Antibiotics History, Nomenclatures, Stereochemistry, SAR

Antibiotics are chemical substances obtained from various species of microorganisms that kill or inhibit the growth of another microorganism in low concentration.
Eg- Penicillin kills bacteria but is produced from fungi

1. ADD TITLE Add Subtitle MEDICINAL CHEMISTRY ANTIBIOTICS By S Maheen Abdul Rahman, M. Pharm Assistant professor PA Pharmacy College Mangalore.

2. ANTIBIOTICS 2 These are chemical substances obtained from various species of microorganisms that kill or inhibit the growth of another microorganism in low concentration. Eg- Penicillin kills bacteria but is produced from fungi History

3. 3 According to their spectrum Broad Spectrum Narrow spectrum Broad Spectrum These types of antibiotics have a wide range of actions & inhibit/kill both types of bacteria such as gram +ve & -ve E.g., Tetracyclines, Chloramphenicol, etc.… Classification of Antibiotics

4. 4 Narrow Spectrum These types of antibiotics have a short range of action & inhibit/kill only a kind of bacteria ( Gram +ve / -ve) E.g.- Penicillin G, Streptomycin 2. According to their Origin/ sources Natural Semisynthetic Synthetic

5. 5 Natural These types of antibiotics are obtained naturally from microorganisms Semisynthetic These antibiotics are commercially synthesized from natural antibiotics E.g., ampicillin, methicillin, cloxacillin, and oxacillin. Synthetic These types of antibiotics are synthesized commercially. E.g., Chloramphenicol Sr. No Micro organism Isolated antibiotics 1. Pencillium chrysogenum Penicillin 2. Bacillus subtilis Bacitracin 3. Bacillus polymyxa Polymyxin 4. Streptomyces grises Streptomycin 5. Streptomyces erythreus Erythromycin

6. 6 3. According to their MOA (site of action) Cell wall synthesis inhibitors ( mainly bactericidal- kills bacteria) Drugs that interfere with the biosynthesis of bacterial cell wall E.g.- Penicillin, Cephalosporin, Cycloserine , Carbapenams , Aztreonam Plasma membrane inhibitors Drugs that interfere with the functioning of the cytoplasmic membrane. E.g., Amphotericin B, Nystatin, etc. Protein synthesis inhibitors ( mainly bacteriostatic- inhibit the growth of bacteria) Drugs that interfere with protein synthesis. Eg- Tetracyclins , Erythromycins Nucleic acid Drugs that interfere with Nucleic acid biosynthesis. Eg- Actinomycin, Rifampin

7. 7 3. According to their Chemical structure β- lactam Antibiotics E.g.- Penicillin, Cephalosporin, Monobactams, Carbapenams Aminoglycosides E.g., Streptomycin, Neomycin, Kanamycin, Gentamycin, Tobramycin, Amikacin etc. Tetracyclines Eg- Tetracyclins , Oxytetracycline, Chlortetracycline, Minocycline, Doxycycline Macrolide Eg- Erythromycin, Clarithromycin, Azithromycin, Roxithromycin etc. Miscellaneous Chloramphenicol, Clindamycin

8. 8 BETA-LACTAM ANTIBIOTICS β-lactam is a cyclic amide with four atoms (3C & 1N) in its ring named as azetidinone β-lactam antibiotics are a class of antibiotics that contain a β-lactam ring and mainly their action by inhibiting the cell wall synthesis of bacteria (bactericidal) Eg- Penicillin & its derivatives ( Penams ) Cephalosporins & its derivatives Monobactams Carbapenems

9. 9 Penicillins Monobactams Cephalosporins Carbapenems β-lactam Antibiotics Natural Semisynthetic Penicillin G Penicillin V Amoxicililin Ampicillin Oxacillin Cloxacillin Methicillin 1 st generation Cefadroxil Cephalexin 2 nd generation Cefaclor Cefuroxime Cefoxitin 3 rd generation Cefixime Cefotaxime 4 th generation Cefipime Aztreonam Imipenem Meropenam

10. 10 MOA All beta-lactam antibiotics are bactericidal which gives their action by inhibiting the synthesis of cell wall (bactericidal) which causes the lysis of bacteria

11. 11 PENICILLINS It is the 1 st antibiotic, which was discovered & reported in 1929 by sir Alexander fleming Biological Source- Penicillium notatum & Penicillium chrysogenum In their structure, beta lactam ring is located- Beta lactam antibiotics Structure It contains 2 rings fused with each other- a Thiazolidine ring & ß- lactam ring Penicillin is composed of a 6-aminopenicillanic acid nucleus with a side chain ß-lactam ring Thiazolidine ring Amide linkage 6-aminopenicillanic acid

12. 12 Nomenclature It is done by 2 different systems Chemical abstract system (CAS) Numbering starts from ‘S’ atom Sulfur atom assigned the 1 st position & ‘N’ atom assigned 4 th position and is called as 6- acylamino-2,2- dimethyl-3- carboxylic acid 1 3 2 4 6 5 7

13. 13 2. USP system Numbering starts from ‘N’ atom Nitrogen atom assigned the 1 st position & ‘S’ atom assigned 4 th position and is called as 4-thia-1-azabicycloheptone 1 3 2 4 6 5 7

14. 14 Stereochemistry Three chiral carbon atoms are present in penicillin molecule ( C3, C5, C6) All naturally occurring and microbiologically active synthetic and semisynthetic penicillins have the same absolute configuration about these 3 centers The absolute stereochemistry of penicillin is 3S: 5R: 6R 1 3 2 4 6 5 7 The acyl amino group amino group & carboxyl group are trans to each other The atoms composing the 6- 6-aminopencillanic acid are biosynthetically derived from 2 amino acids, L-cysteine & D- valine

15. 15 SAR ( Structural Activity Relationship) Penicillin molecules contain a highly strained 4 membered ß -lactam ring fused to 5- membered Thiazolidine ring ß- lactam ring is unstable & responsible for the antibiotic potency, but the side chain determines the antibacterial spectrum & pharmacological properties 1 3 2 4 6 5 7 Position 1 st – Sulfur is essential for activity, if it oxidizes to a sulfone/sulfoxide, it improves acid stability but decreases activity Position 2 nd - di methyl group are essential for activity ( No substitution)

16. 16 Position 3 rd – Carboxylic acid is essential for activity, changing to alcohol/ ester decreases activity Position 4 th – Nitrogen is essential for activity Position 5 th – No substitution allowed Position 6 th – Substitutions are allowed on the side chain on ‘R’ An electron-withdrawing group decreases the electron density & provide compounds with better acid stability (oral) A bulky group added close to the ring will make the compound more resistant to ß lactamases Position 7 th – Carbonyl group is essential

17. 17 Chemical degradation The deterioration of penicillin occurred due to hydrolysis of the strained ß- lactam ring Penillic acid Penicillin Methyl penicilloic acid 6- Aminopenicillanic acid Penicilloic acid Penilloic acid amidases CH 3 OH Acidic pH Alkaline pH Decarboxylation Penilloaldehyde + Penicillamine

18. 18 Important products with structure Drug Name ‘R’ group Penicillin G (Benzyl penicillin) Penicillin V (Phenoxy methyl penicillin)- Acid resistant Amoxicillin (X= OH) Ampicillin ( X=H)

19. 19 Important products with structure Drug Name ‘R’ group Methicillin Oxacillin ( X,Y= H) Cloxacillin (X= Cl, Y= H) Dicloxacillin ( X,Y=Cl)

20. 20 Use of Penicillins Used to treat a wide variety of bacterial infections. (Pneumonia, Other respiratory tract infection, Meningitis, syphilis, endocarditis, tooth & gum infecions etc..) ADRs Diarrhea, Fever, Body aches Severe skin rashes, itching, Nausea, Vomitting etc..

21. 21 2.CEPHALOSPORINS These are the 2 nd major group of ß- lactam antibiotics, they also contain ß lactam ring It was 1 st isolated by Guiseppe Brotzy in 1945 from the fungus Cephalosporium acremonium & it inhibited the growth of wide varieties of gram + ve & - ve bacteria Cephalosporin has identical MOA with Penicillins ( inhibits cell wall synthesis)

22. 22 Structure Cephalosporin contains ß lactam ring which is fused with a 6-membered dihydro thiazine ring Cephalosporins contain 7-aminocephalosporanic acid (7-ACA) nucleus & side chain ß-lactam ring Dihydrothiazine ring Amide linkage

23. 23 Nomenclature The chemical nomenclature of cephalosporins is slightly more complex than the penicillin due to presence of double bond 1 2 6 5 7 3 7-aminocephalosporanic acid 1 2 3 5 6 7 -5- thia- 1- azabicyclo - oct- 2-ene

24. 24 Stereochemistry 2 chiral carbon atoms C6 & C7 ( 6R: 7R) SAR Cephalosporin molecules contain a 4 membered ß lactam ring fused to 6- membered dihydro thiazine ring 1 2 5 7 4 3 6 Now, the addition of a different side chain at position 7 th of ß lactam ring & position 3 rd of dihydro thiazine ring formed new semi-synthetic compounds Position 1 st – Oxidation of sulfur to sulphoxide / sulfone destroys or reduce the antimicrobial activities Replacement of ‘S’ to ‘O’, increases the antibacterial activity Replacement of ‘S’ to methyl group, increases chemical stability

25. 25 Position 2 nd – No change Position 3 rd - R1= acetoxymethyl group( ↑ activity) R1→ CH 3 /Cl ( Orally active compound) R1→ Aromatic thiols/ S- membered heterocycle ( ↑ activity) 1 2 5 7 4 3 6 Saturation of double bond b/w C3 to C4 decreases the antibacterial activity Position 4 th - if the carboxyl group is replaced with the ester group then it will enhance the bioavailability by forming a prodrug Position 5 th - ‘N’ essential for activity Position 6 th - No substitution Position 7 th - Acylation of amino group increases the activity against gram + ve

26. 26 R 2 → Phenyl ring/ other heterocyclic ring improved spectrum of activity( eg - Thiophene, Tetrazole etc.) Replacement of hydrogen with ‘–OR’ ,↑ ses antibacterial activity Position 8 th – No change 1 2 5 7 4 3 6

27. 27 Classification of cephalosporins 1 st generation These were developed in the 1960s, have high activity against gram + ve but weaker against gram – ve bacteria Eg - Cefadroxil (Oral) Cephalexin (Oral) Cefazolin( Parentral )

28. 28 Classification of cephalosporins 2 nd generation These compounds are more active against gram – ve organism. But they are weaker than the 1 st generation compounds against gram + ve bacteria Eg - Cefaclor (Oral) Cefprozil (Oral) Cefoxitin( Parentral )

29. 29 Classification of cephalosporins 3 rd generation Introduced in the 1980s, they are highly active against gram – ve bacteria than 2 nd generation Eg - Cefixime (Oral) Cefotaxime( parentral )

30. 30 Classification of cephalosporins 4 th generation They have similar antibacterial spectrum as 3 rd generation, but they are highly resistant to ß lactamases. So they posses excellent activity against both Eg - Cefepime ( parentral ) Cefpirome( Parentral )

31. 31 Classification of cephalosporins 5 th generation Cephalosporins with anti- MRSA activity (methicillin- resistant Staphylococcus aureus) They have ability to kill MRSA Eg - Ceftaroline fosamil

32. 32 Chemical degradation of cephalosporins Cephalosporin Acylase H 2 O H + /H 2 O 7- ACA Desacetyl-7-ACA lactone (Inactive lactone) H + Desacetyl cephalosporin In presence of acid Lactonise acid Lactone (Inactive)

33. 33 Cephalosporin Cephalosproric acid Fragmentation & rearrangement product (Inactive) ß lactamase Anhydro desacetyl cephalosporic acid

34. 34 Uses Alternative to penicillin Respiratory tract infections caused by klebsilla , Enterobacter, and Haemophilus species Gonorrhoea Typhoid Fever Meningitis ADR More toxic than penicillin Diarrhoea , hypersensitivity reaction etc.

35. 35 3. ß lactamase Inhibitors ß lactamase are family of enzymes produced by many gram + ve & - ve bacteria that inactivates ß lactam antibiotics by opening the ß lactam ring(↓ anti bacterial) To overcome this, ß lactamase inhibitors drug discovered in 1980s which basically inactivate this beta lactamases enzyme & ↑ ses the antibacterial activity of ß lactam antibiotics They are not used alone, they used in combination with ß lactam antibiotics Eg - Clavulanic acid, Sulbactam, Tazobactum

36. 36 MOA ß lactamase inhibitors contains ß lactam ring, which strongly bind with ß lactamase enzyme at its active sites Then inactivates ß lactamase enzyme which further ↑ ses the activity of ß lactams & ↑ ses antimicrobial activity DRUGS Clavulanic acid It is a semisynthetic inhibitor isolated from Streptomyces clavuligerus Used to treat skin, respiratory, ear, & urinary tract infection

37. 37 Sulbactum Given in combination with ampicillin Tazobactum More potent than sulbactam

38. 38 4. MONOBACTAMS Monobactums are obtained by the fermentation of Chromobacterium violaceum Monobactams have monocyclic beta-lactam ring They are effective against ß lactamases & gram – ve bacteria ( eg - pseudomonas) Not effective against gram + ve bacteria Aztreonam is the commercially available monobactam Penicillin-allergic patients tolerate aztreonam without a reaction

39. Aztreonam 39 Parentral monobactum with narrow spectrum

40. 40 Previous year questions : What are antibiotics? Discuss the stereochemistry & SAR of tetracyclines. Degradation products of cephalosporins & penicillin Write a note on penicillinase resistance penicillins Define antibiotics. Classify them with structural examples. Discuss the chemistry & MOA of aminoglycoside antibiotics Define & classify the cephalosporins based on generation giving their str What are beta lactam antibiotics? Classify them with structural eg. Write note on chemistry & beta-lactamase inhibitors What are tetracyclines? SAR & MOA of tetracyclines. What are monobactam antibiotics? 2 ex. What are aminoglycoside? MOA & SAR of aminoglycoside antibiotics Chem & synthesis of Chloramphenicol Classify penicillins with eg. ? & MOA

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