Delamanid

合成路线和反应条件： 德拉曼尼德是通过多步合成工艺制备的，该工艺涉及形成咪唑并恶唑核心，然后引入各种官能团。主要步骤包括：

• 形成咪唑并恶唑环。
• 引入硝基。
• 连接三氟甲氧基苯氧基和哌啶基苯氧基。

工业生产方法： 德拉曼尼德的工业生产涉及使用优化的反应条件进行大规模合成，以确保高产率和纯度。该过程包括：

• 使用高压均质进行乳化。
• 喷雾干燥形成干燥粉末。
• 通过纳米包封确保稳定性，以提高水溶解动力学 .

反应类型： 德拉曼尼德会经历各种化学反应，包括：

还原： 硝基被还原为胺。

氧化： 咪唑并恶唑环可以在特定条件下进行氧化。

取代： 咪唑并恶唑环上的官能团可以被其他基团取代。

常用试剂和条件：

还原： 使用钯碳催化加氢。

氧化： 使用高锰酸钾等氧化剂。

取代： 使用适当亲核试剂的亲核取代反应。

主要产物：

• 硝基的还原导致形成胺衍生物。
• 咪唑并恶唑环的氧化可以产生各种氧化衍生物。
• 取代反应会生成各种取代的咪唑并恶唑化合物 .

德拉曼尼德具有广泛的科学研究应用，包括：

化学： 用作研究硝基咪唑衍生物的模型化合物。

生物学： 研究其对结核分枝杆菌和其他细菌菌株的影响。

医学： 主要用于治疗多重耐药结核病。 .

工业： 用于开发新的抗结核药物和制剂.

德拉曼尼德通过抑制甲氧基和酮基分枝菌酸的合成发挥作用，而分枝菌酸是分枝杆菌细胞壁的重要组成部分。它是一种前药，需要由分枝杆菌 F420 辅酶系统（包括脱氮黄素依赖性硝基还原酶）激活。 这种活化会导致活性氮物种的产生，从而破坏分枝菌酸的合成，最终杀死细菌 .

类似化合物：

普雷托曼尼德： 另一种用于治疗结核病的硝基咪唑衍生物。

异烟肼： 一种一线抗结核药物，抑制分枝菌酸合成。

利福平： 一种抑制细菌 RNA 合成的抗生素。

比较：

德拉曼尼德与普雷托曼尼德： 与普雷托曼尼德相比，德拉曼尼德在体外对多重耐药性和广泛耐药性结核菌株表现出更高的效力.

德拉曼尼德与异烟肼： 虽然两者都抑制分枝菌酸合成，但德拉曼尼德具有独特的机制，涉及 F420 辅酶系统。

德拉曼尼德与利福平： 德拉曼尼德靶向分枝菌酸合成，而利福平抑制 RNA 合成，使它们在联合治疗中具有互补性

德拉曼尼德独特的作用机制及其对耐药菌株的有效性使其成为抗结核药物库中的宝贵补充。

Delamanid vs. Pretomanid (PA-824)

Mechanistic Similarities :
Both are nitroimidazoles derived from Streptomyces eurocidicus, targeting mycolic acid synthesis and inducing respiratory toxicity via nitric oxide release .

Key Differences :

Research Findings :

• Preclinical studies identified shared resistance mutations (e.g., fbiA, fgd), but clinical isolates show divergent susceptibility profiles .
• Pretomanid exhibits broader anti-mycobacterial activity, including non-replicating bacilli, while this compound excels in tissue penetration .

This compound vs. Bedaquiline

Mechanistic Contrast :

• This compound : Inhibits cell wall synthesis.
• Bedaquiline : Targets ATP synthase, disrupting bacterial energy metabolism .

Clinical Outcomes :

Combination Therapy :

• Co-administration with bedaquiline achieves sputum culture conversion (SCC) rates of 74–100% at 6 months .
• Pharmacodynamic models suggest additive effects without competitive interactions .

Cross-Resistance and Pharmacokinetic Challenges

Cross-Resistance :

• Preclinical models show high cross-resistance between this compound and pretomanid (23/32 isolates) due to shared metabolic activation pathways (fbiA, ddn mutations) .
• Clinical isolates exhibit lower overlap (2/12 resistant to both), suggesting divergent resistance mechanisms in humans .

Table 1: Clinical Trial Outcomes

Table 2: Pharmacokinetic Comparison

Delamanid, a novel compound from the nitro-dihydro-imidazooxazole class, has emerged as a significant agent in the fight against multidrug-resistant tuberculosis (MDR-TB). Its unique mechanism of action, coupled with potent biological activity against various strains of Mycobacterium tuberculosis (MTB), positions it as a valuable addition to existing tuberculosis therapies.

This compound primarily functions by inhibiting the synthesis of mycolic acids, crucial components of the mycobacterial cell wall. This inhibition is mediated through the activation of this compound by the enzyme deazaflavin-dependent nitroreductase (Ddn), which facilitates its conversion into a reactive intermediate that disrupts mycolic acid production .

Key Mechanistic Insights:

• Pro-drug Activation : this compound is a pro-drug that requires metabolic activation by Ddn, which is specific to mycobacteria and not present in human cells, thereby minimizing potential toxicity .
• Inhibition of Mycolic Acid Synthesis : The drug targets methoxy-mycolic and keto-mycolic acid synthesis pathways, critical for mycobacterial cell wall integrity .
• Selective Activity : The selective activation mechanism helps explain this compound's efficacy against mycobacteria while avoiding genotoxic effects in humans .

In Vitro Studies

This compound has demonstrated potent antibacterial activity in vitro against both drug-susceptible and drug-resistant strains of MTB. The minimum inhibitory concentration (MIC) ranges from 0.006 to 0.024 μg/ml, indicating high potency . Notably, studies reveal:

• No Cross-Resistance : this compound does not exhibit cross-resistance with first-line anti-TB drugs such as rifampicin and isoniazid, making it an effective option for patients who have failed previous treatments .
• Post-Antibiotic Effect : It shows a significant post-antibiotic effect on intracellular organisms after pulsed therapy, comparable to rifampicin .

Clinical Trials

Clinical investigations have confirmed this compound's efficacy in real-world settings:

• Early Bactericidal Activity : A study involving smear-positive TB patients showed that this compound significantly reduced colony-forming units (CFUs) over a 14-day treatment period, with higher doses correlating with greater reductions .
• Randomized Trials : In a placebo-controlled trial on MDR-TB patients, this compound combined with an optimized background regimen resulted in higher sputum culture conversion rates compared to placebo .

Case Studies

A review of clinical outcomes indicated that treatment with this compound for six months led to improved patient outcomes and reduced mortality rates among MDR-TB patients .

Summary of Research Findings

Resistance Mechanisms

Despite its effectiveness, resistance to this compound can occur. Mutations in coenzyme F420 genes have been implicated as mechanisms for resistance in mycobacteria . Understanding these resistance pathways is crucial for developing strategies to mitigate treatment failures.

Basic Research Questions

Q. What is the molecular mechanism of Delamanid’s antimycobacterial activity, and how can this inform experimental design?

this compound inhibits mycolic acid synthesis by targeting the F420-dependent deazaflavin nitroreductase (Ddn) system in Mycobacterium tuberculosis (Mtb), disrupting cell wall integrity . To validate this mechanism experimentally:

• Use in vitro assays with F420-deficient Mtb strains to confirm target specificity.
• Combine lipidomic profiling (e.g., HPLC) to quantify mycolic acid inhibition .
• Reference clinical pharmacokinetic data (e.g., protein binding >99%, half-life 30–38 hours) to optimize dosing in animal models .

Q. How should researchers design studies to evaluate this compound’s efficacy in multidrug-resistant TB (MDR-TB) patients?

• Cohort selection : Prioritize participants with baseline sputum culture positivity and documented MDR/RR-TB resistance, excluding those with concurrent CYP3A4 inducer use (e.g., rifampicin) to avoid pharmacokinetic interference .
• Outcome metrics : Use two consecutive negative cultures ≥15 days apart as the primary endpoint for culture conversion .
• Control for confounders : Adjust for variables like prior TB drug exposure, comorbidities, and regimen changes using inverse probability weighting .

Q. What are the key considerations for interpreting this compound’s clinical trial data, particularly conflicting results on culture conversion?

• Example : In the endTB cohort, adding this compound to 3-drug regimens did not significantly improve 2-month culture conversion (49.6% vs. 55.6% in controls) but reduced mortality with prolonged use .
• Methodological resolution : Conduct time-to-event analysis to assess delayed conversion and stratify by treatment duration (e.g., ≥6 months vs. shorter courses) .

Advanced Research Questions

Q. How can this compound’s pharmacokinetic variability be addressed in preclinical-to-clinical translation?

• Challenge : this compound’s absorption increases 3-fold with high-fat meals, complicating dosing consistency .
• Solutions :

• Standardize fed/fasted conditions in animal studies and correlate with plasma exposure (AUC/MIC ratios).
• Use physiologically based pharmacokinetic (PBPK) modeling to predict human outcomes from nonclinical data .

Q. What experimental strategies can elucidate this compound’s resistance mechanisms?

• Hypothesis : Mutations in F420 biosynthetic genes (e.g., fgd, fbiA) reduce prodrug activation .
• Methods :

• Perform whole-genome sequencing of post-treatment Mtb isolates to identify resistance-associated variants.
• Validate using in vitro susceptibility testing with isogenic mutant strains .

Q. How should researchers evaluate this compound’s synergy with other anti-TB drugs in combination regimens?

• Approach :

• Use checkerboard assays or time-kill curves to quantify synergy with bedaquiline, linezolid, or pretomanid .
• Monitor for QT prolongation when combining with other CYP3A4-metabolized drugs (e.g., clofazimine) via electrocardiogram in phase II trials .

Q. How can contradictory findings on this compound’s efficacy be resolved in meta-analyses?

• Case : Early studies reported 70–95% culture conversion with this compound, while later trials showed marginal benefits .
• Resolution :

• Apply GRADE criteria to assess bias risk, heterogeneity, and publication bias.
• Perform subgroup analyses by region (e.g., high vs. low TB burden) and resistance profiles .

Q. Methodological Rigor and Reproducibility

Q. What steps ensure reproducibility in this compound-related studies?

• Data transparency : Publish raw culture conversion timelines and regimen adjustments in supplementary materials .
• Protocol adherence : Follow WHO guidelines for MDR-TB treatment duration and outcome definitions (e.g., "cured" vs. "completed") .
• Statistical rigor : Pre-specify endpoints and adjust for immortal time bias in observational studies using Cox models .

Q. How can researchers adapt preclinical models for this compound’s extrapulmonary TB applications?

• Model selection : Use murine or rabbit models of TB meningitis or osteomyelitis to assess blood-brain barrier penetration .
• Metrics : Compare this compound concentrations in infected tissues (e.g., lymph nodes) via LC-MS/MS .

Q. Tables for Key Data

Table 1. This compound Pharmacokinetic Parameters

Table 2. Clinical Outcomes from Key this compound Studies