Doripenem side-chain
[CAS# 491878-06-9]

Identification

• Classification: API >> Antibiotics >> Beta-lactamase inhibitor
• Name: Doripenem side-chain
• Synonyms: 4-Nitrobenzyl (2S,4S)-4-acetylthio-2-[[N-sulfamoyl-N-(tert-butoxycarbonyl)amino]methyl]pyrrolidine-1-carboxylate
• Molecular Formula: C₂₀H₂₈N₄O₉S₂
• Molecular Weight: 532.59
• CAS Registry Number: 491878-06-9
• SMILES: CC(=O)S[C@H]1C[C@H](N(C1)C(=O)OCC2=CC=C(C=C2)[N+](=O)[O-])CN(C(=O)OC(C)(C)C)S(=O)(=O)N

Properties

• Density: 1.45±0.1 g/cm³, Calc.^*
• Melting point: 124-132 °C
• Index of Refraction: 1.616, Calc.^*
• Boiling Point: 686.8±65.0 °C (760 mmHg), Calc.^*
• Flash Point: 369.2±34.3 °C, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H332-H335
• Safety Statements: P261-P280-P305+P351+P338

Discovery and Applications

Doripenem, a member of the carbapenem class of antibiotics, is widely recognized for its effectiveness against a broad spectrum of bacterial pathogens. The molecule’s design includes a β-lactam ring, which is central to its antibacterial activity, but the side-chain of doripenem plays a crucial role in its ability to resist degradation by bacterial enzymes and extend its spectrum of action. The side-chain contributes significantly to its pharmacological properties, stability, and antibacterial activity.

The discovery of doripenem itself occurred through a long-standing effort by pharmaceutical companies to develop new antibiotics capable of combating increasingly resistant bacterial strains. Its side-chain, like other carbapenems, was engineered to enhance stability and effectiveness against β-lactamase enzymes that are commonly produced by resistant bacteria. These enzymes typically hydrolyze the β-lactam ring, rendering the antibiotic ineffective. Doripenem’s side-chain modifications were made with the goal of preventing this enzymatic breakdown while also broadening its activity profile.

The side-chain of doripenem is a key structural feature that contributes to its stability in the presence of bacterial β-lactamases. In particular, the side-chain includes groups that resist cleavage by these enzymes, allowing doripenem to retain its activity even against bacteria that have developed mechanisms of resistance. This modification makes doripenem effective against a wide range of resistant pathogens, including both Gram-positive and Gram-negative bacteria, which makes it an important therapeutic option in hospitals and intensive care units, where multidrug-resistant infections are common.

One of the unique aspects of doripenem’s side-chain is its ability to bind to penicillin-binding proteins (PBPs), which are involved in bacterial cell wall synthesis. This binding prevents the cross-linking of peptidoglycan chains in bacterial cell walls, leading to bacterial lysis. The side-chain structure enhances doripenem's affinity for PBPs, improving its effectiveness against certain resistant organisms.

The side-chain of doripenem also has a role in its pharmacokinetics. It influences the distribution of the drug within the body and its ability to reach the site of infection. Additionally, modifications to the side-chain have implications for doripenem’s ability to be metabolized and excreted by the body, which affects dosing regimens. By altering the side-chain structure, pharmaceutical researchers have been able to fine-tune the drug’s properties for maximum therapeutic effect while minimizing side effects.

Clinically, doripenem, including its side-chain features, is used to treat severe infections caused by multidrug-resistant pathogens. It is commonly used to manage infections such as pneumonia, intra-abdominal infections, urinary tract infections, and complicated skin and soft tissue infections. The drug is administered intravenously, allowing for rapid and effective distribution in critical care settings.

In summary, the side-chain of doripenem plays an essential role in its antibacterial efficacy and stability. Through careful structural modification, researchers have developed a molecule that is both potent against a wide range of bacteria and resistant to enzymatic degradation. As the global challenge of antibiotic resistance continues to grow, the side-chain of doripenem represents an important advancement in the development of effective therapies for resistant infections.

References

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