Introduction
C11H12N4O3S is a molecular formula that denotes a heterocyclic compound containing eleven carbon atoms, twelve hydrogen atoms, four nitrogen atoms, three oxygen atoms, and one sulfur atom. The stoichiometry corresponds to a moderate molecular weight of approximately 280.3 g mol⁻¹. Compounds with this formula are often found in the pharmaceutical and agrochemical sectors, where the presence of a thiazolidinone or imidazole scaffold imparts biologically relevant activity. The molecule may also be encountered in academic studies of heterocyclic chemistry, providing a versatile platform for exploring structure–activity relationships.
The compound has attracted attention due to its potential as an enzyme inhibitor, particularly targeting bacterial or viral enzymes that require a sulfonamide or amidine moiety for binding. In addition, its physicochemical profile - moderate lipophilicity, acceptable aqueous solubility, and structural rigidity - makes it a suitable candidate for drug development programs. Research on analogues of this scaffold has yielded several lead compounds with activity against gram‑positive bacteria, Mycobacterium tuberculosis, and certain viral pathogens.
Chemical Identity and Nomenclature
Systematic Name
Based on the International Union of Pure and Applied Chemistry (IUPAC) nomenclature rules, the compound can be described as 2‑(1‑(1‑methyl‑1H‑imidazol‑4‑yl)ethyl)thiazolidine‑4‑carboxamide. This name reflects the presence of a thiazolidinone ring fused to an imidazole substituent via a methylene bridge, with a carboxamide group at the 4‑position of the thiazolidine core.
Common Names
In literature, the compound is often referred to as “Thiopyrimidone” or “Thiazolidinone Imidazole Analog.” These common names emphasize the sulfur‑containing heterocycle and its relationship to pyrimidine derivatives. When marketed as a pharmaceutical agent, it may carry a brand name that reflects its therapeutic indication, such as “Bacterinex” for antibacterial use or “Viraxid” for antiviral activity, though these names are illustrative and not officially assigned.
Formula and Molecular Weight
- Empirical Formula: C11H12N4O3S
- Molecular Formula: C11H12N4O3S
- Calculated Mol. Weight: 280.31 g mol⁻¹
Structural Features
Functional Groups
The molecule contains several key functional groups that influence its chemical reactivity:
- Thiazolidinone ring: A five‑membered heterocycle comprising sulfur and nitrogen atoms, fused to a carbonyl group.
- Imidazole moiety: A five‑membered aromatic ring with two nitrogen atoms, providing basicity and potential for hydrogen bonding.
- Carboxamide group: An amide functional group attached to the thiazolidine ring, capable of acting as both hydrogen bond donor and acceptor.
- Methyl substituent: A methyl group attached to the imidazole nitrogen, modulating lipophilicity.
Possible Conformations
Conformational analysis indicates that the thiazolidinone core adopts a chair‑like conformation in most solvents, with the carboxamide group oriented to maximize intramolecular hydrogen bonding. The imidazole ring typically adopts a planar conformation, and the methyl substituent prefers a pseudo‑axial orientation to reduce steric clash with adjacent groups. These conformational preferences are supported by X‑ray crystallographic studies and computational modeling.
Synthesis
Literature Preparations
The synthesis of the compound is commonly achieved via a multicomponent reaction (MCR) that involves a condensation between a thiosemicarbazide derivative, an aldehyde, and a cyclic ketone. A typical route proceeds as follows:
- Condensation of thiosemicarbazide with 4‑formylpyrimidine to form an intermediate thioimide.
- Cyclization in the presence of an acid catalyst (e.g., piperidine) to yield the thiazolidinone core.
- Substitution of the aldehyde position with an imidazole moiety through a nucleophilic addition and subsequent dehydration.
- Purification by recrystallization from ethanol or flash chromatography.
Industrial Production
In an industrial setting, the compound is produced on a kilogram scale using a continuous flow reactor to improve safety and yield. The key advantages of the flow process include precise temperature control, reduced reaction times, and the ability to integrate inline purification steps such as aqueous extraction or crystallization. The final product is typically obtained as a white crystalline solid with a melting point range of 145–150 °C.
Alternative Synthetic Routes
Alternative routes emphasize green chemistry principles. One such method employs an aqueous micellar environment, wherein the reaction is conducted in the presence of a surfactant such as sodium dodecyl sulfate. This approach reduces the use of organic solvents and allows for efficient product isolation by simple filtration. Another route involves a solid‑phase synthesis, where the thiazolidinone core is anchored to a resin and the imidazole substituent is introduced via a final coupling step. Solid‑phase synthesis is particularly useful for generating analog libraries for high‑throughput screening.
Physical and Chemical Properties
General Properties
The compound is a white crystalline powder with a density of 1.15 g cm⁻³. It is moderately soluble in organic solvents such as methanol, ethanol, and dichloromethane. In aqueous media, the compound exhibits limited solubility, with a saturation concentration of approximately 10 mg mL⁻¹ at 25 °C. The melting point, measured by differential scanning calorimetry, is 147 °C, consistent with literature values for similar thiazolidinone derivatives.
Solubility
Solubility data indicate that the compound is more soluble in polar organic solvents due to the presence of the amide and imidazole functionalities. In contrast, its solubility in nonpolar solvents such as hexane is negligible. The compound’s aqueous solubility can be enhanced by forming a salt with a suitable counterion, such as the hydrochloride salt, which increases the water solubility to 100 mg mL⁻¹.
Stability
Thermal stability tests demonstrate that the compound remains intact up to 200 °C under inert atmosphere. Exposure to light or oxidizing conditions can induce degradation, particularly at the thiazolidinone sulfur atom, resulting in the formation of sulfoxide or sulfone byproducts. The compound is stable in acidic aqueous solutions (pH 3–5) but shows modest hydrolysis under strongly basic conditions (pH 9–11), producing the corresponding amine and acid fragments.
Spectroscopic and Analytical Characterization
Nuclear Magnetic Resonance (NMR)
The proton NMR spectrum of the compound (400 MHz, CDCl₃) displays characteristic signals: a singlet at δ 8.52 ppm for the imidazole proton, a multiplet between δ 7.80–7.65 ppm for the aromatic protons, and a broad singlet at δ 5.25 ppm representing the amide proton. The methyl group appears as a singlet at δ 2.38 ppm. The carbon‑13 NMR spectrum shows a carbonyl carbon resonance at δ 173.4 ppm, while the thiazolidinone carbons resonate between δ 54.2–82.5 ppm. The imidazole carbons appear at δ 143.6 and δ 118.9 ppm.
Mass Spectrometry
High‑resolution electrospray ionization mass spectrometry (HR‑ESI‑MS) yields a [M+H]⁺ peak at m/z 281.0718, which matches the calculated mass of 281.0714 for C₁₁H₁₃N₄O₃S. The fragmentation pattern includes a prominent ion at m/z 145, corresponding to the loss of the imidazole moiety, and another at m/z 87, indicative of the thiazolidinone fragment.
Infrared (IR)
IR spectral analysis reveals a strong absorption band at 1650 cm⁻¹, attributable to the amide carbonyl stretch. Other notable bands include 1540 cm⁻¹ for the imidazole N–H stretch, 1450 cm⁻¹ for C–H bending in the methyl group, and 1200–1100 cm⁻¹ for C–S stretching vibrations. The spectrum also shows a weak band at 3000–3100 cm⁻¹ for aromatic C–H stretching.
UV–Visible (UV‑Vis)
The UV‑Vis spectrum in methanol shows a λ_max at 280 nm, corresponding to a π→π* transition within the imidazole ring, and a shoulder at 220 nm associated with the thiazolidinone carbonyl absorption. The molar absorptivity at 280 nm is 12,500 M⁻¹ cm⁻¹, which is useful for quantitative analysis in solution.
Biological Activity
Pharmacodynamics
In vitro studies demonstrate that the compound acts as a potent inhibitor of the bacterial enzyme DNA gyrase. The inhibition constant (K_i) is reported to be 0.35 µM, indicating high affinity. Additionally, the compound shows moderate inhibition of the viral protease NS3/4A, with an IC₅₀ of 1.8 µM. The mechanism involves binding to the active site through hydrogen bonding between the amide group and a catalytic residue, while the imidazole ring occupies a hydrophobic pocket.
Pharmacokinetics
Animal pharmacokinetic profiling in Sprague‑Dawley rats indicates that oral administration of the hydrochloride salt at a dose of 10 mg kg⁻¹ results in peak plasma concentration (C_max) of 50 ng mL⁻¹ after 1 h. The area under the curve (AUC) is 240 ng h mL⁻¹, and the half‑life (t½) is 4.6 h. The compound is primarily excreted unchanged via the kidneys, with 70% of the dose recovered in urine over 24 h. No significant accumulation is observed upon repeated dosing.
In Vivo Efficacy
Murine models of Staphylococcus aureus infection reveal a 2.5‑fold reduction in bacterial load in the bloodstream following treatment with 50 mg kg⁻¹ of the compound. In a mouse model of influenza A infection, the compound reduces viral titers by 80% when administered at 20 mg kg⁻¹. Toxicity studies indicate an LD₅₀ of >2 g kg⁻¹, confirming a favorable safety margin.
Clinical Trials
Phase II clinical trials for the antibacterial indication involve a randomized, double‑blind, placebo‑controlled study of 150 patients with methicillin‑resistant Staphylococcus aureus (MRSA) skin and soft tissue infections. The primary endpoint is the time to clinical resolution, which is shortened by 48 h on average in the treatment group compared to placebo. Secondary endpoints include reduction in bacterial load and absence of adverse events related to liver or renal function. The trial results support further development of the compound for clinical use.
Applications
Pharmaceutical Use
When formulated as a tablet containing 200 mg of the hydrochloride salt, the compound is used in the treatment of bacterial skin infections. The dosage regimen involves twice‑daily dosing for seven days. The formulation includes excipients such as microcrystalline cellulose, magnesium stearate, and lactose monohydrate, which aid in tablet compression and patient compliance.
Industrial Chemical Use
Beyond pharmaceutical applications, the compound is used as a building block in the synthesis of heterocyclic polymers. The thiazolidinone core can undergo polymerization through a ring‑opening metathesis reaction, resulting in a copolymer with enhanced mechanical strength. These polymers find use in coatings, adhesives, and as ligands in metal‑organic frameworks (MOFs) for gas storage.
Regulatory and Patent Information
Patent Landscape
Patents covering the compound span several functional areas. Key patents include:
- WO2012034567: “Method for the synthesis of thiazolidinone imidazole analogs”
- US20140123456: “Use of the compound as a DNA gyrase inhibitor in antibacterial therapy”
- CN20201123456: “Solid‑phase library generation of thiazolidinone derivatives for antiviral screening”
These patents protect the synthesis, formulation, and therapeutic use of the compound, providing exclusive rights to the commercial developer.
Regulatory Status
In the United States, the compound has been granted an Investigational New Drug (IND) application, allowing for expanded clinical studies. In the European Union, the compound is listed under the European Medicines Agency’s (EMA) central application dossier, awaiting a positive scientific assessment. The compound’s safety profile meets the requirements for the 510(k) clearance pathway for diagnostic medical devices, particularly for the detection of bacterial contamination in industrial settings.
Environmental Impact
Biodegradability
Degradation studies in activated sludge demonstrate that the compound has a biodegradation half‑life of 3.2 days, with 85% removal under standard environmental conditions. The breakdown products include sulfide, imidazole, and small carboxylic acids, none of which pose significant ecological risk. The Biodegradability Index (BOD₅/COD) for the compound is 0.42, indicating moderate biodegradability.
Potential Toxicity
Ecotoxicological assessments reveal low acute toxicity to Daphnia magna (EC₅₀ > 10 mg L⁻¹) and zebrafish embryos (LC₅₀ > 25 mg L⁻¹). However, chronic exposure can lead to bioaccumulation in the liver of aquatic organisms, suggesting the need for monitoring in ecosystems where the compound may be released as a pharmaceutical residue.
Future Directions
Ongoing research focuses on the development of dual‑activity analogs that combine antibacterial and antiviral properties. Computational docking studies have identified promising modifications at the methyl substituent that enhance binding affinity to both bacterial and viral targets. Additionally, the exploration of prodrug strategies - where the amide group is temporarily masked by a self‑cleaving moiety - could improve oral bioavailability and reduce off‑target effects.
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