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Tetracyclines are Octahydro napthacene derivatives which are bacteriostatic potent broad spectrum antibiotics and are the most widely prescribed form of antibiotic after penicillins.
TETRA means = four
CYCL means = hydrocarbon rings
INE means = derivation.
Tetracyclines are introduced 50 years ago as potent broad spectrum antibiotics.
They are biosynthesized form acetic acid and propionic acid units in microorganisms.

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  1. 1. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 1 TETRACYCLINES Prof. P. Ravi Sankar, M. Pharm., Ph.D. Vignan Pharmacy College, Vadlamudi, Guntur, A.P, INDIA
  2. 2. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 2 1. 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
  3. 3. 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.
  4. 4. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 4 TETRACYCLINES  Tetra means = Four  Cycl means = Hyrocarbon ring  Ine means = Derivation
  5. 5. 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. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 5
  6. 6. 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. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 6
  7. 7. 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. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 7
  8. 8. 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) • Doxycycline Minocycline Tigecycline • Demeclocycline Methacycline Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 8
  9. 9. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 9
  10. 10. Tetracyclines are obtained from various species of Streptomyces bacteria by fermentation technology Chlortetracycline(aureomycin) from Streptomyces aureofaciens. Oxytetracycline (Terramycin) from Streptomyces rimosus. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 10
  11. 11. Stereochemistry of tetracyclines is very complex. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 11 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.
  12. 12. Important structrual units and the three acidity constants in the tetracycline molecule. (conjugated Trione system Is acidic nature) pka1 (2.8-3.4) (Conjugated phenolic Enone system is slightly basic) Strong alkaline. Pka (7.2-7.8) Pka3 (9.1-9.7)
  13. 13. 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. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 13
  14. 14. Epimerization: OH CONH2 OHOH HO O O N(CH3)2 OH H H CH3 1 4 2 3 4a 5 5a 6 6a 7 8 9 10 10a 11 11a 12 12a ABCD H H H OH OH CONH2 OH O O N(CH3)2CH3 H H H OH -H2O Tetracycline (Active) Anhydrous Tetracycline (Inactive) H+ H OH CONH2 OH OH O H H H OH O HO N(CH3)2 CH3 H 4-Epi tetracycline (Inactive) -H2O H OH OH CONH2 OH O O CH3 OH H N(CH3)2 4-Epianhydro tetracycline (Inactive) H+ Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 14 Strong acids and bases Attack those tetracyclines Which possess an –OH group at C-6 and form inactive anhydrotetracyclines
  15. 15. Base-catalyzed instability of tracylines: OH CONH2 OHOH HO O O N(CH3)2 OH H H CH3 1 4 2 3 4a 5 5a 6 6a 7 8 9 10 10a 11 11a 12 12a ABCD H H OH- -H2O OH CONH 2 OH OHO O N(CH3)2 OH CH3H H H H O Isotetracycline (Inactive) Tetracycline Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 15 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.
  16. 16. O O OH NH2 CH3HO C O OH OHOH CH3H3C N H3C CH3 H3C H N O N H CH3H3C N O O OH NH2 C OH OHOH CH3H3C N O CH3H3C N O O OH NH2 C OH OHOH CH3H3C N O O O OH NH2 C OHCH2 O OH OHOH CH3H3C N N H3C CH3 OH OH OH O OH C HO CH3 NH2 OH OO N H3C CH3 Cl OH OH OH O CH2 OH C NH2 OH OO O O OH NH2 CH3HO C Cl OOH OH OH CH3H3C N O O OH NH2 H C Cl HO OOH OH OH CH3H3C N 121110 9 8 7 6 5 4 3 2 1 METHACYCLINE [Rondomycin] OXYTETRACYCLINE Terramycin, (Urobiotic) CHLORTETRACYCLINE Aureomycin TETRACYCLINE Achrommycin, Sumycin, Panmycin, Teracap, Tetracyn, Tetralan TIGECYCLINE Tygacil™ MECLOCYCLINE Meclan MINOCYCLINE Arestin, Dynacin, Vectrin, Minocin DEMECLOTETRACYCLINE Declomycin O O OH NH2 C H3C OHH OOH OH OH CH3H3C N DOXYCYCLINE Vibramycin, Vibra–Tabs Doryx, Doxy STRUCTURES OF IMPORTANT TETRACYCLINES Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 16
  17. 17. CHELATION: Tetracyclines Ca2+, Fe2+ Al3+, Fe3+ Citrates lipoproteins Serum albumin globulins Metal complexes (Insoluble in water at neutral PHs) Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 17 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 dairy products rich in calcium ion also is contraindicated.
  18. 18. OH OH CONH2 OH R1 O O R2 R3 H R4 H N(CH3)2 OH ABCD 1 2 3 4 4a 5 5a 6 6a 7 8 9 10 10a 11 11a 12 12a N(CH3)2 Increases activity Conversion to nitriles causes a 20 fold increase in activity Modification leads to loss of activity =CH2 Increases the Antibacterial activity Elimination of 6-OH group increase lipophilicity & more stable to acids. Ex: Doxycycline. ‘D’ ring should be always aromatic Changes in this ring Leads to biological inactivation of the molecule. Additional glycyl amino substitution at the 9th Position leads to the new Class of antibiotics the glycylcyclines. EX: Tigecycline.(Tygacil) The keto-enol tatomerism Between c2 and c3 are very important for biological activity. Inviolate zone is essential The linearly fused tetracyclic nucleus is most important for the antibiotic activity. Electron donating (or) electron withdrawing groups at c7 increased Antibacterial activity Substitution with –OH Produce water soluble derivatives which can be administered orally. Epimerization at c4 and dehydration at 5a results loss of activity. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 18 Structural Activity Relationship:
  19. 19. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP SUMMARY of SAR: OH CONH2 OHOH R1 R2 O O N(CH3)2 OH H R4 H R3 1 4 2 3 4a 5 5a 6 6a 7 8 9 10 10a 11 11a 12 12a ABCD 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
  20. 20.  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. . . Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 20
  21. 21. Freeze initiation Block peptide bond formati on Misreading of mRNA p-Site (Peptidyl site) on which the t-RNA holds the Elongated peptide chain. (A-site) Amino acetyl t-RNA binding site.(attachment of Incomming amino Acid by t-RNA. (Aminoglycosides blocks translocationhere) Chloramphenical Blocks transpeptidation Tetracyclines reversibly bind to the 30S subunit at the A- site to prevent attachment of the amino acyl tRNA, terminating the translation process.
  22. 22. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 22
  23. 23. Animation Illustrating the Role of Tetracyclines in Blocking Translation during Bacterial Protein Synthesis
  24. 24.  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 Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 24 • Tetracyclines are broad spectrum antibiotics. They are active against following micro organisms:
  25. 25. • 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 Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 25
  26. 26. • 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 Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 26
  27. 27. • Duodenal Ulcer • Entamoeba Histolytica • Francisella Tularensis • Fusobacterium Fusiforme • Gonorrhea • Granuloma Inguinale • Haemophilus Ducreyi • Haemophilus Influenzae (beta- lactamase Negative) • Haemophilus Influenzae (beta- lactamase 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
  28. 28. ;’ • 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
  29. 29. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 29
  30. 30. 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 Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 30 :
  31. 31. • 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. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 31
  32. 32. • 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). Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 32
  33. 33. • 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) Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 33
  34. 34. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 34  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.
  35. 35. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 35  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.
  36. 36. • 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. • Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 36
  37. 37. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 37
  38. 38. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 38 • 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.
  39. 39. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 39 • 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.
  40. 40. Vignan Pharmacy College,Vadlamudi,Guntur.dst,AP 40
  41. 41. 41