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.

Design, synthesis and biological evaluation of novel triaryldimethylaminobutan-2-ol derivatives against Mycobacterium tuberculosis.

Bedaquiline (TMC207), a typical diarylquinoline anti-tuberculosis drug, has been approved by FDA to specifically treat MDR-TB. Herein we describe design, synthesis, and in vitro biological evaluation against Mycobacterium tuberculosis of a series of triaryldimethylaminobutan-2-ol derivatives obtaining from the structural modification of TMC207. Compounds 23, 25, 28, 32, 39 and 43 provided superior anti-mycobacterial activity than positive control PC01 which shows the same configuration and contains TMC207. Compounds 16, 20, 29, 34, 37, 45 and 47 exhibited the similar activity to positive control PC01. Most importantly, the series of compounds showed excellent activity against XDR-Mtb. The result of acute toxicity suggested that this class of triaryldimethylaminobutan-2-ol derivatives should be graded as low. Further SAR analysis indicates that a large steric bulk of triaryl and 7-Br, 3-OCH3 on 1-naphthyl are critical.

Synthetic approaches towards bedaquiline and its derivatives.

Bedaquiline is a diarylquinoline drug that demonstrates potent and selective inhibition of mycobacterial ATP synthase, and is clinically administered for the treatment of multi-drug resistant tuberculosis. Due to its excellent activity and novel mechanism of action, bedaquiline has been the focus of a number of synthetic studies. This review will discuss these synthetic approaches, as well as the synthesis and bioactivity of the numerous derivatives and molecular probes inspired by bedaquiline.

Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876-A Less Toxic and More Potent Analogue of Bedaquiline.

Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.

Design, Synthesis and Biological Evaluation of Anti-tuberculosis Agents based on Bedaquiline Structure.

BACKGROUND: Bedaquiline is a novel anti-tuberculosis drug that inhibits Mycobacterial ATP synthase. However, studies have found that bedaquiline has serious side effects due to high lipophilicity. Recently, the complete structure of ATP synthase was first reported in the Journal of Science. OBJECTIVE: The study aimed to design, synthesise and carry out biological evaluation of antituberculosis agents based on the structure of bedaquiline. METHODS: The mode of action of bedaquiline and ATP synthase was determined by molecular docking, and a series of low lipophilic bedaquiline derivatives were synthesized. The inhibitory activities of bedaquiline derivatives towards Mycobacterium phlei 1180 and Mycobacterium tuberculosis H37Rv were evaluated in vitro. A docking study was carried out to elucidate the structureactivity relationship of the obtained compounds. The predicted ADMET properties of the synthesized compounds were also analyzed. RESULTS: The compounds 5c3, 6a1, and 6d3 showed good inhibitory activities (MIC=15.62 ug.mL-1). At the same time, the compounds 5c3, 6a1, and 6d3 also showed good drug-like properties through molecular docking and ADMET properties prediction. CONCLUSION: The results of in vitro anti-tuberculosis activity assays, docking studies and ADMET predictions indicate that the synthesized compounds have potential antifungal activity, with compounds 6a1 being further optimized and developed as lead compounds.

Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology.

Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.

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.

Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-Dimethylaminomethyl)phenyl)quinoline-Derived Antitubercular Lead Compounds.

Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 µm, one had IC50 >66 µm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets.

New synthetic approaches towards analogues of bedaquiline.

Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.

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.

Bedaquiline: a new hope to treat multi-drug resistant tuberculosis.

Each year, a huge number of new cases accounts of TB with added problems due to multidrug resistant TB varieties. Globally, TB is one of the top causes of loss of life among people living with HIV who are more likely than others to get TB infection. Current TB treatment includes long term administration of cocktail of drugs; hence, the development of an alternative armamentarium against TB is the primary requirement. In fact, new drugs with novel activity against mycobacteria are of significant importance in order to combat existing levels of resistance. The present report covers the discovery of a diarylquinoline TB drug, bedaquiline, its antituberculosis effects and mode of action. Clinical studies conducted on bedaquiline which brought it to the accelerated FDA acceptance have been described. This report is of great attention for therapeutic apothecaries working in TB medication growth in terms of creating further diarylquinoline applicants with a wide variety of antimycobacterial results.

N-Heterocyclic carbene (NHC)-modulated Pd/Cu cocatalyzed three-component synthesis of 2,6-diarylquinolines.

Two new NHC adducts of cyclopalladated ferrocenylpyrazine complexes 1-2 have been prepared and characterized. An efficient NHC-modulated Pd/Cu cocatalyzed three-component coupling reaction for the synthesis of 2,6-diarylquinolines from aminobenzyl alcohols, aryl ketones, and arylboronic acids in air is described. The reaction involves oxidation, cyclization and Suzuki reactions. The luminescence of the resulting arylquinolines 3-30 was also investigated.

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.