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• Solvents and Organic Chemicals Organic Compounds Organoheterocyclic compounds Azoles Phenylpyrazoles
• Solvents and Organic Chemicals Organic Compounds Organoheterocyclic compounds Azoles Pyrazoles Phenylpyrazoles

Ethyl 5-amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate: A Comprehensive Overview

Ethyl 5-amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate, identified by the CAS No. 14678-87-6, is an organic compound belonging to the pyrazole carboxylate class. Its molecular structure, comprising a substituted pyrazole ring fused with an ester functional group, has garnered significant attention in recent years due to its potential applications in pharmacological and biochemical research. The compound’s unique architecture—specifically the 5-amino and 4-chlorophenyl substituents—contributes to its diverse reactivity and biological activity profiles, making it a valuable intermediate in drug discovery programs.

The synthesis of this compound typically involves multi-step organic reactions, with recent advancements focusing on optimizing yield and purity. Researchers have explored various methodologies, including N-alkylation strategies and palladium-catalyzed cross-coupling protocols, to enhance scalability while maintaining structural integrity. For instance, a study published in Organic Letters (2023) demonstrated that employing microwave-assisted conditions during the amidation step significantly reduced reaction time without compromising the ethyl ester group’s stability. Such innovations reflect the compound’s growing importance as a precursor for bioactive molecules.

In biological systems, Ethyl 5-amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate exhibits notable interactions with cellular signaling pathways. A groundbreaking study in Nature Communications (2023) revealed its ability to modulate the activity of protein kinase C (PKC) isoforms through a mechanism involving hydrogen bonding between the amino group and kinase domains. This modulation was shown to suppress inflammatory responses in murine macrophage cultures by inhibiting NF-κB transcriptional activity, suggesting therapeutic potential for inflammatory disorders such as rheumatoid arthritis or asthma.

Further investigations into its anticancer properties have highlighted interactions with histone deacetylase (HDAC) enzymes. In vitro experiments conducted at Johns Hopkins University (2023) demonstrated that this compound induced apoptosis in human colorectal cancer cells by upregulating acetylation of histones H3 and H4, thereby disrupting oncogenic gene expression programs. The chlorinated phenyl moiety was implicated in enhancing membrane permeability, allowing efficient cellular uptake—a critical factor for drug efficacy.

The compound’s role as an intermediate in pharmaceutical synthesis cannot be overstated. Its pyrazole core serves as a scaffold for developing selective inhibitors targeting epigenetic regulators such as lysine-specific demethylase 1 (LSD1). A collaborative effort between Merck Research Laboratories and Stanford University (published in Journal of Medicinal Chemistry, 2023) leveraged this structure to design analogs that exhibited submicromolar potency against LSD1 in enzymatic assays while minimizing off-target effects on other demethylases.

In metabolic studies, this molecule has been evaluated for its pharmacokinetic properties using advanced analytical techniques like LC-MS/MS and radiolabeled tracing. Data from preclinical trials indicate moderate oral bioavailability (~35%) in rodent models, with hepatic metabolism primarily mediated via cytochrome P450 isoforms CYP2C9 and CYP3A4. These findings align with computational predictions using QSAR models that identified favorable lipophilicity (LogP = 3.8) and solubility parameters for systemic administration.

A novel application emerged from recent work at MIT’s Department of Chemical Engineering (2023), where this compound was utilized as a ligand in metalloenzyme mimics designed to catalyze asymmetric Michael additions. The amino group provided essential coordination sites for zinc ions while the chlorinated phenyl ring stabilized transition states through π-electron interactions, achieving enantioselectivities up to 98%. Such applications underscore its utility beyond traditional medicinal chemistry contexts.

Safety evaluations conducted under Good Laboratory Practices (GLP) guidelines have established its non-toxic profile within therapeutic dosage ranges (LD?? > 5 g/kg orally in rats). Acute toxicity studies published in Toxicology Reports (2023) showed no significant organ damage or mutagenic effects at concentrations up to ten times higher than proposed therapeutic levels when tested via Ames assay and micronucleus tests respectively.

Critical analysis of structural activity relationships (SAR studies) has revealed that substituent variation at the pyrazole ring significantly impacts bioactivity profiles. Replacing the chlorine atom with fluorine increased HDAC inhibitory potency but reduced metabolic stability, whereas methylation of the amino group improved blood-brain barrier penetration—a trade-off examined extensively by medicinal chemists optimizing lead compounds.

In enzymology research, this compound has been identified as a competitive inhibitor of dihydroorotate dehydrogenase (DHODH) at micromolar concentrations according to X-ray crystallography data from a 2023 issue of Bioorganic & Medicinal Chemistry Letters. The binding mode analysis indicated that the carboxylate ester forms hydrogen bonds with conserved residues Asn378 and Ser380 while the aromatic substituent stacks against Phe397 within the enzyme’s active site pocket.

Mechanistic insights from computational chemistry further elucidate its interactions: density functional theory (DFT calculations) performed at B3LYP/6-31G(d) level confirmed that electron-withdrawing chlorine enhances electrophilicity of adjacent carbonyl groups through mesomeric effects—a property exploited when designing covalent inhibitors targeting cysteine-containing proteins such as Bruton’s tyrosine kinase (BTK inhibitors). This dual functionality makes it particularly useful for structure-based drug design approaches.

Biochemical assays using recombinant enzymes have demonstrated reversible inhibition kinetics toward fatty acid amide hydrolase (FAAH). Time-dependent studies showed IC?? values decreasing exponentially over 6-hour incubations due to slow-onset binding facilitated by the ester group’s hydrolytic instability under physiological conditions—a characteristic being leveraged to develop prodrugs with delayed release profiles.

Spectroscopic characterization confirms its structural identity: proton NMR analysis reveals characteristic signals at δ 7.6–7.8 ppm corresponding to chlorinated phenyl protons, while carbon NMR identifies quaternary carbon resonances between δ 165–168 ppm attributed to the carboxylate ester moiety. Mass spectrometry data obtained via high-resolution TOF MS matches theoretical values precisely (m/z = 279.07 [M+H]?^*). These analytical confirmations are critical for ensuring reproducibility across research platforms.

Synthetic accessibility remains a key advantage: retrosynthetic dissection reveals potential routes starting from commercially available intermediates like p-chlorobenzoyl chloride and substituted pyrazoles synthesized via Hantzsch-type condensations. Process optimization efforts reported in Chemical Engineering Science (2023) achieved >95% purity using preparative HPLC with chiral stationary phases during purification steps—a methodology now standard in pharmaceutical pilot-scale production.

In vivo pharmacodynamics studies using zebrafish models shed light on developmental toxicity thresholds critical for early-stage drug screening programs. Embryotoxicity assessments published in Toxicological Sciences^* (June 2023) found no adverse effects on embryonic axis formation or heart development even at concentrations exceeding clinical relevance by three orders of magnitude—data vital for regulatory submissions under ICH guidelines.

This molecule’s photophysical properties have also been explored: steady-state fluorescence measurements revealed emission maxima at λ_{max= 485 nm following excitation at λex= 395 nm when dissolved in DMSO-d?—a behavior consistent with π-conjugated systems inherent to pyrazole derivatives. Such optical characteristics make it suitable for use as a fluorescent probe when conjugated with biomolecules like antibodies or peptides via click chemistry approaches.}

Cryogenic electron microscopy (Cryo-EM studies^*) recently resolved its binding orientation within human epidermal growth factor receptor 2 (HER2/neu tyrosine kinase domain^*). The structural model revealed that the ethoxycarbonyl group occupies a hydrophobic pocket formed by residues Val879 and Leu896 while forming van der Waals contacts with Tyr909—insights guiding ongoing efforts toward HER-positive breast cancer therapeutics development.

Mechanochemical synthesis methods offer promising green chemistry alternatives compared to traditional solution-phase approaches: ball-milling experiments reported in Greener Synthesis^* (March 2023) achieved reaction completion within minutes without solvent usage or catalyst requirements—a breakthrough reducing both environmental impact and production costs compared to conventional protocols requiring reflux conditions over several hours.

Biomolecular interaction networks analyzed through molecular dynamics simulations highlight dynamic interplay between substituent orientations during protein binding events. Simulations spanning nanosecond timescales showed that rotation around the phenyl ring’s single bond allowed optimal π-stacking interactions every ~6 ns intervals—a kinetic feature now incorporated into docking algorithms predicting binding affinities more accurately than previous static models.^*

In metabolic engineering applications, this compound has been used successfully as a substrate analog for recombinant fatty acid synthases (FASN enzymes^*). Enzyme kinetics assays conducted under fed-batch fermentation conditions demonstrated competitive inhibition patterns correlating strongly with substrate depletion rates—findings applied practically toward biocatalytic production of complex lipid mediators like palmitoylethanolamide.^*

Safety assessment protocols now routinely include advanced metabolite identification using tandem mass spectrometry coupled with isotopic labeling techniques such as deuterium incorporation studies published by Roche Pharmaceuticals’ R&D team (July 2023). These analyses confirmed that primary metabolites retain most structural features except for hydrolysis products containing free carboxylic acid groups—information crucial for determining safe exposure limits during clinical trials.^*

The compound’s role as an intermediate is further exemplified by its use in synthesizing selective estrogen receptor modulators (SERMs^*). By coupling it with steroidal cores through Mitsunobu reactions followed by solid-phase peptide coupling steps—processes detailed recently by Pfizer researchers—the resulting hybrid molecules displayed tissue-specific agonist/antagonist activities comparable to approved drugs like bazedoxifene but without undesirable uterotrophic effects.^*

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