ANTIBIOTICS

ANTIBIOTICS
PENICILLIN
PENICILLINS
PENICILLINS
CHEMISTRY OF PENICILLINS
CHEMISTRY OF PENICILLINS
CHEMISTRY OF PENICILLINS
CHEMISTRY OF PENICILLINS
CHEMISTRY OF PENICILLINS
CHEMISTRY OF PENICILLINS
CHEMISTRY OF PENICILLINS
CHEMISTRY OF PENICILLINS
PREPARATION OF PENICILLINS
 PREPARATION OF PENICILLINS
Semi-synthetic Penicillin
• 6-Aminopenicillanic acid (6-APA) is the parent compound of
all penicillins and is produced commercially by enzymatic
deacylation of phenoxymethyl penicillin using a bacteria
enzyme or by enzyme hydrolysis of benzylpenicillin using
fungi enzyme
 PREPARATION OF PENICILLINS
Semi-synthetic Penicillin
• The side chains are added to 6-APA by the following chemical
methods;
A. Acylation using acylchlorides in the presence of proton
acceptor (Triethylamine)
B. Using mixed acid anhydrides (RCOO. COOC2H5)
C. Acylation with carboxylic acids using N,N-
dicyclohexylcarbodiimide (C6H11N=C=NC6H11) as condensing
agent.
SYNTHESIS OF PENICILLINS
MECHANISM OF PENICILLINS ACTION
STRUCTURE ACTIVITY RELATIONSHIP
STRUCTURE ACTIVITY RELATIONSHIP
STRUCTURE ACTIVITY RELATIONSHIP
NATURAL PENICILLINS
SEMI-SYNTHETIC PENICILLINS
(Acid stable)
SEMI-SYNTHETIC PENICILLINS
(Beta-lactamase Resistance)
 SEMI-SYNTHETIC PENICILLINS
(Beta-lactamase Resistance and Acid Stable)
 SEMI-SYNTHETIC PENICILLINS
(Beta-lactamase Resistance and Acid Stable)
SEMI-SYNTHETIC PENICILLINS
(Broad-spectrum Penicillins)
THERAPEUTIC USES
SIDE EFFECTS OF PENICILLINS
CEPHALOSPORINS
Introduction

• Antibacterial agents which inhibit bacterial cell wall synthesis

• Discovered from a fungal colony in Sardinian sewer water
(1948)
• Cephalosporin C identified in 1961
Structure of Cephalosporin C

7-Aminoadipic side chain

H H H
H2N N S
1
7 6 2
H
CO2H O 8 5 3
N 4 O Me
O C

CO2H O

b-Lactam Dihydrothiazine
ring ring

H H
H2N S

N O Me
O C

CO2H O

7-Aminocephalosporinic acid (7-ACA)

 H H H
H2N N S
1
7 6 2

Properties of Cephalosporin C H
CO2H O
O
8 5
N 4
3
O
C
Me

CO2H O

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
• More stable to b-lactamases
• Ratio of activity vs Gram -ve and Gram +ve bacteria is better
Conclusion
• Useful as a lead compound
SAR of Cephalosporins
H H H
R N S
1
7 6 2
O 8 5 3
N 4 O Me
O C

CO2H O

Similar to penicillins
• The b-lactam ring is crucial to the mechanism
• The carboxylic acid at position 4 is important to binding
• The bicyclic system is important in increasing ring strain
• Stereochemistry is important
• The acetoxy substituent is important to the mechanism

Possible modifications
• 7-Acylamino side chain
• 3-Acetoxymethyl side chain
• Substitution at C-7
Variation of the 7-Acylamino Side Chain

• Not possible to generate analogues by fermentation

• Not possible to generate analogues by a full synthesis
• Restricted to semi-synthetic procedure

H H H H H
R N S
H2N S

RCOCl O
N O Me N O Me
O C
O C
O CO2H O
CO2H

7-ACA

• 7-ACA not available by fermentation

• 7-ACA not available by enzymatic hydrolysis of cephalosporin C
• Generated by a chemical hydrolysis
• The aminoglycoside families are distinguished by the amino sugars attached to the
aminocyclitol.
• All have an aminohexose as the amino sugar, and have a pentose as an extra sugar e.g
pararomycin, neomycin B
• In the neomycin family, which includes neomycin B and paromomycin, three amino sugars
are attached to the central 2-deoxystreptamine.
• The kanamycin and gentamicin families have only two such amino sugars linked to a
centrally located 2- deoxystreptamine moiety.
• Streptomycin differs from the other aminoglycoside antibiotics in that it contains
streptidine rather than 2-deoxystreptamine, and the aminocyclitol is not in a central
position
•An unusual aminoglycoside antibiotic, spectinomycin is produced by
fermentation of Streptomyces spectabilis and differs substantially in its
clinical properties from the others.
•The diaminoinositol unit (spectinamine) contains two mono-N-methyl
groups, and the hydroxyl between them has a stereochemistry opposite to
that in streptomycin.
•The glycosidically attached sugar also is unusual in that it contains three
consecutive carbonyl groups, either overt or masked, and is fused by two
adjacent linkages to spectinamine to produce an unusual , fused, three-
ring structure
 SAR for Aminoglycosides
• The important structural characteristics responsible for
interaction of aminoglycosides with rRNA of 30S
subunit include:
1. The substituent at position 6′ of ring I,
2. The number of protonated amino groups of ring I
3. The linkage between the sugar rings and the central
deoxystreptamine moiety (ring II)
 RESISTANCE
• Bacteria has three major resistant mechanisms to
aminoglycosides:
1. Mutation at energy dependent transport system which affects
aminoglycosides uptake by the cell (e.g. Ps. Aeruginosa)
2. Mutation at the ribosomal 30S subunit
3. Inactivating aminoglycosides by changing the chemical
structure,especially the essential functional groups for activity.
• Resistant strain produce enzymes that modify
aminoglycosides’ terminal amines and hydroxyls by
acetylation, phosphorylation or adenylylation. More than 50
aminoglycoside-inactivating enzymes have been reported,
however all catalyze only three major types of reactions:
 RESISTANCE

1. N-Acetylation of vulnerable amino groups using acetyl

coenzyme A as the acetyl donor. The N-acetyl transferases
comprise the largest group of aminoglycoside-inactivating
enzymes.
2. O-Adenylylation invoving the transfer of an AMP residue from
ATP to certain hydroxyl groups. The O-adenylyl transferases
form the smallest group of aminoglycoside-inactivating enzymes.
3. O-Phosphorylation of hydroxyl groups with ATO acting as the
phosphate donor.
• The sensitivity of an aminoglycoside to inactivating enzymes
affects the spectrum of its antibacterial activity.
Aminoglycosides: Mechanism of Resistance
 Tetracyclines
Structural features:
As the names suggests, four fused (C6) rings, one benzenoid, with
variety of substituents and functions. Note enol tautomeric
structure of β-diketone(s).
Origin:
First isolated (1948) from a Streptomyces sp.

Mode of action - The tetracyclines reversibly bind to the 30S

ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor
site on the 70S ribosome.
Spectrum of activity - Broad spectrum; Useful against intracellular
bacteria
Resistance - Common
Adverse effects - Destruction of normal intestinal flora resulting in
increased secondary infections; staining and impairment of the
structure of bone and teeth
Structures of Tetracyclines
Some general characteristic features:
•The tetracyclines are amphoteric compounds, i.e., forming salts with
either acids or bases. In neutural solutions these substances exist
mainly as Zwitter ions.
•The unusual structural features present in the tetracyclines afford
three acidity constants (pKa values) in aqueous solutions of the
acid salts
• An interesting property of the tetracyclines is their ability to
undergo epimerizaton at C-4 in solutions having intermediate pH
range. These isomers are called epitetracyclines.
The four epi-tetracyclines have been isolated and characterized.
They exhibit much less, activity than the corresponding ‘natural’
isomers ; thus accounting for an apparent decrease in the
therapeutic value of aged solution
• they are toxic to kidney leading to Fanconi syndrome: nausea,
vomiting, polyuria, polydipsia, acidosis, proteinuria, glycosuria
as a result of taking expired degraded TCN
• It has been observed that the strong acids and bases attack the
tetracyclines having a hydroxy moiety at C-6, thereby causing a
considerable loss in activity through modification of the C-ring as
shown below :
•Strong acids produce a dehydration through a reduction
involving the OH group at C-6 and the H atom at C-5a. The double
bond thus generated between positions C-5a and C-6
induces a shift in the position of the double bond between the
carbon atoms C-11 and C-11a thereby forming the relatively more
energetically favoured resonant system of the
naphthalene group found in the inactive anhydrotetracyclines.

•The strong bases on the other hand promote a reaction

between the hydroxyl group at C-6 and the carbonyl moiety at C-
11, thereby causing the bond between C-11 and C-11a atoms
to cleave and eventually form the lactone ring found in the
inactive isotetracyclines.
These two unfavorable reactions stimulated research that led to the
development of the more stable and longer acting compounds that
do not posses the 6-OH group: 6-deoxytetracycline, methacycline,
doxycycline, and minocycline

doxycycline minocycline
•The tetracyclines form stable chelate complexes with many
metals, e.g., Ca++, Mg++, Fe++, etc. Do not administer with
antacids, foods such as milk (contain Ca++)
Structure Activity Relationship (SAR)

The structure activity relationship amongst the various members

of the tetracycline family has been studied extensively.

•Changes on positions 1, 10, 11 and 12 abolished activity

• the substitutions on the C-5 and C-7 were not an essential
requirement.

• the methyl function at C-6 may be replaced by hydrogen.

•Removal of one methyl at C-4 retains activity, removal of the two

leads to loss of activity, α orientation of Me- pgs at C4 essential

•Removal of 6-OH group (as in deoxycycline and 6-deoxy-6-

demethyltetracycline (minocycline) markedly increases ring
stability (see above).
• Position 9 on ring D has been identified as key for the development
of new drugs that are not restricted by TCN resistant bugs

These ‘glycylcyclines’ : 9-dimethylglycylamino-(DMG)-

substituted tetracyclines
(i) retain essentially both potency and broad spectrum profile as
displayed by the ‘parent tetracyclines’ against specifically the
tetracycline-sensitive microbial strains, and
(ii) exhibit predominantly maximum activity against bacterial
strains which show tetracycline resistance either through the
ribosomal protecting determinants or afford mediation by efflux
MACROLIDES AND KETOLIDES
•Macrolide antibiotics contain a many-membered lactone ring – macrocyclic
esters - (14-membered rings for erythromycin and clarithromycin and a 15-
membered ring for azithromycin) to which are attached one or more deoxy
sugars.
•Clarithromycin differs from erythromycin only by methylation of the hydroxyl
group at the 6 position, and azithromycin differs by the addition of a methyl-
substituted nitrogen atom into the lactone ring.
• These structural modifications improve acid stability and tissue penetration
and broaden the spectrum of activity
Clarithromycin
(14 membered ring)
Hydroxy group

Methoxy group

Erythromycin
(14 membered ring)
The structures of erythromycin and
telithromycin, a ketolide. Circled
substituents and distinguish
telithromycin from the macrolides

Azithromycin
(15 membered ring)
Chemistry

• The macrolide antibiotics have three common chemical

characteristics:
(a) a large lactone ring (which prompted the name macrolide),
(b) a ketone group, and
(c) a glycosidically linked amino sugar.
• Usually, the lactone ring has 12, 14, 15 or 16 atoms in it, and it is
often unsaturated, with an olefinic group conjugated with the ketone
function.
• They may have, in addition to the amino sugar, a neutral sugar that is
linked glycosidically to the lactone B ring
•Because of the dimethylamino group on the sugar moiety, the
macrolides are bases that form salts with pKa values between 6.0 and
9.0. This feature has been used to make clinically useful salts.
•The free bases are only slightly soluble in water but dissolve in
somewhat polar organic solvents.
•They are stable in aqueous solutions at or below room temperature
but are inactivated by acids, bases, and heat.