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

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.

Potentiality of Actinomycetia Prevalent in Selected Forest Ecosystems in Assam, India to Combat Multi-Drug-Resistant Microbial Pathogens

“…-ol, 11. beta,19-epoxy, have been identified to have anticancer, antimicrobial, antitumor, antimalaria, anti- M. tuberculosis , and anti-inflammation activities, respectively. The results are also found to be in agreement with previous studies [ 50 , 51 , 52 , 53 , 54 , 55 ]. Two compounds, L-cysteine, N-acetyl-, methyl ester, acetate, and desflurane, detected in Streptomyces sp.…”

Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy

“…(E) Flow cytometry of M. smegmatis (GFP-labeled)-infected THP-1 cells treated with PhX1 over a period of 2 h, with red fluorescence measured in the APC channel ( x axis) and GFP measured in the FITC channel ( y axis). M. tuberculosis efficacies and ADME-PK of phenoxazines PhX1, -2, -6, -8, -10, and -14 reported in Tanner et al ( 118 ).…”

Accumulation of TB-Active Compounds in Murine Organs Relevant to Infection by Mycobacterium tuberculosis

“…The compounds RMB041 and PhX1 were synthesized and were shown by high-performance liquid chromatography (HPLC) analyses to be ≥96% pure (Shi et al, 2011;Beteck et al, 2018;Tanner et al, 2019a;Tanner et al, 2019b). Potassium dihydrogen phosphate and dipotassium hydrogen phosphate were purchased from Merck (Darmstadt, Germany).…”

“…Blood samples, approximately 20 µl, were collected via tail bleeding 10 min before murine euthanasia at 1, 6, and 24 h post-drug administration. The organ collection was completed at set time points determined by the previous PK studies of the specific compounds (Tanner et al, 2019a;Tanner et al, 2019b). Following complete anesthesia, the mice (n = 3 per time-point) were then euthanized by exsanguination (cardiac puncture and the removal the majority of vascular blood), with both femoral arteries cut and approximately 20 ml of saline injected into the right aorta to rinse the circulatory system of blood, which continues until the organs experience a pale colour change which was followed by the surgical procedure.…”

“…In turning to our own work, following in-depth in vivo murine studies, novel decoquinate derivative (RMB041) and a phenoxazine derivative (PhX1) ( Figure 1) are now selected for murine organ analysis based on their promising in vitro ADME properties and their relatively long half-lives (62.5 ± 6.73 h and 3.71 ± 0.67 h) and large volumes of distribution (1.2 ± 0.03 L/kg and 11.1 ± 0.1 L/kg), respectively (Tanner et al, 2019a;Tanner et al, 2019b).…”