Classes of tetracyclines antibiotics

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Chapter: Medicinal Chemistry : Antibiotics

I. Natural tetracyclines II. Semisynthetic tetracyclines i. Methacycline ii. Doxycycline (Vibramycin) iii. Minocycline (Cynomycin, Minolox) iv. Rolitetracycline III. Pro-tetracyclines


Classes of tetracyclines antibiotics
Tetracycline antibiotics

Tetracyclines have a ring system of four linear annelated six-membered rings and are characterized by a common octahydronaphthacenes skeleton. They are potent, broad-spectrum antibacterial agents effective against gram-positive and gram-negative aerobic and anaerobic bacteria. As a result, the tetracyclines are drugs of choice or well-accepted alternatives for a variety of infectious diseases. Among these, they also play a role in the treatment of sexually transmitted and gonococcal diseases, urinary tract infections, bronchitis, and sinusitis remain prominent.

The majority of the marketed tetracyclines (tetracycline, chlorotetracycline, oxytetracycline, and demeclocycline) are naturally occurring compounds obtained by the fermentation of Streptomyces spp. broths. The semisynthetic tetracyclines (methacycline, doxycycline, minocycline) have the advantage of longer duration of antibacterial action. However, all these tetracyclines exhibit a similar profile in terms of antibacterial potency. In general, their activity encompasses many strains of gram-negative E. coli, Proteus, Klebsiella, Enterobacter, Niesseria, and Serratia spp., as well as gram-negative Streptococci and Staphylococci of particular interest is the potency of tetracylines against Haemophilus, Legionella, Chlamydia, and Mycoplasma.

 
Classes of tetracyclines

I. Natrual tetracyclines (biosynthetic)

II. Semisynthetic tetracyclines

III. Protetracyclines

I. Natural tetracyclines


II. Semisynthetic tetracyclines


III. Pro-tetracyclines


 

I. Natural tetracyclines

General mode of action of tetracyclines: In bacterial protein synthesis, the messenger RNA attaches itself to 30S ribosomes. The initiation complex of mRNA starts the protein synthesis and polysome formation of the nascent peptide that is attached to 50S ribosomes. Its specific tRNA transports the next amino acid to the acceptor site of the ribosome, which is complementary to the base sequence of the next mRNA codon. The nascent peptide is transferred to the newly attached amino acid by peptide bond formation. Tetracyclines bind to 30S ribosomes and the attachment of aminoacyl tRNA to mRNA ribosome complex is interfered.

Physicochemical properties: These are amphoteric due to the acidic and the basic substituents, and have low solubility in water (0.5 mg/ml) with strong acids and bases. They form water-soluble salts in each tetracycline, there are three ionizable groups present: tricarbonyl methane moiety (pKa 3.3), phenol diketone moiety (pKa 7.7), and ammonium cation moiety (pKa 9.7).


Effect of pH on tetracyclines: An interesting property of tetracyclines is their ability to undergo epimerization at C-4 position in solutions of intermediate pH range. These isomers are called epitetracyclines. Under the influence of the acidic conditions, equilibrium is established in about a day consisting of approximately equal amount of isomers. Epitetracyclines exhibit much less activity than natural isomers.


Strong acids and bases attack the tetracyclines having a hydroxyl group on C-6, causing a loss in activity through the modification of C-ring. Strong acids produce dehydration through a reaction involving the C-6 hydroxyl group and C-5a hydrogen. The double bond formed between the positions C-5a and C-6 induces a shift in the position of double bond between C-11a and C-12 to a position between C-11 and C-11a forming the more energetically favoured resonance of the naphthalene group found in the inactive anhydro tetracyclines.


Bases promote a reaction between the C-6 hydroxyl group and the ketone group at the C-11 position, causing the bond between the C-11 and C-11a atoms to cleave and to form the lactone ring found in the isotetracycline.

Effect of metals on tetracyclines: Tetracyclines form stable chelate complexes with many metals, including calcium, magnesium, and iron. The chelates thus formed are insoluble in water accounting for the impairment in absorption of most of the tetracyclines in the presence of milk, calcium, magnesium, and aluminium containing antacids and iron salts.

The affinity of tetracyclines for calcium causes them to be laid down in newly formed bones and teeth as tetracycline calcium orthophosphate complexes. Deposits of these antibiotics in tooth cause yellow discolouration that darkens because of photochemical reaction. Tetracyclines are distributed into the milk of lactating mothers and also cross the placenta into the foetus. The possible effect of these agents on bones and teeth of the child should be taken into consideration before they are used during pregnancy or in children under eight years of age.

 

II. Semisynthetic tetracyclines

 

i. Methacycline


Synthesis


Properties and uses: Methacycline is a yellow crystalline powder, sparingly soluble in water. It is obtained by the chemical modification of oxytetracycline. It has an antibiotic spectrum similar to tetracyclines, but greater potency; about 600 mg of methacycline is equivalent to 1 g of tetracycline.

 

ii. Doxycycline (Vibramycin)


Synthesis


Properties and uses: It was first obtained in small yields by a chemical transformation of oxytetracycline. The 6α-methyl epimer is more than three times as active as its β epimer.

Dose: In adults, the oral dosage is 100 mg every 12 h.

Dosage forms: Doxcycline HCl capsules I.P., Doxcycline HCl tablets I.P.

 

iii. Minocycline (Cynomycin, Minolox)


Synthesis


Properties and uses: It is a yellow crystalline powder with slightly bitter taste, soluble in water. It is very active against gram-positive bacteria. It is especially effective against Mycobacterium marinum. As a prophylactic against streptococcal infections, it is the drug of choice. It lacks the 6-hydroxyl group, therefore, it is stable to acids and does not dehydrate or rearrange to anhydro or lactone forms.

Dose: The dose orally for adults is 200 mg.

 

iv. Rolitetracycline


Synthesis



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