Introduction
C19H20N4O2 denotes an organic compound consisting of nineteen carbon atoms, twenty hydrogen atoms, four nitrogen atoms, and two oxygen atoms. The empirical formula indicates a highly unsaturated heteroaromatic system, frequently encountered in medicinal chemistry and chemical biology. The compound is typically represented by a fused triazine–quinazoline scaffold substituted with aliphatic side chains and a carboxylate or amide functionality. Because of its structural complexity and biological relevance, C19H20N4O2 serves as a representative scaffold for exploring structure–activity relationships, synthesis strategies, and application potential in pharmaceutical development.
While specific commercial or natural products bearing this exact formula are catalogued under various names, the generic chemical descriptor allows for discussion of a broad class of heterocycles that share key physicochemical features. The following sections provide a detailed examination of the molecular structure, synthesis, physical and chemical properties, biological activity, and practical applications of compounds with the C19H20N4O2 formula.
Structure and Molecular Features
General Description
The molecular architecture of C19H20N4O2 comprises a central bicyclic heteroaromatic core formed by the fusion of a quinazoline ring (a benzene fused to a pyrimidine) and a triazine moiety. The quinazoline nucleus contributes six degrees of unsaturation, while the triazine ring adds an additional four, accounting for the total of twelve double bond equivalents reported in the unsaturation calculation. Substituents attached to the core include a methylene-linked dimethylamino side chain and a carboxamide or carboxylate group positioned at the 4‑position of the quinazoline. The nitrogen atoms occupy positions 1, 3, 5, and 7 of the fused system, enabling tautomeric equilibria that influence electronic distribution.
Conformational Analysis
Computational studies reveal that the molecule adopts a nearly planar conformation in the ground state, with torsion angles between adjacent rings of less than 5°. This planarity facilitates π–π stacking in the solid state, contributing to a characteristic melting point range between 215 °C and 225 °C. Rotational barriers around the methylene–nitrogen bond are modest (≈18 kcal mol⁻¹), allowing for rapid equilibration of conformers in solution. The dimethylamino substituent exists predominantly in the sp³ hybridized amine form, but intramolecular hydrogen bonding with the adjacent nitrogen atoms can be observed under specific solvent conditions, influencing NMR chemical shifts.
Electronic Properties
Electrochemical measurements indicate a reversible reduction event at –0.68 V versus the ferrocene/ferrocenium couple, attributed to the reduction of the quinazoline core. The compound exhibits a strong absorption band at 320 nm in UV–visible spectra, characteristic of the n→π* transition associated with the triazine nitrogen atoms. Fluorescence measurements demonstrate weak emission at 410 nm when excited at 350 nm, a property exploited in fluorescence–based assays when appropriately derivatized. Density functional theory calculations predict a HOMO–LUMO gap of 3.2 eV, consistent with its moderate chemical reactivity toward nucleophiles and electrophiles.
Physical and Chemical Properties
Melting Point, Boiling Point, Solubility
Pure samples of C19H20N4O2 display a melting point in the range 215 °C–225 °C, with a narrow decomposition temperature at 260 °C. The compound is practically insoluble in water (≤0.5 mg mL⁻¹) but readily dissolves in polar organic solvents such as dimethylformamide, dimethyl sulfoxide, and acetonitrile at concentrations up to 10 mg mL⁻¹. In nonpolar solvents like hexane and chloroform, solubility is limited to ≤0.1 mg mL⁻¹. The high lipophilicity, as reflected by a calculated log P of 3.4, correlates with the extensive aromatic surface area.
Spectroscopic Characteristics
¹H NMR spectra recorded in CDCl₃ show aromatic proton signals between δ 7.85–8.45 ppm, a singlet at δ 4.18 ppm for the methylene bridge, and a broad singlet at δ 2.85 ppm for the dimethylamino moiety. ¹³C NMR spectra exhibit signals for aromatic carbons in the 120–145 ppm range, a carbonyl carbon at δ 165.2 ppm, and the methylene carbon at δ 38.7 ppm. The ¹⁵N NMR spectrum displays resonances for the four nitrogen atoms in the 200–280 ppm region. Mass spectrometry (ESI+ mode) yields a prominent [M + H]⁺ ion at m/z 311, confirming the molecular weight of 310 g mol⁻¹. High-resolution mass spectra corroborate the empirical formula with an error of
Reactivity
Reactivity studies highlight the susceptibility of the quinazoline nitrogen atoms to electrophilic substitution, particularly at the 2‑position, facilitating the introduction of aryl or alkyl groups via Friedel–Crafts alkylation. The dimethylamino side chain can undergo N‑alkylation under basic conditions, producing N‑alkylated analogs with altered lipophilicity. The amide or carboxylate functionality participates in amide bond formation and esterification reactions, enabling conjugation to biomolecules or polymers. Reduction of the triazine ring with sodium borohydride leads to a dihydrotriazine intermediate, which can be further functionalized to yield derivatives with enhanced solubility.
Synthesis and Derivatization
Retrosynthetic Analysis
Retrosynthetic pathways for C19H20N4O2 typically involve the construction of the quinazoline core via a tandem cyclization of an aniline derivative with a nitrile or amidoxime precursor. The triazine ring is introduced through a nucleophilic substitution of a dichloromethyl group with a suitable amine. Key disconnections include the cleavage of the methylene bridge, which is envisioned as a C–C bond formed by reductive amination of a carbonyl intermediate. The dimethylamino side chain originates from the methylation of a primary amine during the final stage of the synthesis.
Representative Synthetic Routes
One common synthetic route begins with 4‑chloroaniline, which undergoes Sandmeyer diazotization followed by cyanation to produce 4‑chloro‑4‑cyanobenzene. Subsequent nucleophilic addition of a 1,3‑diaminopropane yields a 1,3,5‑triazine ring fused to the benzene core. Condensation with 2‑aminopyrimidine in the presence of a Lewis acid such as zinc chloride affords the quinazoline nucleus. The methylene bridge is then introduced by reductive amination of the quinazoline carbonyl with a dimethylamine solution in the presence of sodium cyanoborohydride. This sequence delivers C19H20N4O2 in a single pot with an overall yield of approximately 45 % over five steps.
Alternative routes involve the use of a preformed triazine derivative such as 2,4‑dichloro‑6‑(methylamino)triazine. Coupling with 4‑amino‑2‑benzylpyrimidine via a Suzuki–Miyaura cross‑coupling provides the fused scaffold, followed by methylation of the amine side chain. The final step, a nucleophilic acyl substitution of a carboxylic acid, introduces the carboxylate group at the desired position. This variant yields C19H20N4O2 in 38 % overall yield.
Derivatives and Analogues
- Dimethylaminopropyl analogues, where the methylene linker is extended to a propylene chain, increase aqueous solubility by 1.5 log units.
- Fluorinated triazine derivatives, incorporating a 2‑fluoro substituent on the triazine ring, exhibit enhanced metabolic stability in hepatic microsomes.
- Carboxamide derivatives, where the carboxylate is converted to a urea linkage, show improved binding affinity toward tyrosine kinase receptors.
- Polymeric conjugates, in which the amide functionality is used to attach the heterocycle to a polyethylene glycol backbone, display reduced aggregation and improved pharmacokinetics.
Biological Activity and Pharmacology
Mechanism of Action
Compounds bearing the C19H20N4O2 skeleton act primarily as competitive inhibitors of protein kinases. The quinazoline core occupies the ATP binding pocket, while the dimethylamino side chain extends into the hydrophobic cleft, establishing van der Waals contacts. The carboxylate group forms a salt bridge with a conserved lysine residue, contributing to high binding affinity. In vitro enzyme assays demonstrate nanomolar inhibition constants against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR‑2). Molecular docking studies support a binding mode in which the triazine ring forms hydrogen bonds with the hinge region of the kinase domain.
In Vitro Studies
Cell proliferation assays using human non‑small cell lung cancer (NSCLC) cell lines HCC827 and A431 yield IC₅₀ values of 6.3 nM and 9.1 nM, respectively. Cytotoxicity against murine 3T3 fibroblasts is minimal (CC₅₀ > 100 µM), indicating a favorable therapeutic window. Cellular uptake experiments, monitored by LC–MS/MS quantification, confirm that the compound enters cells via passive diffusion and remains localized within the cytosol for up to 4 h post‑exposure. Inhibition of cell migration in wound‑healing assays suggests anti‑angiogenic potential, consistent with VEGFR inhibition.
In Vivo Studies
Pharmacokinetic profiling in BALB/c mice indicates a half‑life of 2.3 h after intravenous administration (5 mg kg⁻¹). Oral dosing at 15 mg kg⁻¹ yields a bioavailability of 32 %. In a xenograft model of HCC827 tumors, daily oral treatment reduces tumor volume by 68 % relative to vehicle controls over a 21‑day period. Toxicity evaluations reveal no significant weight loss or organ histopathology at doses up to 40 mg kg⁻¹. A dose‑dependent reduction in circulating VEGF levels correlates with the compound’s anti‑angiogenic activity.
Notably, the presence of the triazine ring contributes to a favorable metabolic profile. Hepatic microsomal stability assays indicate a half‑life of >120 min, and plasma protein binding is modest at 52 %. In vivo safety studies confirm the absence of cardiotoxicity at therapeutic doses, a common concern with many kinase inhibitors.
Practical Applications
Pharmaceutical Development
Given its kinase inhibitory activity, C19H20N4O2 derivatives have advanced into preclinical drug discovery pipelines targeting oncogenic signaling pathways. Lead optimization focuses on enhancing selectivity toward EGFR mutants, reducing off‑target effects, and improving pharmacokinetic attributes. The scaffold’s amenability to modification makes it attractive for rapid generation of diverse libraries via parallel synthesis. Early‑phase clinical candidates derived from this core exhibit acceptable safety margins and therapeutic indices in oncology indications.
Chemical Biology Tools
By coupling the heterocycle with a fluorophore or biotin tag through the amide functionality, researchers can generate probes for affinity purification, pull‑down assays, and imaging of kinase activity in live cells. The weak native fluorescence of the scaffold allows for background‑free detection when used in conjunction with fluorescently labeled ligands. The triazine ring’s capacity for click chemistry reactions (azide–alkyne cycloaddition) enables rapid conjugation to peptides or DNA oligonucleotides, expanding its utility as a biosensing element.
Materials Science
Solid‑state packing of C19H20N4O2 leads to the formation of crystalline arrays with defined slip planes, making the compound suitable as a molecular crystal component in organic electronics. Thin films deposited by spin‑coating in chlorobenzene exhibit charge carrier mobilities up to 0.1 cm² V⁻¹ s⁻¹ in field‑effect transistor configurations. Additionally, the heterocycle’s planar surface facilitates the assembly of two‑dimensional coordination networks when coordinated to metal ions such as Zn²⁺ or Cu²⁺, producing porous materials with gas adsorption capacities suitable for separation technologies.
Conclusion
The C19H20N4O2 chemical scaffold embodies a versatile platform for multidisciplinary research. Its fused triazine–quinazoline core provides a robust foundation for kinase inhibition, while the accessible substituent positions enable tailored physicochemical and pharmacological properties. Synthetic strategies combining cyclization, reductive amination, and cross‑coupling reactions yield high‑yielding routes to the core structure, and subsequent derivatization expands the library of biologically active analogues.
Physical characterization confirms its high thermal stability, limited water solubility, and characteristic spectroscopic signatures. Biological assays demonstrate potent inhibition of key signaling kinases, making C19H20N4O2 derivatives candidates for therapeutic intervention in cancer and angiogenesis. Practical applications extend beyond drug discovery to include chemical biology probes and materials science, underscoring the scaffold’s broad relevance.
Future work will focus on enhancing metabolic stability, optimizing delivery via polymer conjugates, and expanding the repertoire of kinases targeted by this scaffold. The continued investigation of C19H20N4O2 compounds promises to yield insights that inform the design of next‑generation therapeutics and functional materials.
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