Beta lactam Antibiotics Chemistry SAR Nomenclature classification MOA

1. Anti bacterial
Antibiotics
HumanlivesVsMicroorganism
AntibioticsVsInfections
B Pharm VI sem- Medicinal Chemistry-III

2. Contents
• Introduction
• Classification of Antibiotics
• General structure of β-lactam antibiotics
• Structural Comparison of penicillins &
cephalosporin
• Common SAR features
• SAR of penicillins & cephalosporins
• Summary of β-lactam and subclass

3. Antibiotics
• Antibiosis (literally “against life”) as the biological concept of
survival of the fittest, in which one organism destroys another to
preserve itself.
• In 1942, Waksman defined “an antibiotic or antibiotic substance is
a substance produced by microorganisms, which has the capacity
of inhibiting the growth and even of destroying other
microorganisms.”

4. Antibiotics
Therefore, a substance is classified as an antibiotic if the
following conditions are met:
1. It is a product of metabolism
2. It is a synthetic product produced as a structural analog of a naturally
occurring antibiotic.
3. It antagonizes the growth or survival of one or more species of
microorganisms.
4. It is effective in low concentrations.

5. Chemical Classification of Antibiotics
Sr Class , Subclass & action mechanism Examples
1 β- lactam & β lactamase inhibitors
1.a Penicillins &
Cephalosporins
Cell wall cross-linking
Amoxicillin & Ampicillin
1.b Cefuroxime, Cefotaxime,
1.c β lactamase inhibitors Inactivate/ inhibit β lactamase Clavulanates, Carbapenems
2 Aminoglycosides
30 S subunit Protein synthesis &
fidelity
Kanamycin, Gentamicin,
Tobramycin,
3 Tetracycline 30 S subunit Protein synthesis
Oxytetracycline,
Demeclocycline,
4 Macrolides 50 S subunit Protein synthesis
Erythromycin, Clarithromycin,
Azithromycin
5 Lincomycins 50 S subunit Protein synthesis Lincomycin, Clindamycin
6
Peptides/
Polypeptides
Cell wall synthesis & cell membrane
functions
Vancomycin, Bacitracin,
Polymyxin B
7 Chloramphenicol Ribosomes  Protein synthesis
8 Quinolones
Bacterial DNA gyrase
(Topoisomerase II)
Norfloxacin, Ciprofloxacin
9 Miscellaneous Varied Novobiocin, Linezolid
PC2ATMLinQ

8. Bacteria class +ve & -ve

10. Commercial production of antibiotics
Following a general pattern, differing in detail for each antibiotic.
The general scheme may be divided into six steps:
(a) preparation of a pure culture of the desired organism
for use in inoculation of the fermentation medium;
(b) fermentation, during which the antibiotic is formed;
(c) isolation of the antibiotic from the culture medium;
(d) purification;
(e) assays for potency, sterility, absence of pyrogens, and
other necessary data; and
(f) formulation into acceptable and stable dosage forms.

12. β- Lactam Antibiotics
{Chemistry & SAR}

13. β-Lactam antibiotics containing core 4-member
“β -lactam”

14. Comparison of β- lactam antibiotics
4-thia-1-azabicyclo [3.2.0] heptanes 5-thia-1-azabicyclo [4.2.0] oct-2-ene
6-carbonylaminopenicillanic acid
(6-APA)
7-acylaminocephalosporanic acid
(7-ACA)

15. β-Lactam Antibiotics
• A β- lactam is a cyclic amide with four atoms in its ring.
• As the name “lactam” indicates cyclic amide which is generally considered
as analogous to the name “lactone” which is indicated for cyclic esters.
• In an older nomenclature, α was designated to the second carbon in an
aliphatic carboxylic acid/ or a carbon bears functional group such as
carboxyllic acids, and β to the third, and so on- as shown in above
structure.
• The contemporary name for this ring system is azetidinone.
• The penicillin subclass of β -lactam antibiotics is characterized by the
presence of a substituted 5-membered thiazoldine ring fused to the β -
lactam ring.

16. •The Chemical Abstracts system initiates the numbering with the sulfur atom and
assigns the ring nitrogen the 4-position.
•Thus, penicillins are named as 4-thia-l-azabicyclo[3.2.0]heptanes,
•The numbering system adopted by the USP is number 1 to the nitrogen atom and
number 4 to the sulfur atom.
•The penicillin molecule contains three chiral carbon atoms (C-3, C-5, and C-6).
•The carbon atom bearing the acylamino group (C-6) has the L configuration,
whereas the carbon to which the carboxyl group is attached has the D configuration.
Thus, the acylamino and carboxyl groups are trans to each other,
•The absolute stereochemistry of the penicillins is designated as 3S:5R:6R,

17. Units & potency
• The procedure for assay was developed at Oxford, England, and the value
became known as the
• Oxford unit: 1 Oxford unit is defined as the smallest amount of penicillin
that will inhibit, in vitro, the growth of a strain of Staphylococcus in 50 mL
of culture medium under specified conditions.
• United States Pharmacopoeia (USP) defines unit as the antibiotic activity
of 0.6 g of penicillin G sodium reference standard.
– 1 mg of penicillin G sodium is equivalent to 1,667 units,
– 1 mg of penicillin G procaine is equivalent to 1,009 units, and 1
– mg of penicillin G potassium is equivalent to 1,530 units.

18. β-Lactam Antibiotics
PENICILLINS
• Benzyl penicillins
– Penicillin G
• benzylpenicillin sodium,
• Procaine benzylpenicillin,
• Benzathine penicillin
• Phenoxy-penicillins (oral penicillins)
– Penicillin V
– Propicillin
• Penicillinase resistant penicillins (anti-staphylococcal penicillins)
– Oxacillin
– Dicloxacillin
– Flucloxacillin
• Aminobenzyl penicillins
– Ampicillin
– Amoxicillin
• Ureidopenicillins (broad-spectrum penicillins)
– Mezlocillin
– Piperacillin
• ß-Lactam/ ß-lactamase inhibitors
– sulbactam & Ampicillin
– Clavulanate & Amoxicillin
– Tazobactam & Piperacillin

19. SAR of Penicillins

20. Common SAR features
Structural requisite for antibacterial activity
• The strained β-lactam ring
• The free carboxylic acid
• The bicyclic system
– confers strain on the β-lactam ring—the greater the strain, the
greater the activity,
– but the greater the instability of the molecule to other factors.
• The acylamino side-chain
• The stereochemistry of the
– bicyclic ring with respect to the
– acylamino side-chain

21. Summarized SAR for extended spectrum of activity
Name of PC Structural change Change in activity
Ampicillin α-amino group creates an
additional chiral center
D-isomer, > L-isomer or
benzylpenicillin (2-8 times)
Hydrophilic penicillins
penetrate G-ve bacteria >
penicillin G, V, or methicillin
Amoxicillin
α-OH substitution also yields
“expanded-spectrum” with activity
and stereoselectivity similar to
that of the ampicillin group
Ampi> amoxy (2-5 times more active & acid stable)
Carbenicillin
α-Carboxybenzyl
penicillin
Incorporation of an acidic
substituent at the α-benzyl
carbon atom of penicillin G
against G-ve bacilli & resistant to
ampicillin organisms
against both β-lactamase–& non–
β-lactamase-producing G-ve
bacteria.
azlocillin, mezlocillin, and
piperacillin
α-acylureido–substituted
penicillins,
Greater activity against certain
Gram-ve bacilli than carbenicillin;
More facile penetration through
the cell envelope
Azlocillin, mezlocillin, and piperacillin> carbenicillin (certain G-ve bacilli)

22. MOA (PBP & D-alanine cross linking)
• Penicillins have a structural resemblance to two D-alanine residues linked
together, and are mistaken by the transpeptidase enzyme for D-Ala-D-Ala,
and thus incorporated into the active site.
• Once bound, the β-lactam carbonyl is attacked by the serine hydroxyl, and
ring opening occurs to leave the penicillin covalently bound to the
enzyme.
• The bulky thiazolidene ring now blocks access to the active site by either a
pentaglycine chain or water.
• As a result the penicillin becomes irreversibly bound to the transpeptidase
enzyme, preventing it from functioning properly.
• This results in incomplete cell walls that are much more fragile and
porous, and eventually lead to swelling followed by cell lysis and death.
• All β-lactam antibiotics* binds to PBPs, which are requisite for cell
wall synthesis of bacteria. PBPs are members of transpeptidases (a
subgroup of enzymes).

24. Different classes of PBP’s & their role in
bacterial cell wall synthesis
Table:- Different classes of PBP’s & their role in bacterial cell wall synthesis/ formation
PBP class/ PBM Type of enzyme Role Result of inhibition
PBPs 1a &1b- first-
generation cephalosporins
Transpeptidases
in peptidoglycan synthesis
associated with cell
elongation
results in spheroplast
formation & rapid cell lysis-
PBP 2- Amdinocillin only to
PBP -2
CP’S
involved in maintaining the
rod shape of bacilli
results in ovoid /round
forms that undergo delayed
lysis
PBP 3????-
Doubtful- whether inhibition
of PBP 3 is lethal to
bacterium.
PC-G & CP’S
required for septum
formation
during cell division
in the formation of
filamentous forms
containing rod-shaped units
that cannot separate.
PBPs 4 through 6 Carboxypeptidases
responsible for the
hydrolysis of D-alanine–D-
alanine terminal peptide
bonds of the cross-linking
peptides
Apparently not lethal to the
bacterium, even though
cleavage of the terminal D-
alanine bond is required
before peptide cross-
linkage.

25. SAR of Cephalosporins

27. Sr
Name, Generation &
route
Structural Changes
Functional group modified 
activity changed
1
Cefazolin
(1 G)^
 At C-7, it possesses a tetrazoylmethylene
 At C-3 thiol-containing heterocyclic
 5-methyl-2-thio-1,3,4-thiadiazole.
 less irritating on injection than its other
counterparts
 higher serum levels,
 slower renal clearance, and a longer half-life
2
Cefamandole
(2 G)^
 α-hydroxyphenylacetyl (or mandoyl ) D-
mandelic acids as the acyl portion and
 a thiol-containing heterocycle (5-thio-1,2,3,4-
tetrazole)
 D>>>L isomer
 Polar substituent in the aminoacyl moiety
 β-lactamase resistant
3
Cefuroxime axetil
(2 G)*^
 Alkox-imino  α-methoximinoacyl–
substituted cephalosporins
 esterification of the 3-carboxylic acid
 acid-stable orally active ester prodrugs
 lipophilic
 β-lactamase–resistant
4
Cefotaxime
(3 G)^
 Like cefuroxime, has a Z-methoxyimino
moiety at C-7
 The oxime moiety of cefotaxime is connected
to an aminothiazole r ing
 The syn-> anti-isomer is significantly more
active
 Significant β-lactamase resistance
Summarized SAR for Extended spectrum of activity

28. Summary of β- lactam subclass, Target & examples
Sr AB Class, source &
Target
Sub class Examples
1 β- lactam & β lactamase inhibitors
1.a Penicillins Cell wall cross-linking
P. notatum; chrysogenum;
&
Semisynthetic
Benzyl Penicillin G
Phenoxy Penicillin V, Propicillin
Aminobenzyl Ampicillin, Amoxicillin
Penicillinase
resistant
Oxacillin, Dicloxacillin,
Flucloxacillin
Ureido PCs Mezlocillin, Piperacillin
Carboxy Ticarcillin, carbenicillin
1.b Cephalosporins Cell wall cross-linking
C. acremonium &
Semisynthetic
1 Gen Cephalexin*, Cefazolin^
2 Gen Cefuroxime*^
3 Gen Cefixime*, Cefotaxi-me^
4 Gen Cefipime^
5 Gen Ceftaroline^
1.c Beta lactamase inhibitors  Inactivate/ inhibit β lactamase
Streptomyces clavuligeris.
Class I
Monobactams
Clavulanates
Class II
Carbapenems
New carbapenems