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Tetracycline
- 1. • Mr. Hitesh Vishwanath Shahare • Assistant Professor • Dept. Ph.’ Chem. OH CONHR5 OOHOOH R1 H R4 OH R2 R3 H N H3C CH3 1 2 3456 7 8 9 10 11 12 4a5a 11a 12a 6a ABCD TETRACYCLINES
- 2. Learners will be able to know; 2 1. Classification 2. SAR of Tetracycline 3. MOA of Tetracycline 4. Adverse effect of Tetracyclines 4 3 2 1
- 3. Introduction 3 • Isolated from Streptomyces species • Biosynthesized from Acetic acid & Propionic acid units in microorganism • 1945: Chlortetracycline (Prototype) of Tetracyclines was discovered. • USA: Dr. Benjamin Duggar produced Chlortetracycline from golden-colored soil (Actinomycetes) bacterium by fermentation technology Streptomyces aureofacien
- 4. 4 • 1950: Oxytetracycline from S. rimosus • Orally effective, • Broad spectrum: • 1953: Tetracycline
- 5. 5 Source Based Naturally obtained Semisynthetic
- 6. 6 Tetracyclines (Based on duration of action) Short Acting Intermediate Acting Long Acting • Half Life: 6-8 hrs • Tetracycline Chlortetracycline • Half Life: 12 hrs • Demeclocycline Methacycline • Half Life: 16 hrs • Doxycycline Minocycline
- 7. 7 • Octahydro naphthacene Derivative Derivation Tetra Four Cycle Hydrocarbon rings Ine TETRACYCLINE
- 8. SAR 8 Result in loss of activity Result in similar or increase in activity Modifications in part 2 OH CONHR5 OOHOOH R1 H R4 OH R2 R3 H N H3C CH3 1 2 3456 7 8 9 10 11 12 4a5a 11a 12a 6a ABCD Part 1 Part 2
- 9. SAR 9 1) All Tetracyclines is a polycyclic napthacene carboxamide: Comprised of four fused six membered rings A, B, C and D All tetracycline derivatives containg less than four rings are inactive 2) The enolized tri-carbonyl methane system at C1, C2 and C3 must be intact for maximum activity Keto-enol system is vital for magnesium cation binding and subsequent tetracycline uptake by the bacterial cell. OH CONHR5 OOHOOH R1 H R4 OH R2 R3 H N H3C CH3 1 2 3456 7 8 9 10 11 12 4a5a 11a 12a 6a ABCD
- 10. 10 3) C 2 substitution: Carboxmide moiety is present in all naturally occurring Tetracycline required for activity 4) C 2 substitution: Monosubstitution on amine is acceptable for activity: Amino acylation of amide nitrogen by Mannich reaction gives more water soluble derivative which on hydrolysis gives Rolitetracycline OH CONH OOHOOH H H H OH H3C OH H N H3C CH3 1 2 3456 7 8 9 10 11 12 4a5a 11a 12a 6a N Rolitetracycline
- 11. 11 5) C 4 substitution: Naturally occurring Tetracyclines contain C4-Dimethyl amino group and are having alpha orientation: Epimerization at C4 gives Epitetracyclines: Less potent Replacement of dimethylamino group with a hydrazone, oxime, or hydroxyl group leads to a pronounced loss of activity, probably due to the increase in heteroatom basicity. 6) C 4 substitution: Replacement of C4-Dimethyl amino groupO O NH2 OH H H3C CH3 O O NH2 OH H Epi Natural CH3 H3C
- 12. 12 7) C 5 substitution: 5-OH group in Oxytetracycline and Doxycycline influences the Pharmacokinetic properties and potentiate the action. Alkylation of 5-OH group result in loss of activity OH CONH2 OHOOH H H OHH3C OH OH N H3C CH3 1 2 3456 7 8 9 10 11 12 4a5a 11a 12a 6a Oxytetracycline 8) Tetracyclines contain C5a Alpha Hydrogen. 5a Epitetracyclines are active molecules
- 13. 13 9) C 6 substitution: Neither 6-alpha methyl nor 6- beta hydroxy group is essential for activity 10) C 7 & 9 substitution: Electrophillic substitution like with NO2 or Halogen: Retain the activity OH CONH2 OOHOOH Cl H H OH H3C OH OH N H3C CH3 1 2 3456 7 8 9 10 11 12 4a5a 11a 12a 6a Chlortetracycline OH CONH2 OOHOOH N H H OH H H OH N H3C CH3 1 2 3456 7 8 9 10 11 12 4a5a 11a 12a 6a Minocycline H3C CH3
- 14. 14 11) C 10 substitution: Phenolic moiety is essential 12) C 11 substitution: Conjugated carbonyl moiety part of keto-enol system: Essential Alkylation at Carbon 11 leads to inactive compound 13) A cis A/B ring fusion with beta OH group at 12a is essential for activity OH CONHR5 OOHOOH R1 H R4 OH R2 R3 H N H3C CH3 1 2 3456 7 8 9 10 11 12 4a5a 11a 12a 6a ABCD
- 15. 15
- 16. Peptidyl (P-site) binds the tRNA bearing the peptide chain 30S Subunits binds mRNA and initiate the protein synthesis 50S Subunits & 30S subunit-mRNA complex allow to bind aminoacyl tRNA Bacterial ribosome 70S made up of 30S and 50S Subunits Two main binding sites for tRNA Acceptor Aminoacyl site (A-site) Tetracycline reversibly binds to 30S subunit at A-site: Prevent the attachment of amino acyl tRNA Inhibit Translation Process (Protein Synthesis) 50S 30S70S P A MOA Tetracycline Aminoacyl tRNA with protein code of mRNA on complex: Forms Peptides
- 17. 17 Chelation Ca2+, Fe2+, Fe3+, Citrates, Lipoproteins Tetracycline Metal Complexes (Insoluble in water) Incompatible with co-administered multivitamin iron- rich antacids & Hematinics Also incompatible with consumption of products rich in calcium ion
- 18. Indications 18 RTI Skin and soft tissue infections Relapsing fever Cholera Acne UTI Anthrax In Neurodegenerative disorders
- 19. Side Effects 19 GI Disturbances: Nausea, Diarrhea Superinfections: disturbances in normal flora Liver damage: Fatty infiltration Sore Throat Headache Stomatitis Photosensitivity Nails discoloration Erythromatous rash
- 21. 21
- 22. 5 September 2020 SNJB's SSDJ College of Pharmacy, Chandwad (Nasik) 22 Thank You!