Dalfopristin

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Dalfopristin
Dalfopristin.png
Systematic (IUPAC) name
(3R,4R,5E,10E,12E,14S,26R,26aS)-26-[[2-(diethylamino)ethyl]sulfonyl]-8,9,14,15,24,25,26,26a- octahydro-14-hydroxy-3-isopropyl-4,12-dimethyl-3H-21,18-nitrilo-1H,22H-pyrrolo[2,1-c][1,8,4,19]-dioxadiazacyclotetracosine-1,7,16,22(4H,17H)-tetrone
Clinical data
AHFS/Drugs.com International Drug Names
MedlinePlus a603007
Legal status
Pharmacokinetic data
Half-life 1 hour
Identifiers
CAS number 112362-50-2 YesY
ATC code None
PubChem CID 6435782
DrugBank DB01764
ChemSpider 16736919 N
UNII R9M4FJE48E N
KEGG D00853 N
ChEMBL CHEMBL1200937 N
Chemical data
Formula C34H50N4O9S 
Mol. mass 690.85 g/mol
 N (what is this?)  (verify)

Dalfopristin is a semi-synthetic streptogramin antibiotic analogue of ostreogyrcin A (virginiamycin M, pristinamycin IIA, streptogramin A).[1] The combination quinupristin/dalfopristin (marketed under the trade name Synercid) was brought to the market by Rhone-Poulenc Rorer Pharmaceuticals in 1999.[2] Synercid (weight-to-weight ratio of 30% quinupristin to 70% dalfopristin) is used to treat infections by staphylococci and by vancomycin-resistant Enterococcus faecium.[3]

Synthesis[edit]

Through the addition of diethylaminoethylthiol to the 2-pyrroline group and oxidation of the sulfate of ostreogrycin A, a structurally more hydrophobic compound is formed. This hydrophobic compound contains a readily ionizable group that is available for salt formation.[1]

Large Scale Preparation[edit]

Dalfopristin is synthesized from pristinamycine IIa through achieving a stereoselective Michael-type addition of 2-diethylaminoethanethiol on the conjugated double bond of the dehydroproline ring [4] . The first method found was using sodium periodate associated with ruthenium dioxide to directly oxidize the sulfur derivative into a sulfone. However, using hydrogen peroxide with sodium tungstate in a 2-phase medium produces an improved yield, and is therefore the method of choice for large scale production.

The production of the dalfopristin portion of quinupristin/dalfopristin is achieved through purifying cocrystallization of the quinupristin and dalfopristin from acetone solutions.[4]

Physical Characteristics (as mesylate salt)[edit]

Appearance White to yellow solid
Physical State Solid
Solubility Soluble in ethanol, methanol, DMSO, DMF, and water (0.072 mg/ml)
Storage -20°C
Boiling Point 940.5°C at 760 mmHg
Melting Point 150°C
Density 1.27 g/cm^3
Refractive Index n20D 1.58
pK Values pKa: 13.18 (Predicted), pKb: 8.97 (Predicted)

Antimicrobial Activity[edit]

Alone, both dalfopristin and quinupristin have modest in vitro bacteriostatic activity. However, 8-16 times higher in vitro bactericidal activity is seen against many gram-positive bacteria when the two streptogramins are combined [5] . While quinupristin/dalfopristin is effective against staphylococci and vancomycin-resistant Enterococcus faecium, in vitro studies have not demonstrated bactericidal activity against all strains and species of common gram-positive bacteria.

Mechanism of Action[edit]

Both dalfopristin and quinupristin bind to sites located on the 50S subunit of the ribosome. Initial dalfopristin binding results in a conformational change of the ribosome, allowing for increased binding by quinupristin.[5] A stable drug-ribosome complex is created when the two drugs are used together. This complex inhibits protein synthesis through prevention of peptide-chain formation and blocking the extrusion of newly formed peptide chains. In many cases, this leads to bacterial cell death.

Mechanism of Resistance[edit]

Streptogramin resistance is mediated through enzymatic drug inactivation, efflux or active transport of drug out of the cell, and most commonly, conformational alterations in ribosomal target binding sites.[5] Enzymatic drug inactivation may occur in staphylococcal and enterococcal species through production of dalfopristin-inactivating acetyltransferase or quinupristin-inactivating hydrolase. Efflux or active transport of the drug may occur in coagulase-negative staphylococci and Enterococcus faecium. Constitutive ribosome modification has been seen in staphylococci with resistance seen in quinupristin only.

While resistance to dalfopristin may be conferred via a single point of mutation, quinupristin/dalfopristin offers the benefit of requiring multiple points of mutation targeting both dalfopristin and quinupristin components to confer drug resistance.[5] Comparatively, only 2-5% of staphylococcal isolates collected in France show resistance to a related streptogramin, pristinamycin, in over 35 years of use.

Drug Interactions[edit]

Both dalfopristin and quinupristin are extensively hepatically metabolized, excreted from the feces, and serve as an inhibitor of cytochrome P450 (CYP) 3A4 enzyme pathway.[5] Caution should be taken with concommitent use with drugs metabolized by the CYP3A4 pathway. Concomitant use of quinupristin/dalfopristin with cyclosporine for 2–5 days has shown to result in a two-fold increase in cyclosporine levels.

No adverse effects have been seen in patients with hepatic impairment and no recommendations by the manufacturer have been made for dose reduction of quinupristin/dalfopristin in this patient population.

Commercialization[edit]

While little information is available regarding the regulatory and commercialization history of Dalfopristin alone, Synercid (quinupristin/dalfopristin), made by Rhone-Poulenc Rorer Pharmaceuticals, was approved in 1999 as an IV injectable for the treatment of vancomycin resistant Enterococcus faecium and complicated skin and skin structure infections.[2] Dalfopristin can be purchased alone on the internet from various chemical manufacturers as a mesylate salt.

References[edit]

  1. ^ a b Dalfopristin (as mesylate) (CAS 112362-50-2)
  2. ^ a b http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/50747_Synercid.cfm
  3. ^ Allington DR, Rivey MP (2001). "Quinupristin/dalfopristin: a therapeutic review". Clin Ther 23 (1): 24–44. doi:10.1016/S0149-2918(01)80028-X. PMID 11219478. 
  4. ^ a b Barriere, J.C.; Berthaud, N.; Beyer, D.; Dutka-Malen, S.; Paris, J.M.; Desnottes, J.F. (April 1998). "Recent Developments in Streptogramin Research". Current Pharmaceutical Design 4 (2): 155–190. PMID 10197038. Retrieved 24 November 2013. 
  5. ^ a b c d e Allington, Douglas R.; Rivey, Michael P. (January 2001). "Quinupristin/Dalfopristin: A Therapeutic Review". Clinical Therapeutics 23 (1): 1–21. doi:10.1016/S0149-2918(01)80028-X. PMID 11219478.