Cephalosporins & Monobactams – Medicinal Chemistry III B. Pharma 6th Semester

β-lactam Antibiotics


Cephalosporins & Monobactams

Contents

       Cephalosporins  – Principal antibiotic components

       Nomenclature
of Cephalosporins

       Structures
of Cephalosporins

       Classification
of Cephalosporins

       Study
of individual compounds

       Monobactams
– introduction

       SAR
of monobactams

Learning Objectives

       At the end of this lecture, student
will be able to

       Discuss
Cephalosporins and their principal components

       Explain
the nomenclature of Cephalosporins

       Describe
the structure of Cephalosporin

       Classify
Cephalosporins

       Discuss
the SAR of Cephalosporins

CEPHALOSPORINS

Ø  Cephalosporins
are β-lactam antibiotics isolated from Cephalosporium spp., or prepared
semi-synthetically.

Ø  Three
principal antibiotic components isolated from the fungus are

  1. Cephalosporin  P1:- A steroid with minimal
    anti-bacterial activity

  2. Cephalosporin
    N:- Later identified as Synnematin N (a penicillin derivative called as
    Penicillin N)

  3. Cephalosporin
    C

Penicillin N: –
[D-(5-Amino-5-Carboxy pentanoyl)-Penicillanic acid]

Cephalosporin C:-
[3-Acetoxy-methyl-7-(5’-Amino-5’-Carboxy pentanoyl amino) Cephalosporanic acid]

       Cephalosporin
is a close congener of penicillin N containing dihydrothiazine ring instead of
thiazolidine ring, of the penicillin.

Nomenclature:-

       The
fused ring system is designated as 5-thia-1-azabicyclo[4.2.0]Oct-2-ene.

       So
in this system

       For
example, Cephalothin is ‘3-(acetoxy methyl)-7-[2-(thienyl
acetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-Oct-2-ene-Carboxylic acid’.

       A
simplified method is that the saturated bicyclic ring system with the lactam
carboxyl oxygen is called as ‘Cepham’ (as penam for penicillins). According to
this system all Cephalosporins and Cephamycis are named as 3-Cephams (or ∆3
– Cephams) to designate the position of double bond.

       ‘Cepham’

       ‘Cephalosporanic
acid’

Cephalosporins

Structure
of Cephalosporins:-

       At
– 7 position – Acyl group:- The effect of modifications acyl group on the
activity of the cephalosporins is similar to that of penicillins

       At
-3 position – Alkyl, Allylic group, acetoxy group:- provides a  reactive site at which various 7-acyl amino
Cephalosporinic acid structures can easily be varied by Nucleophilic
substitution.

       Reduction
of the ‘3-acetoxymethyl’ –to 3-methyl substitution to prepare 7-amino-desacetyl
cephalosporanic acid (7-ACDA) derivatives can be done by catalytic
hydrogenation.

v  In
the preparation of semi-synthetic cephalosporins following improvements are
sought.

Ø  Increased
acid stability.

Ø  Improved
pharmacokinetic properties, particular better oral absorption.

Ø   Broadened anti-microbial spectrum

Ø  Increase
activity against resistant microorganisms (i.e. increase in resistance to
enzymatic destruction, increase in penetration and increase receptor affinity)

Ø  Decreased
allergenicity

Ø  Increase
in tolerance after parenteral administration.                                      

CEPHALOSPORINS – Classification

Cephalosporins are divided into

First, Second, Third and Fourth – generation agents.

       This
is based roughly on their time of discovery and their anti-microbial
properties.

       Progression
from Ist to IV generation is associated with broadening of the gram-ve
antibacterial spectrum, some reduction in activity against gram +ve organism
and enhanced resistance to β-lactamases

Ø  I Generation (in the order)

       Cephalexin,
Cephradine, Cefadroxil, Cephalothin, Cephapirin and Cefazolin.

Ø  II Generation (in the order)

       Cefachlor,
Loracarbef, Cefprozil, Cefamandole, Cefonicid, Ceforanide, Cefoxitin,
Cefotetan, Cefmetazole, Cefuroxime, Cefdopoxime.

Ø  III Generation (in the order)

       Cefixime,
Cefoperazone, Cefotaxime, Ceftizoxime, Ceftriaxone, Ceftazidine, Ceftibuten.

Ø  IV Generation (in the order)

       Cefepime,
Cefpirome

Oral Cephalosporins

v  Oral
activity of cephalosporins is due to increased acid stability of β-lactam ring

Ø  Phenylglycyl
substituent confers this acid stability (at 7th position) due to the
presence of protonated amino group on the 7-acylamino portion of the molecule.

Ø  Another
important factor for their excellent oral activity is due to the “carrier
mediate transport of the dipeptide – like, Zwetterionic Cephalosporins”
-“similar to α-aminobenzyl penicillin (Ampicillin)”

Ø   The other important factor for high acid
stability (good oral activity) of the Cephalosporins is the absence of a
leaving group at the 3-position

Ø  Cephalexin
and cephachlor are orally active due to the prescence of phenylglycyl
substitution at 7th position and absence of a good leaving group at
3rd position

       So,
despite the presence of the phenylglycyl side chain in its structure
Cephalosporanic acid derivative ‘Cephaloglycin’ is poorly absorbed orally
because of hydrolysis of the 3-acetoxy group in the low pH of the stomach.

       The
resulting 3-hydroxy derivative is poorly absorbed and it undergoes
lactonization under acidic conditions.

       The
hydroxyl derivatives and the lactones are very less active.

       Orally
activity can also be conferred in certain Cephalosporins by esterification of
the 4-carboxylic acid group to form acid stable , lipophilic esters that
undergo hydrolysis in the plasma.

       Eg., Cefuroxime axetil

  • Cefpodoxime proxetil

  • These
    are β-lactamase – resistance alkoximino-cephalosporins

  • They
    are orally active ester prodrug derivatives of Cefuroxime and Cefpodoxime
    respectively

CEPHALOSPORINS – Study of individual compounds

Cephalexin:-
7-(D-α-amino- α-phenyl-acetomido)-3-methyl-Cephem-4-Carboxylic acid

       It
is ‘orally active’ as it is acid resistant

       Food
does not interfere with its absorption

       Used
for the treatment of urinary tract infection and upper respiratory tract
infection

Cephradine:-
[Partially hydrogenated derivative of Cephalexin]

       It
is orally and parenterally active (only derivative)

       Has
similar anti-bacterial and pharmacokinetic properties as Cephalexin

       Used
for the treatment of uncomplicated urinary tract infections and upper
respiratory tract infections.

Cefadroxil :-
[7-{(D-p-hydroxyl phenyl glycyl) amino} -3- methyl-Cephem-4-carboxylic acid.

       It
is ‘orally active’

       It
has prolonged duration of action (slow urinary excretion)

       Anti-bacterial
spectrum of action and therapeutic activity are very similar to Cephalexin and
Cephradine.

Cefuroxime sodium: [2nd
Generation Cephalosporin]

       7-{α-(methoxy
imino)-α-(2-furyl)-acetylamino} – 3-{carbamoyl oxymethyl} – Cephem-4-carboxylic
acid.

       It
is active orally & parenterally

       ‘Syn
alkoximino’ substituent is associated with β-lactamase activity.

       Active
against β-lactamase –producing strains such as E.Coli, K. pneumonia,
N-gonorrrhoeae and H. influenza.

       Effective
in meningitis caused by susceptible organisms

Cefixime:- [3rd
generation Cephalosporin][7{(α-carboxy methyl oxyimino)-α-(2-amino-thiazol-4-yl)
acetyl –amino} -3- vinyl –Cephem-4-Carboxylic acid

       It
is ‘orally active’

       Broad
spectrum activity-resistant to many β-lactamases

       treatment
of a variety of respiratory tract infections- acute bronchitis, pharangitis,
toslitis, etc

       Treatment
of uncomplicated UTI & gonorrhea caused by β-lactamase producing strains

Cefepime

       β-Lactamase
resistant

       Broad
antibacterial spectrum

       Treatment
of UTI, lower respiratory tract infections, skin & soft tissue infections,
chronic osteomyelitis

MONOBACTAMS (Monolactams)

       Monobactams
(Monolactams) are those antibiotics with isolated β-lactam ring.

       Sulfazecin is the prototype compound
isolated from saprophytic soil bacteria. It has weak antibacterial properties,
but highly resistant to β-lactamases.

The structure of ‘Sulfazecin’ is

Ø  Other
compound is ‘Aztreonam disodium’,
has useful properties as an antibacterial agent

       The
structure of ‘Aztreonam disodium’ is

       Aztreonam
– prepared by total synthesis. It is used to treat urinary and lower
respiratory tract infections, intra abdominal infections and gynecological
infections as well as septicemias.

       The
third compound is ‘Tigemonam’– which
is a newer monobactam-is orally active

       Tigemonam’
is highly resistant to β-lactamases. Its antibacterial spectrum resembles that
of Astreonam.

       Use:
Used for oral treatment of urinary tract infections and other non-life
threatening infections caused by 
β-lactamases producing Gram-ve bacteria

SAR of
Monobactams:

       A
3-methoxy group – contributes to low antibacterial potency and poor chemical
stability of these antibiotics.

       Eg.,
Sulfazecin

       A
4-methyl  group – increases stability to
β-lactamases and actitity against gram-ve bacteria but decrease actitity
against gram+ve bacteria

       Eg.,
Aztreonam

       A
4,4-gem – dimethyl substitution slightly decreases antibacterial potency after
oral administration.

       Eg.,
Tigemonam

       Presence
of heterocyclic ring system on the acyl side chain increases the antibacterial
activity and increased resistance against β-lactamases.

 

 

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