Introduction
C11H12N4O3S is a small organic molecule that features a combination of nitrogen, oxygen, and sulfur heteroatoms within a relatively compact carbon skeleton. The presence of these heteroatoms gives the compound a range of physicochemical properties that make it a useful scaffold in medicinal chemistry, agrochemicals, and materials science. In the literature it is frequently encountered as a thioamidated urea derivative or as a member of the thiazolidinone family, both of which are known for their bioactive potential. Because of its modest molecular weight (260.29 g mol⁻¹) and high polarity, the compound is typically obtained as a white crystalline solid with a melting point in the range of 120 – 140 °C and moderate solubility in polar organic solvents such as methanol, ethanol, and dimethyl sulfoxide.
Molecular Formula and Composition
The formula C11H12N4O3S indicates that the molecule consists of eleven carbon atoms, twelve hydrogen atoms, four nitrogen atoms, three oxygen atoms, and one sulfur atom. Calculation of the degree of unsaturation (also known as the index of hydrogen deficiency) gives a value of 8, suggesting the presence of multiple rings or double bonds within the structure. This is consistent with the common core of a thiazolidinone fused to a urea moiety or with a thiohydantoin ring system. Isotopically, the compound is composed almost entirely of the most abundant isotopes: ¹²C, ¹H, ¹⁴N, ¹⁶O, and ³⁴S. The sulfur atom is typically present as ³⁴S, which has a natural abundance of about 4 % and contributes to mass spectrometric fragmentation patterns that include the characteristic ³⁴S isotopic doublet.
Structural Isomers and Chemical Class
Because the formula contains no halogen or additional heteroatoms, the principal structural variations arise from the positioning of the nitrogen, oxygen, and sulfur atoms within the carbon framework. Two major classes of isomers are commonly reported: thioamidated urea derivatives and thiazolidinone-based scaffolds. In the thioamidated urea class, the sulfur atom is incorporated as a thioamide (C=S) functional group, whereas the nitrogen atoms are present in amide linkages. In the thiazolidinone class, the sulfur and one nitrogen are part of a five‑membered ring that bears a carbonyl group at the 2‑position, and the remaining nitrogen atoms are incorporated into an exocyclic urea or amidine group.
- Thioamidated urea isomers typically possess a central thioamide carbonyl (C=S) flanked by two urea or amide nitrogen atoms.
- Thiazolidinone isomers contain a 1,3‑thiazolidine ring fused to an amidinium or urea side chain.
- Both families exhibit planar aromatic character due to conjugation between the heteroatoms and adjacent carbonyl groups.
Physical and Chemical Properties
Key physical properties of the compound are summarized below. Values can vary slightly depending on crystal polymorph and solvent of recrystallization.
- Melting point: 124 – 138 °C
- Boiling point: >250 °C (decomposes prior to boiling)
- Density (solid): 1.28 – 1.32 g cm⁻³
- Solubility: insoluble in hexane and diethyl ether; moderately soluble in methanol (≈10 mg mL⁻¹), ethanol (≈20 mg mL⁻¹), and DMSO (≈50 mg mL⁻¹)
- Log P (octanol/water partition coefficient): −0.5 to −0.8
- Water solubility: 0.3 – 0.5 mg mL⁻¹ at 25 °C
- UV‑Vis absorption: a strong absorption band around 230 nm attributable to the π→π* transition of the thioamide group; a weaker band near 280 nm due to the urea carbonyl.
The compound displays a characteristic thioamide infrared absorption band near 1160 cm⁻¹ and a carbonyl stretch of the urea moiety around 1650 cm⁻¹. In addition, the ¹H NMR spectrum in CDCl₃ shows signals for the aromatic or heteroaromatic protons in the range 7.5 – 8.5 ppm and for the urea methylene protons as a singlet or doublet around 4.8 ppm.
Synthesis and Industrial Production
The synthesis of C11H12N4O3S typically follows a multistep route that introduces the sulfur atom through a thiolation step, followed by formation of the urea linkage. The most common laboratory scale approach employs an aromatic amine precursor, a suitable thioanhydride, and a carbonyldiimidazole (CDI) coupling reagent. Industrial processes often replace CDI with more cost‑effective coupling agents such as triphosgene or dimethyl carbonate, and the thiolation step is carried out in a continuous flow reactor to improve safety.
Laboratory Scale Synthesis
- Formation of the thioanhydride. 4‑Chlorobenzoyl chloride (1 equiv) is reacted with potassium thioacetate (2 equiv) in dry THF under nitrogen at 0 °C, followed by warming to room temperature. The resulting thioanhydride is isolated by filtration and evaporated to dryness.
- Coupling with an aromatic amine. 4‑Amino‑2‑(tert‑butyl)phenylamine (1.1 equiv) is dissolved in dry DMF and the thioanhydride is added portionwise. The reaction mixture is stirred for 4 h at 60 °C. The intermediate amide is purified by column chromatography (silica gel, hexane/ethyl acetate 4:1).
- Carbonyldiimidazole activation. The purified amide (1 equiv) is dissolved in dry DCM, cooled to 0 °C, and CDI (1.2 equiv) is added. The mixture is stirred for 30 min to form the activated imidazolyl carbamate.
- Introduction of the urea group. An aqueous solution of urea (3 equiv) is added dropwise, and the reaction is allowed to proceed at 25 °C for 12 h. The product is extracted with ethyl acetate, washed with brine, dried over anhydrous Na₂SO₄, and concentrated.
- Final purification. The crude product is recrystallized from methanol/hexane to yield pure C11H12N4O3S as a white crystalline solid.
Industrial Routes
Large‑scale production typically incorporates a continuous synthesis of the thioanhydride in a sealed reactor. After formation of the thioanhydride, the amide coupling step is performed in a high‑temperature autoclave with in‑line monitoring of reaction progress by FTIR. The CDI activation step is replaced with a chlorocarbonylation using phosgene derivatives under strict temperature control. Purification is achieved by crystallization from a mixture of ethanol and isopropanol, followed by vacuum drying at 60 °C.
Spectroscopic and Analytical Characterization
Standard analytical techniques are employed to confirm the identity and purity of C11H12N4O3S.
- Elemental analysis (C, H, N) matches calculated values within ±0.2 %.
- ¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 1H, aromatic), 7.68 (d, 2H, aromatic, J = 8.8 Hz), 4.86 (s, 2H, urea methylene), 3.45 (s, 3H, N‑CH₃).
- ¹³C NMR (100 MHz, CDCl₃): δ 175.3 (C=O), 162.5 (C=S), 136.7 (aryl‑C), 119.9 (aryl‑C), 55.2 (N‑CH₃).
- IR (KBr): 1650 cm⁻¹ (C=O), 1160 cm⁻¹ (C=S), 3360 cm⁻¹ (N–H).
- High‑resolution mass spectrometry (ESI+): m/z 260.0763 (M + H) matching calculated 260.0761.
- Single‑crystal X‑ray diffraction: confirms a thioamidated urea core with a planar heteroaromatic ring; crystallographic parameters include a monoclinic space group P2₁/c.
Biological Activity and Pharmacology
C11H12N4O3S has been investigated as a potential inhibitor of several enzymes involved in bacterial cell wall synthesis and fungal ergosterol biosynthesis. Its thioamide functionality is believed to act as a warhead that forms a covalent adduct with active‑site cysteine residues, leading to irreversible inhibition. In addition, the compound shows moderate affinity for human carbonic anhydrase II (K_i ≈ 8 µM) and displays weak activity against acetylcholinesterase (K_i ≈ 200 µM).
Mechanism of Action
Crystallographic studies of the compound bound to bacterial transpeptidase (class A) reveal that the thioamide nitrogen coordinates to the zinc ion in the active site, while the urea oxygen participates in hydrogen bonding with a conserved serine residue. The sulfur atom forms a transient sulfenic acid intermediate that permanently inactivates the enzyme. In fungal lanosterol 14‑α‑demethylase, the compound binds to the heme iron through its thioamide, blocking substrate access.
Pharmacokinetics
In vivo studies in mice demonstrate that oral administration of 10 mg kg⁻¹ leads to peak plasma concentrations of 0.5 µM at 30 min. The compound shows a distribution volume of 0.9 L kg⁻¹ and a half‑life of 2.3 h. Metabolic profiling indicates phase I oxidation at the thioamide sulfur to a sulfoxide, followed by glucuronidation of the urea nitrogen. Renal excretion accounts for 60 % of the dose, with the remainder eliminated via fecal routes.
Toxicology and Safety
Acute toxicity data from the rat model yield an LD₅₀ of 350 mg kg⁻¹ when administered orally. Subchronic exposure (28 days) at 50 mg kg⁻¹ causes mild hepatocellular vacuolation without significant changes in serum alanine aminotransferase. No teratogenic effects are observed in pregnant rabbit studies up to 200 mg kg⁻¹. The compound is not mutagenic in the Ames test (Salmonella typhimurium TA98/100) and shows no clastogenicity in the micronucleus assay.
- Skin and eye irritation: no significant irritation observed in the Draize test.
- Reactivity: mild reaction with strong bases, forming a sulfonate salt that can be hydrolyzed under acidic conditions.
- Handling precautions: use of a glove box and fume hood is recommended due to the potential formation of sulfenic acid intermediates.
Applications in Industry
Beyond pharmaceutical development, the compound finds utility as a catalyst in polymerization reactions, particularly in the synthesis of heterocyclic polythioamides. It also serves as a building block in the manufacture of high‑performance coatings for aerospace components, where its resistance to hydrolysis and thermal stability are valued.
- Polymers: cross‑linking of poly(ethylene terephthalate) with C11H12N4O3S yields a material with a glass transition temperature of 165 °C.
- Coatings: a thin film of the compound mixed with polyurethane resin shows enhanced adhesion to metal surfaces and improved UV stability.
- Water‑disinfection: aqueous solutions at 2 mg mL⁻¹ effectively reduce bacterial CFU counts by 3 log units within 15 min.
Regulatory Status
As of 2023, C11H12N4O3S has not yet received FDA approval for any indication. However, it is listed as a “Investigational New Drug” (IND) under the U.S. Food and Drug Administration (FDA) for Phase I clinical trials targeting multidrug‑resistant tuberculosis. In the European Union, the compound is classified under the European Medicines Agency (EMA) as a “Class I” hazardous chemical, requiring an Environmental Risk Assessment (ERA) for release into the atmosphere.
Environmental Impact
The environmental persistence of C11H12N4O3S is limited due to its rapid hydrolysis in aqueous media. Degradation products, primarily the sulfoxide and urea derivatives, are readily biodegradable with a half‑life of 4 days in soil under aerobic conditions. Aquatic toxicity studies show a LC₅₀ for Daphnia magna of 1.2 mg L⁻¹, indicating moderate toxicity to invertebrate species. Biosorption by algae can reduce surface concentrations by up to 30 % in natural waters.
Future Directions
Current research focuses on modifying the thioamide linker to improve selectivity toward bacterial enzymes while reducing off‑target effects. One strategy involves replacing the exocyclic urea with a cyclic imidazolidinylidene moiety, resulting in a new derivative (C₁₃H₁₄N₅O₃S) with a K_i ≈ 2 µM against β‑lactamases. In silico docking studies suggest that the addition of a fluorine substituent at the 4‑position of the aromatic ring increases lipophilicity without compromising hydrogen‑bonding capacity.
No comments yet. Be the first to comment!