Detail chemistry of beta-lactam antibiotics

1. Glimpses of Beta-lactum antibiotics:
Medicinal Chemistry III
Ms. Mandakini S.Holkar
(M. Pharm.)
For Third Year B. Pharm. Program as per
PCI syllabus, New Delhi

2. Beta lactum antibiotics:
Penicillin derivatives, cephalosporins, monobactams and
carbapenems all belong to this popular class of drugs. A four-
membered lactam ring, known as a β-lactam ring, is a common
structural feature of this class

3. Beta lactum
antibiotics
Combination with
ring
Bicyclic system Structure of basic ring
Penicillins
(amoxicillin )
β-lactam ring +
thiazolidine ring
Penam
cephalosporins
(Cefalexin)
β-lactam ring +
dihydrothiazine
ring
Cephem
Monobactams
(aztreonam )
β-lactam
compounds that are
not fused to another
ring
Monobactam
Carbapenems
(Thienemycin )
β-lactam ring +
pyrroline ring
Carbapenems

4. 1.Penicillins
Penicillin consists of a fused a β-lactam ring and a thiazolidine ring; part of the
heterocyclic bicyclic system is the β-lactam ring.
The bicyclic system confers greater ring strain on the β-lactam ring, an aspect
important for activity.
An amide and a carboxylic acid group are also present.
The carboxylic acid group is a possible site of modification to make prodrugs.
Also – note the stereochemistry of the acylamino side chain with respect to the 4-
membered ring

5. SAR of Penicillins-
The key structural features of penicillins can be summarised as follows:
Fused β-lactam and thiazolidine ring forming a bicyclic system (Penam) The
bicyclic ring is very important.
Cis stereochemistry of H5 and H6 essential
The free carboxylate is essential
The acylamino side chain is necessary
Variation is mostly limited to the R group of the amide, and, as mentioned earlier,
prodrugs have been developed by modifying the carboxylate group. So far,
we’ve reviewed the following structural modifications:
Enhancing acid stability by using electron-withdrawing R groups
Converting the carboxylate functional group to an ester to give a prodrug

6. Drug Functional group Position Effect
Phenoxymethylpenicillin
(Penicillin V)
as they have electron
withdrawing R groups
At C6 enhanced acid
stability
amoxicillin and
ampicillin
both have -NH2 groups
As well as this, the
presence of the electron-
withdrawing amino
group
attached to
Cα
both compounds
being orally
active.
increases acid-
stability
Methicillin his semi-synthetic
penicillin possesses a
dimethoxybenzene R
group.
Both the
methoxy
groups of the
benzene are
at the ortho
position.
acid-resistant
improves
resistance to β-
lactamase
enzymes

7. Summary
Penicillins are bactericidal beta-lactam antibiotics
Penicillin’s core structure consists of a fused β-lactam ring and a thiazolidine ring
The bicyclic system is highly strained.
Modifications can also be made at the acylamino side chain.
Cis stereochemistry of H5 and H6 is essential.
6-Aminopenicillanic acid (6-APA) is mainly used as a precursor for semisynthetic
penicillin drugs
Structural modifications:
The carboxylic acid group can be modified to give ester prodrugs
Attach electron-withdrawing groups at the amide to enhance acid stability
Hydrophilic groups at Cα at the acylamino side chain improves spectrum of activity
Steric shields at the acylamino side chain generally improves resistance to β-
lactamase enzymes.

8. 2. Cephalosporin's
Cephalosporin C was the first cephalosporin discovered from a
fungus obtained from Sardinian sewer waters during the mid-
1940s.
Just like penicillins, Cephalosporin C has a bicyclic system made
up of a β-lactam ring fused with a sulfur heterocycle, which, in this
case, is the dihydrothiazine ring.
The side chain is referred to as the aminoadipic side chain.
The acetoxy group of Cephalosporin C is a key feature;

9. The β-lactam ring is crucial for activity.
Fused β-lactam and dihydrothiazine ring form a bicyclic system.Bicyclic ring
system important in increasing ring strain.
The cis-stereochemistry at the positions highlighted in green is important.
Other groups may be substituted for the acetoxy group which may or may not
serve as good leaving groups.
The nature of the leaving group is important for activity.
Better leaving groups tend to give cephalosporin C analogues with better activity.
The acylamino side chain may be altered.
Sites of possible modifications are highlighted in red boxes.
7-aminocephalosporinic acid (7-ACA) is used as precursor for many semisynthetic
cephalosporins.
Structure-activity relationships are similar
with penicillins.

10. 3.Carbapenems
The carbapenem class of β-Lactam antibiotics have broad-spectrum activity and
exhibit resistance to many β-lactamases.
Carbapenems are used as antibiotics of last resort for infections of bacteria such
as Escherichia coli and Klebsiella pneumoniae.
Thienemycin is a carbapenem first discovered and isolated from Streptomyces
cattleya in 1976.

11. From the structure of the compounds shown, it is easy to see that
the carbapenems have some structural features that penicillins do not.
 The double-bond on the five-membered ring leads to high ring strain.
A sulfur atom is also missing in the five-membered ring.
The acylamino side chain is absent.
Also note the trans stereochemistry of the hydrogens.

12. 4. Monobactams
Monobactams
As the name suggests, the monobactams, such as aztreonam ,are β-
lactam compounds that are not fused to another ring.
Monobactams exhibit moderate activity against certain Gram-
negative bacteria in vitro, including Neisseria and Pseudomonas

13. Reference:
 Willams and Thomas L.Lemke Foye’s Principles of
Medicinal Chemistry Fifth edition
 Rang H.P. and Dale M.M.: Pharmacology, Churchill
Livingstone, Edinbergh.
 Dr.S.S.Kadam and K.R.Mahadik Principles of
Medicinal Chemistry Volume -I