Azithromycin
Overview
Description
Azithromycin is a broad-spectrum macrolide antibiotic used to treat a variety of bacterial infections. It was discovered in the 1980s by the pharmaceutical company Pliva in Croatia and approved for medical use in 1988 . This compound is known for its long half-life and high tissue penetration, making it effective against respiratory, enteric, and genitourinary infections .
Mechanism of Action
Azithromycin is a broad-spectrum macrolide antibiotic with a high degree of tissue penetration . It is primarily used for the treatment of respiratory, enteric, and genitourinary infections .
Target of Action
This compound’s primary target is the 23S rRNA of the bacterial 50S ribosomal subunit . This component plays a crucial role in bacterial protein synthesis.
Mode of Action
This compound binds to the 23S rRNA of the bacterial 50S ribosomal subunit . This binding inhibits the transpeptidation/translocation step of protein synthesis and prevents the assembly of the 50S ribosomal subunit . As a result, it stops bacterial protein synthesis, leading to the inhibition of bacterial growth and multiplication .
Biochemical Pathways
This compound disrupts crucial biochemical pathways by binding to specific targets, thereby preventing cell growth and, in the case of bactericidal agents, causing cell death . It inhibits bacterial protein synthesis, quorum-sensing, and reduces the formation of biofilm .
Pharmacokinetics
This compound has a long half-life and a high degree of tissue penetration . Approximately 37% of a single oral dose of 500 mg is bioavailable, producing a peak serum concentration of 0.4 mg/l . It is carried to the site of infection by human phagocytic cells . Biliary excretion of this compound, primarily as unchanged drug, is a major route of elimination .
Result of Action
The result of this compound’s action is the inhibition of bacterial growth and multiplication . By disrupting protein synthesis, it prevents the bacteria from growing and reproducing, which eventually leads to the death of susceptible bacteria .
Action Environment
This compound’s action, efficacy, and stability can be influenced by environmental factors. For instance, it has been found that higher concentrations of this compound are reported in diseased (inflamed) gingiva compared with healthy gingiva . This suggests that using a higher first dose of this compound with an acute infection, when the inflammatory response is most pronounced and phagocytic cells are likely to be most abundant, may result in increased absorption and delivery to an infection site within the first 24 hours, causing greater bacterial clearance .
Biochemical Analysis
Biochemical Properties
Azithromycin is part of the azalide subclass of macrolides, and contains a 15-membered ring, with a methyl-substituted nitrogen instead of a carbonyl group at the 9a position on the aglycone ring . This allows for the prevention of its metabolism . This compound is a weak substrate for CYP3A4, and is minimally metabolized by the enzyme .
Cellular Effects
This compound is known to have both antiviral and immunomodulatory effects . It interferes with receptor-mediated binding, viral lysosomal escape, intracellular cell-signaling pathways, and enhances type I and III interferon expression . It also disrupts immune and metabolic networks, including down-regulation of mucin production .
Molecular Mechanism
This compound works by decreasing the production of protein, thereby stopping bacterial growth . It binds to the 23S rRNA of the bacterial 50S ribosomal subunit . This inhibits protein synthesis, which is essential for bacterial replication .
Temporal Effects in Laboratory Settings
This compound is used long term for the prevention of exacerbations of bronchiectasis and COPD . The usual dose is 250mg three times a week . It has been demonstrated to maintain this compound concentrations at sites of infection and continues to be effective for several days after administration has ceased .
Dosage Effects in Animal Models
In animal models, the effects of this compound can vary with different dosages . For example, a single oral dose of 10 to 40 mg/kg provided tissue levels that were proportional to the dose in rats . Two- to 4-fold increases in tissue concentration were observed in rats after being dosed with 20 mg/kg for 7 days .
Metabolic Pathways
This compound is associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles . In vitro, this compound exposure inhibited T-cell cytotoxicity against tumor cells and impaired T-cell metabolism through glycolysis inhibition .
Transport and Distribution
This compound gains rapid and high concentration in a number of cells including polymorphonuclear leucocytes, monocytes, and macrophages . Extensive and rapid distribution from serum into the intracellular compartments is followed by rapid distribution to the tissues . Tissue concentrations exceed serum concentrations by up to 100-fold following a single this compound 500mg dose .
Subcellular Localization
This compound gains entry into cells by both passive and active transport due to its dibasic amphophilic character . It acts by inhibiting protein biosynthesis at the 50S ribosomal level . Intracellular penetration is greatest in the first 24 hours, but continues for up to 72 hours in human fibroblasts .
Preparation Methods
Synthetic Routes and Reaction Conditions: Azithromycin is synthesized from erythromycin A through a series of chemical reactions. The process involves the conversion of erythromycin A into its oxime, followed by Beckmann rearrangement to form the amino ether of erythromycin A. This intermediate is then reduced to 9-deoxo-9a-aza-9a-homoerythromycin, and finally, reductive N-methylation yields this compound .
Industrial Production Methods: Industrial production of this compound often involves hot-melt extrusion to prepare this compound amorphous solid dispersion. This method improves the solubility and taste-masking properties of the drug. The optimal extrusion parameters include a temperature of 150°C, a screw speed of 75 rpm, and a drug percentage of 25% .
Chemical Reactions Analysis
Types of Reactions: Azithromycin undergoes various chemical reactions, including oxidation, reduction, and substitution. For example, during oxidation, the bromine ion attaches to the lone pair electron of this compound, forming a yellow coupling product .
Common Reagents and Conditions: Common reagents used in the reactions of this compound include bromine ions for oxidation and various solvents and surfactants for nanoparticle preparation .
Major Products: The major products formed from these reactions include this compound nanoparticles and amorphous solid dispersions, which enhance the drug’s solubility and bioavailability .
Scientific Research Applications
Azithromycin has a wide range of scientific research applications in chemistry, biology, medicine, and industry. It is used to treat bacterial infections, including respiratory, skin, and sexually transmitted infections . In recent years, this compound has been studied for its potential use in treating COVID-19, although more research is needed to confirm its efficacy . Additionally, this compound-loaded microemulsions have been developed for the treatment of bacterial skin infections, showing prolonged release and accumulation inside the skin .
Comparison with Similar Compounds
- Erythromycin
- Clarithromycin
- Roxithromycin
Azithromycin’s unique structure and properties make it a valuable antibiotic with broad applications in medicine and research.
Properties
| Azithromycin usually is bacteriostatic, although the drug may be bactericidal in high concentrations against selected organisms. Bactericidal activity has been observed in vitro against Streptococcus pyogenes, S. pneumoniae, and Haemophilus influenzae. Azithromycin inhibits protein synthesis in susceptible organisms by penetrating the cell wall and binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. The site of action of azithromycin appears to be the same as that of the macrolides (i.e., erythromycin, clarithromycin), clindamycin, lincomycin, and chloramphenicol. The antimicrobial activity of azithromycin is reduced at low pH. Azithromycin concentrates in phagocytes, including polymorphonuclear leukocytes, monocytes, macrophages, and fibroblasts. Penetration of the drug into phagocytic cells is necessary for activity against intracellular pathogens (e.g., Staphylococcus aureus, Legionella pneumophila, Chlamydia trachomatis, Salmonella typhi). | |
CAS No. |
83905-01-5 |
Molecular Formula |
C38H72N2O12 |
Molecular Weight |
749.0 g/mol |
IUPAC Name |
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-(5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl)oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one |
InChI |
InChI=1S/C38H72N2O12/c1-15-27-38(10,46)31(42)24(6)40(13)19-20(2)17-36(8,45)33(52-35-29(41)26(39(11)12)16-21(3)48-35)22(4)30(23(5)34(44)50-27)51-28-18-37(9,47-14)32(43)25(7)49-28/h20-33,35,41-43,45-46H,15-19H2,1-14H3/t20-,21?,22+,23-,24-,25?,26?,27-,28?,29?,30+,31-,32?,33-,35?,36-,37?,38-/m1/s1 |
InChI Key |
MQTOSJVFKKJCRP-FHZDSTMTSA-N |
SMILES |
CCC1C(C(C(N(CC(CC(C(C(C(C(C(=O)O1)C)OC2CC(C(C(O2)C)O)(C)OC)C)OC3C(C(CC(O3)C)N(C)C)O)(C)O)C)C)C)O)(C)O |
Isomeric SMILES |
CC[C@@H]1[C@@]([C@@H]([C@H](N(C[C@@H](C[C@@]([C@@H]([C@H]([C@@H]([C@H](C(=O)O1)C)OC2CC(C(C(O2)C)O)(C)OC)C)OC3C(C(CC(O3)C)N(C)C)O)(C)O)C)C)C)O)(C)O |
Canonical SMILES |
CCC1C(C(C(N(CC(CC(C(C(C(C(C(=O)O1)C)OC2CC(C(C(O2)C)O)(C)OC)C)OC3C(C(CC(O3)C)N(C)C)O)(C)O)C)C)C)O)(C)O |
Appearance |
Solid powder |
Color/Form |
Amorphous solid |
melting_point |
113-115 °C White crystalline powder. mp: 126 °C. Optical rotation: -41.4 deg at 26 °C/D (c = 1 in CHCl3) /Azithromycin dihydrate/ |
| 83905-01-5 | |
physical_description |
Solid |
Pictograms |
Irritant; Health Hazard; Environmental Hazard |
Purity |
>98% (or refer to the Certificate of Analysis) |
Related CAS |
117772-70-0 (dihydrate) 121470-24-4 (monohydrate) |
shelf_life |
>2 years if stored properly |
solubility |
soluble in ethanol and DSMO, minimally soluble in water 5.14e-01 g/L |
storage |
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
Synonyms |
Azadose Azithromycin Azithromycin Dihydrate Azithromycin Monohydrate Azitrocin Azythromycin CP 62993 CP-62993 CP62993 Dihydrate, Azithromycin Goxal Monohydrate, Azithromycin Sumamed Toraseptol Ultreon Vinzam Zentavion Zithromax Zitromax |
vapor_pressure |
2.65X10-24 mm Hg at 25 °C (est) |
Origin of Product |
United States |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
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