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

Sutherland, Hamish S.; Tong, Amy S.T.; Blaser, Adrian; Conole, Daniel; Franzblau, Scott G.; Lotlikar, Manisha U.; Cooper, Christopher B.; Upton, Anna M.; Denny, William A.; Palmer, Brian D.

doi:10.1016/j.bmc.2019.02.026

Cited by 80 publications

(109 citation statements)

References 14 publications

(30 reference statements)

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“…This raises concerns regarding co-administration of BDQ with other QT interval-prolonging drugs (e.g., fluoroquinolones) [32]. To address these liabilities, a medicinal chemistry campaign was conducted [33][34][35][36][37]. This chemistry-driven work, using Mtb whole-cell activity as a read-out, resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ [37].…”

Section: Stalling Of Rotation Of the Mycobacterial F-atp Synthase C-ringmentioning

confidence: 99%

“…To address these liabilities, a medicinal chemistry campaign was conducted [33][34][35][36][37]. This chemistry-driven work, using Mtb whole-cell activity as a read-out, resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ [37]. TBAJ-876 ( Figure 1) was selected from this series to progress to pre-clinical development due to its lower lipophilicity, lower hERG ion channel inhibition, higher clearance and retention of BDQ's potent activity against Mtb [37].…”

Section: Stalling Of Rotation Of the Mycobacterial F-atp Synthase C-ringmentioning

confidence: 99%

“…This chemistry-driven work, using Mtb whole-cell activity as a read-out, resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ [37]. TBAJ-876 ( Figure 1) was selected from this series to progress to pre-clinical development due to its lower lipophilicity, lower hERG ion channel inhibition, higher clearance and retention of BDQ's potent activity against Mtb [37]. The reason for TBAJ-876 s lower lipophilicity is its different structure compared to BDQ.…”

Section: Stalling Of Rotation Of the Mycobacterial F-atp Synthase C-ringmentioning

confidence: 99%

“…TBAJ-876 was discovered through a chemistry-driven approach, using Mtb whole cell activity as readout. This novel BDQ analogue is structurally (Figure 1), as well as physico-chemically [37], distinct from the parental drug. Thus, TBAJ-876 provided an opportunity to revisit the mechanisms of action of BDQ.…”

Section: Insights Into Bdq's Mechanisms Of Action Derived From Tbaj-8mentioning

confidence: 99%

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Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

2019

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Bedaquiline (BDQ) inhibits ATP generation in Mycobacterium tuberculosis by interfering with the F-ATP synthase activity. Two mechanisms of action of BDQ are broadly accepted. A direct mechanism involves BDQ binding to the enzyme's c-ring to block its rotation, thus inhibiting ATP synthesis in the enzyme's catalytic α 3 β 3 -headpiece. An indirect mechanism involves BDQ uncoupling electron transport in the electron transport chain from ATP synthesis at the F-ATP synthase. In a recently uncovered second direct mechanism, BDQ binds to the enzyme's ε-subunit to disrupt its ability to link c-ring rotation to ATP synthesis at the α 3 β 3 -headpiece. However, this mechanism is controversial as the drug's binding affinity for the isolated ε-subunit protein is moderate and spontaneous resistance mutants in the ε-subunit cannot be isolated. Recently, the new, structurally distinct BDQ analogue TBAJ-876 was utilized as a chemical probe to revisit BDQ's mechanisms of action. In this review, we first summarize discoveries on BDQ's mechanisms of action and then describe the new insights derived from the studies of TBAJ-876. The TBAJ-876 investigations confirm the c-ring as a target, while also supporting a functional role for targeting the ε-subunit. Surprisingly, the new findings suggest that the uncoupler mechanism does not play a key role in BDQ's anti-mycobacterial activity.Concentration (MIC) of 0.002-0.013 µg/mL [10,11]). This potent activity holds true in vivo where BDQ has demonstrated accelerated sterilizing activity [12], with four months of BDQ treatment being as efficacious as six months of first-line drug treatment of Mtb-infected mice [13]. Importantly, BDQ also displays bactericidal activity against non-replicating Mtb at therapeutically attainable concentrations [14,15]. In the clinical setting, the usage of BDQ has produced promising results. Studies have shown that the usage of the drug for drug-resistant TB treatment improved sputum conversion and reduced chemotherapy duration and relapse [16][17][18][19]. Hence, new BDQ-containing drug regimens are currently being explored in Phase III clinical trials, such as the STREAM and SimpliciTB trials [20]. One such trial, the Nix-TB trial, resulted in the recent US FDA approval of the BDQ-pretomanid-linezolid six months, all-oral regimen for the treatment of drug-resistant TB [21,22].

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Section: Stalling Of Rotation Of the Mycobacterial F-atp Synthase C-ringmentioning

confidence: 99%

Section: Stalling Of Rotation Of the Mycobacterial F-atp Synthase C-ringmentioning

confidence: 99%

Section: Stalling Of Rotation Of the Mycobacterial F-atp Synthase C-ringmentioning

confidence: 99%

Section: Insights Into Bdq's Mechanisms Of Action Derived From Tbaj-8mentioning

confidence: 99%

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Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

2019

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“…Due to such potential toxicities, the WHO advises caution when using bedaquiline, and recommends that strict monitoring procedures be put in place for patients taking bedaquiline [9].With such limitations present with bedaquiline, the identification of new analogues with similar or better anti-bacterial potency but lower clogP and diminished inhibition of hERG channel activity would be of tremendous interest. In light of this, an exploration of the diarylquinolines to identify improved second generation analogues of bedaquiline was initiated [10][11][12][13][14][15]. After extensive drug discovery efforts, TBAJ-876 2 was selected for preclinical evaluation as a more potent, less lipophilic analogue with lower cardiotoxic potential than bedaqiline 1 (Table 1) [16].…”

mentioning

confidence: 99%

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

et al. 2020

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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.

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Asymmetric Synthesis of Anti‐tuberculosis‐specific Drug TBAJ‐876 through Synergistic Li/Li Catalysis

Gao

Ahmad

et al. 2023

Chin. J. Chem.

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Comprehensive Summary TBAJ‐876, developed by TB Alliance, a novel anti‐tuberculosis‐specific drug, has entered Phase II clinical trials. Herein, the first asymmetric synthesis of TBAJ‐876 has been realized using synergistic Li/Li catalysis with excellent yield of 95% and 88 : 12 er (99.6 : 0.4 er, 10 : 1 dr after simple recrystallization). Furthermore, DFT calculations and 7Li‐NMR analysis illustrated the mechanism of the synergistic reaction: a chiral Li‐complex activates the nucleophile to control the stereoselectivity, while the other achiral Li‐complex activates the electrophile to catalyze the carbonyl addition reaction. Additionally, this protocol has been successfully carried out at 5 gram‐scale, showing its industrial potential.

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

Abstract: Graphical abstract

Cited by 80 publications

References 14 publications

Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

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

Asymmetric Synthesis of Anti‐tuberculosis‐specific Drug TBAJ‐876 through Synergistic Li/Li Catalysis

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