THE CARBOXYPENICILLINS

(Antipseudomonal Penicillins)

❖ Carbenicillin was the first example of this class of compounds. It shows a broad-spectrum
of activity due to the hydrophilic carboxylic acid group (ionized at pH 7) on the side chain.
❖ It is active against Pseudomonas aerugenosa and wide range of Gram-negative bacteria
❖ Carbenicillin is a malonic acid derivative and it is decarboxylated in acid solutions and
thus, it is not administered orally.

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 bulky group
used to block penicillin
from accessing the β-
lactamase to active site

Temocillin is β-lactamase resistant penicillin and is interesting in

that it has a 6-methoxy group present

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 THE CARBOXYPENICILLINS
(Antipseudomonal Penicillins)
Carfecillin and indanyl carbenicillin

❖ Are prodrugs for carbenicillin and show an improved absorption through the
gut wall (administered orally).
❖ Aryl esters are better than alkyl esters since the former are chemically more
susceptible to hydrolysis because of the electron-withdrawing inductive
effect of the aryl ring.
❖ An extended ester is not required in this case since the aryl ester is further
from the β-lactam ring and is not shielded (cf. aminopenicillins prodrugs)
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 THE CARBOXYPENICILLINS
(Antipseudomonal Penicillins)

Ticarcillin is similar in structure to carbenicillin but has a

thiophene ring in place of the phenyl group

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 THE UREIDOPENICILLINS

❖ Ureidopenicillins are the newest class (developed in Japan) of broad-spectrum

penicillins and have a urea functional group at the α-position. .

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 THE UREIDOPENICILLINS
Azlocillin, Mezlocillin, and Pipracillin

(2-oxo-imidazolidine- (3-methylsulfonyl-2-oxo-imidazolidine- (4-ethyl-2,3-dioxo-piperazine-1-

1-carbonyl) amino penicillin 1-carbonyl) amino penicillin carbonyl) amino penicillin

❖ They generally have better properties than the carboxypenicillins and have largely
replaced them in the clinic.
❖ Their ability to penetrate cell envelope is 8-16 times more potent than carbenicillin.
❖ They are available as water soluble sodium salt for intramuscular injection.

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Cephalosporins
Discovery and structure
of cephalosporin

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 Discovery
Giuseppe Brotzu (1895-1976)
❖ The first cephalosporin (cephalosporin C) was derived from a fungus obtained in
the mid 1940s from sewer waters on the island of Sardinia.

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 Discovery
Giuseppe Brotzu (1895-1976)
❖ Who noted that the waters surrounding the sewage outlet
periodically cleared of microorganisms
❖ He reasoned that an organism might be producing an
antibacterial substance and so he collected samples and
managed to isolate a fungus called Cephalosporium
acremonium (now called Acremonium chrysogenum).

Edward Abraham (1913-1999)

in 1948, Edward and Co-workers at Oxford University isolated cephalosporin
C, but it was not until 1961 that the structure was established by X-ray
crystallography.

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 Structure features of cephalosporins

The basic skeleton is β-lactam ring fused with

dihydrothiazine nucleus

The fused rings are not coplanar but folded along the C-6, N-5
bond but less markedly than in penicillin

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 Structure Features Of Cephalosporins

❖ The loss of strain relative to penicillin resulted from ring expansion

(6 member dihydrothiazine ring) is regained by the unsaturation
between C-3 &C-4 which reduces the flexibility of this ring.

❖ Saturation of these carbons abolishes the activity.

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 Structure of Cephalosporin C

7-Aminocephalosporinic acid (7-ACA)

7-Aminoadipic side chain

Dihydrothiazine ring
β-lactam

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 Adipic acid

Hexanedioic acid

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 Biosynthetic precursors of cephalosporin C

Cephalosporins can be derived from the same biosynthetic precursors as penicillin

(i.e. cysteine and valine)

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 3D Structure of Cephalosporin C

Planar structure of amide linkage

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 Properties of cephalosporin C
Disadvantages
❖ Polar due to the side chain - difficult to isolate and purify
❖ Low potency - limited to the treatment of urinary tract infections where it is
concentrated in the urine
❖ Not absorbed orally
Advantages
❖ Non toxic
❖ Lower risk of allergic reactions compared to penicillins
❖ More stable to acid conditions (WHY???????????????)
❖ More stable to β-lactamases
❖ Ratio of activity vs Gram -ve and Gram +ve bacteria is better
Therefore, cephalosporin C became a useful lead compound for the
development of broad-spectrum antibiotics
The aim was to produce analogues with increased potency, while retaining the
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 Mechanisms of Antibacterial Agents
There are Five main mechanisms by which antibacterial agents act.

1. Inhibition of bacterial cell wall synthesis: e.g. Penicillins, Cephalosporins and

Vancomycin
2. Inhibition of cell metabolism: e. g. Sulfonamides
3. Interactions with the plasma membrane: e.g. Polymyxins
4. Disruption of protein synthesis: e.g. Rifamycins, Aminoglycosides, Tetracyclines, and
Chloramphenicol
5. Inhibition of nucleic acid transcription and replication: e.g. Nalidixic acid and Proflavin

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 Mechanism of Action

H H H
R N S
H H H
R N S
7
O -CH3CO2-
N O Me O
O C N
O
CO2H O
O
CO2H
OH Ser

Ser Enzyme
Enzyme

Note
The acetoxy group acts as a good leaving group and aids the mechanism

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