{{Short description|Chemical compound}} {{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 375046138 | IUPAC_name = (3''R'',4''R'',5''E'',10''E'',12''E'',14''S'',26''R'',26a''S'')-26-<nowiki>[[</nowiki>2-(diethylamino)ethyl]sulfonyl]-8,9,14,15,24,25,26,26a- octahydro-14-hydroxy-3-isopropyl-4,12-dimethyl-3''H''-21,18-nitrilo-1''H'',22''H''-pyrrolo[2,1-''c''][1,8,4,19]-dioxadiazacyclotetracosine-1,7,16,22(4''H'',17''H'')-tetrone | image = Dalfopristin.svg | image_class = skin-invert-image
<!--Clinical data--> | tradename = | Drugs.com = {{drugs.com|international|dalfopristin}} | MedlinePlus = a603007 | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_category = | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> | legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> | legal_US = Rx-only | legal_status = | routes_of_administration =
<!--Pharmacokinetic data--> | bioavailability = | protein_bound = | metabolism = | elimination_half-life = 1 hour | excretion =
<!--Identifiers--> | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 112362-50-2 | ATC_prefix = none | ATC_suffix = | PubChem = 6435782 | DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank = DB01764 | UNII_Ref = {{fdacite|changed|FDA}} | UNII = R9M4FJE48E | KEGG_Ref = {{keggcite|changed|kegg}} | KEGG = D00853 | ChEBI = 4309 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 1200937 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 16736919
<!--Chemical data--> | C=34 | H=50 | N=4 | O=9 | S=1 | smiles = CCN(CC)CCS(=O)(=O)[C@@H]1CCN2[C@H]1C(=O)O[C@@H]([C@@H](/C=C/C(=O)NC/C=C/C(=C/[C@H](CC(=O)CC3=NC(=CO3)C2=O)O)/C)C)C(C)C | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 1S/C34H50N4O9S/c1-7-37(8-2)16-17-48(44,45)28-13-15-38-31(28)34(43)47-32(22(3)4)24(6)11-12-29(41)35-14-9-10-23(5)18-25(39)19-26(40)20-30-36-27(21-46-30)33(38)42/h9-12,18,21-22,24-25,28,31-32,39H,7-8,13-17,19-20H2,1-6H3,(H,35,41)/b10-9+,12-11+,23-18+/t24-,25-,28-,31-,32-/m1/s1 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = SUYRLXYYZQTJHF-VMBLUXKRSA-N |drug_name=|alt=|type=|licence_EU=|licence_US=}}
'''Dalfopristin''' is a semi-synthetic streptogramin antibiotic analogue of ostreogyrcin A (virginiamycin M, pristinamycin IIA, streptogramin A).<ref name=scbt>{{cite web | url = http://www.scbt.com/datasheet-362728.html | title = Dalfopristin (as mesylate) (CAS 112362-50-2) | publisher = Santa Cruz Biotechnology, Inc }}</ref> The combination quinupristin/dalfopristin (marketed under the trade name Synercid) was brought to the market by Rhone-Poulenc Rorer Pharmaceuticals in 1999.<ref name=fda>{{cite web | title = Synercid (Quinupristin/Dalfopristin) I.V. | work = Drug Approval Package| publisher = U.S. Food and Drug Administration | url = http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/50747_Synercid.cfm | archive-url = https://web.archive.org/web/20130208065943/http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/50747_Synercid.cfm | url-status = dead | archive-date = February 8, 2013 }}</ref> Synercid (weight-to-weight ratio of 30% quinupristin to 70% dalfopristin) is used to treat infections by staphylococci and by vancomycin-resistant ''Enterococcus faecium''.<ref>{{cite journal | vauthors = Allington DR, Rivey MP | title = Quinupristin/dalfopristin: a therapeutic review | journal = Clinical Therapeutics | volume = 23 | issue = 1 | pages = 24–44 | date = January 2001 | pmid = 11219478 | doi = 10.1016/S0149-2918(01)80028-X }}</ref>
==Synthesis== 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.<ref name=scbt />
==Large Scale Preparation== 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 <ref name=recentdevelopments>{{cite journal | vauthors = Barrière JC, Berthaud N, Beyer D, Dutka-Malen S, Paris JM, Desnottes JF | title = Recent developments in streptogramin research | journal = Current Pharmaceutical Design | volume = 4 | issue = 2 | pages = 155–80 | date = April 1998 | pmid = 10197038 }}</ref> . 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.{{cn|date=February 2023}}
The production of the dalfopristin portion of quinupristin/dalfopristin is achieved through purifying cocrystallization of the quinupristin and dalfopristin from acetone solutions.<ref name=recentdevelopments />
==Physical Characteristics (as mesylate salt)== {| class="wikitable" |- | '''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<sup>3</sup> |- | '''Refractive index''' || n20D 1.58 |- | '''pK values''' || pKa: 13.18 (Predicted), pKb: 8.97 (Predicted) |}
==Antimicrobial activity== 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 <ref name=therapeuticreview>{{cite journal | vauthors = Allington DR, Rivey MP | title = Quinupristin/dalfopristin: a therapeutic review | journal = Clinical Therapeutics | volume = 23 | issue = 1 | pages = 24–44 | date = January 2001 | pmid = 11219478 | doi = 10.1016/S0149-2918(01)80028-X }}<!--|access-date=24 November 2013 --></ref> . 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.{{cn|date=February 2023}}
==Mechanism of action== 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.<ref name=therapeuticreview /> 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.{{cn|date=February 2023}}
==Mechanism of resistance== 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.<ref name=therapeuticreview /> 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.{{cn|date=February 2023}}
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.<ref name=therapeuticreview /> Comparatively, only 2-5% of staphylococcal isolates collected in France show resistance to a related streptogramin, pristinamycin, in over 35 years of use.{{cn|date=February 2023}}
==Drug interactions== Both dalfopristin and quinupristin are extensively hepatically metabolized, excreted from the feces, and serve as an inhibitor of cytochrome P450 (CYP) 3A4 enzyme pathway.<ref name=therapeuticreview /> 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.{{cn|date=February 2023}}
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.{{cn|date=February 2023}}
==Commercialization== 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.<ref name=fda /> Dalfopristin can be purchased alone on the internet from various chemical manufacturers as a mesylate salt.{{cn|date=February 2023}}
== References == {{reflist}}
Category:Antibiotics Category:Oxazoles Category:Diethylamino compounds