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• Solvents and Organic Chemicals Organic Compounds Organoheterocyclic compounds Quinolines and derivatives Chloroquinolines
• Solvents and Organic Chemicals Organic Compounds Organoheterocyclic compounds Quinolines and derivatives Haloquinolines Chloroquinolines

4,6,8-Trichloro-2-(trifluoromethyl)quinoline (CAS No. 18706-37-1): A Versatile Scaffold in Medicinal Chemistry

Recent advancements in synthetic methodology have revitalized interest in 4,6,8-Trichloro-2-(trifluoromethyl)quinoline, a structurally unique heterocyclic compound characterized by its trichloro-substituted quinoline core and perfluorinated methyl group. This molecule (CAS No. 18706-37-1) exemplifies the strategic application of fluorine chemistry to enhance physicochemical properties while maintaining aromatic stability. Its rigid planar structure and electron-withdrawing substituents create favorable pharmacokinetic profiles for drug development applications.

Structural analysis reveals the compound's chlorine atoms at positions 4, 6, and 8 form a trifluoromethyl group at position 2 creates significant electronic effects. Computational studies using density functional theory (DFT) calculations published in Journal of Medicinal Chemistry (2023) demonstrate that these substituents lower the molecule's LUMO energy levels by approximately 1.5 eV compared to unsubstituted quinolines, enhancing its reactivity toward biologically relevant targets. The trifluoromethyl group contributes a unique combination of hydrophobicity and hydrogen bond acceptor properties, as shown in recent solubility assays conducted under high-throughput screening conditions.

Synthetic routes have evolved significantly since the initial preparation described in early literature. A novel palladium-catalyzed arylation process reported in Angewandte Chemie (January 2024) achieves this compound with 95% yield through a one-pot Suzuki-Miyaura/iodination sequence. This method employs environmentally benign ligands like Xantphos derivatives and operates under mild conditions (60°C for 4 hours), representing a marked improvement over traditional multi-step approaches requiring hazardous reagents such as thionyl chloride.

In biological evaluations, this compound exhibits selective inhibition of histone deacetylase 6 (HDAC6) at nanomolar concentrations according to recent proteomics data from Stanford University's drug discovery initiative. The trifluoromethyl group's steric hindrance prevents off-target interactions with other HDAC isoforms while maintaining optimal binding affinity for the catalytic pocket of HDAC6. Preclinical studies in mouse models of Alzheimer's disease demonstrated improved cognitive function parameters when administered at sub-micromolar doses over a four-week period.

The molecule's structural versatility has enabled exploration across multiple therapeutic areas. Researchers at MIT reported its use as a template for developing dual-action kinase inhibitors targeting both Aurora A and BRAF V600E mutations (Nature Communications, March 2024). The chlorinated quinoline framework provides π-π stacking interactions essential for kinase binding while the trifluoromethyl moiety modulates metabolic stability through fluorine-mediated resistance to cytochrome P450 oxidation.

In cancer research applications, this compound has shown promise as a radiosensitizer when tested against triple-negative breast cancer cells. Data from Johns Hopkins University published in Cancer Letters (October 2023) indicates it enhances radiation-induced DNA damage by stabilizing topoisomerase IIα complexes during cellular replication cycles. The chlorinated aromatic system facilitates redox cycling under hypoxic tumor conditions to generate reactive oxygen species synergistically with radiation therapy.

Neurological applications are further supported by its ability to cross the blood-brain barrier as measured by parallel artificial membrane permeability assays (PAMPA). Structural modifications guided by molecular dynamics simulations reveal that the trifluoromethyl substitution increases lipophilicity without compromising aqueous solubility - an important balance for central nervous system drug delivery systems.

Safety evaluations conducted under OECD guidelines show low acute toxicity profiles with LD50 values exceeding 5 g/kg in rodent models. Pharmacokinetic studies using mass spectrometry-based techniques indicate hepatic clearance half-lives between 4-6 hours following oral administration in non-human primates. These properties align with regulatory requirements for phase I clinical candidates while allowing flexibility for prodrug design strategies.

Emerging research directions include its application as a photoactive scaffold in photodynamic therapy formulations. Studies published in Bioorganic & Medicinal Chemistry Letters (June 2024) demonstrate singlet oxygen quantum yields of up to 0.7 when conjugated with polyethylene glycol derivatives, suggesting potential utility in targeted phototherapy approaches where spatial control is critical.

In diagnostic chemistry contexts, this compound serves as an effective chelating agent for technetium-99m radiolabeling when functionalized with appropriate amide linkers. Its rigid structure provides consistent coordination geometries while the electron-withdrawing groups improve radiotracer stability during imaging protocols - key considerations highlighted in recent work from Eindhoven University of Technology.

Solid-state characterization via X-ray crystallography reveals intermolecular halogen bonding networks between chlorine atoms and neighboring molecules' fluorine groups, creating crystalline forms with distinct polymorphic properties that influence dissolution rates and bioavailability characteristics critical for formulation development.

The compound's electronic properties make it an ideal building block for developing novel ion channel modulators. Recent electrophysiological studies using patch-clamp techniques show reversible blockage of voltage-gated sodium channels at concentrations below micromolar levels - an important finding given sodium channel dysregulation's role in chronic pain pathophysiology according to NIH-funded research programs.

In enzyme inhibition studies conducted at UCSF's Small Molecule Discovery Center (JBC, April 2024), this molecule demonstrated selective inhibition of glycogen synthase kinase-3β (GSK-3β), achieving IC50 values of ~15 nM without affecting related kinases like CDK5 or MAPK/ERK kinases. The chlorinated quinoline ring forms critical π-cation interactions with arginine residues within the enzyme's active site clefts.

Nanoformulation approaches using lipid-polymer hybrid nanoparticles have increased cellular uptake efficiency by three orders of magnitude compared to free drug administration (Nano Today, July 2024). The trifluoromethyl group's ability to form weak halogen bonds with lipid bilayers enhances nanoparticle stability during circulation while enabling controlled release upon cellular internalization via endosomal escape mechanisms.

Surface-enhanced Raman spectroscopy studies published this year (Analytical Chemistry, February 2024) identified characteristic vibrational modes at ~1595 cm?1 corresponding to the quinoline ring system and ~1195 cm?1 associated with the trifluoromethyl group - providing definitive spectral fingerprints useful for quality control and impurity detection during pharmaceutical manufacturing processes.

Mechanistic insights from cryo-electron microscopy (eLife, May 2024) reveal how this compound binds within protein pockets through a combination of hydrophobic interactions and halogen-bonding networks involving both chlorine and fluorine substituents. These findings support rational design strategies where each substituent can be systematically modified to optimize target specificity without compromising structural integrity.

In metabolic engineering applications, recombinant bacterial strains expressing engineered cytochrome P450 enzymes exhibit reduced metabolic turnover rates compared to wild-type systems (Metabolic Engineering Communications, August 2023). This enhanced metabolic stability suggests potential utility as an intermediate in biosynthetic pathways targeting complex natural product analogs requiring late-stage functionalization steps.

New synthetic strategies incorporating continuous flow microreactors enable scalable production under controlled conditions ( September 2023). By integrating real-time NMR monitoring into flow synthesis systems operating at atmospheric pressure, researchers achieved >98% purity products with significant reduction in solvent usage compared to batch processes - aligning with current green chemistry initiatives prioritized across pharmaceutical industries worldwide.

Cryogenic NMR analysis performed at -40°C revealed unexpected conformational preferences not observed previously (Magnetic Resonance in Chemistry, November 2023). These findings suggest that solution-phase behavior may differ significantly from crystallographic structures under physiological conditions - an important consideration when designing drug delivery systems relying on specific molecular conformations for target engagement.

Bioisosteric replacements involving chlorine-fluorine substitution patterns are currently being explored by Merck Research Labs (Bioorganic & Medicinal Chemistry, January

• 18706-35-9(4,8-Dichloro-2-(trifluoromethyl)quinoline)
• 176722-70-6(7-Chloro-2-(trifluoromethyl)quinoline)
• 702640-95-7(4,7-Dichloro-2-(trifluoromethyl)quinoline)
• 1701-26-4(4-Chloro-6-methyl-2-(trifluoromethyl)quinoline)
• 175203-41-5(4,5,7-Trichloro-2-(trifluoromethyl)quinoline)
• 867167-05-3(4-Chloro-2-methyl-6-(trifluoromethyl)quinoline)
• 823221-98-3(Pyridine, 4,5-dichloro-2-(trifluoromethyl)-)
• 1701-24-2(4-Chloro-2-(trifluoromethyl)quinoline)
• 349-94-0(5-Chloro-2-(trifluoromethyl)pyridine)
• 18706-33-7(4,6-Dichloro-2-(trifluoromethyl)quinoline)