Levofloxacin

Core Synthetic Routes for Levofloxacin Production

Nucleophilic Displacement with N-Methyl Piperazine

The primary synthesis route involves reacting (S)-(-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]benzoxazine-6-carboxylic acid (Compound I) with N-methyl piperazine. Patent EP1451194B2 details two optimized protocols:

Method A :

• Conditions : Reflux (110–120°C) for 40 minutes in N-methyl piperazine solvent.
• Workup : Cooling to 80°C, addition of isopropyl alcohol (IPA) and n-heptane, filtration, and drying.
• Yield : 76% (4.9 g from 5 g starting material).

Method B :

• Conditions : 110°C for 1.5 hours in dimethylacetamide (DMA) with N-methyl piperazine.
• Workup : Slurrying in IPA at ambient temperature, filtration, and vacuum drying.
• Yield : 89.3% (11.48 g from 10 g starting material).

These methods highlight the trade-off between solvent choice and yield. DMA-based reactions achieve higher yields but require stringent solvent removal.

Alternative Route via Intermediate Alkylation

CN1594320A describes a two-step process using compound (V) and L-aminopropanol:

• Alkylation : Reacting compound (V) with L-aminopropanol in DMF at 60–70°C for 3 hours.
• Piperazine Substitution : Adding N-methyl piperazine at 70–80°C, followed by cyclization at 120–130°C.

• Yield : 57.9% for intermediate (IX); 92.3% after hydrolysis.

This route reduces side reactions but involves energy-intensive high-temperature steps.

Table 1: Comparison of this compound Synthesis Methods

*Yield for intermediate; final hydrolysis yield reaches 92.3%.

Solid-State Transformations and Polymorph Control

Mechanochemical Amorphization

Ball milling induces phase transitions in this compound hemihydrate (LVXh):

• Pathway : LVXh → γ-anhydrate (LVXγ) → amorphous (LVXam).
• Conditions : 30 Hz frequency, stainless steel jars, 4 mm balls.
• Kinetics : LVXγ forms within 15 minutes; complete amorphization after 2 hours.

Spray Drying for Amorphous Form

Spray drying aqueous LVXh solutions produces LVXam with:

• Glass Transition Temperature (Tg) : 80°C.
• Stability : Recrystallizes to LVXh at 75% relative humidity.

Table 2: Polymorph Preparation Methods

Impurity Profiling and Mitigation Strategies

Major Process-Related Impurities

HPLC analysis identifies three critical impurities in this compound batches:

• Imp-1 (0.1–0.3%) : Dimer from elimination of HF during cyclization.
• Imp-2 (0.1–0.3%) : Oxidative degradation product with opened piperazine ring.
• Imp-3 (0.1–0.3%) : N-demethylated analog.

Formation Pathways

• Imp-1 : Dimerization of intermediate (II) during fluorination.
• Imp-2 : Ring-opening of this compound followed by re-cyclization.
• Mitigation : Controlled reaction temperatures (<80°C) and inert atmospheres reduce oxidation.

Derivative Synthesis and Modifications

Peptide Conjugates

Solid-phase peptide synthesis attaches this compound to cyclic peptides (e.g., [R4W4K]):

• Method : Fmoc/tBu chemistry on 2-chlorotrityl resin.
• Yield : 31–45% after HPLC purification.
• Activity : Conjugation reduces antibacterial efficacy by 4–8× compared to parent drug.

Thienylethyl Derivatives

Introducing 5-chlorothiophen-2-yl groups enhances lipophilicity:

• Synthesis : Piperazine substitution with 2-(5-chlorothiophen-2-yl)-2-oxoethyl groups.
• Characterization : IR 1721 cm⁻¹ (C=O stretch); 1H-NMR δ 7.53 (thiophene-H).

Industrial-Scale Optimization

Solvent Recovery Systems

• N-Methyl Piperazine Recycling : Distillation under reduced pressure recovers >90% solvent.
• DMF Replacement : Isoamyl alcohol reduces toxicity in alkylation steps.

Crystallization Control

• Seeding : LVXh seeds added at 80°C ensure uniform crystal growth.
• Antisolvent Use : n-Heptane precipitates >95% pure product.

Types of Reactions

Levofloxacin undergoes various chemical reactions, including:

Oxidation: This compound can be oxidized under certain conditions, leading to the formation of different metabolites.

Reduction: Reduction reactions can alter the functional groups in this compound, affecting its activity.

Substitution: This compound can undergo substitution reactions, particularly with metal ions, forming stable coordination compounds.

Common Reagents and Conditions

Common reagents used in the reactions involving this compound include oxidizing agents, reducing agents, and metal ions such as aluminum, copper, and zinc . The reaction conditions vary depending on the desired outcome but often involve controlled temperatures and pH levels .

Major Products

The major products formed from these reactions include various metabolites and coordination compounds, which can have different pharmacological properties compared to the parent compound .

Respiratory Infections

Levofloxacin has demonstrated significant efficacy in treating community-acquired pneumonia (CAP). A meta-analysis showed that this compound monotherapy achieved a clinical success rate of 95% in treating CAP caused by various pathogens, including macrolide-resistant strains of Streptococcus pneumoniae .

Table 1: Efficacy of this compound in CAP Trials

Urinary Tract Infections

In the treatment of urinary tract infections (UTIs), this compound has been shown to be more effective than ciprofloxacin, particularly in cases caused by Escherichia coli .

Table 2: Comparison of this compound and Ciprofloxacin in UTI Treatment

Chronic Bacterial Prostatitis

A study involving patients with chronic bacterial prostatitis indicated that this compound was superior to ciprofloxacin, with a notable improvement in symptoms and eradication rates of the pathogen .

Skin and Soft Tissue Infections

In a clinical trial assessing this compound’s effectiveness for skin infections, it was found to have a comparable success rate to other standard treatments while reducing hospital stay duration significantly .

Safety Profile and Adverse Effects

While this compound is generally well-tolerated, it is associated with potential adverse effects such as:

• Tendinitis and tendon rupture
• Peripheral neuropathy
• Central nervous system effects

Due to these risks, its use is recommended primarily when alternative treatments are not available .

Levofloxacin exerts its antimicrobial effects by inhibiting two key bacterial enzymes: DNA gyrase and topoisomerase IV . These enzymes are essential for bacterial DNA replication, transcription, and repair. By inhibiting these enzymes, this compound prevents the bacteria from replicating and ultimately leads to bacterial cell death .

Comparison with Other Fluoroquinolones

Structural and Stability Comparisons

Levofloxacin shares a core quinolone structure with other fluoroquinolones like ofloxacin, norfloxacin, and moxifloxacin. Key differences include:

• Ofloxacin : this compound is the L-isomer of ofloxacin, which exists as a racemic mixture. The L-isomer confers superior antibacterial activity due to enhanced DNA gyrase inhibition .
• Stability: Under forced degradation conditions (e.g., acidic, alkaline, oxidative), this compound degrades more slowly than norfloxacin and at rates comparable to moxifloxacin (Table 9) .
• Spectroscopic Properties : Thionated this compound (a derivative) exhibits distinct absorption at λmax = 404 nm, absent in the parent compound, enabling analytical differentiation (Figure 5) .

Pharmacokinetic and Pharmacodynamic Profiles

• QTc Effects : Moxifloxacin causes greater QTc interval prolongation than this compound, particularly in women due to higher plasma concentrations .
• Tissue Penetration : this compound achieves higher lung tissue concentrations than ciprofloxacin, making it preferable for respiratory infections .

Antimicrobial Resistance Patterns

• Mycoplasma catarrhalis: this compound susceptibility declined from 100% (2009–11) to 91.3% (2013–14) using EUCAST criteria, mirroring trends seen with other fluoroquinolones .
• Resistance Mitigation: Combining this compound with daptomycin reduces resistance development in Staphylococcus aureus by 50% compared to monotherapy .

Analytical Methods for Quantification

• HPLC-UV: Simultaneous quantification of this compound, norfloxacin, and moxifloxacin in plasma shows high sensitivity (LOD: 2 µg/mL) and precision (<13% variability) .
• Chromatographic Separation : this compound and ciprofloxacin, with similar pKa (6.05–6.09), require optimized mobile phases for resolution, whereas moxifloxacin (pKa 6.4) is more separable .

Role in Combination Therapies

• Synergy with Daptomycin : In meningitis models, this compound combined with daptomycin increased bactericidal activity by 30% and reduced relapse rates .
• Gemcitabine/Nab-Paclitaxel : Preclinical studies suggest this compound enhances antitumor efficacy in pancreatic cancer, though clinical data remain preliminary .

Structural Modifications and Derivatives

• Thionated this compound : Replacing the carbonyl group with thiocarbonyl alters absorption spectra (λmax shift to 404 nm), enabling analytical detection without interference from the parent compound .

Special Populations and Pharmacokinetic Considerations

• Obese Patients : this compound clearance varies in obese adults, but pediatric data are lacking .
• Age-Dependent Clearance : Children under 5 eliminate this compound twice as fast as adults, requiring adjusted dosing .

Levofloxacin is a fluoroquinolone antibiotic widely used for treating various bacterial infections. Its biological activity encompasses a range of mechanisms, efficacy against different pathogens, and implications for clinical use. This article provides a comprehensive overview of the biological activity of this compound, including data tables, case studies, and detailed research findings.

This compound exerts its antibacterial effects primarily through the inhibition of bacterial DNA gyrase and topoisomerase IV, essential enzymes for DNA replication and transcription. This inhibition leads to the disruption of bacterial cell division and ultimately results in cell death. The drug is particularly effective against both Gram-positive and Gram-negative bacteria.

Efficacy Against Bacterial Strains

This compound has demonstrated significant antibacterial activity against a variety of pathogens. The following table summarizes its comparative efficacy against selected bacteria:

Case Study: Efficacy in Community-Acquired Pneumonia (CAP)

A study comparing this compound with ceftriaxone in patients with CAP showed that this compound had a clinical success rate of 96% compared to 90% for ceftriaxone. Bacteriologic eradication was achieved in 98% of cases treated with this compound versus 85% with ceftriaxone, indicating a statistically significant advantage for this compound in this context .

Retrospective Study: Safety and Efficacy in Children

A recent retrospective study involving children with serious infections highlighted that this compound treatment led to a decrease in inflammatory markers such as white blood cell count (WBC) and C-reactive protein (CRP) in approximately 50% and 46% of cases, respectively. This suggests that this compound is effective not only in eradicating infections but also in reducing systemic inflammation .

Comparative Analysis with Other Antibiotics

This compound has been compared with other antibiotics in various studies. A systematic review indicated that while this compound is generally more effective than ciprofloxacin, the difference was not statistically significant across all studies analyzed .

Pharmacokinetics

This compound exhibits favorable pharmacokinetic properties, including good oral bioavailability and tissue penetration. It achieves higher concentrations in serum and tissues compared to ciprofloxacin, enhancing its efficacy against systemic infections .

Adverse Effects and Considerations

Despite its effectiveness, this compound is associated with certain adverse effects, including potential tendon ruptures and neuropsychiatric events. A case report documented a patient developing psychosis after taking this compound for cystitis, illustrating the need for careful monitoring during treatment .

Basic Research Questions

Q. What analytical methods are recommended for quantifying levofloxacin in pharmaceutical formulations, and how do their accuracies compare?

• Methodology : High-performance liquid chromatography (HPLC) and UV-spectrophotometry are widely used. HPLC offers higher specificity and sensitivity (e.g., detection limits of 0.1 µg/mL) due to its ability to separate complex matrices, while UV-spectrophotometry is cost-effective but less precise in multi-component systems . For method optimization, Box-Behnken designs can evaluate factors like pH, flow rate, and column temperature to balance resolution and runtime .

Q. How do physicochemical properties (e.g., solubility, stability) influence this compound’s experimental design in aqueous systems?

• Methodology : this compound’s low water solubility (data not fully reported) and stability at pH 4–6 require pre-formulation studies using techniques like shake-flask solubility assays and accelerated stability testing (e.g., 40°C/75% RH for 6 months). Adsorption studies using chitosan–walnut shell composites highlight pH-dependent removal efficiency, with optimal adsorption at pH 5–7 .

Q. What are the standard protocols for evaluating this compound’s adsorption efficiency in environmental decontamination studies?

• Methodology : Central Composite Design (CCD) with factors like adsorbent dose, pH, and initial concentration is used to model removal efficiency. Nonlinear kinetic models (e.g., pseudo-second-order) and isotherm analyses (Freundlich/Langmuir) validate adsorption mechanisms. Residual analysis (e.g., externally studentized residuals) ensures model reliability .

Advanced Research Questions

Q. How can response surface methodology (RSM) optimize this compound degradation in photocatalytic systems?

• Methodology : Ternary heterojunction catalysts (e.g., BPQDs/Au/TiO₂) are tested using RSM to maximize degradation efficiency (93.7% in 60 minutes). Factors like catalyst loading, light intensity, and pH are modeled, with degradation pathways inferred via LC-MS and density functional theory (DFT) calculations .

Q. What pharmacokinetic/pharmacodynamic (PK/PD) models predict this compound’s efficacy against Streptococcus pneumoniae?

• Methodology : Monte Carlo simulations assess target attainment (PTA) for PK/PD indices (fAUC/MIC ≥30; fCmax/MIC ≥5). Free drug fractions (0.7) and MIC distributions from clinical isolates are incorporated. Limited sampling strategies (e.g., 2- and 6-hour post-dose) reduce AUC estimation errors (R² = 0.96 with Bayesian methods) .

Q. How do combination therapies (e.g., this compound + cefixime) improve clinical outcomes in pneumonia treatment?

• Methodology : Randomized controlled trials (RCTs) compare monotherapy (84.91% efficacy) versus combination therapy (96.23%) using endpoints like symptom resolution and microbiological eradication. Stratified analysis controls for variables like disease severity and antibiotic resistance profiles .

Q. What statistical approaches resolve contradictions in meta-analyses comparing fluoroquinolone efficacies for urinary tract infections?

• Methodology : Cochrane risk-of-bias tools assess RCT quality. Fixed-effects models calculate pooled odds ratios, with subgroup analyses for dosing regimens (e.g., oral vs. IV). Sensitivity analyses exclude outliers to address heterogeneity, revealing moxifloxacin’s lower efficacy vs. This compound (P < 0.05) .

Q. How are experimental designs adapted for this compound’s bio-analytical method development under regulatory constraints?

• Methodology : Box-Behnken designs optimize HPLC parameters (e.g., pH 4.5, 0.93 mL/min flow rate) while adhering to ICH guidelines. Validation includes precision (RSD <2%), accuracy (recovery 98–102%), and robustness testing across column batches .

Q. Methodological Notes

• Experimental Design : Use CCD or Box-Behnken designs to minimize runs while capturing interactions between variables .
• Data Validation : Employ residual plots and Cook’s distance to detect outliers in adsorption or degradation studies .
• PK/PD Simulations : Leverage logarithmic-normal distributions for AUC/MIC simulations in 5,000-patient cohorts to ensure clinical relevance .
• Meta-Analysis Protocols : Follow PRISMA guidelines for literature screening and use Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for evidence quality .