4-[2-[[(6R,7R)-2-Carboxy-7-[[(2Z)-(ethoxyimino)[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]thio]-4-thiazolyl]-1-methylpyridinium acetate hydrate
[CAS 400827-55-6]

Identification

• Classification: API >> Inhibitor drug
• Name: 4-[2-[[(6R,7R)-2-Carboxy-7-[[(2Z)-(ethoxyimino)[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]thio]-4-thiazolyl]-1-methylpyridinium acetate hydrate
• Synonyms: Teflaro;Ceftaroline fosamil acetate;(6R,7R)-7-({(2Z)-2-(Ethoxyimino)-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl}amino)-3-{[4-(1-methyl-4-pyridiniumyl)-1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbox ylate acetate hydrate (1:1:1)
• Molecular Formula: C₂₂H₂₂N₈O₈PS₄.C₂H₃O₂.H₂O
• Molecular Weight: 762.74
• CAS Registry Number: 400827-55-6 (866021-48-9)
• EC Number: 617-889-1
• SMILES: CCO/N=C(/C1=NSC(=N1)NP(=O)(O)O)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)SC4=NC(=CS4)C5=CC=[N+](C=C5)C)C(=O)[O-].CC(=O)O.O

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H350
• Safety Statements: P280-P305+P351+P338

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Respiratory sensitization	Resp. Sens.	1	H334
Skin sensitization	Skin Sens.	1	H317

Discovery and Applications

4-[2-[[(6R,7R)-2-Carboxy-7-[[(2Z)-(ethoxyimino)[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]thio]-4-thiazolyl]-1-methylpyridinium acetate hydrate is a complex, highly functionalized organic compound belonging to the class of semisynthetic β-lactam antibiotics, specifically a cephalosporin derivative bearing multiple heterocyclic substituents, ionic groups, and a hydrated salt form. Its structure reflects extensive medicinal chemistry optimization aimed at improving antibacterial spectrum, stability, and pharmacokinetic behavior.

The core of the molecule is based on the 5-thia-1-azabicyclo[4.2.0]oct-2-ene-8-one framework, which is characteristic of the cephalosporin nucleus. This bicyclic system contains a strained β-lactam ring fused to a dihydrothiazine ring. The β-lactam moiety is the key pharmacophore responsible for antibacterial activity, as it interacts with bacterial penicillin-binding proteins (PBPs), which are enzymes involved in the cross-linking of peptidoglycan in bacterial cell walls.

Inhibition of PBPs by β-lactam antibiotics disrupts cell wall biosynthesis, leading to weakened structural integrity and ultimately bacterial cell lysis. This mechanism is bactericidal and highly dependent on the ability of the β-lactam ring to acylate the active site serine residue of PBPs, forming a stable covalent complex that inactivates the enzyme.

The side chain at the 7-position of the cephalosporin core is heavily substituted and includes an (ethoxyimino) group linked to a 1,2,4-thiadiazole ring system bearing a phosphonoamino substituent. These modifications are commonly introduced in advanced cephalosporins to enhance resistance to β-lactamase enzymes produced by resistant bacteria. The oxime (ethoxyimino) functionality, particularly in the Z-configuration, is known to provide steric hindrance that reduces enzymatic hydrolysis of the β-lactam ring.

The presence of a phosphonoamino group introduces a strongly acidic, highly polar functional group that contributes to the molecule’s ionic character and water solubility. Phosphonate-containing substituents can also enhance binding interactions and influence distribution in biological environments, particularly in aqueous systems.

Another key feature of the molecule is the presence of multiple heterocyclic rings, including thiazole and thiadiazole systems. These sulfur- and nitrogen-containing aromatic heterocycles are frequently used in medicinal chemistry to modulate electronic properties, improve metabolic stability, and enhance binding interactions with biological targets. The sulfur atom linking the cephalosporin core to the thiazolyl substituent provides additional structural flexibility and influences overall molecular conformation.

The quaternary pyridinium group in the structure introduces a permanent positive charge, forming a pyridinium cation. This ionic center significantly increases aqueous solubility and promotes interaction with negatively charged biological environments. Quaternary ammonium and pyridinium groups are commonly incorporated into antibiotic structures to enhance pharmacokinetic properties and tissue distribution.

The compound is present as an acetate salt hydrate, indicating that acetate serves as a counterion balancing the overall charge, while water molecules are incorporated into the crystal lattice. Hydration is common in highly polar, ionic pharmaceuticals and can influence solid-state stability, crystallinity, and dissolution behavior.

From a physicochemical perspective, this compound is extremely polar and highly water soluble due to the presence of multiple ionic groups, including carboxylate, phosphonate, and pyridinium functionalities. At the same time, it contains several hydrophobic ring systems, resulting in a highly heterogeneous amphiphilic structure. Such balance is typical of advanced cephalosporin antibiotics designed for systemic or parenteral administration.

The historical development of cephalosporins involved progressive structural modifications to overcome bacterial resistance mechanisms, particularly β-lactamase enzymes. Substituents such as oxyimino groups, bulky heterocycles, and charged functional groups were introduced to enhance stability and broaden antibacterial activity against Gram-negative organisms.

Overall, 4-[2-[[(6R,7R)-2-Carboxy-7-[[(2Z)-(ethoxyimino)[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]thio]-4-thiazolyl]-1-methylpyridinium acetate hydrate is a highly complex cephalosporin antibiotic derivative characterized by a β-lactam core, multiple heterocyclic substituents, and several ionic functional groups. Its significance lies in its role as a structurally advanced antibacterial agent designed to inhibit bacterial cell wall synthesis while maintaining enhanced stability against enzymatic degradation.

References

2007. In Vivo Efficacy of Ceftaroline (PPI-0903), a New Broad-Spectrum Cephalosporin, Compared with Linezolid and Vancomycin against Methicillin-Resistant and Vancomycin-Intermediate Staphylococcus aureus in a Rabbit Endocarditis Model. Antimicrobial Agents and Chemotherapy.
DOI: 10.1128/aac.01242-06