1. Presented by:-
Naveen Kadian
Department of Pharma . Chemistry
KLE’S College of Pharmacy
Belgaum-10

2. CONTENTS
 Antibiotics and its Introduction
 β- Lactam antibiotics
 Penicillins
Introduction
Nomenclature
Stereochemistry
Classification
Mechanism of Action
Biosynthesis
Structure activity relationship

3. Resistance
Hypersensitivity
Drug Interaction
Clinical Uses
 Amidopenicillins
Amoxicillin
Ampicillin
Bacampicillin
 Cephalosporins
Classification
Resistance
Adverse Reactions
Uses
Biosynthesis
 Recent Developments
 References

4. Antibiotics
 Antibiotics are the chemical substances produced by
various species of micro organisms and other living
systems which in small concentration kill or inhibit the
growth of micro organisms.
Classification
β- Lactam antibiotics
Monobactams
Aminoglycosides
Tetracyclines
Macrolides
Lincomycins
Polypeptides

5. β- Lactam antibiotics
 These includes both penicillins and cephalosporins.
 The name “lactam” is given to cyclic amides and is
analog to the name “lactone”, which is given to cyclic
esters.
 This ring ultimately proven to be the main component
of pharmacophore.
 This ring is more reactive and sensitive to
nucleophilic attack when compared to normal planar
amides.

6. Penicillins
 In 1928 Alexander Fleming accidentally discover
the antibacterial property of penicillin.
 1940 Flore extracted the penicillin from the
penicillium culture and analyzed its antibacterial
activity.
 They are destroyed by the enzyme amidase and β-
lactamase.
 The correct structure was analyzed by X-ray
crystallography in 1954.

7. Nomenclature
 According to chemical abstract naming starts from
sculpture atom and is called 5-acyl amino -2,2-
dimethyl penam 3-carboxylic acid
 But in USP naming starts from nitrogen atom (4-thia-
azobicyclo) heptones.

8. N
S
NH
CO O H
O
COR
1
2
34
56
7
N
S
C O O H
O
P enicillanic A cid
N
S
O
Penam

9. Stereochemistry
N
S
NH
CO O H
O
COR
1
2
34
56
7
It contains three chiral carbon atoms at C3, C5 and C6.
C6-L configuration, C3 and C6 chiral centers are trans to each
other.
All synthetic and semi synthetic penicillin have same absolute
configuration that of natural
3S:5S: 6R

10. Classification of penicillins
1. Natural penicillins:
Ex: penicillin-G
2. Semi synthetic penicillins
Penicillinase resistance Pencillins
Ex; Methacillin, oxacillin, cloxacillin.
3. Extended spectrum Penicillins
 Amino Penicillins:
Ex: Ampicillin, Bacampicillin, Amoxicillin.
 Carboxy penicillins:
Ex; Carbicillin, Ticarcillin.
 Ureido penicillins:
Ex; Pipericillin, Mezlocillin.

11. Mechanism of action
Mainly interferes with cell wall synthesis of bacteria.
These drugs inhibit the enzyme transpeptidase which is
responsible for cross linkage of peptidoglycan during
bacterial cell wall synthesis.

12. Biosynthesis of Penicillins
N C H C H O
C O O C4
H9
te r-b u tyl-p h th a lim id o m a lo n a ld e h yd e
+ S H
C H
C
NH2
C O O H
D -p e n icilla m in e
C o n d e n sa tio n
N C H
S
C O O C4
H9
N H C O O H
N H2
- N H2
H cl
NH2 C H
S
C O O H
C O O C4
H9
N H
p h e n o xy a ce tyl ch lo rid e
trie th yl a m in e

13. S
CO O H
COC H2
O NHC H
HCl
Pyridine
1. KO H (one equiv.)
2. N,N dicyclo-hexyl carbomide
N
S
CO O H
NHCO
NH
CO O H
O C H2
O
Penecillin-V.

14. Structural activity relationship
N
O
β- Lactam ring and R should be
cyclic, aromatic or heterocyclic
for their minimal activity.
Substitution on α-position of benzyl penicillin have
resistance to acid hydrolysis.
Increase in stability is due to electron withdrawing group
on amide carbonyl group.
α -carbon atom of an acyl group could be a part of an
aromatic or heterocyclic ring .
Ex: cloxacillin, oxacillin.

15.  Substitution at ortho position of phenyl ring increases
steric hindrance of acyl group thus increase β-
lactamase resistance.
 Nature of acyl amino side chain determines the
plasma protein binding.
 Substitutions of lipophillic group increases the protein
binding
Ex: oxacillin and cloxacilin have 80-90% protein
binding, where as ampicillin and amoxicillin have 20-
30% protein binding.

16. Resistance and Hypersensitivity
 Resistance may be intrinsic and involve decreased
cellular uptake of drug or lower binding affinity to
PBPs.
 β-lactamase enzymes produced by micro organism
catalyze hydrolysis of β-lactam bond and inactivates
β-lactam antibiotics.
 Allergy results from the formation of an allergen
when the beta-lactam ring reacts with a terminal
amine on a lysine residue in a polypeptide.
 Every time a person is exposed to this
allergen, immune system causing rash most
commonly and sometimes an anaphylactic reaction.

17. Penicillin Hypersensitivity
 Some specific symptoms including: an itchy
rash, swelling of the throat/mouth area and difficulty
breathing.
 A simple skin allergy test can be performed to
determine allergy to penicillin.
 Erythromycin and clindamycin are alternative choices
 Because the origin of allergy is a reaction with host
protein , the side effect is caused by pharmacophore
and is unlikely to over come by molecular
manipulation.

18. Drug interactions
 Oral contraceptives – Penicillins may interact with
oral contraceptives and decrease the effectiveness of
the oral contraceptives.
 Probenecid – This may compete with penicillin for
renal tubular secretion and result in higher serum
levels of penicillin.
 Methotrexate - decrease the ability of kidneys to
remove methotrexate from your body resulting in
increased levels of methotrexate in the body.

19. Clinical uses
 Urinary tract infections
 Respiratory tract infections
 Meningitis
 To treat Gonorrhea, Syphilis, typhoid, bacillary
dysentery.
 Sub acute bacterial endocarditis.
 Bone and joint infections.
 Bronchitis, Pneumonia.
 Skin and Soft tissue infections.

20. Amido penicillins
 6β-acylamino side chain replacement usually results
in loss of activity.
 In 1972 Lund and tiring reported that 6-amidino
penicillinic acids have good activity against G-ve
bacteria.
 SAR studies reviewed that N,N-dialkyl formamides
tend toresemble the analogs of pencillins active
against G-ve bacteria.
 Ex: homopiperidine derived from
formamide, Mecillinam.
N C H N
N
S
C O O H
O

21.  Mecillinam's mechanism of action differs from other -
lactam antibiotics, that its primary target is penicillin-
binding protein 2.
 mecillinam and ß-lactam antibiotics showed synergy
in most instances.
 Synergy was not found with combinations of
mecillinam and
aminoglycosides, chloramphenicol, tetracycline, or
polymyxins.
 Mecillinam was combined with
amoxicillin, carbenicillin, and cefoxitin and tested
against most members of the Enterobacteriaceae and
Pseudomonas.

22. Synthesis of Mecillinam
NC H
O Me
O Me
+
S
N
O C O O H
NH2
6-am ino penicillanic acid
1-hexam ethylenim ine dim ethyl acetal
E ther
S
N
O C O O H
N C H N
M ecillinam

23. Amoxicillin
 It is derived semi-synthetically from the fermentation
of Penicillium sp.
 The C-6 substitute contains a secondary amine that
can be protonated as well as a phenol group that can
be deprotonated.
 The carboxylic acid at position 3 is also capable of
deprotonation.
 When these groups are ionized, the molecule contains
a net negative charge and therefore is less Zwitterionic
and more capable of being orally absorbed

24. Mechanism of action
 Inhibition of the bacterial cell wall
biosynthesis, preventing cross-linking of peptidoglycan.
 It is an alternative substrate for transpeptidases because of
its structural similarity to the transition state of the Ala-
Ala terminal during cross-linking.
Dosage forms and dosing.
Amoxicillin is available as 250 mg and 500 mg capsules.
 500 mg and 875 mg tablets.
 125mg, 200 mg, 250 mg, 400 mg chewable tablets.
 50mg/5ml, 125mg/5ml, 200mg/5ml, 250mg/5ml, and
400mg/5ml suspensions.

25. Ampicillin
 α- amino moiety induces
its ability to cross cell
wall, hence
play an important role in activity.
 Water soluble, stable in acidic condition.
 Absorbed from intestinal tract, excreted rapidly unchanged in
kidney.
 D (-) Ampicillin is active.
 Interactions: hydrocortisones inactivates
when mixed in I V solutions.
 Dose; 0.5-2gms.
 AMPILLIN, ROSCILLIN, BIOCILLIN.
AMOXL

26. Synthesis
N
S
COO H
NH
O
CO
N
S
COO H
NH2
O
COO HC H
NH2
5-amino penicillanic acid
+
(1) Acylation
(2) NaOH
C H
NH2
Ampicillin
amino-phenyl acetic acid

27. Bacampicillin
 Ester of ampicillin (ethoxy carbonyl oxyethyl ester)
 Prodrug of ampicillin after oral absorption hydrolysed
by esterase in plasma to form ampicillin.
 Having high tissue penetration.
 Dose: 400-800mg twice a day (PENGLOBE)
N
S
NH
O
COC H
NH2
CO O C H CO O C2
H5
C H3

28. Prodrugs of Ampicillin
 Pivampicillin
 Bacampicillin
 Talampicillin

29. Cephalosporins
 Cephaolosporins are the second major class of β- lactam
antibiotics.
 They differ from penicillins as they have 6 membered
dihydrothiazine ring.
 The first member of this series was extracted from
Cephalosporium acremonium in 1956.

30. Classification of Cephalosporins
 First Generation Drugs
Parentral
Cephalothin
Cefazolin
Oral
Caphalenin
Caphradine
Cefadroxil

31.  Second Generation
Parentral
Cefuroxime
Cefoxitin
Oral
Cefaclor
Cefuroxime axetil
 Third generation
Parentral
Cefotaxime
Ceftizoxime
Ceftrixone
Ceftazidine
Cefoperazone

32.  oral
 Cefixime
 Cefpodoxime proxetil
 Cefdinir
 Ceftibutem
Fourth Generation
Parentral
Cefepime
Cefpirone

33. Resistance
 alteration in target proteins (PBP) reducing the
affinity for antibiotic
 impermiability
elaboration of β- lactamase
Inhibition of β- Lactamase
 polar group in aminoacyl moeity (cefomandole)
 steric factor (cefoperazone)
 methoxyl group at 7th position
(cefuroxime, cefotaxime)

34. Adverse Reactions
 pain after i.m. administration (cephalothin)
 diarrohea (cephradine, cefoperazone)
 hypersensitivity
 nephrotoxicity (cephaloridine, cephalothin)
 bleeding (cefaperazone, ceftriaxone)
 neutropenia, thrombocytopenia

35. Uses-
 allergic reactions
 respiratory, urinary, soft tissues infections
 staphylococcal infection
 septicaemia
 surgical prophylaxis
 meningitis
 gonorrhoea
 typhoid

36. Biosynthesis-
C O NH
HO O C
NH2
O
N
S C H3
C H3
C O O H
C O NH
HO O C
O
N
S C H3
C H3
C O O H
H H
NH2
C O NH
HO O C
O
N
S
H H
C H3
C O O H
NH2
1
3
Is openic illin N
2
H H
epimerizati
on
Oxidation
hydroxylation

37. N
S
O H
O
H H
CO NH
COO H
NH2
HOO C
N
S
O Ac
O
H H
CONH
COO H
NH2
HOO C
N
S
O CO NH2
O
H H
CO NH
COO H
NH2
HOO C
4
5
CEPHALOSPORIN C
CEPHAMYCIN
acetylation

38. Recent articles-
Extraction of penicillin G from aqueous solutions: Analysis of reaction
equilibrium and mass transfer
Authors-
Department of Chemical & Petroleum Engineering, United Arab Emirates
University, P.O. Box 17555, Al Ain, United Arab Emirates
Abstract-
Analysis of the reaction equilibrium and mass transfer in the extraction of penicillin G (Pen G) into an
organic phase is an important research area to develop a cost-effective process for its separation from
an aqueous fermentation media. In order to evaluate this, equilibrium experiments were first carried out
to select the organic phase (composed of the carrier and solvent) that gives good values for the
distribution of penicillin G between the aqueous and organic phases. An organic phase of Amberlite
LA-2 in any of the solvents (Shellsol TK/butyl acetate/tributyl phosphate) gave high distribution
coefficient and the stoichiometry of the reaction has been shown to follow a simple ratio of 2:2. The
performance of the organic phases was evaluated in a membrane contactor and very high percentage
extraction was achieved. The extraction was performed by contacting a “feed” solution containing
penicillin G (flowing in the fiber side) with an “organic phase” of Amberlite LA-2 in one of the
solvents (flowing on the shell side) of the contactor. The antibiotic solutes formed complex with the
Amberlite LA-2 molecules which were transported across the fiber wall to the shell side and extracted
in the organic phase. The extraction in once-through mode was low and the feed/organic solutions need
to be recycled to increase the percentage extraction. In the recycle mode operated at flow rates of 3.6–
4.4 mL/s, an extraction of 90–98% was achieved. A simple mathematical model and its semi-analytical
solution presented here can be used to determine the overall mass transfer coefficient using the
experimental values of the distribution coefficient, operating parameters and the dimensions of the
membrane module

39. Hybrid penicillin acylases with improved properties for
synthesis of β-lactam antibiotics
Authors-
Simon A.W. Jager , Peter A. Jekel and Dick B. Janssen
Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of
Groningen, 9747 AG Groningen, The Netherlands
Abstract-
Penicillin acylase (PA) from Escherichia coli can catalyze the acylation of 6-
aminopenicillanic acid (6-APA), a conversion that is applicable in the biocatalytic preparation
of semi-synthetic β-lactam antibiotics such as ampicillin. The efficiency of this kinetically
controlled conversion, in which an amide or ester acts as the acyl donor, is dependent on the
kinetic properties of the enzyme. To further improve the synthetic properties of PAs, family
gene shuffling was performed with the PA-encoding genes of the PAs from E. coli, Kluyvera
cryocrescens and Providencia rettgeri. Of these three PAs, the E. coli enzyme possessed the
best properties for the synthesis of ampicillin. Shuffled recombinant libraries were pre-
screened for activity by growth selection, followed by testing the catalytic performance in
ampicillin synthesis using HPLC. Three clones with improved synthetic properties were
selected and sequence analysis showed that the shuffled genes were hybrids of the PA-
encoding genes from E. coli and K. cryocrescens, with additional point mutations. The hybrid
enzymes displayed a 40–90% increase in the relative rate of acyl transfer to the β-lactam
nucleus during ampicillin synthesis. This increase was not accompanied by a reduction of
synthetic activity that has previously been reported for mutants of E. coli PA constructed by
site-directed mutagenesis. Similar improvements in acyl transfer were obtained for the
synthesis of amoxicillin, cephalexin and cefadroxil, making the new hybrid enzymes
interesting candidates for the biocatalytic synthesis of several β-lactam antibiotics.

40. References
1. Block J.K, beale J. M. Wilson and Gisvold’s text book of
organic medicinal and pharmaceutical chemistry.11th
Edition london: lippincot williams and wilkins.; 2004;
299-318.
2. William D. A, Thomas.L. Foye’s Principals of medicinal
chemistry, 6th Edition Lippincott Williams and Wilkins.
Philadelphia; 2007; 1046-55.
3. Tripathi KD. Essentials of Medical Pharmacology. 5th
Edition New Delhi: Jaypee Brothers Medical Publishing
(P) Ltd.; 2004; 770-4.
4. Abraham D. J, Burgers medicinal chemistry and drug
discovery,6th Edition ; vol 2; new jersey: John willey and
sons, 2003; 626-637.
5. Corwin Hansch. Comprehensive Medicinal chemistry.vol
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6. www.sitemaker.umich.edu/mc3/peni.