N-(3-(3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino)phenyl)acetamide

Target of Action

The primary target of this compound is the BRAF V600E or V600K mutations . These mutations are commonly found in patients with unresectable or metastatic melanoma .

Mode of Action

This compound is a kinase inhibitor . It interacts with its targets by inhibiting the kinase activity of the BRAF V600E or V600K mutations . This inhibition results in a decrease in the proliferation of cancer cells and potentially leads to their death .

Biochemical Pathways

The compound affects the MAPK/ERK pathway , which is involved in cell proliferation and survival . By inhibiting the kinase activity of the BRAF V600E or V600K mutations, the compound disrupts this pathway, leading to decreased proliferation and survival of cancer cells .

Pharmacokinetics

The recommended dosage of this compound is 2 mg orally once daily , as a single agent or in combination with dabrafenib, until disease progression or unacceptable toxicity

Result of Action

The molecular and cellular effects of the compound’s action include a decrease in the proliferation of cancer cells and potentially their death . This can lead to a reduction in the size of tumors and potentially improve the prognosis for patients with unresectable or metastatic melanoma .

N-1,3-benzodioxol-5-yl-N'-(4,6-dimethylpyrimidin-2-yl)guanidine is a compound of significant interest in medicinal chemistry due to its potential biological activities. This article explores its pharmacological properties, mechanisms of action, and therapeutic implications based on diverse research findings.

Chemical Characteristics

• Molecular Formula : C15H17N5O2
• Molecular Weight : 299.33 g/mol
• CAS Number : 1306738-73-7

Biological Activity Overview

Research indicates that this compound exhibits a range of biological activities, particularly in the fields of oncology and infectious diseases.

Anticancer Activity

Studies have demonstrated that N-1,3-benzodioxol-5-yl-N'-(4,6-dimethylpyrimidin-2-yl)guanidine has significant anticancer properties. For instance:

• In vitro studies showed that the compound inhibits cell proliferation in various cancer cell lines, including breast and lung cancer cells. The IC50 values ranged from 10 to 30 µM, indicating moderate potency compared to standard chemotherapeutics .

Antimicrobial Activity

The compound also exhibits antimicrobial properties:

• Antibacterial assays revealed activity against Gram-positive bacteria such as Staphylococcus aureus and Gram-negative bacteria like Escherichia coli. The minimum inhibitory concentration (MIC) was noted to be around 25 µg/mL for both bacterial strains .

The mechanisms underlying the biological activities of N-1,3-benzodioxol-5-yl-N'-(4,6-dimethylpyrimidin-2-yl)guanidine involve several pathways:

• Inhibition of Kinases : The compound selectively inhibits specific kinases involved in cancer cell signaling pathways, leading to reduced cell survival and proliferation .
• Induction of Apoptosis : It promotes apoptosis in cancer cells through the activation of caspases and modulation of Bcl-2 family proteins .
• Antioxidant Properties : The benzodioxole moiety contributes to its antioxidant activity, which may protect normal cells from oxidative stress during cancer treatment .

Case Studies

Several case studies have highlighted the efficacy of N-1,3-benzodioxol-5-yl-N'-(4,6-dimethylpyrimidin-2-yl)guanidine:

Structural Formula

The molecular formula of N-(3-(3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino)phenyl)acetamide is C26H23FIN5O4. Its structure includes multiple functional groups that contribute to its biological activity.

Anticancer Research

This compound has been studied for its potential as an anticancer agent. Its structural similarity to known kinase inhibitors suggests that it may inhibit specific signaling pathways involved in tumor growth and proliferation. Preliminary studies indicate that it may exhibit cytotoxic effects on various cancer cell lines.

Targeting Kinase Pathways

The compound is of particular interest in the study of kinase pathways due to its ability to interact with specific enzymes involved in cell signaling. Inhibitors of these pathways are crucial for developing targeted therapies for cancers and other diseases characterized by aberrant signaling.

Neurological Applications

Research has also suggested that compounds similar to this compound may have neuroprotective effects. Studies are ongoing to evaluate its efficacy in models of neurodegenerative diseases.

Case Study 1: Antitumor Activity

In a recent study published in a peer-reviewed journal (source not specified), this compound was tested against a panel of human cancer cell lines. The results demonstrated significant inhibition of cell proliferation and induction of apoptosis at micromolar concentrations.

Case Study 2: Kinase Inhibition

Another study focused on the compound's role as a kinase inhibitor. It was found to selectively inhibit certain kinases involved in cancer progression while sparing others that are critical for normal cellular functions. This selectivity suggests a favorable therapeutic window for potential clinical applications.

Basic Research Questions

Q. What are the recommended analytical techniques for validating the synthesis and purity of this compound?

• Methodological Answer : Nuclear Magnetic Resonance (NMR) spectroscopy (1H and 13C) and Liquid Chromatography-Mass Spectrometry (LC-MS) are critical. For example, 1H NMR peaks in DMSO-d6 (δ 2.03 ppm for CH3 groups, δ 7.23–8.33 ppm for aromatic protons) and LC-MS ([M+H]+ ion detection) confirm structural integrity and purity . High-resolution mass spectrometry (HRMS) and elemental analysis further validate molecular composition.

Q. How can researchers optimize the synthetic route for this compound?

• Methodological Answer : Utilize multi-step protocols involving cyclocondensation, nucleophilic substitution, and amide coupling. Reaction conditions (e.g., solvent polarity, temperature) must be tailored for intermediates. For pyrido[2,3-d]pyrimidine scaffolds, cyclopropyl and iodo-substituted phenyl groups require inert atmospheres and palladium catalysts for cross-coupling steps . Purification via column chromatography (silica gel, gradient elution) or recrystallization ensures high yields (>50%) .

Q. What computational tools predict physicochemical properties relevant to drug discovery?

• Methodological Answer : Tools like ACD/Labs Percepta Platform calculate logP, solubility, and pKa. Molecular dynamics simulations (e.g., Schrödinger Suite) model interactions with biological targets. For instance, substituents like the 2-fluoro-4-iodophenyl group influence lipophilicity and binding affinity . PubChem-derived data (InChIKey, SMILES) aids in database comparisons .

Advanced Research Questions

Q. How can contradictory spectral data (e.g., NMR splitting patterns) be resolved during structural elucidation?

• Methodological Answer : Perform 2D NMR (COSY, HSQC, HMBC) to assign overlapping signals. For example, coupling constants in aromatic regions (δ 6.77–7.56 ppm) differentiate para- versus meta-substituted phenyl groups . X-ray crystallography (monoclinic P21/c space group, β = 108.76°) provides absolute configuration validation .

Q. What strategies address low bioavailability in preclinical studies?

• Methodological Answer : Modify substituents to enhance solubility: replace the cyclopropyl group with polar moieties (e.g., morpholine) or introduce prodrug motifs (e.g., esterification of acetamide). Pharmacokinetic studies in rodent models (plasma t1/2, Cmax) guide lead optimization .

Q. How do electronic properties (HOMO-LUMO gaps) influence reactivity in derivatization reactions?

• Methodological Answer : Density Functional Theory (DFT) calculations (Gaussian 09) reveal frontier molecular orbitals. The electron-withdrawing fluoro and iodo substituents lower the LUMO energy, facilitating nucleophilic attacks at the pyrimidine ring . MESP maps identify electrophilic hotspots for functionalization .

Q. What experimental designs resolve conflicting biological activity data across cell lines?

• Methodological Answer : Employ embedded mixed-methods designs: quantitative dose-response assays (IC50) paired with qualitative transcriptomics (RNA-seq). Control variables (cell passage number, serum concentration) minimize variability. For instance, contradictory cytotoxicity data may arise from differential expression of metabolic enzymes (e.g., CYP450 isoforms) .

Q. Contradiction Analysis & Technical Challenges

Q. How should researchers interpret discrepancies in synthetic yields reported across studies?

• Methodological Answer : Analyze reaction parameters: catalysts (e.g., Pd(PPh3)4 vs. CuI), solvent systems (DMF vs. THF), and stoichiometry. For example, yields drop in polar aprotic solvents due to side reactions with the acetamide group . Replicate conditions with inert gas purging to suppress oxidation .

Q. What computational and experimental approaches validate hypothesized binding modes with target proteins?

• Methodological Answer : Combine molecular docking (AutoDock Vina) with mutagenesis studies. For instance, alanine scanning of kinase active sites identifies critical hydrogen bonds (e.g., between the pyrido[2,3-d]pyrimidine core and ATP-binding pockets). Surface Plasmon Resonance (SPR) measures binding kinetics (ka/kd) .

The target compound shares structural motifs with several pyrimidine and pyrido-pyrimidine derivatives. Below is a comparative analysis based on substituents, core structure, and functional properties.

Structural and Functional Comparisons

Table 1: Key Structural and Molecular Features

Key Differentiators

Core Saturation and Ring System: The target compound’s hexahydropyrido[2,3-d]pyrimidine core provides partial saturation, balancing rigidity and conformational flexibility. Compound 24 () incorporates a cyclopenta-thieno-pyrimidine system, introducing a fused bicyclic structure absent in the target .

Halogen Substituents :

• The iodine atom in the target compound’s aryl group increases molecular weight and polarizability compared to Trametinib’s fluoro -only substituents. This may enhance target affinity via halogen bonding but reduce solubility .

Functional Groups :

• The trioxo system in the target compound (2,4,7-trioxo) enables extensive hydrogen bonding, a feature shared with Trametinib but absent in sulfur-containing analogs (e.g., ) .

Research Findings and Implications

Bioactivity and Therapeutic Potential

• Kinase Inhibition : Trametinib’s structural similarity () suggests the target compound may act as a RET or MEK inhibitor , leveraging the acetamide moiety for ATP-binding pocket interactions .
• Metabolic Stability: The cyclopropyl group may reduce oxidative metabolism, extending half-life compared to non-cyclopropyl analogs .

Physicochemical Properties

• Lipophilicity: The iodine substituent increases logP compared to non-halogenated analogs (e.g., ), likely enhancing membrane permeability but requiring careful PK/PD optimization .