Josamycin propionate
[CAS# 40922-77-8]

Identification

• Classification: API >> Antibiotics
• Name: Josamycin propionate
• Synonyms: 9-Propionyljosamycin; Josaxin
• Molecular Formula: C₄₅H₇₃NO₁₆
• Molecular Weight: 884.06
• CAS Registry Number: 40922-77-8 (56111-35-4)
• EC Number: 255-140-7
• SMILES: CCC(=O)O[C@H]1/C=C/C=C/C[C@H](OC(=O)C[C@H]([C@@H]([C@H]([C@H](C[C@H]1C)CC=O)O[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)C)O[C@H]3C[C@@]([C@H]([C@@H](O3)C)OC(=O)CC(C)C)(C)O)N(C)C)O)OC)OC(=O)C)C

Properties

• Solubility: Slightly soluble (1.6 g/L) (25 ºC), Calc.^*
• Density: 1.19±0.1 g/cm³ (20 ºC 760 Torr), Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2016 ACD/Labs)

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P280-P305+P351+P338

Discovory and Applicatios

Josamycin propionate is a propionate ester derivative of josamycin, a macrolide antibiotic produced by *Streptomyces narbonensis*. Macrolides are characterized by their large macrocyclic lactone rings and glycosidic linkages to deoxy sugars. Josamycin, in particular, contains a 16-membered macrolactone core substituted with multiple hydroxyl and glycosidic groups, conferring potent antibacterial properties, especially against Gram-positive cocci and atypical pathogens. The propionate ester form is developed to enhance pharmacokinetic properties such as stability, solubility, and bioavailability, while preserving the pharmacodynamic profile of the parent compound.

The chemical structure of josamycin propionate involves esterification of one or more hydroxyl groups present on the josamycin molecule with propionic acid. These esterifications are typically aimed at modifying the molecule’s physicochemical properties without altering its fundamental mode of action. Upon administration, esterases in the human body hydrolyze the propionate group(s), releasing the active josamycin moiety in situ. This approach is often used in prodrug strategies, allowing for improved formulation flexibility, extended shelf-life, and modified absorption profiles. As such, josamycin propionate may exhibit improved pharmacological behavior in oral or parenteral dosage forms.

Like other macrolides, josamycin exerts its antibacterial effect by binding to the 50S subunit of the bacterial ribosome. This binding interferes with the translocation step of protein synthesis, thereby inhibiting bacterial growth. Josamycin and its esters are considered primarily bacteriostatic but may exhibit bactericidal activity at high concentrations or against particularly susceptible organisms. The compound shows notable activity against *Mycoplasma*, *Chlamydia*, *Legionella*, and various Gram-positive bacteria such as *Streptococcus pneumoniae* and *Staphylococcus aureus*. Additionally, its effectiveness against intracellular pathogens makes it especially useful in the treatment of respiratory and soft tissue infections.

The use of ester derivatives such as josamycin propionate can contribute to more consistent pharmacokinetics, particularly in pediatric or veterinary applications. These modified forms are better tolerated and sometimes less bitter in taste, aiding in patient compliance. Josamycin has been marketed in various countries, especially in Europe and Asia, and is considered to have a favorable safety profile with fewer gastrointestinal side effects compared to other macrolides like erythromycin.

In medicinal chemistry, the esterification of macrolide antibiotics is a common strategy to address stability challenges. Macrolides are sensitive to acidic environments, and certain ester derivatives can provide protection during passage through the stomach or improve membrane permeability. The propionate ester, in this context, represents a small, aliphatic acyl group that introduces only minimal steric hindrance, thereby maintaining enzymatic accessibility for activation while enhancing lipophilicity for better tissue penetration.

Furthermore, the ester group can be leveraged to create depot formulations for sustained drug release. This is of particular interest in veterinary medicine, where long-acting injectable formulations of macrolides, including josamycin derivatives, are in use for managing infections in livestock and companion animals. The slow hydrolysis of the ester in such formulations results in prolonged plasma levels and reduced dosing frequency.

In the field of synthetic antibiotic development, structural modification of josamycin—either through esterification or glycoside alteration—has been explored to overcome resistance. While josamycin remains effective against many macrolide-sensitive strains, resistance mechanisms such as methylation of the 23S rRNA or active efflux can diminish efficacy. Modifications like the propionate ester do not directly address resistance but may support formulation innovations and niche applications where the parent compound still holds therapeutic value.

Josamycin propionate exemplifies how minor chemical modifications can substantially influence the pharmacological and therapeutic utility of an existing antibiotic scaffold. It remains a topic of interest in drug formulation, pediatric therapeutics, and antibiotic stewardship programs.

References

1977. Structure-activity relationships among the O-acyl derivatives of leucomycin. Correlation of minimal inhibitory concentrations with binding to Escherichia coli ribosomes. Journal of Medicinal Chemistry, 20(5).
DOI: 10.1021/jm00215a025

1984. Clinical multicentre trial with josamycin propionate in paediatric patients. International Journal of Clinical Pharmacology Research, 4(3).
URL: https://pubmed.ncbi.nlm.nih.gov/6386705

2004. Application of liquid chromatography-ion trap mass spectrometry to the characterization of the 16-membered ring macrolide josamycin propionate. Journal of Mass Spectrometry, 39(3).
DOI: 10.1002/jms.612