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TETRACYCLINSDr. P. Ravisankar, M. Pharm., Ph.D.

By

V. Laya Sri.Vignan Pharmacy College, Vadlamudi, Guntur, A.P, INDIA

TETRACYCLINES

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contents1. Definition

2. Introduction

3. Classification

4. Historical background

5. Sources

6. Chemistry

7. SAR of tetracyclines

8. Mechanism of action of tetracyclines

9. Spectram activity

10.Uses of tetracyclines

11.Side effects of tetracyclines

Definition:

Tetracyclines are octahydro napthacene derivatives

which are bacteriostatic and broad spectrum antibiotics

that kills certain infection - causing microorganisms and

are used to treat wide variety of infections.

TETRACYCLINES

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TETRACYCLINES

Tetra means = Four

Cycl means = Hyrocarbon ring

Ine means = Derivation

INTRODUCTION

Tetracyclines are introduced 50 years ago as potent broad spectrum antibiotics.

They are biosynthesized from acetic acid and propionic acid units in microorganisms.

Tetracyclines possess a wide specturm of acitivty i.e. gram+ve and gram-ve bacteria.

They are mainly designed for oral route but parenteral and topical forms are available.

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Historical background:

In 1945 Chlortetracycline (prototype) of tetracyclines was discovered by Dr. Benjamin, M. Duggar under the guidance of Yellapragada Subba Rao.

He was born in a poor Telugu Niyogi Brahmin family in Bhimavaram in West Godavari district, Andhra Pradesh.

He was an employee of Lederle Laboratories in U.S.A.

Dr. Duggar produced Chlortetracycline (Aureomycin) form golden – colored soil bacterium called Streptomyces aureofaciens by fermentation technology.

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He discovered many life saving drugs. Vitamin B-12 (Cyanocobalamine). Folic acid vitamin : A remedy medicine to cure “sprue” Aureomycine (world’s first Tetracycline and cure cholera, typhoid, plague

& dysentry). He was the first to discover Gramicidine (polypeptide antibiotic). Methotrexate (To prevent blood cancer in children).Hetrazin (elephantiasis & isnophelia, filariasis). This Fisco Subbarao method got recognition amongst the world famous

scientists.

Isonicotinic acid Hydrazide (INH) ( To cureTuberculosis).Discovered the role of ATP which are the sources of energy in human body.

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According to duration of action: Short-acting (Half-life is 6-8 hrs)

• Tetracycline Chlortetracycline Oxytetracycline

Intermediate-acting (Half-life is ~12 hrs)

Long-acting (Half-life is 16 hrs or more)

Classification

• Doxycycline Minocycline Tigecycline

• Demeclocycline Methacycline

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According to source

Semi-synthetic

Doxycycline

Meclocycline

Methacycline

Minocycline

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:Naturally-occurring

•Tetracycline•Chlortetracycline•Oxytetracycline•Demeclocycline

sources

Tetracyclines are obtained from various species of Streptomyces bacteria by fermentation technology

Chlortetracycline(aureomycin) from Streptomyces aureofaciens.

Oxytetracycline (Terramycin) from Streptomyces rimosus.

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Chemistry

Stereochemistry of tetracyclines is very complex.

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4,4a,5,5a,6,12a

Methacycline , Oxytetracycline, Meclocycline, Doxycycline possess 5-hydroxy Substituent have 6 chiral carbon atoms.Others have only 5 chiral carbon atoms.

Important structrual units and the three acidity constants in the tetracycline molecule.

(conjugatedTrione system Is acidic nature)pka1 (2.8-3.4)

(Conjugated phenolicEnone system is slightly basic)

Strong alkaline.Pka (7.2-7.8) Pka3 (9.1-9.7)

O O

OH

NH2

CH3HO

C

OOH

OHOH

CH3H3CN

H3C CH3

H3CHN

O

NH

CH3H3C N

O O

OH

NH2COH

OHOH

CH3H3CN

O

CH3H3CN

O O

OH

NH2C

OHOHOH

CH3H3CN

O

O O

OH

NH2C

OHCH2

OOH

OHOH

CH3H3C N

NH3C CH3

OH OHOH

O

OH

C

HO CH3

NH2

OH

OO

NH3C CH3

Cl

OH OHOH

O

CH2 OH

CNH2

OH

OO

O O

OH

NH2

CH3HO

C

Cl

OOHOH

OH

CH3H3CN

O O

OH

NH2

H

C

Cl HO

OOH OHOH

CH3H3C N

121110

9

8

76

54 3

21

METHACYCLINE[Rondomycin]

OXYTETRACYCLINETerramycin, (Urobiotic)CHLORTETRACYCLINE

Aureomycin

TETRACYCLINEAchrommycin, Sumycin,Panmycin, Teracap, Tetracyn, Tetralan

TIGECYCLINETygacil™

MECLOCYCLINEMeclan

MINOCYCLINEArestin, Dynacin,Vectrin, Minocin

DEMECLOTETRACYCLINEDeclomycin

O O

OH

NH2C

H3C OHH

OOH OHOH

CH3H3CN

DOXYCYCLINEVibramycin, Vibra–TabsDoryx, Doxy

STRUCTURES OF IMPORTANT TETRACYCLINES

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OH OH

CONH2

OH

R1

O O

R2

R3H

R4

HN(CH3)2

OH

ABCD

1

2

3

4

4a

5

5a6

6a

7

8

9

10

10a

11

11a

12

12a

N(CH3)2 Increasesactivity

Conversion to nitrilescauses a 20 fold increasein activity

Modif ication leadsto loss of activity

=CH2 Increases theAntibacterial activity

Elimination of 6-OH groupincrease lipophilicity& more stable to acids.Ex: Doxycycline.

‘D’ ring should bealways aromatic

Changes in this ringLeads to biologicalinactivation of themolecule.

Additional glycyl aminosubstitution at the 9thPosition leads to the newClass of antibioticsthe glycylcyclines.EX: Tigecycline.(Tygacil)

The keto-enoltatomerismBetween c2 and c3 areveryimportant forbiologicalactivity.

Inviolate zone is essential

The linearly fused tetracyclicnucleus is most importantfor the antibiotic activity.

Electron donating (or)electron withdrawing

groups at c7 increasedAntibacterial activity

Substitution with –OH Produce watersoluble derivatives which canbe administered orally.

Epimerization at c4and dehydration at 5aresults loss of activity.

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Structural Activity Relationship:

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SUMMARY:OH

CONH2

OHOH

R1 R2

O O

N(CH3)2

OH

HR4

HR3

1

4

2

34a

5

5a

6

6a

7

8

9

10

10a

11

11a

12

12aABCD

S.NO Structural Modifications Effects

1. Any modification No bacterial activity

2. Acetyl group only Slightly activity retained

3. Any modification No bacterial activity

4. α dimethylamino group NHCH3 retains more activity

5a. Loss of H Inactive degradation product

6. Remove OH,CH3 or both More stable compound

7. Cl,Br,NO2,(CH3)2N- Activity retained

8. Little information available _

9. Cl and CH3 Decreased activity

10,11,11a,12. “Inviolate zone” including C-1 Diminished activity

Epimerization:

OH

CONH2

OHOH

HO

O O

N(CH3)2

OH

H HCH3

1

4

2

34a

5

5a

6

6a

78

910

10a

11

11a

12

12aABCD

H H

H

OH OH

CONH2

OH

O O

N(CH3)2CH3H

HH

OH

-H2O

Tetracycline(Active)

Anhydrous Tetracycline(Inactive)

H+

H

OH

CONH2

OH

OH O

HH

H

OHO

HO N(CH3)2CH3 H

4-Epi tetracycline(Inactive)

-H2O

H

OH OH

CONH2

OH

O O

CH3

OH

HN(CH3)2

4-Epianhydro tetracycline(Inactive)

H+

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Strong acids and basesAttack those tetracyclines Which possess an –OH group at C-6 and form inactive anhydrotetracyclines

Base-catalyzed instability of tracylines:

OH

CONH2

OHOH

HO

O O

N(CH3)2

OH

H HCH3

1

4

2

34a

5

5a

6

6a

78

910

10a

11

11a

12

12aABCD

H H

OH-

-H2O

OH

CONH2

OH

OHO O

N(CH3)2

OH

CH3HH

HH

O

Isotetracycline(Inactive)

Tetracycline

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Under alkaline condition, OH at C6 change into oxygen anion and

then attacks the C-11 (ketone group) lead to intramolecular

nuclear reaction, by electron transfer, C ring rupture to generate

inactive isotetracycline lactone.

CHELATION:

Tetracyclines

Ca2+, Fe2+

Al3+, Fe3+

Citrateslipoproteins

Serum albumin

globulins

Metal complexes(Insoluble in water at

neutral PHs)

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This insolubility is not only inconvenient for the preparation of

solutions but also interferes with blood levels on oral administration.

The tetracycline's are incompatible with co-administered,

multivalent ion-rich antacids and with hematinics and concomitant

consumption of daily products rich in calcium ion also is

contraindicated.

Amphoteric nature of tetracyclines:

• Tetracyclines are amphoteric compounds.

• Amphoteric = form salts with both strong acids and bases.

Three structrual units of tetracyclines representing 3pka values.

Pka1--- Conjugated trione system extending from C1 to C3 of

ring A is acidic nature of Pka 2.8-3.4.

Pka2--- Conjugated phenolic enone system from C10-C12 is

associated with weak basic Pka values ranging from 7.2-7.8.

Pka3-- C4 atom and its substituents exhibits Pka3 ranging from

9.1 to 9.7. which represents strong alkaline nature.

Because of the amphoteric nature tetracyclines forms water soluble salts

with strong acids such as HCl and strong bases such NaOH, KOH.

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Mechanism of action of Tetracyclines

Tetracyclines inhibit protein synthesis by binding to the bacterial ribosome involved in the translation(protein synthesis) process and making them bacteriostatic.

The bacterial ribosome is a 70s particle made up of 30s subunit and 50s subunit.

The 30s subunit binds mRNA and initiates the protein synthesis.

The 50s subunit combines with the 30s subunit-mRNA complex to form a ribisome then binds aminoacyl tRNA and catalyses the building of the protein chain..

There are two main binding sites for the tRNA molecule.

The peptidyl(p-site) binds the tRNA bearing the peptide chain

The acceptor aminoacyl site (A-site)

Tetracyclines reversibly bind to the 30S subunit at the A-site to prevent attachment of the amino acyl tRNA, terminating the translation process. 

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Animation Illustrating the Role of Tetracyclines in Blocking Translationduring Bacterial Protein Synthesis

Spectrum of activity of Tetracyclines

Gram +ve & -ve bacteria

Spirochetes

Mycoplasms

Rickettsiae

Candida Albicans

Mycoplasma Pneumoniae

Chlamydia Trachomatis

Borrelia Recurrentis

Yersinia Pestis

Vibrio Cholerae

Campylavacter Fetus

Brucella Specie

Streptococcus Pneumonia

Neisseerie Gonorrhoeae

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• Tetracyclines are broad spectrum antibiotics.

They are active against following micro organisms:

Uses of Tetracyclines

• Tetracyclines are called "broad-spectrum" antibiotics, because they can be used to treat a wide variety of infections.

• Physicians may prescribe these drugs to treat eye infections.

• Tetracyclines are generally a low-cost alternative among antibiotics.

• Interestingly, a form of tetracycline has recently been used in prevention of cancer recurrence.

• Tetracyclines may be used in the treatment of infections of the respiratory tract, sinuses, middle ear, intestines.

• Gonorrhoea

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• Acne Rosacea • Acne vulgaris • Actinomyces Israelii• Actinomycosis• Anthrax• Bacillus Anthracis• Bacterial Conjunctivitis• Balantidium coli• Bartonella Bacilliformis• Bartonellosis• Bordetella Pertussis• Borrelia Burgdorferi• Borrelia Recurrentis• Bronchitis- acute• Brucella Sp.

• Brucellosis• Burkholderia Mallei• Burkholderia Pseudomallei• Campylobacter Fetus• Cervicitis• Chancroid• Chlamydia Psittaci• Chlamydia Trachomatis• Chlamydial Conjunctivitis• Chlamydia Trachomatis• Chlamydial Conjunctivitis• Clostridium Tetani• Coxiella Burnetii

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• Duodenal Ulcer• EntamoebaHistolytica• Francisella Tularensis• Fusobacterium Fusiforme• Gonorrhea• Granuloma Inguinale• Haemophilus Ducreyi• Haemophilus Influenzae (beta-

lactamase Negative)• Haemophilus Influenzae (beta-la

ctamase Positive)• Helicobacter Pylori• Klebsiella Granulomatis• Legionella Pneumophila• Leptospira Sp.• Leptotrichia Buccalis

• Listeria Monocytogenes• Lower Respiratory Tract Infections• Listeria Monocytogenes• Lower Respiratory Tract Infections• Lower Respiratory Tract Infections• Listeria Monocytogenes• Lower Respiratory Tract Infections• Lymphogranuloma Venereum• Murine Typhus• Mycobacterium Fortuitum• Mycoplasma Hominis• Mycoplasma Pneumoniae• Neisseria Gonorrhoeae• Neisseria Meningitidis• Nocardia Sp.• Non-gonococcal Urethritis (NGU)• Ophthalmia Neonatorum

Prophylaxis• Otitis Media• Pasteurella Multocida• Periodontitis• Pharyngitis

;’• Plague• Plague Prophylaxis• Plasmodium Falciparum• Pneumonia• Proctitis• Propionibacterium Acnes• Propionibacterium Propionicum• Psittacosis• Q Fever• Relapsing Fever• Rickettsia Akari• Rickettsia Prowazekii• Rickettsia Rickettsii• Rickettsia Tsutsugamushi• Rickettsial Pox• Rocky Mountain Spotted Fever• Shigella Sp.• Shigellosis• Sinusitis• Skin And Skin Structure Infections

• The tetracyclines will not work for colds, flu, and other infections caused by viruses

• Spirillum Minus• Streptobacillus Moniliformis• Syphilis• Treponema Pallidum• Tularemia• Upper Respiratory Tract Infection• Ureaplasma Urealyticum• Urinary Tract Infection• Vibrio Parahaemolyticus• Yaws• Yersinia Enterocolitica• Yersinia Pestis• Amebiasis• Anthrax Prophylaxis• Bejel• Biliary Tract Infections• Cholera• Dentoalveolar Infection• Dyspepsia• Endodontic Infection• Enterocolitis• Gastric Ulcer• Legionnaire's Disease• Lyme Disease• Malaria• Pinta• Tertiary Syphilis

Cautions, contraindications, side-effects:

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Contraindications of Tetracycline Antibiotics :

Can stain developing teeth (even when taken by the mother during pregnancy)

Inactivated by Ca2+ ion, not to be taken with milk, yogurt, and other dairy products.

Skin photosensitivity; exposure to the Sun or intense light is not recommended

Drug-induced lupus, and hepatitis Can induce microvesicular fatty liver. May interfere with methotrexate by displacing it from the various protein

binding sites

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:

• Tetracyclines should therefore be avoided in pregnant or lactating women.

• Tetracycline might cause stains to developing adult teeth,which cannot be easily removed with conventional tooth whitening.

• Tetracycline can cause skin reaction.

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What are the possible side effects of Tetracycline?

• Mild nausea, vomiting, diarrhea.

• White patches or sores inside your mouth or on your lips .

• Swollen tongue, trouble swallowing.

• Vaginal itching or discharge. • Loss of appetite, jaundice (yellowing

of the skin or eyes).

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What other drugs affect Tetracycline?

• Cholesterol-lowering medications such as cholestyramine (Prevalite, Questran) .

• Isotretinoin (Accutane). • Tretinoin (Renova, Retin-A, Vesanoid) .

• A blood thinner such as warfarin (Coumadin).

• A penicillin antibiotic such as amoxicillin (Amoxil, Trimox, others).

• Penicillin (BeePen-VK, Pen-Vee K, Veetids, others).

• Dicloxacillin (Dynapen)

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What warnings do you have for Tetracycline?

Finish the prescription.

Take on empty stomach. Take with plenty of water.

Shake well.

Do not take with milk, antacids, or iron. Avoid exposure to sun.

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What is the most important information I should know about Tetracycline?

Do not use this medication if you are pregnant..

Tetracycline passes into breast milk and may affect bone and tooth development in a nursing baby.

Do not give tetracycline to a child younger than 8 years old.

Avoid exposure to sunlight or artificial UV rays.

Do not take iron supplements, multivitamins, calcium supplements, antacids.

Throw away any unused tetracycline when it expires or when it is no longer needed.

• KEY POINTS

• The tetracyclines are bacteriostatic antibiotics that have a broad spectrum of activity and are the most widely prescribed form of antibiotic after penicillins.

• The tetracyclines are broad-spectrum antibiotics that are active against both Gram-positive and Gram-negative bacteria.

• The tetracyclines inhibit protein synthesis by binding to the 30S subunit of ribosomes and preventing aminoacyl-tRNA from binding. This stops the further addition of amino acids to the growing protein chain. Protein release is also inhibited.

• The tetracyclines were originally used for many types of respiratory infections, but have been largely replaced by beta-lactams because of the problems of resistance. However, they are still the agents of choice for the treatment of Lyme disease, rickettsia, and infections caused by chlamydia.

• They are also used to treat acne and a variety of different infections including respiratory and genital infections. Doxycycline has been found to be useful for the treatment and prophylaxis of malaria, and is cheaper than other antimalarial agents.

• The drug can also be used for the treatment of a variety of diseases including syphilis, sinusitis, oral herpes simplex, and acne. It is a possible agent for the treatment or prophylaxis of anthrax.

• Tetracyclines should be avoided for young children and pregnant mothers since they can bind to developing teeth and bone, leading to tooth discolouration.

• Resistance to tetracyclines can arise through several mechanisms. Some organisms have effective efflux mechanisms that pump the drug back out of the cell. Resistance can also arise from alterations in the bacterial ribosomes, such that they have lower affinity for the agents.

•  

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Conclusion:

Tetracyclines are broad-spectrum antibiotics. Despite numerous reports of resistance they are still the drugs of choice for treatment of a wide variety of infections.

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References:

• D. Sri Ram, P. Yogeswari., Medicinal Chemistry;

2nd Edition;316-321.

• K.Illango , P. Valentina., Text book of Medicinal Chemistry;

vol-II;150-158.

• Dr. S. S. Kadam., Principles of Medicinal Chemistry;

Vol-I;5.26.

• Wilson and Gisvold’s., Text book of Organic Medical and

Pharmaceutical Chemistry;12th Edition;341-348.

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• G. L. Patrick., Introduction to Medicinal Chemistry

• William O. Foye., Textbook of Medicinal Chemistry,

Lea & Febiger , Philadelphia.

• S. N. Pandeya., Medicinal Chemistry; Vol-II; 837-850.

• Rama Rao., Medicinal Chemistry ; 120 – 124.

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T H A N Q