novel mechanisms of action. Riminophenazines such as clofazimine are clinically efficacious against both drug-susceptible and drug-resistant strains of M. tuberculosis We determined the in vitro anti-M. tuberculosis activities, absorption, distribution, metabolism, and excretion properties, and in vivo mouse pharmacokinetics of a series of structurally related phenoxazines. One of these, PhX1, displayed promising drug-like properties and potent in vitro efficacy, supporting its further investigation in an M. tuberculosis-infected animal model.

Keywords: ADME; TB chemotherapy; pharmacokinetics; phenoxazines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antitubercular Agents / pharmacokinetics*
Antitubercular Agents / pharmacology*
Clofazimine / pharmacokinetics
Clofazimine / pharmacology
Disease Models, Animal
Mice
Microbial Sensitivity Tests / methods
Mycobacterium tuberculosis / drug effects*
Oxazines / pharmacokinetics*
Oxazines / pharmacology*
Tuberculosis / drug therapy
Tuberculosis / microbiology

Substances

Antitubercular Agents
Oxazines
phenoxazine
Clofazimine