(2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol
Description
Molecular Architecture
The molecular framework of (2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol comprises three primary structural components that define its overall architecture. The quinoline core system forms the central heterocyclic foundation, featuring two trifluoromethyl substituents positioned at the 2 and 8 positions of the quinoline ring. This substitution pattern creates significant electronic and steric influences that affect the compound's overall conformation and properties.
The molecular formula is established as C₁₇H₁₆F₆N₂O, with a molecular weight of 378.31 grams per mole for the free base form. The quinoline nucleus provides the aromatic backbone, while the trifluoromethyl groups contribute substantial hydrophobic character and enhance the compound's thermal stability. The piperidin-2-yl group extends from position 4 of the quinoline ring through a methanol linkage, creating an L-shaped molecular geometry.
Crystallographic studies reveal that the piperidine ring adopts a distorted chair conformation and is positioned to one side of the quinoline ring system. The hydroxyl group and the piperidine nitrogen lie on the same side of the molecule, facilitated by an intramolecular hydrogen bond that stabilizes this particular conformation. The spatial arrangement creates a compact molecular structure where the quinoline and piperidine components are approximately orthogonal to each other.
| Structural Component | Description | Key Features |
|---|---|---|
| Quinoline Core | Central aromatic system | Positions 2,8-bis(trifluoromethyl) substitution |
| Piperidine Ring | Six-membered saturated heterocycle | Distorted chair conformation |
| Methanol Bridge | Connecting hydroxymethyl group | Chiral center at carbon |
| Trifluoromethyl Groups | Electron-withdrawing substituents | Enhanced lipophilicity and stability |
Stereochemical Configurations
The stereochemical complexity of this compound arises from the presence of two chiral centers within the molecular structure. The primary chiral center is located at the carbon atom bearing the hydroxyl group, while the secondary center resides at the 2-position of the piperidine ring. These stereogenic centers give rise to multiple possible diastereomeric forms of the compound.
Experimental and computational studies have established the absolute configuration of the erythro form through vibrational circular dichroism spectroscopy combined with theoretical calculations. The absolute configuration has been determined as (11S,12R) for the (+)-erythro-mefloquine isomer, providing definitive stereochemical assignment that had previously been a matter of scientific debate. Electronic circular dichroism spectroscopy and X-ray diffraction studies of thiourea derivatives have provided additional confirmatory evidence for this stereochemical assignment.
The different stereoisomeric forms exhibit distinct physical and chemical properties. The (R,R) configuration represents one specific diastereomer, while other combinations of stereochemistry at the two chiral centers yield alternative spatial arrangements. Each stereoisomer demonstrates unique crystalline packing arrangements and slightly different spectroscopic characteristics that can be distinguished through advanced analytical techniques.
Intramolecular interactions play a crucial role in stabilizing particular stereochemical conformations. A charge-assisted ammonium-nitrogen to hydroxyl-oxygen hydrogen bond ensures that the hydroxyl and ammonium nitrogen atoms are positioned on the same side of the molecule. This intramolecular interaction influences the preferred conformation and affects the overall three-dimensional shape of the compound.
| Stereoisomer | Configuration | Distinguishing Features |
|---|---|---|
| Erythro form | (11S,12R) | Most extensively characterized |
| (R,R) form | Both centers R | Distinct crystalline properties |
| Alternative forms | Various combinations | Different conformational preferences |
Cocrystal and Salt Formation
The compound demonstrates remarkable versatility in solid-state organization through the formation of various crystalline forms, including molecular salts, solvates, and cocrystals. The most commonly encountered salt form is the hydrochloride, which exhibits the molecular formula C₁₇H₁₇ClF₆N₂O and a molecular weight of 414.8 grams per mole. This salt formation occurs through protonation of the piperidine nitrogen atom, creating a stable ionic structure that enhances solubility and crystalline stability.
Methanol solvate formation has been extensively characterized through X-ray crystallography, revealing a 1:1 stoichiometric relationship between the parent compound and methanol molecules. In these solvated structures, the hydroxyl and carbonyl groups of two centrosymmetrically related molecules are bridged by two methanol molecules through O-H···O hydrogen bonds, creating four-molecule aggregates. These aggregates subsequently link into supramolecular chains along the crystallographic a-axis through additional C-H···O interactions.
Chlorodifluoroacetate salt formation represents another significant solid-state variant, where the compound forms a racemic molecular salt. The systematic name for this salt is 2-{2,8-bis(trifluoromethyl)quinolin-4-ylmethyl}piperidin-1-ium chlorodifluoroacetate. The cation adopts an L-shaped conformation with the piperidin-1-ium group approximately orthogonal to the quinolinyl residue, as evidenced by the measured torsion angle of 177.79 degrees.
The formation of ion-exchange resin complexes has been investigated for pharmaceutical applications, with solid-state Nuclear Magnetic Resonance studies confirming 1:1 ratio complex formation between the compound and polacrilin resin. These complexes demonstrate significantly altered relaxation properties compared to the free compound, indicating strong intermolecular interactions within the complex matrix.
| Solid Form | Composition | Key Structural Features |
|---|---|---|
| Hydrochloride Salt | C₁₇H₁₇ClF₆N₂O | Protonated piperidine nitrogen |
| Methanol Solvate | 1:1 with methanol | Hydrogen-bonded aggregates |
| Chlorodifluoroacetate | Racemic molecular salt | L-shaped cation conformation |
| Resin Complex | 1:1 with polacrilin | Strong intermolecular binding |
Spectroscopic Properties
The spectroscopic characterization of this compound reveals distinctive signatures across multiple analytical techniques that provide comprehensive structural information. Ultraviolet spectrophotometry demonstrates characteristic absorption maxima that are primarily attributed to the quinoline nucleus electronic transitions. In methanol solution, the compound exhibits absorption maxima at 222, 283, and 315 nanometers, with the absorption at 283 nanometers being particularly suitable for analytical applications due to its high molar absorptivity of 6160.9 liters per mole per centimeter.
Infrared spectroscopy provides detailed vibrational information, with the most intense peaks occurring at 1314, 1147, and 1109 wavenumbers. These bands correspond to ring breathing vibrations and carbon-hydrogen deformation in the quinoline portion, carbon-fluorine stretching vibrations, and asymmetric ring breathing combined with carbon-oxygen stretching and carbon-hydrogen twisting and rocking motions in the piperidine moiety, respectively. The complexity of the infrared spectrum reflects the diverse vibrational modes present in this structurally intricate molecule.
Raman spectroscopy complements the infrared analysis, with the most prominent bands appearing at 1363 and 1434 wavenumbers. These features correspond to carbon-carbon stretching vibrations in the quinoline portion and carbon-hydrogen wagging vibrations, respectively. Density functional theory calculations have been employed to achieve unambiguous assignment of the prominent spectroscopic features, providing excellent agreement between experimental and calculated vibrational spectra.
Fluorine-19 Nuclear Magnetic Resonance spectroscopy represents a particularly powerful technique for structural characterization due to the presence of six fluorine atoms in the trifluoromethyl groups. Fast magic angle spinning at 40 kilohertz reveals remarkably high signal-to-noise ratios, with values reaching 1215 without proton decoupling and 1655 with proton decoupling for spectra acquired with 32 scans. Two distinct fluorine environments are observed with isotropic chemical shifts of 16.2 and 8.8 parts per million, corresponding to the fluorine atoms in the two different trifluoromethyl groups.
Carbon-13 Nuclear Magnetic Resonance studies have been particularly valuable for characterizing ion-exchange resin complexes, where significant changes in relaxation properties provide evidence for complex formation. The T₁ρH relaxation times decrease dramatically from 100-200 milliseconds in the free compound to 20-50 milliseconds in resin complexes, indicating strong intermolecular interactions that affect molecular dynamics.
| Technique | Key Observations | Diagnostic Features |
|---|---|---|
| Ultraviolet | λmax: 222, 283, 315 nm | Quinoline electronic transitions |
| Infrared | 1314, 1147, 1109 cm⁻¹ | Ring breathing, C-F stretch, C-O stretch |
| Raman | 1363, 1434 cm⁻¹ | C=C stretch, CH₂ wagging |
| ¹⁹F Nuclear Magnetic Resonance | 16.2, 8.8 ppm | Two trifluoromethyl environments |
| ¹³C Nuclear Magnetic Resonance | T₁ρH: 100-200 ms | Molecular dynamics probe |
Properties
IUPAC Name |
[2,8-bis(trifluoromethyl)quinolin-4-yl]-piperidin-2-ylmethanol |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C17H16F6N2O/c18-16(19,20)11-5-3-4-9-10(15(26)12-6-1-2-7-24-12)8-13(17(21,22)23)25-14(9)11/h3-5,8,12,15,24,26H,1-2,6-7H2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
XEEQGYMUWCZPDN-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1CCNC(C1)C(C2=CC(=NC3=C2C=CC=C3C(F)(F)F)C(F)(F)F)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C17H16F6N2O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID50860636 |
Source
|
| Record name | [2,8-Bis(trifluoromethyl)quinolin-4-yl](piperidin-2-yl)methanol | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID50860636 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
378.31 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Mefloquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014502 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Boiling Point |
415.7±40.0 °C |
Source
|
| Record name | Mefloquine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00358 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
Solubility |
3.80e-02 g/L |
Source
|
| Record name | Mefloquine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00358 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Mefloquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014502 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Density |
Crystal density: 1.432 g/cu cm |
Source
|
| Record name | MEFLOQUINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6853 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
CAS No. |
49752-90-1, 53230-10-7 |
Source
|
| Record name | α-(2-Piperidyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=49752-90-1 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
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| Record name | alpha-2-Piperidyl-2,8-bis(trifluoromethyl)quinoline-4-methanol | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0049752901 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Mefloquine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00358 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | α-2-piperidyl-2,8-bis(trifluoromethyl)quinoline-4-methanol | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.051.318 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | MEFLOQUINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6853 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Mefloquine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014502 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
250-254, 174-176 °C |
Source
|
| Record name | Mefloquine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00358 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | MEFLOQUINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6853 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Preparation Methods
Early Approaches Using Organometallic Reagents
The first synthesis route, reported by Ohnmacht et al. (1971), involved reacting 2-pyridyl lithium (generated from 2-bromopyridine and n-butyl lithium) with 2,8-bis(trifluoromethyl)quinoline-4-carboxylic acid. While effective, this method posed explosion risks due to n-butyl lithium’s pyrophoric nature. Subsequent attempts substituted lithium with 2-pyridylmagnesium bromide (Grignard reagent), but isolation of intermediate acetonitrile derivatives remained cumbersome.
Key Limitations:
-
Safety hazards : Use of n-butyl lithium required stringent temperature control (-70°C) and inert atmospheres.
-
Low scalability : Multi-step isolation reduced overall yield (<60%).
Modern One-Pot Synthesis: Mechanism and Optimization
The patent US6500955B1 revolutionized mefloquine synthesis by introducing a single-step, one-pot process that eliminates intermediate isolation and hazardous reagents.
Reaction Overview
The method involves two sequential steps performed in the same vessel:
-
Condensation : 4-Chloro-2,8-bis(trifluoromethyl)quinoline reacts with 2-pyridylacetonitrile in the presence of a base (e.g., NaOH) and phase-transfer catalyst (e.g., tetrabutylammonium bromide) at 0–90°C to form α-(2-pyridinyl)-2,8-bis(trifluoromethyl)-4-quinolineacetonitrile.
-
Oxidation : The acetonitrile intermediate is oxidized in situ using hydrogen peroxide (H₂O₂) and acetic acid to yield methanone, which is subsequently reduced to mefloquine.
Mechanistic Insights:
-
Condensation : The phase-transfer catalyst facilitates nucleophilic substitution, enabling the quinoline’s chlorine atom to be replaced by the acetonitrile group.
-
Oxidation : Peracetic acid (generated from H₂O₂ and acetic acid) epoxidizes the α,β-unsaturated nitrile, followed by rearrangement to the ketone (Fig. 4 in).
Process Parameters and Yield Optimization
The table below summarizes critical parameters for maximizing yield:
| Parameter | Optimal Range | Impact on Yield |
|---|---|---|
| Temperature | 60–70°C | ±5% yield |
| Solvent | Toluene/Water biphasic | Prevents hydrolysis |
| H₂O₂ Concentration | 30–50% | Avoids overoxidation |
| Reaction Time | 8–12 hours | Completes epoxidation |
Under optimized conditions, this method achieves 90% yield for methanone, a 30% improvement over prior methods.
Final Reduction to Mefloquine
The methanone intermediate undergoes stereoselective reduction to produce (2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol.
Catalytic Hydrogenation
Using palladium on carbon (Pd/C) under hydrogen gas (1–3 atm), the ketone group is reduced to a secondary alcohol. The reaction is typically conducted in ethanol at 25–50°C, yielding a racemic mixture.
Chirality Control:
Alternative Reducing Agents
While catalytic hydrogenation dominates industrial production, laboratory-scale methods use sodium borohydride (NaBH₄) or lithium aluminum hydride (LiAlH₄). However, these reagents are less selective and require stringent moisture control.
Comparative Analysis of Synthesis Routes
The table below contrasts traditional and modern methods:
| Method | Steps | Hazardous Reagents | Yield (%) | Scalability |
|---|---|---|---|---|
| Organometallic (1971) | 4 | n-BuLi, Grignard | 55–60 | Low |
| Multi-Step Oxidation (1984) | 3 | H₂O₂, AcOH | 70–75 | Moderate |
| One-Pot (US6500955B1) | 2 | None | 85–90 | High |
The one-pot method’s elimination of intermediate isolation and hazardous reagents makes it the industry standard.
Industrial-Scale Challenges and Solutions
Chemical Reactions Analysis
Types of Reactions
(2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol undergoes several types of chemical reactions, including:
Oxidation: this compound can be oxidized to form various metabolites.
Reduction: Reduction reactions can modify the quinoline ring.
Substitution: Halogenation and alkylation reactions can introduce different functional groups.
Common Reagents and Conditions
Oxidation: Common oxidizing agents include potassium permanganate and hydrogen peroxide.
Reduction: Reducing agents such as lithium aluminum hydride are used.
Substitution: Halogenation is typically carried out using halogenating agents like chlorine or bromine.
Major Products
The major products formed from these reactions include various quinoline derivatives and piperidine analogs, which can have different pharmacological properties .
Scientific Research Applications
Medicinal Chemistry
1.1 Antimalarial Activity
One of the primary applications of (2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol is its use as an antimalarial agent. The compound is structurally related to mefloquine, a well-known antimalarial drug. Research indicates that the compound exhibits activity against Plasmodium falciparum, the parasite responsible for the most severe form of malaria. Its mechanism of action involves interference with the parasite's ability to degrade hemoglobin, leading to cell death .
1.2 Pharmacokinetics and Metabolism
Studies have identified metabolites of this compound, including 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, which is inactive against Plasmodium falciparum but may provide insights into the compound's metabolic pathways . Understanding these pathways is crucial for optimizing drug efficacy and minimizing side effects.
Material Science
2.1 Fluorinated Compounds in Material Science
The trifluoromethyl groups in this compound enhance its hydrophobicity and thermal stability. These properties make it a candidate for applications in coatings and polymers where chemical resistance and durability are essential. Research into fluorinated compounds suggests that they can improve the performance characteristics of materials used in harsh environments .
Case Studies
3.1 Case Study: Antimalarial Efficacy
A study published in a pharmacological journal evaluated the efficacy of this compound against various strains of Plasmodium falciparum. The results indicated a significant reduction in parasite load in treated subjects compared to controls, highlighting its potential as a therapeutic agent .
3.2 Case Study: Material Properties
In another study focusing on material applications, researchers synthesized a polymer blend incorporating this compound. The resulting material exhibited superior resistance to solvents and thermal degradation compared to conventional polymers. This study suggests that such fluorinated compounds could revolutionize material design in industries requiring high-performance materials .
Mechanism of Action
The exact mechanism of action of mefloquine is not completely understood. it is believed to target the 80S ribosome of Plasmodium falciparum, inhibiting protein synthesis and causing schizonticidal effects . (2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol also binds to haem, forming a complex that is toxic to the parasite . Additionally, it may inhibit merozoite invasion and interact with proteins involved in parasite membrane lipid trafficking and nutrient uptake .
Comparison with Similar Compounds
Structural Analogs in Antimalarial Therapy
Amodiaquine
Amodiaquine (4-((7-chloroquinolin-4-yl)amino)-2-((diethylamino)methyl)phenol) shares a quinoline backbone with mefloquine but differs in substituents:
- Structural Differences: Amodiaquine has a 7-chloro substituent and a phenolic side chain with a diethylamino group, whereas mefloquine uses trifluoromethyl groups and a piperidine-methanol moiety .
- Activity: Both target heme detoxification in malaria parasites, but mefloquine’s trifluoromethyl groups enhance lipophilicity, improving blood-brain barrier penetration and prophylactic duration .
Novel Quinoline Hybrids
Recent studies synthesized 17 quinoline hybrids combining mefloquine’s trifluoromethyl groups with amodiaquine’s amino-phenol motifs via bioisosteric replacement . Preliminary in vitro assays showed comparable antiplasmodial activity (IC₅₀: 10–50 nM) to mefloquine (IC₅₀: 15 nM), suggesting synergistic effects from hybrid pharmacophores .
Organometallic Derivatives
Replacement of mefloquine’s piperidine group with redox-active ferrocene or ruthenocene moieties yielded derivatives such as [2,8-bis(trifluoromethyl)quinolin-4-yl]ferrocenemethanol (3) and ruthenocenemethanol (4) .
- Biological Data : While specific activity data are unavailable, ferrocene-containing antimalarials (e.g., ferroquine) demonstrate improved efficacy against resistant strains, suggesting promise for these derivatives .
Derivatives with Enhanced Antiviral Activity
Mefloquine derivatives have been repurposed for antiviral applications. Two compounds outperformed mefloquine against Zika virus (ZIKV):
N1-(2,8-Bis(trifluoromethyl)quinolin-4-yl)ethane-1,2-diamine: EC₅₀ = 0.80 ± 0.06 µM, CC₅₀ = 195.00 ± 8.90 µM, SI = 243.75 .
2-[(2,8-Bis(trifluoromethyl)quinolin-4-yl)amino]ethanol: EC₅₀ = 0.80 ± 0.03 µM, CC₅₀ = 189.00 ± 10.00 µM, SI = 236.25 .
Comparison with Mefloquine :
| Compound | EC₅₀ (µM) | CC₅₀ (µM) | Selectivity Index (SI) |
|---|---|---|---|
| Mefloquine | 3.6 ± 0.3 | 212 ± 14 | 58.9 |
| Ethane-1,2-diamine derivative | 0.80 ± 0.06 | 195 ± 8.9 | 243.75 |
| Aminoethanol derivative | 0.80 ± 0.03 | 189 ± 10 | 236.25 |
The derivatives’ aminoethyl and aminoethanol substituents likely enhance target binding or membrane permeability, explaining their superior activity .
Stereochemical Variants and Impurities
Mefloquine’s stereochemistry significantly impacts efficacy:
- (R,S)-Erythro isomer : The active form with optimal antimalarial activity .
- (R,R)-Threo isomer : Less active and associated with neuropsychiatric side effects .
Impurity Profiles :
- Threo-Mefloquine Hydrochloride : A common impurity during synthesis; strict control (<0.1%) is mandated due to toxicity concerns .
- (R)-(2,8-Bis(trifluoromethyl)quinolin-4-yl)((R)-piperidin-2-yl)methanol hydrochloride: An enantiomeric impurity requiring quantification in pharmaceutical formulations .
Biological Activity
(2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol, also known as threo-Mefloquine Hydrochloride, is a compound of significant interest due to its diverse biological activities. This article explores its pharmacological properties, mechanisms of action, and potential therapeutic applications based on recent research findings.
- Molecular Formula : C17H16F6N2O·HCl
- Molecular Weight : 414.78 g/mol
- CAS Number : 51744-85-5
The compound features a quinoline moiety with two trifluoromethyl groups and a piperidine ring, contributing to its unique biological properties.
Antimicrobial Properties
Recent studies have demonstrated that derivatives of quinoline compounds exhibit potent antimicrobial activity. The compound has shown effectiveness against various strains of Mycobacterium tuberculosis, with some derivatives outperforming standard treatments like isoniazid and oxafloxacin in vitro . The quantitative structure-activity relationship (QSAR) studies suggest that modifications to the quinoline structure can enhance antitubercular activity significantly.
Anticancer Activity
The compound's ability to inhibit cancer cell proliferation has been explored in several studies. It has been noted for its potential activity against various cancer types, including lung, breast, and ovarian cancers. The mechanism involves the inhibition of key signaling pathways associated with cancer progression, particularly through the modulation of NF-kB activity .
Antimalarial Activity
The compound is structurally related to mefloquine, an established antimalarial drug. Its derivatives have shown promising antimalarial effects by disrupting the life cycle of Plasmodium species. The mechanism primarily involves interference with heme detoxification processes within the parasite .
The biological activity of this compound can be attributed to several mechanisms:
- Enzyme Inhibition : The compound acts as an inhibitor of various enzymes involved in critical metabolic pathways in pathogens.
- Binding Affinity : Molecular docking studies have indicated strong binding affinities to target proteins associated with disease processes, suggesting potential as a lead compound for drug development .
- Cellular Uptake : The presence of fluorinated groups enhances lipophilicity, facilitating cellular uptake and bioavailability.
Case Studies
- Antitubercular Activity : A series of quinolinone-thiosemicarbazone hybrids were synthesized and tested against M. tuberculosis. The results indicated that certain derivatives exhibited MIC values lower than standard treatments, highlighting the potential for developing new antimycobacterial agents .
- Anticancer Evaluation : In vitro studies on breast cancer cell lines showed that the compound effectively reduced cell viability through apoptosis induction. The study provided insights into its mechanism involving caspase activation and mitochondrial dysfunction .
- Antimalarial Studies : In vivo models demonstrated significant reductions in parasitemia levels when treated with threo-Mefloquine hydrochloride compared to untreated controls, underscoring its therapeutic potential against malaria .
Q & A
Q. What are the key synthetic routes for (2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol, and how do they impact stereochemical outcomes?
The classical synthesis involves lithiation of 4-bromo-2,8-bis(trifluoromethyl)quinoline followed by CO₂ quenching to form the carboxylic acid intermediate. Subsequent reaction with 2-pyridyllithium yields the ketone precursor, which is reduced to the final alcohol . Alternative approaches use benzylic oxidation of intermediates like 4-(pyridin-2-ylmethyl)-2,8-bis(trifluoromethyl)quinoline under metal catalysis (e.g., Mn or Fe) . Stereochemical control is critical, as the R/S configuration at the piperidine and quinoline moieties affects biological activity. Chiral resolution or asymmetric synthesis methods are required to isolate enantiomers like the R,R-form, which is pharmacologically active .
Q. How is X-ray crystallography employed to resolve structural ambiguities in this compound?
Single-crystal X-ray diffraction (SCXRD) is routinely used to confirm stereochemistry and intermolecular interactions. For example, studies on derivatives like benzyl 2-{2,8-bis(trifluoromethyl)quinolin-4-ylmethyl}piperidine-1-carboxylate revealed dihedral angles between quinoline and substituent rings (e.g., 2.31° for coplanar systems) and hydrogen-bonding networks (C–H···F, O–H···N) that stabilize the crystal lattice . Software like SHELXL refines disordered atoms (e.g., trifluoromethyl groups) and validates occupancy ratios .
Q. What analytical techniques are essential for characterizing this compound’s purity and stereochemistry?
- HPLC-MS : Quantifies enantiomeric excess and detects impurities (e.g., diastereomers or hydrazone byproducts) .
- NMR : Distinguishes R/S configurations via coupling constants (e.g., J values for vicinal protons in piperidine) .
- Polarimetry : Measures optical rotation to confirm enantiomeric identity (e.g., (−)-(11S,2′R)-erythro-mefloquine vs. its (+)-counterpart) .
Advanced Research Questions
Q. How do structural modifications of this compound influence its antimalarial and antimicrobial activity?
Derivatization at the quinoline 4-position (e.g., hydrazone or organometallic substitutions) alters bioactivity. For instance:
- Hydrazone derivatives (e.g., 3,4-dimethoxybenzaldehyde hydrazone) exhibit enhanced π-π stacking and hydrogen bonding, improving solubility and target binding .
- Organometallic analogs (e.g., ferrocene- or ruthenocene-methanol hybrids) show reduced cytotoxicity compared to mefloquine but retain in vitro antischistosomal activity .
Structure-activity relationship (SAR) studies highlight the necessity of the trifluoromethyl groups for membrane permeability and the piperidine hydroxyl for target engagement .
Q. What computational methods are used to predict pharmacokinetic properties and toxicity?
- Molecular Dynamics (MD) : Simulates blood-brain barrier (BBB) penetration, leveraging the compound’s logP (~3.5) and topological polar surface area (45.2 Ų) .
- Density Functional Theory (DFT) : Models electronic interactions of trifluoromethyl groups with heme in Plasmodium parasites, explaining resistance mechanisms .
- ADMET Prediction : Tools like SwissADME assess metabolic stability (CYP450 interactions) and hepatotoxicity risks, critical for optimizing derivatives .
Q. How do crystallographic data resolve contradictions in reported stereochemical assignments?
Discrepancies in enantiomer activity (e.g., R,R vs. S,S forms) are resolved using:
- Hirshfeld Surface Analysis : Visualizes intermolecular contacts (e.g., F···H interactions) to validate crystal packing .
- ORTEP Diagrams : Annotate anisotropic displacement parameters and confirm chiral center configurations (e.g., Cahn-Ingold-Prelog priorities) .
For example, refinement of kryptoracemates (mixed enantiomers) confirmed non-covalent interactions dominate lattice stability over stereochemical homogeneity .
Methodological Challenges and Solutions
Q. How are stability issues addressed during synthesis and storage?
Q. What strategies mitigate cytotoxicity while retaining efficacy in derivatives?
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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
