Dirithromycin (also known as LY-237216) is an Erythromycin derivative acting as a potent and orally bioactive semi-synthetic macrolide glycopeptide antibiotic, working by binding to the 50S subunit of the 70S bacterial ribosome to inhibit the translocation of peptides. Dirithromycin is a more lipid-soluble prodrug derivative of 9S-erythromycyclamine prepared by condensation of the latter with 2-(2-methoxyethoxy)acetaldehyde. The 9N, 11O-oxazine ring thus formed is a hemi-aminal that is unstable under both acidic and alkaline aqueous conditions and undergoes spontaneous hydrolysis to form erythromycyclamine.
Physicochemical Properties
| Molecular Formula | C42H78N2O14 |
| Molecular Weight | 835.0737 |
| Exact Mass | 834.545 |
| Elemental Analysis | C, 60.41; H, 9.42; N, 3.35; O, 26.82 |
| CAS # | 62013-04-1 |
| PubChem CID | 6473883 |
| Appearance | Solid powder |
| Density | 1.2±0.1 g/cm3 |
| Boiling Point | 871.8±65.0 °C at 760 mmHg |
| Melting Point | 185 - 189ºC |
| Flash Point | 481.0±34.3 °C |
| Vapour Pressure | 0.0±0.6 mmHg at 25°C |
| Index of Refraction | 1.533 |
| LogP | 2.84 |
| Hydrogen Bond Donor Count | 5 |
| Hydrogen Bond Acceptor Count | 16 |
| Rotatable Bond Count | 12 |
| Heavy Atom Count | 58 |
| Complexity | 1300 |
| Defined Atom Stereocenter Count | 20 |
| SMILES | O1[C@]([H])(C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])[H])N([H])[C@@]2([H])[C@]([H])(C([H])([H])[H])C([H])([H])[C@](C([H])([H])[H])([C@@]([H])([C@@]([H])(C([H])([H])[H])[C@@]([H])([C@@]([H])(C([H])([H])[H])C(=O)O[C@]([H])(C([H])([H])C([H])([H])[H])[C@](C([H])([H])[H])([C@]1([H])[C@@]2([H])C([H])([H])[H])O[H])O[C@@]1([H])C([H])([H])[C@](C([H])([H])[H])([C@]([H])([C@]([H])(C([H])([H])[H])O1)O[H])OC([H])([H])[H])O[C@@]1([H])[C@@]([H])([C@]([H])(C([H])([H])[C@@]([H])(C([H])([H])[H])O1)N(C([H])([H])[H])C([H])([H])[H])O[H])O[H] |
| InChi Key | WLOHNSSYAXHWNR-DWIOZXRMSA-N |
| InChi Code | InChI=1S/C42H78N2O14/c1-15-29-42(10,49)37-24(4)32(43-30(56-37)21-52-17-16-50-13)22(2)19-40(8,48)36(58-39-33(45)28(44(11)12)18-23(3)53-39)25(5)34(26(6)38(47)55-29)57-31-20-41(9,51-14)35(46)27(7)54-31/h22-37,39,43,45-46,48-49H,15-21H2,1-14H3/t22-,23-,24+,25+,26-,27+,28+,29-,30-,31+,32+,33-,34+,35+,36-,37-,39+,40-,41-,42-/m1/s1 |
| Chemical Name | (1R,2R,3R,6R,7S,8S,9R,10R,12R,13S,15R,17S)-9-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3-ethyl-2,10-dihydroxy-7-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-15-((2-methoxyethoxy)methyl)-2,6,8,10,12,17-hexamethyl-4,16-dioxa-14-azabicyclo[11.3.1]heptadecan-5-one |
| Synonyms | LY237216; LY 237216; LY-237216;Antibiotic AS-E 136; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Macrolide |
| ln Vitro | Similar to erythromycin, dirithromycin has an antimicrobial activity spectrum in vitro. With MICs of approximately 1.0 and <0.25 μg/mL at pH values of 7.1 and 7.4, respectively, dirithromycin demonstrates good in vitro activity against a number of strains of Legionella. With MICs of less than 0.5 μg/mL, dirithromycin exhibits strong activity against a number of Helicobacter pytori strains[2]. |
| ln Vivo |
With ED50s of 1.0, 0.6, and <0.6 mg/kg, dirithromycin (s.c. for two times) is effective against experimental infections in mice caused by S. aureus, S. pyogenes, and S. pneumoniae[2]. With ED50s of 27, 34, and 23 mg/kg, respectively, dirithromycin (p.o. for two times) is effective against experimental infections in mice caused by S. aureus, S. pyogenes, and S. pneumoniae[2]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Oral dirithromycin is rapidly absorbed, with an absolute bioavailability of approximately 10%. Dietary fat has little or no effect on the bioavailability of dirithromycin. Metabolism / Metabolites Dirithromycin is converted by nonenzymatic hydrolysis during absorption to the active compound, erythromycylamine. Sixty to 90% of a dose is hydrolyzed to erythromycylamine within 35 minutes after dosing, and conversion is nearly complete after 1.5 hours. Erythromycylamine undergoes little or no hepatic biotransformation. No other metabolites of dirithromycin have been detected in the serum. Biological Half-Life The mean plasma half-life of erythromycylamine was estimated to be about 8 h (2 to 36 h), with a mean urinary terminal elimination half-life of about 44 h (16 to 65 h) in patients with normal renal function. |
| Toxicity/Toxicokinetics |
Protein Binding 15 to 30% for erythromycylamine, the active compound. |
| References |
[1]. J Antimicrob Chemother. 1999 Apr;43(4):541-8. [2]. Antimicrob Agents Chemother. 1991 Jun;35(6):1116-26. [3]. Ann Pharmacother, 1996. 30(10): p. 1141-9. |
| Additional Infomation |
Dirithromycin is the hemi-aminal resulting from the condensation of the erythromycin derivative (9S)-erythromycyclamine with 2-(2-methoxyethoxy)acetaldehyde. As the oxazine ring containing the hemi-aminal group is unstable under both acidic and alkaline conditions, dirithromycin functions as a more lipid-soluble prodrug for (9S)-erythromycyclamine. Administered as enteric coated tablets to protect it from acid catalysed hydrolysis in the stomach, it is used to treat respiratory tract, skin, and soft tissue infections caused by susceptible organisms. It has a role as a prodrug. Dirithromycin is a macrolide glycopeptide antibiotic used to treat many different types of bacterial infections, such as bronchitis, pneumonia, tonsillitis, and even skin infections. Dirithromycin is a semi-synthetic macrolide antibiotic pro-drug. Dirithromycin is converted by hydrolysis during intestinal absorption into the microbiologically active erythromycylamine. Eryhtromylamine binds to the 50 S subunit of the 70 S ribosome of susceptible organisms, thereby inhibiting bacterial RNA-dependent protein synthesis. This antibiotic is used in the treatment of infections of the respiratory tract, skin and soft tissue caused by gram-positive microorganisms, including S. aureus, S. pneumonia and pyogenes, gram-negative microorganisms, including H. influenzae, L. pneumophila, M. catarrhalis, and M. pneumoniae. Drug Indication For the treatment of the following mild-to-moderate infections caused by susceptible strains of microorganisms: acute bacterial exacerbations of chronic bronchitis, secondary bacterial infection of acute bronchitis, community-acquired pneumonia, pharyngitis/tonsilitis, and uncomplicated skin and skin structure infections. Mechanism of Action Dirithromycin prevents bacteria from growing, by interfering with their protein synthesis. Dirithromycin binds to the 50S subunit of the 70S bacterial ribosome, and thus inhibits the translocation of peptides. Dirithromycin has over 10 times higher affinity to the subunit 50S than erythromycin. In addition, dirithromycin binds simultaneously in to two domains of 23S RNA of the ribosomal subunit 50S, where older macrolides bind only in one. Dirithromycin can also inhibit the formation of ribosomal subunits 50S and 30S. |
Solubility Data
| Solubility (In Vitro) |
Ethanol : 100~50 mg/mL(59.88 mM) DMSO : 11~33.33 mg/mL ( 13.17~39.91 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.99 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.99 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (2.99 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 10% EtOH+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (2.99 mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1975 mL | 5.9875 mL | 11.9750 mL | |
| 5 mM | 0.2395 mL | 1.1975 mL | 2.3950 mL | |
| 10 mM | 0.1198 mL | 0.5988 mL | 1.1975 mL |