Chlortetracycline Chemical Properties

Melting point:

168-169°

alpha 

D23 -275.0° (methanol)

Boiling point:

821.1±65.0 °C(Predicted)

Density 

1.2833 (rough estimate)

refractive index 

1.6000 (estimate)

storage temp. 

2-8°C

solubility 

DMF: Soluble; DMSO: Soluble; Ethanol: Soluble; Methanol: Soluble

form 

A solid

pka

pKa 3.3 (Uncertain)

Water Solubility 

0.63g/L(25 ºC)

LogP

-0.620

CAS DataBase Reference

57-62-5(CAS DataBase Reference)

EPA Substance Registry System

Chlortetracycline (57-62-5)

Safety Information

Hazard Codes 

Xn

Risk Statements 

22

WGK Germany 

1

RTECS 

QI7750000

MSDS

• Language:English Provider:7-Chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide

Chlortetracycline Usage And Synthesis

Description

Chlortetracycline (Brand name: Aureomycin) is the 7-chloro substitution derivative of the tetracycline and has a golden color. As a veterinary medicine, chlortetracycline is commonly used for the treatment of conjunctivitis of cats. It can also be used in the treatment of infections occurring in the urinary tract, respiratory tract, and the intestines. Its mechanism of action is through inhibiting the protein synthesis, inhibiting the binding of aminoacyl-tRNA to the mRNA-ribosome complex through binding to the 30S ribosome subunit.

Chemical Properties

Golden-yellow crystalline powder, odorless with a bitter taste; decomposes at a melting point of 168-169°C. Slightly soluble in water but soluble in saline solutions. The hydrochloride form is slightly soluble in methanol, water, and ethanol and insoluble in acetone, ether, and chloroform. Stable in air, but the colour gradually darkens upon exposure to light.

Originator

Aureomycin, Lederle, US ,1948

Uses

Chlortetracycline was the first reported member of the tetracycline class, isolated from Streptomyces aureofaciens in 1948. Chlortetracyclines heralded the early wave of antibiotic discoveries from microbes and after 50 years are still widely used as pharmaceuticals. Chlortetracycline is a pigment and, like most pigments, is extremely sensitive to environmental and storage conditions. Commercial chlortetracycline may contain significant levels of degradation products.

Definition

ChEBI: Chlortetracycline is a member of the class of tetracyclines with formula C22H23ClN2O8 isolated from Streptomyces aureofaciens. It has a role as an antiprotozoal drug, a fluorescent probe, a calcium ionophore and an antibacterial drug. It is a member of monochlorobenzenes, a tertiary amino compound, a tertiary alcohol, a monocarboxylic acid amide, a tertiary alpha-hydroxy ketone and a member of tetracyclines. It is a conjugate acid of a chlortetracycline(1-).

Indications

Chlorotetracycline, an antibiotic with a broad spectrum of action, causes a bacteriostatic effect with respect to Gram-positive (staphylococci, including those that produce penicillinase; streptococci, pneumococci; clostridia, listeria, and anthrax bacillus) and Gram-negative microorganisms (gonococci, whooping cough bacillus, colon bacillus, enterobacteria, klebisella, salmonella, shigella), as well as Rickettsia, chlamydia, mycoplasma, and spirochaeta. Blue-pus bacillus, proteus, serracia, most strains of Bacteroides fragilis, most fungi, and small viruses are resistant to this drug. It is used for pneumonia, bronchitis, empyema of the lungs, angina, cholecystitis, whooping cough, endocarditis, endometritis, intestinal infections, prostatitis, syphilis, gonorrhea, brucellosis, osteomyelitis, purulent infections of soft tissues, and others caused by microorganisms sensitive to this drug. Synonyms of this drug are aureomycin, biomycin, xanthomycin, and others.

Manufacturing Process

The following process description is taken from US Patent 2,987,449. An appropriate S. aureofaciens strain such as mutant S1308 (ATCC No. 12,748) is grown aerobically in a suitable inoculum medium. A typical medium used to grow the primary inoculum is prepared according to the following formula: sucrose, 20.0 g; corn steep liquor, 16.5 ml, ammonium sulfate, 2.0 g; calcium carbonate, 7.0 g; and water to 1,000 ml.
A 100 ml aliquot of this medium is placed in a 500 mi Erlenmeyer flask and sterilized by autoclaving for 20 minutes under 15 psi pressure. Spores of mutant strain S. aureofaciens S1308 (ATCC No. 12,748) are washed from an agar slant into the flask with sterile distilled water to form a suspension containing approximately 108 spores per milliliter. A 1.0 ml portion of this suspension is used to inoculate the fermentation media in the example which follows. A fermentation medium consisting of the following ingredients was prepared.
25 ml aliquots of this fermentation medium were placed in each of two 250 ml Erlenmeyer flasks and 0.5 ml of lard oil was added to each flask. Then 0.002 mg/ml of riboflavin was added to one flask, the other flask being retained as a control. The flasks were sterilized in an autoclave for 20 minutes under 15 psi pressure, then cooled to room temperature (25°±5°C). At this point, a 1.0 ml portion of inoculum of mutant strain S. aureofaciens S1308 (ATCC No. 12,748) was added to each of the two flasks. The flasks were incubated at25°C for 120 hours on a rotary shaker operating at 180 rpm. Upon completion of the fermentation period the mashes were assayed for 7-chlorotetracycline content.
The increase in production due to the addition of riboflavin was very noticeable in the above example. A similar effect was reported for cupric sulfate pentahydrate addition according to US Patent 3,050,446.

Therapeutic Function

Antibacterial

Antimicrobial activity

It is slightly less active than tetracycline against many bacteria, with the exception of Gram-positive organisms.

Pharmaceutical Applications

7-Chlortetracycline. A fermentation product of certain strains of Streptomyces aureofaciens. Formulated as the hydrochloride or the free base for oral or topical application.

Pharmacokinetics

Oral absorption：30–60%
C_max 500 mg oral：2.5–7 mg/L：
Plasma half-life： 5–6 h
Volume of distribution： c.2 L/kg
Plasma protein binding： 47–65%
Absorption is relatively poor compared with other tetracyclines. It undergoes rapid metabolism and is largely eliminated by biliary excretion, with only a small proportion eliminated via the kidney. Despite this, chlortetracycline is not recommended for patients in renal failure, since accumulation occurs as a consequence of the half-life increase to approximately 7–11 h.

Clinical Use

Its uses are those common to the group. It has also been used topically in the management of recurrent aphthous ulcers of the mouth, but experience is limited and the mechanism of action is unknown.

Side effects

Side effects are typical of the group. Contact hypersensitivity has been reported with topical application to abraded skin and varicose ulcers.

Safety Profile

Poison by intravenous and intraperitoneal routes. Moderately toxic by ingestion. Experimental reproductive effects. When heated to decomposition it emits toxic fumes of Cland NOx. See also TETRACYCLINE.

Synthesis

Chlorotetracyline, 7-chloro-4-dimethylamino-1,4,4a,5,5a,6,11,12aoxtahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacencarboxamide (32.3.1), is obtained biosynthetically as a result of the activity of a microorganism, the actinomycete S. aureofaciens.

Veterinary Drugs and Treatments

There are a variety of approved chlortetracycline products for use in food animals. It may also be useful in treating susceptible infections in dogs, cats, birds and small mammals (not Guinea pigs). For more information, refer to the Doses section below.

Purification Methods

Aureomycin is dehydrated by azeotropic distillation of its solution with toluene. On cooling, the anhydrous material crystallises out and is recrystallised from *C6H6, then dried under vacuum at 100o over paraffin wax. (If it is crystallised from MeOH, it contains MeOH which is not removed on drying.) [Stephens et al. J Am Chem Soc 76 3568 1954, Laskin & Chan Biochem Biophys Res Commun 14 137 1964]. [Beilstein 14 IV 2631.]

References

[1] LINDSAY GILLAN W. M C M Gareth Evans. Flow cytometric evaluation of sperm parameters in relation to fertility potential[J]. Theriogenology, 2005, 63 2: Pages 445-457. DOI:10.1016/j.theriogenology.2004.09.024.
[2] Y H CHOI Y T. Cyclodextrin removes cholesterol from mouse sperm and induces capacitation in a protein-free medium.[J]. Biology of Reproduction, 1998, 59 6: 1328-1333. DOI:10.1095/biolreprod59.6.1328.
[3] A CACCIAPUOTI. In vitro and in vivo characterization of novel 8-methoxy derivatives of chlortetracycline.[J]. Journal of Antibiotics, 1987, 40 10: 1426-1430. DOI:10.7164/antibiotics.40.1426.
[4] JOHN R. WHITE Frederick L P. Characterization of chlortetracycline (aureomycin) as a calcium ionophore[J]. Biochemistry Biochemistry, 1982, 21 24: 6309-6312. DOI:10.1021/bi00267a041.
[5] CLAUDIA CERELLA. Analysis of Calcium Changes in Endoplasmic Reticulum during Apoptosis by the Fluorescent Indicator Chlortetracycline[J]. Annals of the New York Academy of Sciences, 2007, 1099 1: 490-493. DOI:10.1196/annals.1387.021.

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