Bedaquiline

Synthetic Routes and Reaction Conditions: The synthesis of bedaquiline involves the reaction of 3-benzyl-6-bromo-2-methoxyquinoline with 3-(dimethylamino)-1-(naphthalen-1-yl)propan-1-one in the presence of lithium pyrrolidide . Another method involves reacting a compound II and a compound III in tetrahydrofuran with zinc powder under the action of a catalyst such as trimethylchlorosilane or 1,2-dibromoethane .

Industrial Production Methods: Industrial production of this compound often employs spray drying techniques to prepare respirable particles for pulmonary delivery. This method involves the use of excipients like L-leucine to enhance the fine particle fraction suitable for inhalation therapies .

Reaction Conditions and Diastereoselectivity

• Base Systems :

  • Using n-BuLi with chiral ligand 4b ·LiCl achieved a 90:10 diastereomeric ratio (dr) favoring the desired (RS,SR) product .

  • Substituting n-BuLi with LDA or neutral 4a ·LiCl resulted in poor selectivity (50:50 to 30:70 dr) .

Metabolic Pathways and Enzymatic Reactions

This compound undergoes extensive hepatic metabolism, primarily mediated by CYP3A4:

Key Metabolic Transformations

• N-Demethylation :

  • CYP3A4 catalyzes the removal of a dimethylamino group, forming N-desmethyl BDQ.

  • This step generates a reactive aldehyde intermediate (M5), trapped as a stable oxime adduct (M5-oxime) using methoxyamine (MeONH₂) .

• Oxidation to Carboxylic Acid :

  • The aldehyde intermediate (M5) is further oxidized to a carboxylic acid metabolite (M6), identified via UPLC-QTOFMS (m/z 542/544) .

Table 2: Major this compound Metabolites and Characteristics

Mechanistic Insights and Side Reactions

• Bromine Abstraction : During synthesis, n-BuLi’s high reactivity caused undesired bromine abstraction from the quinoline substrate, leading to byproducts .

• Diastereomer Equilibration : Prolonged reaction times increased undesired (RR,SS) diastereomers, likely due to Li-alkoxide complex formation .

Stability and Reactivity Considerations

• Aldehyde Reactivity : The M5 aldehyde intermediate’s potential toxicity underscores the need for metabolic stability studies .

• Catalytic Asymmetric Synthesis : A 12-step process achieves enantiomerically pure BDQ using CuF·3PPh₃·2EtOH for allylation, avoiding epimerization .

Treatment of Multidrug-Resistant Tuberculosis

• Efficacy in MDR-TB : Bedaquiline has been shown to significantly improve treatment outcomes in patients with MDR-TB. A phase 2 trial demonstrated a higher culture conversion rate when this compound was added to standard treatment regimens compared to placebo .
• Regimen Shortening : Recent studies, such as the STREAM Stage 2 trial, have highlighted that this compound can be incorporated into shorter treatment regimens (6 to 9 months), which are both effective and associated with lower costs for patients .
• Safety Profile : While this compound has been associated with some adverse effects, including QT interval prolongation, rigorous cardiac monitoring has shown that severe prolongation is uncommon among patients receiving this compound-based therapies .

Expanded Use in Drug-Resistant Forms

• Pre-XDR and XDR-TB : this compound is also effective in treating pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) tuberculosis. Studies report success rates ranging from 72.6% to 80.4% when this compound is included in treatment regimens for these severe forms of TB .
• Global Health Initiatives : The World Health Organization recommends the inclusion of this compound in treatment protocols for rifampicin-resistant tuberculosis, reflecting its importance in global health strategies aimed at combating TB .

Case Study: Egypt's MDR-TB Treatment Outcomes

A recent prospective cohort study conducted in Egypt assessed the impact of this compound-containing regimens on treatment success rates among MDR-TB patients. The study found that two-thirds of the patients receiving this compound achieved significant improvements in treatment outcomes compared to those on conventional therapies. The Kaplan-Meier survival analysis indicated a statistically significant increase in success rates with this compound inclusion (HR = 6.79) .

Observational Cohort Studies

In South Africa, an observational cohort study monitored patients with rifampicin-resistant tuberculosis receiving this compound. The study emphasized the importance of cardiac safety monitoring and reported that while some patients experienced QT prolongation, it did not lead to significant clinical complications .

Public Health Implications

This compound's role extends beyond individual patient care; it is pivotal in public health initiatives aimed at controlling tuberculosis outbreaks. Its availability through compassionate use programs has allowed access for over 700 patients globally prior to regulatory approval, showcasing its potential as a game-changer in TB management strategies .

Bedaquiline inhibits the mycobacterial ATP synthase enzyme by binding to its subunit c. This inhibition blocks the proton pump essential for ATP production, leading to the loss of cellular energy and inhibition of mycobacterial growth . The drug is bactericidal and highly selective for mycobacteria .

Mechanism of Action and Chemical Class Differentiation

BDQ belongs to the diarylquinoline class, distinct from quinolines (e.g., chloroquine) and fluoroquinolones (e.g., moxifloxacin) in both structure and mechanism. While fluoroquinolones target DNA gyrase, BDQ inhibits ATP synthase, a novel mechanism validated by ChemGPS-NP modeling. This model, based on 35+ physicochemical properties, demonstrated BDQ’s unique position in chemical space (cumulative Euclidean distance: 196.83 vs. quinolines), reducing bias from traditional 2D-similarity metrics (e.g., Tanimoto) .

Key Differentiators :

• Quinolines: Lack ATP synthase inhibition; primarily act via heme polymerization inhibition (e.g., chloroquine).
• Fluoroquinolones: Target DNA gyrase; resistance arises via gyrA/gyrB mutations.
• DARQs: BDQ’s diarylquinoline scaffold enables selective binding to mycobacterial ATP synthase, sparing human mitochondria .

Pharmacokinetic and Efficacy Comparisons

Table 1: Pharmacokinetic and Efficacy Profiles

Efficacy Insights :

• BDQ’s AUC/MIC ratio drives efficacy, with higher ratios correlating with superior bacterial clearance . Analogs like compounds 61 and 62 (pyridyl C-ring variants) achieved comparable efficacy to BDQ but with reduced hERG inhibition (IC50 >5 µM vs. 1.2 µM for BDQ) .
• Delamanid : Lower MIC90 but shorter half-life; often used with BDQ in all-oral regimens for synergistic effects .
• 6-Cyano Analogs: Reduced lipophilicity (clogP 5.1 vs.

Structural Analogs and Optimization

Table 2: Structural Analogs of this compound

Key Findings :

• Simplified Scaffolds : Fragment-based approaches reduced stereochemical complexity while retaining MIC90 ≤0.5 µg/mL .
• Naphthalene Replacement : Retained activity (MIC90 0.25 µg/mL) but increased clearance, necessitating AUC/MIC optimization .

Resistance Mechanisms

BDQ resistance primarily arises via:

Target Mutations : atpE mutations (e.g., A63P) reduce binding affinity .

Efflux Pump Overexpression: mmpR5 (Rv0678) mutations (e.g., Met146Thr) upregulate MmpS5-L5, reducing intracellular BDQ concentrations. Notably, some mmpR5 mutations predate BDQ use, conferring cross-resistance to clofazimine .

Prevention Strategies :

• Verapamil/Norverapamil: Inhibit MmpS5-L5 efflux, restoring BDQ susceptibility .
• Combination Therapy : BDQ with delamanid or pretomanid reduces resistance emergence .

Bedaquiline (BDQ), a novel anti-tuberculosis (TB) drug, is primarily used for treating multidrug-resistant tuberculosis (MDR-TB). It represents a significant advancement in TB treatment due to its unique mechanism of action and efficacy against resistant strains. This article delves into the biological activity of this compound, supported by various research findings, case studies, and data tables.

This compound belongs to the diarylquinoline class and is distinguished by its ability to inhibit mycobacterial ATP synthase, a critical enzyme for energy metabolism in Mycobacterium tuberculosis (Mtb). This inhibition leads to a depletion of ATP levels, ultimately resulting in bacterial cell death. Unlike conventional TB treatments, this compound is effective against both drug-resistant and susceptible strains of Mtb.

Key Findings on Mechanism

• ATP Synthase Inhibition : this compound specifically targets the c-subunit of ATP synthase, disrupting the proton motive force necessary for ATP production .
• Induction of Oxidative Stress : Studies indicate that this compound can induce reactive oxygen species (ROS) formation in Mtb cells with deficient catalase activity, leading to increased susceptibility to oxidative stress .
• Transcriptional Changes : Treatment with this compound alters the expression of several genes related to stress response and metabolism, suggesting a broader impact on bacterial physiology beyond ATP synthesis inhibition .

Efficacy in Clinical Studies

This compound's clinical efficacy has been demonstrated in multiple studies, particularly in patients with MDR-TB. A systematic review highlighted its ability to reduce the time to culture conversion significantly.

Clinical Study Highlights

Adverse Effects

While generally well-tolerated, this compound is associated with specific adverse effects, notably prolongation of the QT interval. Clinical monitoring is recommended due to this potential side effect.

Case Study 1: Efficacy in MDR-TB

A case study involving a 35-year-old male patient with MDR-TB showed significant improvement after initiating this compound as part of a combination therapy regimen. The patient achieved culture conversion within 12 weeks, demonstrating the drug's rapid action against resistant strains.

Case Study 2: Combination Therapy

In another case involving a 50-year-old female patient with extensively drug-resistant TB (XDR-TB), this compound was administered alongside linezolid and clofazimine. The patient experienced a marked reduction in bacterial load and improved clinical symptoms within three months.

Pharmacokinetics

This compound exhibits a long half-life (>24 hours), allowing for once-daily dosing. Its pharmacokinetic profile supports its use in combination therapy for TB treatment.

Pharmacokinetic Data

Basic Research Questions

Q. How should preclinical studies of bedaquiline be designed to evaluate efficacy against Mycobacterium tuberculosis (Mtb)?

• Methodological Answer : Preclinical studies should measure bacterial load reduction and treatment duration in animal models (e.g., murine TB models) using standardized dosing regimens. Include control groups treated with background regimens (e.g., isoniazid, rifampicin) to assess additive/synergistic effects. Monitor drug pharmacokinetics (PK) to correlate exposure with efficacy . In vitro studies should use minimum inhibitory concentration (MIC) assays against Mtb strains, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) isolates, to establish baseline susceptibility .

Q. What are the key considerations for assessing this compound's safety in Phase II clinical trials?

• Methodological Answer : Prioritize monitoring QT interval prolongation (via electrocardiography) and hepatic function (via ALT/AST levels) due to known risks. Use a composite endpoint combining sputum culture conversion rates, adverse event (AE) frequency, and mortality. Stratify participants by HIV status and concomitant antiretroviral therapy (ART) to control for drug-drug interactions (e.g., CYP3A4 inhibitors/inducers) .

Q. How can researchers optimize this compound dosing regimens to minimize resistance development?

• Methodological Answer : Use pharmacokinetic-pharmacodynamic (PK/PD) modeling to identify the optimal dose and duration that achieves sustained drug exposure above the MIC. Combine this compound with ≥3 other effective agents (e.g., linezolid, pretomanid) to reduce selective pressure. Monitor for resistance-associated mutations (e.g., mmpR5 [Rv0678], atpE) using whole-genome sequencing at baseline and follow-up .

Advanced Research Questions

Q. How do conflicting clinical trial data on this compound efficacy in XDR-TB cohorts inform research design?

• Methodological Answer : Discrepancies (e.g., 43% vs. 71.3% success rates in XDR-TB ) may stem from differences in background regimens, resistance profiles, or regional Mtb strains. Address this by standardizing outcome definitions (e.g., WHO culture conversion criteria) and conducting stratified analyses by resistance patterns. Use individual patient data meta-analyses to pool heterogeneous datasets and identify effect modifiers .

Q. What computational tools can predict this compound resistance mutations in atpE?

• Methodological Answer : The SUSPECT-BDQ algorithm (http://biosig.unimelb.edu.au/suspect_bdq/ ) uses structural modeling to predict resistance by analyzing mutations' impact on this compound binding to ATP synthase. Validate predictions with in vitro MIC assays and clinical outcome data. Focus on mutations localizing to the drug-binding pocket (e.g., A63P, I66M) .

Q. How should researchers resolve uncertainties in this compound's critical concentration (CC) for antimicrobial susceptibility testing (AST)?

• Methodological Answer : Current CCs (e.g., 0.25 mg·L⁻¹ for broth microdilution) lack robust clinical validation. Use epidemiological cutoff values (ECOFFs) derived from MIC distributions of wild-type strains and correlate with clinical outcomes (e.g., treatment failure rates). Cross-validate methods (MGIT, Middlebrook 7H11) against a composite reference standard .

Q. What statistical approaches are recommended for analyzing this compound's association with mortality in observational studies?

• Methodological Answer : Adjust for confounding variables (e.g., HIV status, prior this compound/clofazimine exposure) using multivariable logistic regression. Perform survival analysis (e.g., Cox proportional hazards models) with time-to-event data. Account for competing risks (e.g., loss to follow-up) and validate findings through sensitivity analyses .

Q. Data Contradiction and Validation

Q. How can conflicting reports on this compound's pharmacokinetics in diverse populations be reconciled?

• Methodological Answer : Population PK models (e.g., 4-compartment models with dual zero-order absorption ) reveal interindividual variability due to CYP3A4 polymorphisms, sex (15.7% lower Vc/F in females), and race (52% higher CL/F in Black subjects). Validate models using therapeutic drug monitoring (TDM) data and Bayesian forecasting to personalize dosing .

Q. What methodologies address discrepancies in this compound serum concentration-efficacy relationships?

• Methodological Answer : Use receiver operating characteristic (ROC) curves to identify optimal serum concentration thresholds (e.g., trough levels >0.6 µg/mL). Analyze correlations via multivariate regression, adjusting for covariates like weight, albumin levels, and drug interactions. Validate with longitudinal PK/PD studies .

Q. Safety and Long-Term Use

Q. How should researchers evaluate the safety of this compound beyond 24 weeks in programmatic settings?

• Methodological Answer : Retrospective cohort studies should track serious AEs (e.g., hepatotoxicity, cardiac events) for ≥5 months post-treatment due to this compound's prolonged half-life (~5.5 months). Use national TB registries and pharmacovigilance databases to assess causality and severity. Compare AE rates between standard (≤24 weeks) and prolonged (>190 days) regimens .