Aminoglycosides & tetracyclines Classification and SAR.pptx
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The document discusses aminoglycosides and tetracyclines, both classes of broad-spectrum antibiotics with distinct mechanisms of action. Aminoglycosides, such as streptomycin and gentamicin, are bactericidal and primarily target gram-negative bacteria, while tetracyclines inhibit protein synthesis and have both gram-positive and gram-negative activity. The document also details their chemical structures, side effects, and classifications, along with various important products and their uses.
Aminoglycosides & tetracyclines Classification and SAR.pptx
- 1. ADD TITLE Add Subtitle MEDICINAL CHEMISTRY AMINOGLYCOSIDES & TETRACYCLINS By S Maheen Abdul Rahman, M. Pharm. Assistant Professor PA College of Pharmacy Mangalore, Karnataka.
- 2. Aminoglycosides 2 • Aminoglycosides are one of the class of antibiotics which are basically bactericidal in nature. • Streptomycin was isolated from Streptomyces griseus and neomycin was isolated from Streptomyces fradiae in the 1940’s • Gentamicin isolated from Micromonospora in 1963 • Others later developed amikacin, netilmicin tobramycin • These drugs are broad spectrum antibiotics but they have greater activity against gram –ve than gram +ve • They mainly used as gram –ve antibacterial medications • They also have some undesirable side effects particularly ototoxicity & nephrotoxicity restricted their systemic use
- 3. 3 History Sr. No Antibiotic Source Year of introduction 1. Streptomycin Streptomyces griseus 1944; Waksman 2. Neomycin S. fradiae 1949; Waksman 3. Kanamycin S. kanamyceticus 1957; Limezawa 4. Gentamicin Micromonospora purpurea 1964 5. Tobramycin S. tenebrarius 1967; Higgins
- 4. Nomenclature • The aminoglycosides which are derived from bacteria of streptomyces genus are named with the suffix ‘mycin’ • While those derived from micromonospora are named with the suffix ‘micin’ • However this nomenclature system is not specific for aminoglycosides MOA • Aminoglycosides are bactericidal which gives their action by inhibiting the protien synthesis • Aminoglycosides penetrates into bacterial cell wall → Reach into periplasmic space through porins → further transport into cytoplasm through active transport by proton pump → binds to 30s ribosomal subunits
- 5. • binds to 30s ribosomal subunits • Aminoglycosides Inhibits initiation of protien synthesis Induce misreading of genetic code Binds to the 30S ribosomal subunit to form complex Cuase misreading mutation of genetic code of mRNA Cannot initiate proper amino acid polymerization Incorporation of improper amino acid into peptide chain
- 6. Inhibits the synthesis of protiens Inhibits the synthesis of peptide chain No protien synthesis No peptide chain Cuase death of bacterial cell No cell wall Classification 1. Systemic Aminoglycosides- Streptomycin, Kanamycin, Gentamicin, Tobramycin 2. Topical Aminoglycosides- Neomycin, framycetin
- 7. 7 SAR • Aminoglycosides contain 2 or more amino sugar joined to a aminocyclitol as a centrally placed ring via glycosidic linkage O O O OH H2N NH2 HO HO NH2 OH OH NH2 O OH H2N • Substitute possible on 2 structures- Amino sugar portion & centrally placed hexose ring • Amino sugar portion • Methylation of C6 increases enzymatic resistance • The amino function at C6 & C2 are the major target sites for bacterial inactivating enzymes • The whole ring is essential for activity O H2N OH OH NH2 O 1 2 3 4 5 6
- 8. 8 Aminocylital ring • NH2 at C1 can be acylated ( amikacin) with retention of activity • Substitution of OH group at C2 can increase the activity Important products 1.Streptomycin • It is an aminoglycoside antibiotic derived from Streptomyces grises (Broad S) • MOA- Protien synthesis inhibitor • Used in the treatment of TB in the combination with other antituberculosis agents • Also used for infective endocarditis ADR- Ototoxicity, Neurotoxicity & Nephrotoxicity NH2 O H2N O OH Amino sugar sugarAmino 1 2 3 4 5 6
- 9. 9 • Streptomycin 2. Neomycin • It is a broad spectrum aminoglycoside obtained from S. fradiae • Uses- Used in the treatment of GI infection, dermatological infections • Used in topical preparation O O OH OH N NH2 NH2 OH N H2N O O OH HO HO NH O
- 10. 10 • Neomycin 3. Kanamycin • It is obtained from the bacterium kanamyceticus • Uses • Mainly used to treat bacterial functions of intestinal tract & systemic infections O O O OH OH H2N NH2 NH2 OH H2N O OH O OH O HO OH R2 R1 Neomycin R1 R2 B CH2NH2 H C H CH2NH2
- 11. 11 Kanamycin R1 R2 A OH NH2 B NH2 NH2 C NH2 OH NH2 O O R2 OH OH R1 OH O O HO HO H2N OH H2N Uses of Aminoglycosides • Mainly active against gram –ve • Only few gram +ve Kanamycin
- 12. Tetracyclins • These are broad spectrum antibiotics • They are obtained by fermentation from streptomyces species, or by chemical transformation of natural products Structure • These are derivatives of octanhydronaphthacene, a hydrocarbon system that compromise 4 annulated 6-member rings O OH O NH2 N OH O OH OH OH 1 2 3 4 5 6 7 8 9 10 11 12 4a 5a 11a 10a 6a 12a • Tetracyclines are amphoteric compounds ( forming salts with either acids or bases) • In neutral solution, these substances exist mainly as zwitter ions
- 13. • Tetracyclines forms stable chelate complex with many metals such as Ca2+ , Mg2+ , Fe2+ , Al3+ Stereochemistry • The stereochemistry of the tetracyclins is very complex O OH O NH2 N OH O OH OH OH 1 2 3 4 5 6 7 8 9 10 11 12 4a 5a 11a 10a 6a 12a • Carbon atoms 4, 4a, 5, 5a, 6 & 12a are potential carbon , depending on substitution
- 14. Classification • According to sources- 1. Natural sources- Tetracyclins, Oxytetracyclines, Chlortetracyclins etc. 2. Semi-synthetic- Methacyclins, Doxycyclines, Minocyclins, Meclocyclins, etc. • According to their actions- 1. Short-acting ( half life 6-8 hrs)- Clortetracylines, Oxytetracyclines, etc. 2. Intermediate-acting ( half-life about 12 hrs)- Methacyclins 3. Long-acting ( Half life 16 hrs or more)- Doxycycline, Minocycline, Meclocyclins, etc.
- 15. MOA • Tetracyclines are primarly bacteriostatic, they inhibit growth of bacteria by inhibiting its protien synthesis • TC’s reversibly binds to the 30s ribosomal subunit & prevent the binding of aminoacyl tRNA to the mRNA ribosome complex, which inhibits the initiation of protien synthesis SAR • All derivatives containing fewer than 4 rings are inactive or nearly inactive • C1 & C3 → Keto enol is essential for activity O OH O NH2 N OH O OH OH OH 1 2 3 4 5 6 7 8 9 10 11 12 4a 5a 11a 10a 6a 12a • C2 → Replacement of amides with other aldehyde/nitrile reduces the activity
- 16. • C4→ Removal of 4- dimethyl group reduces the activity • C4a→ No changes, Essential for activity • C5→ Substitute with OH give orally active compound • C5a→ No change, Essential for activity O OH O NH2 N OH O OH OH OH 1 2 3 4 5 6 7 8 9 10 11 12 4a 5a 11a 10a 6a 12a • C6 → substitute increases the antibacterial activity( dimethyl) • C7 → electron withdrawing group (Cl, NO2) & electron donating group ( dimethyl amino ) alter the activity • Ring D → Modification in this ring leads to biological activity • C11 & C12 → Keto enol is essential for activity CH2 • C11a →Alkylation cuase loss of activity D A
- 17. • C12a→ OH is essential for activity Chemical degradation Tetracyclins undergoes epimerization at C4 & forms epitetracyclines which are less active than tetracyclines Important products 1. Tetracyclin O O OH OH OH OH O NH2 N HO • It’s broad spectrum tetracycline antibiotics produced by the streptomyces genus of actinomycetes bacteria • Used in the treatment of gonnorrhea, respiratory tract, ear infection & acne vullagaris ( topical) etc..
- 18. 2. Oxytetracyclin • It’s isolated from streptomyces rimosus • Used in the treatment of infection caused by gram +ve & gram –ve bacteria such as mycoplasma, pneumonia, haemophilus influenza, respiratory infections O O OH OH OH OH O NH2 N OH HO
- 19. 3. Chlortetracyclin • Isolated from Streptomyces aureofaciens • Used in the treatment of infection of respiratory tract, sinuses, middle ear, intestines & eye infections • Also used in the treatment of skin infections O O Cl OH OH OH OH O NH2 N HO
- 20. 4. Minocyclin • It’s a tetracycline analogue having a dimethyl amino group at position 7 & lacking the methyl & hydroxy group at position 5 • It has activity towards Gram +ve bacteria, especially staphylococci & streptococci • Used to treat respiratory tract , eye infection & UTI’s N O O O NH2 OH OH OH OH N
- 21. 5. Doxycyclin • It is a semi synthetic tetracyclins in which the 5ß hydrogen is replaced by a hydroxy group , while 6α hydroxy group is replaced by hydrogen • It is broad spectrum antibiotics & has a role as an antibacterial drug and an antimalarial • Used to treat respiratory infections, UTI’s, eye infections etc. • Also used in the treatment of infection like syphilis, sinusitis, acne & malaria • Recently in Covid 19 treatment O O OH OH OH OH O NH2 N OH
- 22. Uses • Various gram +ve & gram –ve bacterial infections, including vibrio infections • Drug of choice – Rickettsiae • Treat gastric & duodenal ulcer disease caused by Helicobacter pylori • Most chlamydial infections, including sexually transmitted infections • In combination with other antibiotics- plague, brucellosis • Prophylaxis of protozoal infections
- 23. 23 Previous year questions: 1. What are antibiotics? Discuss the stereochemistry & SAR of tetracyclines. 2. Degradation products of cephalosporins & penicillin 3. Write a note on penicillinase resistance penicillins 4. Define antibiotics. Classify them with structural examples. Discuss the chemistry & MOA of aminoglycoside antibiotics 5. Define & classify the cephalosporins based on generation giving their str 6. What are beta lactum antibiotics? Classify them with structural egs. Write note on chemistry & beta-lactamase inhibitors 7. What are tetracyclines? SAR & MOA of tetracyclines. 8. What are monobactam antibiotics? 2 ex. 9. What are aminoglycoside? MOA & SAR of aminoglycoside antibiotics 10. Chem & synthesis of Chloramphenicol 11. Classify penicillin with e.g.? & MOA
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