Current Perspective of ATP Synthase Inhibitors in the Management of the Tuberculosis.

INTRODUCTION: Tuberculosis is a life-threatening disease, and the drugs discovered during the era of 1950 and 1970 are found to be inefficient due to emergent MDR and XDR-TB. Tuberculosis is difficult to treat due to the development of antibiotic resistance. ATP synthase consists of two units, F1 and F0 units. These are present in the cytoplasm and membrane of mitochondria, respectively. F1 unit comprises of a, b, and c subunit while F0 subunit has α, ß, γ, δ, ε subunits. Bedaquiline was the first approved ATP synthase inhibitor in 2012 by USFDA. METHODS: Recent literature from 2005-2020 were collected using Pubmed with the keywords ATP synthase inhibitor, bedaquiline derivatives, tuberculosis. The work describing detailed analyses of bedaquiline (BDQ) was included in the current work, and others were excluded. RESULTS: ATP production occurs via the ATP synthase enzyme, leading to the growth and multiplication of mycobacteria. BDQ inhibits the mycobacterium ATP synthase enzyme, a heteropolymeric complex consisting of two subunits, but it does not interfere with mammalian ATP synthase. Bedaquiline (BDQ) has become a drug of choice in treating MDR-TB and helps in reducing the treatment span. Recently observed triple mutation as wtLeu59A→mtVal59A; wtIle66A→mtMet66A and wtGlu61B→mtAsp61B of ATP synthase led to decrease BDQ binding affinity; thus, researchers are putting efforts for its newer derivative discovery. CONCLUSION: ATP synthase inhibitor could be an alternative approach for better treatment of tuberculosis. Herein we discussed the recent advancements in the development of newer analogues of BDQ with its future perspectives.

3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel.

Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.

Structure-activity relationships for unit C pyridyl analogues of the tuberculosis drug bedaquiline.

The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC90) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions where IC50 values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two compounds with lower potency against hERG exhibited similar clearance to bedaquiline and excellent efficacy in vivo, suggesting further exploration of C-ring pyridyls is worthwhile.

Design and Stereochemical Research (DFT, ECD and Crystal Structure) of Novel Bedaquiline Analogs as Potent Antituberculosis Agents.

A series of bedaquiline analogs containing H-bond donors were designed as anti-Mycobacterium tuberculosis drugs. A pair of diastereoisomers (R/S- and S/S-isomers) was selected from these designed compounds for synthetic and stereochemical research. The title compounds were synthesized from chiral precursors for the first time and the absolute configurations (ACs) were determined by electronic circular dichroism (ECD) with quantum chemical calculations. Moreover, a single crystal of the S/S compound was obtained for X-ray diffraction analysis, and the crystal structure showed high consistency with the geometry, confirming the reliability of ACs obtained by ECD analyses and theoretical simulation. Furthermore, the effect of stereochemistry on the anti-tuberculosis activity was investigated. The MICs of the R/S- and S/S-isomers against Mycobacterium phlei 1180 are 9.6 and 32.1 µg·mL(-1), respectively. Finally, molecular docking was carried out to evaluate the inhibitory nature and binding mode differences between diastereoisomers.

Diarylquinoline compounds induce autophagy-associated cell death by inhibiting the Akt pathway and increasing reactive oxygen species in human nasopharyngeal carcinoma cells.

Diarylquinoline compounds are newly synthesized derivatives of the new anti-tuberculosis drug, TMC207. In this study, nine diarylquinoline compounds were screened for cytotoxic activity against human tumor cells, and their mechanisms of action were investigated. Among the nine compounds, STM-57 [N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methl)-N-(3,4-dichlorophenyl)-3-(4 -methylpiperazin-1-yl)propanamide] showed potent cytotoxic activity. STM-57 induced caspase-independent cell death in the human nasopharyngeal carcinoma cell line, CNE-2. Further investigation showed that STM-57 induced autophagy, as determined with the increased expression of green fluorescent protein-light chain 3 (GFP-LC3) and increased LC3-II levels. STM-57 inhibited the phosphorylation of Akt and the mammalian target of rapamycin (mTOR) in CNE-2 cells. The intracellular calcium concentration and reactive oxygen species levels were increased in CNE-2 cells following treatment with STM-57, whereas the mitochondrial transmembrane potential (ΔΨm) and ATP concentrations were decreased.