3.9 Tetracyclines
The tetracyclines are a conglomerate of broad spectrum
orally active actinomycete antibiotics produced by cultures of Streptomyces
species, and possessing appreciable therapeutic value. Chlortetracycline
was the first bonafide member of this group isolated from Streptomyces
aureofaciens and discovered by Duggar in 1948. It was immediately
followed by oxytetracycline in 1950 from the cultures of Streptomyces
rimosus; and in 1953 tetracycline was eventually discovered
in the antibiotic mixture from S. aureofaciens as a minor antibiotic.
Consequently,
the intensive and extensive research and development in the selection of mutant
strains, and specifically in the manipulations and manifestations to
monitor and control both ‘methylation’ and ‘chlorination’ procedures
have resulted in the fermentative production of a good number of tetracycline
variants, namely: demeclocycline, methacycline, doxycycline, minocycline,
lymecycline as given below:
These
compounds shall now be discussed individually as under:
3.9.1
Tetracycline
Synonyms
Deschlorobiomycin;
Tsiklomitsin; Abricycline; Ambramycin; Bio-Tetra; Cyclomycin; Dumocyclin;
Tetradecin;
Biological
Source It is obtained from a Streptomyces species cultured
in an appropriate nutrient medium.
Preparation
It
may be prepared by removal of chlorine from chlortetracycline and subjecting it
to hydrogenation.
Chemical
Structure Please see Section 3.9.
Characteristic
Features
1. It
is obtained as a yellow crystalline powder; odourless, and stable in air.
2. It
usually darkens on exposure to strong sunlight.
3. Its
potency is seriously affected in solutions of pH < 2.
4. It
is destroyed rapidly by alkali hydroxide solutions.
5. It
is found to be more soluble than chlortetracycline.
6. It
is rather more stable within the physiological and moderately alkaline spectrum
of pH.
7. The
solutions of tetracycline gets darkened more rapidly than chlortetracycline
but less than oxytetracycline.
8. The
pH of an aqueous suspension (1 mg . mL–1) ranges between 3.0 to 7.0.
9. Its
dissociation constant pKa are: 3.3; 7.7; 7.9.
10. Solubility
Profile: 1g is soluble in ~ 2500 mL water; ~ 50 mL ethanol; freely soluble
in dilute HCl or alkali hydroxide solutions; and almost insoluble in ether or
chloroform.
Uses
1. It
is found to be useful in the treatment of toxoplasmosis.
2. The
GI side effects are comparatively less than those from chlortetracycline and oxytetracycline
but more than from demeclocycline.
3. The
plasma half-life ranges between 6 to 11 hours in patients with normal renal
function. Tetracycline Hydrochloride [C22H24N2O8.HCl]
[Synonyms Achro; Achromycin; Ala Tet; Ambracyn;
Ambramicina; Bristaciclina; Cefracycline; Cyclopar; Diocyclin; Hostacyclin;
Mephacyclin; Panmycin; Polycycline; Quadracycln; Remicyclin; Sanclomycine;
Supramycin; Tetramycin; Topicycline; Totomycin; Unicin.
Characteristic
Features
1. The
crystals of tetracycline hydrochloride are obtained from butanol + HCl
which decomposes at 214°C.
2. Its
specific optical rotation [α]D25-257.9° (C = 0.5 in 0.1 N
HCl).
3. It
is freely soluble in water; soluble in methanol, ethanol; and insoluble in
ether and hydrocarbons.
4. The
pH of a 2% (w/v) aqueous solution ranges between 2.1-2.3.
3.9.2
Chlortetracycline
Synonyms
7-Chlorotetracycline;
Acronize; Aureocina; Aureomycin; Biomitsin; Centraureo; Chrysomykine; Orospray.
Biological
Source It is obtained from the substrate of Streptomyces
aureofaciens.
Chemical
Structure Please refer to Section 9.3.9.
Characteristic
Features
1. It
is obtained as golden-yellow crystals having mp 168-169°C.
2. It
has specific optical rotation [α]D23-275.0° (methanol).
3. It
has uvmax (0.1 N HCl): 230, 262.5, 267.5 nm, and (0.1N NaOH): 255,
285, 345 nm.
4. Its
solubility in water ranges between 0.5-0.6 mg mL–1, very soluble in
aqueous solutions above pH 8.5; freely soluble in the cellosolves, dioxane and
carbitol; slightly soluble in methanol, ethanol, butanol, acetone, benzene,
ethyl acetate; and almost insoluble in ether and petroleum ether.
Uses
1. It
exerts antiamebic activity.
2. It
is the first tetracycline antibiotic available for topical application,
including ophthalmic purposes.
3.
Though its general use has been replaced by other tetracycline antibiotics in
human beings, but it is still employed in veterinary medicine.
3.9.3
Oxytetracycline
Synonyms
Glomycin;
Riomistin; Hydroxytetracycline.
Biological
Sources It is an antibiotic substance obtained from the elaboration
products of the actinomycete, Streptomyces rimosus, grown on a suitable
medium. Oxytetracycline may also be obtained from Streptomyces
xanthophaeus.
Chemical
Structure Refert to Section 3.9.
Characteristic
Features
1. It
is obtained as pale yellow to tan, odourless, crystalline powder.
2. It
is fairly stable in air, but an exposure to strong sunlight gets darkened.
3.
Like tetracycline it also gets deteriorated in solution of pH less than 2, and
is quickly destroyed by alkali hydroxide solutions.
4. Its
saturated solution is almost neutral to litmus and shows a pH ~ 6.5.
5. Solubility
Profile: 1g in 4150 mL water; 100 ml ethanol; > 10,000 ml chloroform;
6250 mL ether; and freely soluble in diluted HCl or alkaline solutions.
6. Stability:
Its crystals exhibit no loss in potency on heating for a duration of 4 days
at 100°C; whereas the hydrochloride crystals show < 5% inactivation after 4
months at 56°C. It has been observed that the aqueous solutions of the
hydrochloride at pH 1.0 to 2.5 are quite stable for at least 30 days at 25°C.
It has been observed that the aqueous solutions of the hydrochloride at pH 1.0
to 2.5 are quite stable for at least 30 days at 25°C. However, its solutions at
pH 3.0 to 9.0 show no detectable loss in potency on storage at + 5°C for at
least 30 days. Half life in hours at aqueous oxytetracycline solutions at 37°C:
pH 1.0 = 114; pH 2.5 = 134; pH 4.6 = 45; pH 5.5 = 45; pH 7.0 = 26; pH 8.5 = 33;
and pH 10.0 = 14.
Oxytetracycline
Hydrochloride [C22H24N2O9.HCl] [Synonyms
Alamycin, Duphacycline; Engemycin; Geomycin; Oxlopar; Oxybiocycline;
Oxycyclin Oxy-Dumocyclin; Oxytetracid; Oxytetrin; Tetran; Vendarcin]
It is
obtained as yellow platelets from water and is found to be extremely soluble in
water (1g/mL). It is also soluble in absolute ethanol: 12,000 g/mL; and in 95%
(v/v) ethanol: 33,000 g/mL.
Note:
Its concentrated aqueous solutions at neutral pH hydrolyze on standing and
consequently deposit crystals of oxytetracycline. Oxytetracycline Dihydrate [C22H24N2O9.2H2O]
[Synonyms
Abbocin; Clinimycin; Oxymycin; Stevacin; Terramycin;
Unimycin]
It is
obtained as needles from water or methanol which decompose at 181-182°C. Its
specific optical rotations are: [α]D25-2.1° (0.1N NaOH);
and [α]D25-196.6 (0.1N HCl). It has uvmax (pH 4.5 phosphate
buffer 0.1 M): 249, 276, 353 nm (E1%1cm 240, 322, 301).
It is found to be soluble in water at 23°C at various pH's: pH 1.2 = 31, 400
g/mL; pH 2.0 = 4600 γ/mL; pH 3.0 = 1400 γ/mL; and pH 9.0 = 38,600 γ/mL. It is
soluble in absolute ethanol 12,000 γ/mL and in 95% (v/v) ethanol 200 g/mL.
3.9.4
Demeclocycline
Synonyms
Bioterciclin;
Declomycin; Deganol; Ledermycin; Periciclina; Demethylchlortetracycline (obsolete).
Biological
Source Demeclocycline is related to tetracycline and produced
by Streptomyces aureofaciens.
Preparation
A
suitable strain of S. aureofaciens is grown in an appropriate liquid
nutrient medium under controlled experimental parameters of pH, temperature,
and extent of aeration. Subsequently, the duly harvested broth is acidified
carefully and filtered. The demeclocycline is isolated from the resulting
filtrate, either by solvent extraction or by chemical precipitation.
Chemical
Structure Refer to section 3.9.
Characteristic
Features
Demeclocycline
Hydrochloride [C21H21ClN2O8.HCl]
[Synonyms: Clortetrin; Demetraciclina; Detravis; Meciclin; Mexocine]
1. It
is obtained as yellow, crystalline powder, odourless and having a bitter taste.
2. The
pH of 1 in 100 solution is ~ 2.5.
3. It
essentially has three distinct dissociation constants, namely: pKa1,
2, 3: 3.3, 7.2, 9.3 attributed by three separate zones in its complex
molecule as shown below:
4. Solubility
Profile: 1g soluble in ~ 60 mL water; 200 mL ethanol or 50 mL methanol;
sparingly soluble in alkali hydroxides or carbonates; and almost insoluble in
chloroform.
Uses
1. It
is an intermediate-acting tetracycline and causes comparatively a greater extent
of phytotoxicity than other members of its class.
2. Its
better absorption and slower exeretion by the body render blood levels that
distinctly afford certain minor therapeutic advantages than other members of
its class.
Demeclocycline
Sesquihydrate It has mp 174-178°C (decomposes); and specific optical
rotation [α]25D-258° (C = 0.5 in 0.1 N H2SO4).
3.9.5
Methacycline
Synonyms
Metacycline,
Bialatan; 6-Methylene-5-hydroxytetracycline.
Biological
Source It is broad spectrum, semi-synthetic antibiotic related to tetracycline,
which is obtained from Streptomyces rimosus.
Preparation
It
may be prepared by a chemical dehydration reaction from oxytetracycline; besides,
it has a methylene function at C-6 position.
Chemical
Structure Please refer to Section 3.9.
Characteristic
Features
Methacycline
Hydrochloride [C22H22N2O8.HCl] [Synonyms
Adriamicina; Ciclobiotic;
Germiciclin;
Metadomns; Metilenbiotic; Londomycin; Optimycin; Physiomycine; Rindex; Rondomycin]:
1. It
is invariably obtained as crystals containing 0.5 mole water and 0.5 mole
methanol; and also from a mixture of methanol + acetone + concentrated HCl +
ether. It is a yellow crystalline
powder
which decompose at ~ 205°C and has a bitter taste.
2. It
has uvmax (methanol + 0.1 N HCl): 253, 345 nm (log e 4.37, 4.19).
3. It
is found to be soluble in water; sparingly soluble in ethanol; and practically
insoluble in chloroform and ether.
Uses
1. The
utility of methacycline is particularly associated with good oral absorption.
2. It
has a prolonged serum half-life.
3.9.6
Doxycycline
Synonyms
Jenacylin;
Supracyclin; Vibramycin.
Preparation
Methacycline (i.e.,
6-deoxy-6-demethyl-6-methylene-5-oxytetracycline) is either dissolved or
suspended usually in an inert organic solvent, for instance: methanol and
subjected to hydrogenation under the influence of catalytic quantities of noble
metals, namely: Rhodium or Palladium to yield a mixture of the 6α-and
6β-methyl epimers. The desired epimer i.e., α-6-deoxy-5-hydroxytetracycline,
is subsequently isolated by specific chromatographic methods (US Pat 3,200,149).
Chemical
Structure Refer to Section 3.9.
Characteristic
Features
Doxycycline
Hydrochloride Hemiethanolate Hemihydrate [C22H25Cl N2O8.1/2C2H60.1/2H2O]
[Synonyms
Doxycycline hyclate; Azudoxat; Diocimex; Doxatet; Doxychel hyclate;
Duradoxal; Hydramycin; Paldomycin; Sigadoxin; Tetradox; Unacil; Vibramycin
hyclate; Vibra-Tabs; Zadorin]:
1. It
is obtained as light yellow, crystalline powder from ethanol + HCl; and gets
charred without melting at ~ 201°C.
2. It
has specific optical rotation [α]25D-110°C (C = 1 in 0.01
N methanolic HCl).
3. It
has uvmax (0.01N methanolic HCl): 267, 351 nm (log ε 4.24, 4.12).
4. It
is found to be soluble in water.
5.
Both the inherant ethanol and water of crystallization (1/2 mol of each) are
usually lost by subject to drying at 100°C under reduced pressure.
6. Its
dissociation constant has three values, namely: pKa 3.4, 7.7, and
9.7 (see demeclocycline).
7. Solubility
Profile: It is very slightly soluble in water; freely soluble in dilute
acid or alkali hydroxide solution; sparingly soluble in ethanol; and
practically insoluble in ether or chloroform.
Uses
1. The
6α-isomer of doxycycline is found to be more active biologically than
the corresponding 6β-epimer hydrochloride.
2. It
is active against Gram-positive organisms wherein it is almost twice as
potent as tetracycline; and having an exception that it is virtually 10
times as potent against Streptomyces viridans.
3.
Interestingly, strains of Enterococcus fecalis that are observed to be
more resistant to other tetracyclines may prove to be sensitive to this
drug.
4.
Against Gram-negative organisms it is found to be twice as potent as
tetracycline.
5. It
is considered to be the drug of first choice for the prophylaxis of traveler’s
diarrhea, commonly caused by enterotoxigenic E. coli.
6. It
is found to be the best amongst the ‘tetracyclines’ against anaerobes.
7. It
is absorbed almost completely i.e., 90 to 100% through oral
administration than the rest of tetracyclines, and its absorption does not seem
to be retarded by intake of foods.
8. Its
plasma-protein binding is almost 93%.
9. Its
volume of distribution stands at 0.75 mL g–1.
10. It
is found to penetrate rapidly body fluids, cavities and cells.
11. It
is invariably eliminated upto 65% through hepatic metabolism, and the balance
35% through biliary/renal exertion.
12.
The rate of exertion is rather slow and the half-life is the longest among the ‘tetracyclines’,
namely, 12 to 22 hr.
Note:
1. Photosensitization usually takes place more frequently as compared to other
shorteracting tetracyclines.
2.
Complexation with Ca2+ is to a lesser extent than other
tetracyclines; besides, it is not affected by either dairy products or foods.
3.9.7
Minocycline
Synonyms
Minocyn.
Biological
Source It is a semi-synthetic antibiotic obtained from 6-demethyl
tetracycline.
Preparation
6-Demethyl tetracycline is first dissolved in tetrahydrofuran
(solvent) containing aliquot quantity of methanesulphonic acid, and is
subsequently reacted with dibenzyl azodicarboxylate to form 7-[1, 2-bis
(carbobenzoxy) hydrazino]-6-demethyl-tetracycline. The resulting-product is subjected
to Pd-catalyzed hydrogenation in the presence of formaldehyde to yield the
desired product minocycline.
Chemical
Structure Refer to section 3.9.
Characteristic
Features
1. It
is obtained as bright yellow-orange amorphous solid.
2. Its
specific optical rotation [α]25D-116° (C = 0.524).
3. It
has uvmax (0.1N HCl): 352, 263nm (log ε 4.16, 4.23); (01 N NaOH) :
380, 243 nm (log ε 4.30; 4.38).
Uses
1. It
is readily absorbed from the intestinal tract.
2. It
has a slow renal clearance to afford prolonged blood levels; and is normally
characterized by relatively lower MICs as compared to other tetracycline
antibiotics for certain pathogenic organisms.
Minocycline
Hydrochloride [C23H27N2O7.HCl] [Synonyms
Klinomycin Minomycin; Veetrin]
Characteristic
Features
1. It
is obtained as yellow, crystalline powder, odourless, slightly bitter taste and
slightly hygroscopic in nature.
2. It
is fairly stable in air when protected from light and moisture; however, strong
uv-light and/or moist air causes it to darken rather rapidly.
3. Its
potency* in solution is primarily affected on account of epimerization.
4. The
pH of 1 in 100 solution ranges between 3.5 to 4.5.
5. It
distinctly gives rise to four dissociation constant values, namely: pKa1
2.8; pKa2 5; pKa3 7.8; and pKa4 9.3; mainly
due to an additional dimethylamino moiety at e-7 position (compare
with demeclocycline, Section 9.4).
--------------------------------------------------------
*
Potency: It is equivalent to not less than 785 mcg of minocycline mg–1.
6. Solubility
Profile: 1 g in nearly 60 mL water and ~ 70 mL alcohol; soluble in
solutions of alkali hydroxides or carbonates; and almost insoluble in
chloroform and ether.
Uses
1. Generally,
it is found to be 2-4 times as potent as tetracycline against majority of Gram-positive
bacteria.
2. It
is found to exhibit an equally low-potency against Enterococcus fecalis.
3. It
is almost 8 times as potent as tetracycline against Streptococcus
viridans.
4. It
is 2 to 4 times as potent as tetracycline against Gram-negative
organisms.
5. It
is now the drug of choice for treating infections caused by Mycobacterium
marinum.
Note:
It particularly differs from other tetracyclines wherein the bacterial
resistance to the drug is not only of low incidence but also of a lower order;
which is especially true to staphylococci, in which cross-resistance is
observed to be as low as 4%.
6. It
is absorbed by the oral route to the extent of 90-100%.
7.
Diminution in absorption is caused exclusively by food and milk and
substantially by iron preparations and nonsystemic antacids.
8. It
is normally protein-bound in plasma between 70-75%.
9. Its
‘volume of distribution’* ranges between 0.14 to 0.7 mLg–1.
10.
Its half-life varies between 11 to 17 hours.
3.9.8
Lymecycline
Synonyms
Armyl;
Ciclolysol; Mucomycin; Tetralisal; Tetramyl; Tetralysal; N-Lysinomethyl tetracycline.
Biological
Source It is a semi-synthetic antibiotic related to tetracycline.
It is a classic example of an antibiotic developed by qualified chemical
modification of the primary amide function at C-2.
Preparation
It
may be prepared by the method suggested by Tubaro and Raffaldoni.**
Chemical
Structure Refer to Section 3.9.
Characteristic
Features
Lymecycline
Sodium [C29H37N4NaO10]: It has
uvmax (CH3OH): 376 nm. It is used as a potent antibacterial agent.
3.9.9
Biosynthesis of Chlortetracycline
The
various steps involved in the biosynthesis of chlortetracycline are as
stated below:
1. A
malonamyl-CoA residue probably caters for as a ‘primer’; and eight such
malonate entities undergo stepwise condensations with the addition of C2
units and followed by decarboxylation to yield a linear C19 polyketide.
2.
Subsequently, the carbonyl-methylene condensations give rise to the tetracyclic
pretetramide nucleus.
--------------------------------------------------------
*
Volume of Distribution It is pharmacokinetic parameter representing a proportionality
constant that relates drug
concentration
in a reference fluid, typically plasma, to the amount of drug distributed
throughout the body.
**
Tubaro and Raffaldoni, Bull. Chim. Farm., 100, 9 (1961).
3.
Importantly, methylation at the C-6 position of the pretetramide
is normally regarded an initial step in the biosynthesis of most tetracyclines;
however, this particular step is usually left out in the creation of the
naturally occurring dimethyl tetracyclines.
4.
Hydroxylation at the C-4 position followed by dearomatization to produce a 4-keto
intermediate appears to precede 7-chlorination.
5. It
is necessary that halogenation should precede introduction of the 4-amino
group, which is methylated in a stepwise manner.
6.
Terminal reactions in the biosynthetic sequence are carried out in two stages:
first, hydroxylation at C-6 position; and secondly, reduction of
double bond in ring B.
7. It
is, however, interesting to absence that the presence of a 7-halogen
substituent evidently blocks 5-hydroxylation.
The
various steps involved in the biosynthesis of chlortetracycline may be
summarized as given below:
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