Synthetic Routes and Reaction Conditions

The synthesis of oseltamivir is complex due to its three contiguous chiral centers. One of the initial scalable routes to this compound started from shikimic acid, a natural product . The process involves multiple steps, including protection and deprotection of functional groups, formation of the cyclohexene ring, and introduction of the amino and acetamido groups .

Industrial Production Methods

Industrial production of this compound often involves biocatalytic methods due to their mild, highly selective, and environmentally benign nature . For example, the use of enzymes in the asymmetric synthesis of amino acid components and the fermentative production of structurally complex intermediates are common . Another method involves the use of organic solvents and catalysts like Lindlar catalyst under specific conditions to achieve high yields .

Types of Reactions

Oseltamivir undergoes various chemical reactions, including:

Oxidation: Conversion of the hydroxyl group to a carbonyl group.

Reduction: Reduction of the azido group to an amino group.

Substitution: Introduction of functional groups like acetamido and amino groups.

Common Reagents and Conditions

Common reagents used in these reactions include hydrogen gas, Lindlar catalyst, and organic solvents like methanol and acetone . Reaction conditions often involve specific temperatures and pressures to ensure high yields and purity .

Major Products

The major products formed from these reactions include this compound carboxylate, which is the active metabolite of this compound .

Oseltamivir has a wide range of scientific research applications:

Chemistry: Used as a model compound in the study of chiral synthesis and biocatalysis.

Biology: Studied for its interactions with viral proteins and its role in inhibiting viral replication.

Medicine: Widely used in the treatment and prevention of influenza.

Industry: Employed in the large-scale production of antiviral medications.

Oseltamivir exerts its antiviral activity by inhibiting the activity of the viral neuraminidase enzyme found on the surface of the virus . This inhibition prevents the release of new viral particles from infected cells, thereby reducing the spread of the virus within the body . The drug is a prodrug, which means it is converted into its active form, this compound carboxylate, by hepatic esterases .

Comparison with Similar Compounds

Zanamivir

Zanamivir, the first NA inhibitor, shares a similar mechanism but differs in administration (inhaled vs. oral) and pharmacokinetics. While both target the NA active site, zanamivir exhibits lower oral bioavailability (3.95% intestinal absorption) compared to oseltamivir (79.33%) . Structural analyses reveal that zanamivir and this compound carboxylate bind to the sialic acid cavity of H5N2 NA with comparable hydrogen bond interactions and binding energies (Table 1) . However, zanamivir’s polar structure limits its use in patients with respiratory complications.

Peramivir

Peramivir (RWJ-270201), an intravenous NA inhibitor, shows efficacy equivalent to oral this compound in meta-analyses, particularly in severe influenza cases . A randomized trial reported a median time to symptom alleviation of 59.1 hours for peramivir vs. 60.0 hours for this compound (p=0.94) . Its intravenous route offers advantages for hospitalized patients but lacks the convenience of oral dosing.

Laninamivir

Laninamivir octanoate, a long-acting inhaled NA inhibitor, demonstrated comparable clinical outcomes to this compound in patients with chronic respiratory diseases. Both drugs showed similar rates of influenza-associated complications (16.7% vs. 18.2%) and underlying disease exacerbation (3.0% vs. 3.1%) . Its single-dose regimen improves adherence but requires functional inhalation capacity.

Baloxavir Marboxil

Baloxavir, a cap-dependent endonuclease inhibitor, outperforms this compound in symptom resolution (median difference: -12.6 hours) in a 2023 meta-analysis . However, both drugs share similar safety profiles, with adverse event rates of 22.3% (baloxavir) vs. 23.1% (this compound). Baloxavir’s novel mechanism reduces NA inhibitor resistance concerns but faces limitations in immunocompromised populations.

Structural Analogues and Novel Compounds

Screening of 131 NA inhibitors identified 77 compounds with >80% 3D structural similarity to this compound, including A-315675 and NH2-sulfonyl derivatives . Docking studies revealed that these analogues bind to NA with hydrogen bond lengths of 2.8–3.2 Å, comparable to this compound carboxylate (2.9 Å) . However, their clinical efficacy remains under investigation.

Key Comparative Data

Table 1: Binding Energies and Interactions of NA Inhibitors (H5N2)

Table 2: Pharmacokinetic and Clinical Profile Comparison

*Estimated from historical data.

Resistance and Cost-Effectiveness

USA) . Cost-effectiveness analyses in China show an incremental cost-effectiveness ratio (ICER) of $1,200/QALY for empiric this compound vs. Comparatively, baloxavir’s ICER remains under evaluation but may offset costs through shorter treatment duration.

3-Butoxypropylamine, also known by its synonyms such as γ-Butoxypropylamine and 3-(n-Butoxy)propylamine, is an organic compound with the molecular formula C₇H₁₇NO. This compound has garnered attention for its potential biological activities, particularly in the fields of pharmacology and medicinal chemistry. This article aims to provide a comprehensive overview of the biological activity associated with 3-Butoxypropylamine, supported by data tables, case studies, and detailed research findings.

• Molecular Formula : C₇H₁₇NO
• Molecular Weight : 129.22 g/mol
• Boiling Point : 169–170 °C
• Density : 0.853 g/mL at 25 °C
• Refractive Index : 1.426

Biological Activity Overview

Research indicates that 3-Butoxypropylamine exhibits various biological activities, including:

• Antimicrobial Properties : Studies have shown that compounds with similar structures can inhibit bacterial growth, suggesting potential antimicrobial applications for 3-Butoxypropylamine.
• Immune Modulation : There is evidence that certain amines can influence immune responses, which may extend to 3-Butoxypropylamine based on its structural analogs.

Antimicrobial Activity

A study investigating the antimicrobial properties of various alkylamines found that derivatives similar to 3-Butoxypropylamine demonstrated significant antibacterial effects against Gram-positive bacteria. The study utilized a broth microdilution method to assess minimum inhibitory concentrations (MICs).

Immune Modulatory Effects

Research focusing on immune modulation through synthetic analogs of butoxypropylamines has shown promising results. In vitro assays using murine splenocyte proliferation indicated that modifications in the alkyl chain length could enhance immune suppression.

The proposed mechanisms through which 3-Butoxypropylamine exerts its biological effects include:

• Cell Membrane Interaction : Its hydrophobic nature allows it to integrate into cell membranes, potentially disrupting microbial integrity.
• Immune Cell Modulation : The compound may influence cytokine production and immune cell signaling pathways, leading to altered immune responses.

Safety and Toxicology

While exploring the biological activities of 3-Butoxypropylamine, it is crucial to consider its safety profile. Preliminary studies indicate that at higher concentrations, it may exhibit cytotoxic effects on certain cell types.

Toxicity Data

Q. Basic: How are clinical trials designed to evaluate the efficacy of oseltamivir in influenza treatment?

Clinical trials for this compound typically employ randomized, double-blind, placebo-controlled designs to minimize bias. Key endpoints include:

• Duration of illness : Measured as median time to symptom resolution (e.g., 71.5 vs. 103.3 hours for this compound vs. placebo) .
• Severity scores : Quantified using area-under-the-curve (AUC) metrics for symptom intensity (e.g., 597 vs. 963 score-hours for this compound vs. placebo) .
• Virologic endpoints : Viral shedding duration and titer reduction via qRT-PCR or culture .
• Secondary outcomes : Complications (e.g., bronchitis, hospitalization rates) and safety profiles (e.g., nausea incidence) .
  Methodological considerations : Stratification by influenza confirmation (intention-to-treat vs. intention-to-treat infected populations) and use of accelerated failure time models for time-to-event data .

Q. Basic: What experimental approaches are used to determine the absolute configuration of this compound?

The absolute configuration of this compound’s chiral centers (e.g., C4) is resolved using:

• X-ray crystallography : Direct determination of spatial arrangement in crystalline form.
• Chiral chromatography : Separation of enantiomers via HPLC with chiral stationary phases.
• NMR spectroscopy : Analysis of coupling constants and nuclear Overhauser effects (NOEs) to infer stereochemistry .

Q. Advanced: How do compensatory mutations restore fitness in this compound-resistant influenza strains?

The H274Y mutation in neuraminidase (NA) confers resistance but impairs viral fitness by reducing NA surface expression. Permissive secondary mutations (e.g., V234M, R222Q) restore fitness via:

• Structural stabilization : Compensating for H274Y-induced folding defects in NA.
• Enhanced enzymatic activity : Restoring NA function without reversing resistance .
  Methodology : Fitness is assessed using reverse genetics, viral replication kinetics in MDCK cells, and molecular dynamics simulations to map mutational effects on NA structure .

Q. Advanced: What computational methods are used to evaluate this compound derivatives against novel viral targets?

• Molecular docking : Screening N-substituted this compound derivatives against viral proteases (e.g., SARS-CoV-2 main protease, PDB:6LU7) using AutoDock Vina or Schrödinger.
• Binding affinity analysis : Calculating ΔG values and hydrogen-bond interactions to prioritize candidates .
• Pose validation : Comparing docking poses with experimental crystallographic data to resolve contradictions (e.g., discrepancies in CR6261 combination studies) .

Q. Basic: How are experimental human influenza models utilized to assess this compound’s antiviral activity?

Key steps :

• Viral inoculation : Intranasal administration of defined influenza strains (e.g., A/Texas/36/91) in seronegative volunteers .
• Treatment protocols : Early intervention (e.g., 28 hours post-inoculation) with dose escalation (75–150 mg twice daily) .
• Outcome metrics : Reduction in viral shedding (AUC titer) and symptom severity scores .

Q. Advanced: What methodologies are used to evaluate the economic impact of this compound in influenza management?

• Probabilistic cost-effectiveness models : Incorporate meta-analysis-derived relative risks (RRs), country-specific cost data, and uncertainty distributions for parameters like hospitalization rates .
• Scenario analyses : Compare direct/indirect costs (e.g., medication, lost productivity) between this compound and usual care, excluding drug costs to isolate healthcare savings .
• Sensitivity testing : Monte Carlo simulations to assess robustness of cost-saving conclusions .

Q. Advanced: How can researchers reconcile contradictory findings on this compound’s impact on complications?

Contradictions arise from population heterogeneity and endpoint definitions. Strategies include :

• Subgroup analysis : Stratify by confirmed influenza status (e.g., ITT vs. ITTI populations) .
• Meta-regression : Adjust for covariates like asthma comorbidity, which attenuates efficacy in pediatric trials .
• Outcome standardization : Differentiate acute bronchitis (reduced with this compound) vs. pneumonia (no significant reduction in ITT) .

Q. Advanced: What chemoenzymatic strategies enable efficient synthesis of this compound?

• Key steps :
  • Toluene dioxygenase-mediated dihydroxylation : Generate chiral diols from ethyl benzoate.
  • Hetero-Diels-Alder cycloaddition : Construct the cyclohexene core.
  • Translocation-elimination : Introduce C4 acetamido functionality via olefin migration .
    Advantage : Reduces steps (10 vs. 15+ in traditional routes) and improves enantiomeric purity .

Q. Advanced: How are preclinical models used to assess this compound’s neurological safety profile?

• In vitro : Hippocampal slice assays to measure neuronal excitability changes (e.g., Ro 64-0802 effects on synchronization) .
• In vivo : High-dose toxicity studies in rodents, monitoring blood-brain barrier penetration and behavioral endpoints .
• Mechanistic studies : Carboxylesterase activity assays to quantify prodrug conversion in neural tissue .

Q. Advanced: What are the challenges in meta-analyzing this compound’s efficacy in pediatric populations?

• Heterogeneity : Variability in asthma prevalence, age stratification, and endpoint definitions (e.g., otitis media vs. hospitalization) .
• Statistical approaches : Use restricted mean survival time (RMST) to handle non-proportional hazards in illness duration data .
• Individual patient data (IPD) meta-analysis : Pool raw data to adjust for confounders and perform subgroup analyses (e.g., age <5 vs. 5–18 years) .