Tigecycline

Bezeichnung:Tigecycline

CAS-Nr220620-09-7

Englisch Name:Tigecycline

CBNumberCB6248215

SummenformelC29H39N5O8

Molgewicht585.65

MOL-Datei220620-09-7.mol

Tigecycline physikalisch-chemischer Eigenschaften

Schmelzpunkt	164-166°C
Siedepunkt	890.9±65.0 °C(Predicted)
Dichte	1.45±0.1 g/cm3(Predicted)
storage temp.	Keep in dark place,Inert atmosphere,Store in freezer, under -20°C
Löslichkeit	Soluble in DMSO (up to at least 25 mg/ml).
pka	4.50±1.00(Predicted)
Aggregatzustand	Orange powder
Farbe	Orange
Merck	14,9432
Stabilität	Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.
InChIKey	FPZLLRFZJZRHSY-HJYUBDRYSA-N
SMILES	C1(=O)[C@]2(O)[C@@]([H])(C[C@@]3([H])C(=C2O)C(=O)C2=C(C(N(C)C)=CC(NC(CNC(C)(C)C)=O)=C2O)C3)[C@H](N(C)C)C(O)=C1C(N)=O
CAS Datenbank	220620-09-7(CAS DataBase Reference)

Sicherheit

S-Sätze:	24/25
RIDADR	3077
RTECS-Nr.	QI7619500
HazardClass	9
PackingGroup	III
HS Code	29419090
Giftige Stoffe Daten	220620-09-7(Hazardous Substances Data)

Gefahreninformationscode (GHS)

Tigecycline Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung

The emergence of drug-resistant bacteria has diminished the clinical utility of the tetracyclines. Research to circumvent the efflux and ribosomal protection mechanisms of bacteria has led to the development of the glycylcyclines. Tigecycline is the first glycylcycline antibiotic to launch for the parenteral treatment of baterial infection, including complicated intra-abdominal and skin infections. Its mechanism of action involves inhibiting protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome to effectively prevent incorporation of amino acid residues into elongating peptide chains. Presumably, ribosomal protection proteins are ineffective against tigecycline due to its higher affinity for ribosomal binding compared to tetracyclines (approximately 16-fold). In addition, tigecycline may be resistant to efflux mechanisms by either their inability to translocate it across the cytoplasmic membrane due to steric complications or simply by their failure to recognize the molecule.
Beschreibung
Tigecycline is a broad-spectrum glycylcycline antibiotic that binds to the bacterial 30S ribosome, blocking the entry of transfer RNA, which halts protein synthesis and inhibits bacterial growth. It is active against a panel of 1,924 European clinical bacterial isolates including S. aureus, S. epidermidis, S. pneumoniae, E. faecalis, E. faecium, E. coli, K. pneumoniae, P. aeruginosa, and P. mirabilis strains (MICs = <1-32 μg/ml). In vivo, tigecycline (6.25 mg/kg twice daily for 5 days) decreases levels of C. difficile cytotoxin activity and spore formation in cecum and colon in a mouse model of C. difficile infection. Formulations containing tigecycline have been used in the treatment of a variety of bacterial infections.
Chemische Eigenschaften
Orange Solid
Originator
Wyeth (US)
Verwenden
A broad spectrum glycylcycline antibiotic
Verwenden
antineoplastic
Verwenden
A glycylcycline antibiotic, used to treat infection by drug resistant bacteria such as Staphylococcus aureus (Staph aureus) and Acinetobacter baumannii.
Verwenden
Tigecycline is a semi-synthetic tetracycline prepared by the introduction of a tert-butylaminoacetamido group into a previously unexplored and un-substituted region of existing tetracyclines. Like other tetracyclines, tigecycline acts by reversibly binding to the 30S ribosomal subunit and inhibits protein translation by blocking entry of aminoacyl-tRNA into the ribosome A site. The enhanced activity can be attributed to stronger binding affinity, thus minimising the impact of existing mechanisms of resistance. Tigecycline is regarded as the first of a new class of glycylcyline antibiotics. Critical comparison to the tetracycline class appears to be lacking in the literature.
Definition
ChEBI: Tetracycline in which the hydroxy group at position 5 and the methyl group at position 6 are replaced by hydrogen, and with a dimethylamino substituent and an (N-tert-butylglycyl)amino substituent at positions 7 and 9, respe tively. A glycylcycline antibiotic, it has activity against a broad range of Gram-positive and Gram-negative bacteria, including tetracycline-resistant organisms. It is used for the intravenous treatment of complicated skin and skin structure infections ca sed by susceptible organisms.
Trademarks
Tygacil
Antimicrobial activity
It is as potent as, or more potent than, earlier tetracyclines and activity is retained against strains expressing acquired tetracycline resistance determinants. It displays better activity than tetracycline, doxycycline or minocycline against Streptococcus spp. and against Enterococcus faecalis and E. faecium. Among Gram-negative organisms it displays improved activity against Citrobacter freundii, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Salmonella spp., Serratia marcescens and Shigella spp. The spectrum includes rapidly growing mycobacteria. Ps. aeruginosa, Pr. mirabilis, other Proteus spp. and some strains of Corynebacterium jeikeium are resistant. Activity against strains expressing acquired resistance to earlier tetracyclines is attributed to failure of the MFS efflux pumps to recognize tigecycline, and to a novel mechanism of ribosome binding that permits tigecycline to overcome ribosomal protection mechanisms.
Comparative susceptibility data for some atypical pathogens are not available. However, in common with earlier tetracyclines, it is active against Chlamydophila and Mycoplasma spp. and rapidly growing Mycobacteria spp. It is less active than minocycline or tetracycline against U. urealyticum.
Allgemeine Beschreibung
Tigecycline (Tygacil) is a first-in-class (a glycylcycline) intravenousantibiotic that was designed to circumvent manyimportant bacterial resistance mechanisms. It is not affectedby resistance mechanisms such as ribosomal protection, effluxpumps, target site modifications, β-lactamases, or DNAgyrase mutations. Tigecycline binds to the 30S ribosomalsubunit and blocks peptide synthesis. The glycylcyclinesbind to the ribosome with five times the affinity of commontetracyclines. Tigecycline also possesses a novel mechanismof action, interfering with the mechanism of ribosomal protectionproteins. Tigecycline, unlike common tetracyclines,is not expelled from the bacterial cell by efflux pumpingprocesses.
Tigecycline is recommended for the treatment of complicatedskin and skin structure infections caused by E. coli,E. faecalis (vancomycin-susceptible isolates), S. aureus(methicillin-susceptible and methicillin-resistant isolates),S. pyogenes, and B. fragilis among others. Tigecycline is alsoindicated for complicated intra-abdominal infections causedby strains of Clostridium, Enterobacter, Klebsiella, andBacteroides. To reduce the development of resistance to tigecycline,it is recommended that this antibiotic be used onlyfor those infections caused by proven susceptible bacteria.Glycylcyclines are structurally similar to tetracyclines,and appear to have similar adverse effects. These mayinclude photosensitivity, pancreatitis, and pseudotumorcerebri. Nausea and vomiting have been reported.
Pharmazeutische Anwendungen
9-T-butylglycylamido-minocycline. A compound of the glycylcycline class available as a powder for intravenous infusion.
Pharmakokinetik
C_max 100 mg intravenous infusion (1 h): 0.85–1 mg/L
Plasma half-life: 37–67 h
Volume of distribution: 7–10 L/kg
Plasma protein binding: 68%
Distribution and excretion
It is widely distributed and is concentrated in the gallbladder, colon and lung. The volume of distribution is dose related and variable, but is generally greater than that of older tetracyclines. CSF penetration is poor. Tigecycline is excreted in the feces and urine predominantly as the unchanged molecule. The elimination half-life is long (37–67 h). Tigecycline clearance is decreased by 20% in patients with renal failure. No dosage adjustments are apparently necessary for tigecycline in patients with renal impairment.
Clinical Use
Complicated skin and skin structure infections
Complicated intra-abdominal infections
Community-acquired bacterial pneumonia
Recommended principally for the treatment of infections with multiresistant organisms.
Nebenwirkungen
Side effects typical of the group, including nausea, vomiting, diarrhea and headache, occur. Occasional cases of pancreatitis, hypoproteinemia, antibiotic-associated colitis and thrombocytopenia have also been reported.
Synthese
It does not require dosage adjustment in patients with impaired renal function and is conveniently dosed every 12 hours. Synthesis of tigecycline started with nitration of 138 with potassium nitrate and concentrated sulfuric acid to give 9-nitro derivative 139 in 93 % yield as disulfate salt, which was hydrogenated over Pd/C in 2-methoxyethanol/ 2N sulfuric acid at 40 psi to provide 9-aminominocycline (140). Finally, 9-aminominocycline (140) is acylated directly with N-tert-butylglycyl chloride in a 1:5 mixture of acetonitrile and N, N-dimethylpropyleneurea (DMPU) with anhydrous sodium carbonate to give tigecycline (XX).
in vitro
tigecycline exihibited good in vitro activities. the range of mic90s was 0.12-0.5 μg/ml for vancomycin-susceptible and -resistant strains of enterococcus faecalis and enterococcus faecium [2]. tigecyclinewas concentrated in cells and eliminated primarily via biliary excretion. diminished renal function didn’t significantly alter its systemic clearance. tigecycline didn’t interfere with common cytochrome p450 enzymes, making pharmacokinetic drug interactions uncommon [3].the tissue penetration of tigecycline was excellent and the compound showed equivalence to imipenem/cilastatin in intra-abdominal infection and to vancomycin plus aztreonam in skin and skin structure infection [4].
in vivo
in an intraperitoneal systemic murine infection model, tigecycline exihibited in vivo activities against gisa, methicillin-susceptible s. aureus and methicillin-resistant s. aureus strains [2]. tigecycline and daptomycin showed similar in vivo efficacies against infections caused by the mssa strain (strain gc 4543) with the ed50s of 0.12 and 0.24 mg/kg, respectively. the ed50s of tigecycline was 0.72 mg/kg [2].
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhanced anticoagulant effect of coumarins.
Oestrogens: possibly reduced contraceptive effects of oestrogens (risk probably small).
Stoffwechsel
Tigecycline is not thought to be extensively metabolised, although some trace metabolites have been identified including a glucuronide, an N-acetyl metabolite, and a tigecycline epimer. Tigecycline is primarily eliminated (about 60
%) via biliary excretion of unchanged drug and some metabolites.
Einzelnachweise
1) Greer (2006)?Tigecycline (Tygacil): the first in the glycylcycline class of antibiotics; Proc. (Bayl. Univ. Med. Cent.)?19?155 2) Peterson (2008)?A review of tigecycline – the first glycylcycline; Int. J. Antimicrob. Agents?32 Suppl 4?S215 3) Skrtic?et al.?(2011)?Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia; Cancer Cell?20?674 4) Jia?et al.?(2016)?Tigecyclin targets nonsmall cell lung cancer through inhibition of mitochondrial function; Fundam. Clin. Pharmacol.?30?297 5) Hu?et al.?(2016)?Antibiotic drug tigecycline inhibits melanoma progression and metastasis in a p21CIP1/Waf1-dependent manner; Oncotarget?7?3171 6) D’Andrea?et al.?(2016)?The mitochondrial translational machinery as a therapeutic target in Myc-driven lymphomas.; Oncotarget?7?72415 7) Chen?et al.?(2019)?Inhibition of mitochondrial translation selectively targets osteosarcoma; Biochem. Biophys. Res. Commun. 515 9

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