MedChem3_Part1_2022_Updated.pdf

Al-Zaytoonah University of Jordan
Faculty of Pharmacy
Medicinal Chemistry 3
Course #: 0201414
3 Credit Hours
Part 1
Rima Hajjo, MS, PhD
rima.hajjo@zuj.edu.jo

Course Outline
1) Antibacterial/Antimicrobial Agents
2) Antibiotics
3) Antimycobacterial agents
4) Antifungal agents
5) Anti-parasites
6) Antiviral agents
7) Anticancer agents

Faculty of Pharmacy
MedChem 3
Course #:
3 Credit Hours
Antimicrobial/Antibacterial Agents
Ø Sulfonamides
Ø Quinolones
Ø Nitrofurans
Ø Methenamine
Ø Fosmycin
Ø Metronidazole

Foye’s Medicinal Chemistry Book
Book

Introduction: Mechanisms of Antibacterial Agents
Madigan and Martinko, 2006
Fostomycin

(1) SULFONAMIDES
ØSynthetic Antibacterial Agents
ØUsed Mainly for Urinary Tract Infections (UTIs)
ØGeneral Considerations:
• First, Sulfonamides came into use in the mid 1930’s
• Then Penicillins in the 40’s
• Combination therapies in the 1970’s (Co-trimoxazole)
• FLuoroquinolones in the 1990’s
ØTherapeutic Indications:
• Lower UTI’s – urethritis, cystitis, prostatitis
• Upper UTI’s – Pyelonephritis

The Discovery of Sulfonamides Antibacterial Agents
Prontosil rubrum and patented as Prontosil, is
an azo dye, introduced in 1935 by Gerhard
Domagk, Bayer, Germany.
Inactive in vitro!
Active in vivo.
Natural Bacterial Metabolite
Antimetabolite
PABA
p-aminobenzenesulfonic acid amide
Azo bond confers prodrug qualities
“Azo compound”
The first drug to successfully treat bacterial infections and the first of many sulfa drugs—
forerunners of antibiotics. This achievement earned its creator a Nobel Prize.
reductive
cleavage of the
azo bond

Mechanism of Action: Sulfonmaides Inhibit Microbial
Biosynthetic Pathway of Tetrahydrofolic Acid Synthesis
Glutamic acid
6-hydroxymethyl-7,8-dihydropterin-pyrophosphate
The basis of selective toxicity to bacteria is clear! Bacteria need to synthesize THFA in vivo,
while humans rely on food and supplements for folic acid and don’t synthesize it in vivo.
Sulfonamides are
bacteriostatic
‘THFA’
THFA is required
for DNA synthesis

Structure Activity Relationships (SAR) of
Sulfonamides
SAR:
1. N4 must be unsubstitued or capable of regeneration of NH2
2. No substitution on the aromatic ring
3. Acidic proton on N1
S
H2N
O
O
N
H
H
C
H2N
O
O
H
pKa = 6.5
pKa = 10.4
Acidic
Ar = pKa
N
O
H3C CH3
5.0
MIC
2.15
H 10.4 128.0
O
N
CH3
6.0 0.8
N
N
6.52 0.9
N
N
S
5.5 ---
CH3
S
H2N
O
O
N
H
Ar
4. Exchange SO2NHR by CONHR reduces the activity (because
of decreased acidity of N1 proton)
5. The amine and sulphonamide groups have to be para to each other
PABA
Sulfanilamide
N4
N1
Thiadiazole
Pyrimidine
Isoxazole
Isoxazole

Pharmacokinetics of Sulfonamides
S
H2N
O
O
N
H
Ar
S
NH
O
O
N
H
Ar
C
O
H3C
N4 acetylation (aniline nitrogen)
“Inactive”
1) Metabolism
S
H2N
O
O
N
Ar
Salt
2) Salt formation
“Acidic proton allows salt formation”
Acidic proton
Sodium Salts are very alkaline because Na+ is quite alkaline (more irritation) causing crystalurea
N
OH
OH
H
H
Diethanolamine is close to neutral and its sulfonamide salts are nearly neutral (i.e., less irritation)
Site of acetylation
“less painful/less irritation for eyes”
Diethanolamine
Irritation
Two problems: 1) Inactivated by metabolism and 2) low water solubility

Pharmacokinetics
1) Most sulfonamides are well absorbed orally and they
are widely distributed including to the CNS.
2) The concentrations in the kidney are the highest. So
they are suitable for treating urinary tract infections.
3) Lower solubility in the urine, most sulfonamides and
their metabolites easily cause crystalluria, bloody
urine, and kidney damage.

According to administration route and the degree of absorption in
intestinal tract, can be divided into:
①Oral, absorbable: well absorbed in intestinal tract and mainly
used to treat general infections. On the basis of their half-lives,
also be classified as short-, medium-, or long-acting ones such
as sulfisoxazole, sulfamethoxazole and sulfadoxine;
②Oral, nonabsorbable: poorly absorbed in intestinal tract and
mainly used to treat intestinal tract infections; such as
sulfasalazine.
③Topical: such as SD-Ag and sulfamylone.
Clinical Uses and “Classification of Sulfonamides”

Orally Absorbable
S
O
O H
N
O
N
H2N
S
O
O
NH
H2N
N
N
Sulfamethoxazole Sulfadiazine
Sulfisoxazole Sulfadoxine
Sulfamethizole

Mafenide/Sulfamylone (Burns)
Topical
S
O
O
NH
H2N
O
Sulfacetamide (Eye drops)
Silver sulfadiazine (Wounds, Burns)
Sulfasalazine (intestinal infections)
Orally Nonabsorbable
mafenide acetate

Resistance to Sulfonamides
ØUsually occurs by increasing the PABA concentration or a
change in the enzyme structure to better distinguish between
PABA and the drug.
ØSome bacteria are intrinsically resistant since they can uptake
Folic acid from their surroundings.
ØThe use of sulfamethoxazole and other sulfonamides has been
limited by the increasing incidence of resistant organisms. Their
main use has been in the treatment of acute, uncomplicated
urinary-tract infections, particularly those caused by Escherichia
coli.

Combination Therapy for UTIs: Sulfonamide +
Trimethoprim
N
N
N
N
O
H2N
H
H
O P
O
O
OH
P
O
OH
OH H2N
CO2H
PABA
+ N
N N
N
O
H2N
N
CO2H
H
H
H
Dihydropteroic Acid
Glutamic acid
N
N N
N
O
H2N
N
C N
CO2H
CO2H
Dihydrofolic Acid
H
H
H
o
H
Dihydrofolate
reductase
N
N N
N
O
H2N
N
C N
H
CO2H
CO2H
Tetrahydrofolic Acid
H
H
H
H
O
S
H2N
O
O
N
H
H
Dihydropteroate diphosphate
Trimethoprim
Dihydropteroate
Synthase
Sulfonamide

Trimethoprim
Site of action of
trimethoprim
Antimetabolite

Faculty of Pharmacy
MedChem 3
3 Credit Hours
Rima Hajjo, MS, PhD
rima.hajjo@zuj.edu.jo
(2) Quinolone/Fluoroquinolone Antibacterial Agents

Quinolones: Background
Ø Broad spectrum antibacterial.
Ø The first discovered quinolone antibacterial for clinical use was Nalidixic acid (not in
clinical use anymore because safer quinolones were discovered).
Ø Now, nearly all quinolone drugs in clinical use are fluoroquinolones.
Ø We developed/used as antibacterial agents in the 60s.
Nalidixic acid
Ø Due to increased concerns about toxicities
and side effects, the FDA issued black box
warnings in 2008, 2016, 2018.
Example on black box warning for other drugs

General Structure and Pharmacophore
1
2
3
4
5
6
7
8
Spectrum of activity
Atom number 8 used to be N, then changed
to C to reduce side effects. Most quinolone
drugs in clinical use have C at position 8.

Mechanism of action of Quinolones
ØQuinolones inhibit bacterial
topoisomerase enzymes, resulting in
inhibition of replication and transcription.
ØInhibition of DNA gyrase in G- (also called
topoisomerase II in G-) and
topoisomerase IV in G+, which are key
bacterial enzymes that dictate the
conformation of DNA à that’s why the
quinolones are rapidly bactericidal.

ØNalidixic acid was the first quinolone introduced to clinic in 1962 to fight against
Gram negative urinary tract infections (UTIs) à it is considered a first-
generation quinolone based on its spectrum of activity and pharmacokinetic
properties. It is discontinued.
ØFirst-generation agents are limited to uncomplicated urinary tract infections.
And they have problems with toxicity, antibacterial spectrum, and metabolism.
1
2
3
4
First Generation Quinolones

Second Generation Quinolones
Broader spectrum against Gram Negative
Longer half life
Less protein binding when X = CH

Third Generation Quinolones
The third-generation quinolones include levofloxacin, gatifloxacin, and gemifloxacin.
It is 4th generation in some references

Fourth Generation Quinolones
The first chlorinated
fluoroquinolone developed.
Trovafloxacin
Removed from clinical use in 1999
Hepatotoxic

Summary
Generation Agents
Antimicrobial
Spectrum
Properties
First Nalidixic acid
Cinoxacin
Gram negative
(not Pseudomonas)
Poor serum and
tissue concentration.
Not for systemic
infections
Second Norfloxacin
Lomefloxacin
Enoxacin
Ofloxacin
Ciporfloxacin
Gram negative
(including
Pseudomonas),
Some Gram positive
Adequate serum and
tissue concentrations.
Good for systemic
infections.
Third Levofloxacin
Sparfloxacin
Gatifloxacin
Moxifloxacin
Same as for second-
gen. generation plus
expanded Gram
positive
Once-daily dosing
Fourth Trovafloxacin
Besifloxacin
Same as for third-
gen. plus broad
anaerobic coverage
Active against
anaerobic Gram-
positive and negative

General Structure and SAR
Ring 1
Ring 2

SAR of Quinolones: Rings
N
O
R
COOH
N
O
R
COOH
1
2
3
4
5
6
1
2
3
4
5
6
7
8
Substituted 1,4-dihydro-4-oxo-
3-pyridinecarboxylic
acid
Substituted quinolone 3-carboxylic
acid
Ø1,4-dihydro-4-oxo-3-pyridinecarboxylic acid portion is
necessary for the antibacterial activity.
ØThe pyridone ring (ring 1) must be attached to an aromatic ring
(ring 2), in which isosteric substitution of carbon with nitrogen
maintains the activity.
Ring 1
Ring 2

SAR: Isosteric substitutions on ring 2
ØIsosteric substitution of carbon with nitrogen
maintains the antibacterial activity.
N
N
O
R
COOH
1
2
3
4
5
6
7
8
N
N
O
R
COOH
1
2
3
4
5
6
7
8
N
N
O
R
COOH
1
2
3
4
5
6
7
8
N
N
O
R
COOH
1
2
3
4
5
6
7
8
Cinnolines 1,5-Naphthyridines
1,6-Naphthyridines 1,8-Naphthyridines
Ring 1
Ring 2

SAR: N1 alkyl substitutions
ØN1-Substitution is necessary for the antibacterial activity.
Small alkyl or cycloalkyl groups increase the antibacterial
activity in the following order: cyclopropyl >ethyl >methyl.
N
O
COOH
1
2
3
4
5
8
N
HN
F
7
6
N
O
COOH
1
2
3
4
5
8
CH3
N
HN
F
7
6
Ciprofloxacin Norfloxacin

SAR: N1 aryl substitutions
ØN1- Aryl substitution maintains the activity and
sometimes optimises it.
N
O
COOH
1
2
3
4
5
N
F
7
6
H2N
F
8
F
F
Trovafloxacin

SAR: Substitutions on C2, C5, C6, C7 & C8
N
O
R
COOH
1
2
3
4
5
6
7
8
ØSubstitution at C2 position decreases the activity remarkably or changes the
antibacterial characters.
ØSubstitution at C5 , C6 , C7 and at C8 has good effects on the activity.
ØC6 fluorine substitution increases the activity prominently, That’s why
quinolones are also called fluoroquinolones.
ØSubstituted or unsubstituted piperazinyl or pyrrolidinyl groups at C7 increase the
activity against P. aeroginosa (spectrum of activity)
Sparfloxacin

SAR: New ring (ring fusion) from N1 to C8
N
O
COOH
1
2
3
4
5
N
H3CN
F
7
6
O
CH3
H
8
Ofloxacin
Levofloxacin (-)S
N
X
O
CH3
COOH
O
O
X: N = Cinoxacin
X: CH = Oxolinic acid
1
3
4
5
7
8
2
6
ØRing fusion at N1and C8; C5 and C6; C6 and C7 or C7 and
C8 introduces active compounds:
Examples:

N N
N
O
CO2H
F
F
F
H
H
N
H
O
NH
H3C
H
O
H3C
NH2
Alatrofloxacin
Prodrug
N N
N
O
CO2H
F
F
F
H
H
H2N
Trovafloxacin
SAR: Amino Acid Substitutions
Alanines in alatrofloxacin are introduced to
improve drug transportation into cell/improve
absorption.
Removed from clinical use in 1999
Hepatotoxic

SAR of Toxicity and Side Effects
Can J Infect Dis. 2002 Jan;13(1):54-61.
Associated with CytP450 interactions

SAR Consideration: Metal Chelation
Ø The ability of these drugs to chelate polyvalent metal ions (Ca2+ , Mg2+ , Zn2+ , Fe2+,
Al3+ ), resulting in decreased solubility and reduced drug absorption.
Ø Causes kidney caliculi and crystalluria. (advice patients to drink lots of water)
Ø Chelation occurs between the metal and the 3-carboxylic acid and 4-keto groups.
Ø Agents containing polyvalent metals should be administered separately from the
quinolones.
Molecules. 2013 Sep; 18(9): 11153–11197.
A problem of chemical incompatibility of all Quinolones
Metal chelate

SAR of Toxicity: CNS toxicity
ØUnlike many anti-infective drugs, the quinolones can cause severe CNS effects
even after short-term use.
ØCNS side effects include: Tremor, sleep disorders, anxiety, and convulsions
because they cause GABA antagonism at the receptor.
ØBecause of low penetration to brain this toxicity is rare.
Flumequine (first generation)
Causes severe CNS side effects

Important Structural Modifications
Ø The most active of the
fluoroquinolones against
Gram-negative bacteria.
Ø A cyclopropyl substituent at
position 1 further increased
spectrum of activity.
Ø Replacement of the nitrogen
at position 8 with carbon
reduced adverse reactions
and increased activity against
S. aureus.
ØQuinolones were of little
clinical significance until
the addition of a fluoro
group to C6 greatly
increased the biologic
activity à it improved cell
wall penetration.
ØA piperazinyl ring at position 7,
was also beneficial for a variety
of pharmacokinetic reasons due
to the ability of the basic
substituent to form a zwitterion
with the carboxylic acid group at
position 3. This property appears
to radically enhance the ability of
these compounds to penetrate the
outer membrane of Gram negative
bacteria.

Critical for binding
Improves activity against a variety of organisms
(Spectrum of activity)
O
COOH
HO
OH
OH
O C
O
N
O
R1
F
R
Phase 2
Conjugation
Phase 1
CYP 450 (1A2)
N
O
COOH
R1
N
N
F
R2
HO
Potency
Pharmacophore
F
N
N
O
R1
O
OH
Cell penetration
Gyrase inhibition
Metabolism of Quinolones
Inactive
Reduced activity

Faculty of Pharmacy
MedChem 3
Course #: 0201511
3 Credit Hours
Rima Hajjo, MS, PhD
r.hajjo@zuj.edu.jo
(3) Nitrofurans and Other Antimicrobial Agents

Ø Widely used oral antibacterial since WWII.
It is used for prophylaxis or treatment of
acute urinary tract infections when kidney
function is NOT impaired.
Ø Nausea and vomiting are common. Severe
side effects can be experienced when
using this drug (acute pulmonary
reactions, peripheral neuropathy,
hemolytic anemia, liver toxicity, and
fertility impairment).
Ø Inhibits DNA and RNA functions through
mechanisms that are not well understood.
There is little acquired resistance.
Nitroheteroaromatic compounds:
Ø Used orally for the treatment of
trichomoniasis, giardiasis, and Gardnerella
vaginalis infections. It has found increasing
use of late in the parenteral treatment of
anaerobic infections and for treatment of
pseudomembranous colitis due to
Clostridium difficile (opportunistic pathogen
that occasionally flourishes as a
consequence of broad-spectrum antibiotic
therapy, and infections can be life-
threatening). Important Antiparasitic agent.
Ø It is believed to be metabolically activated
by reduction of its nitro group to produce
metabolites that interfere with DNA and
RNA function.
1) 2)

O
C
H
O2N N N
O
O
Furazolidone
O
C
H
O2N N N
NH
O
O
Nitrofurantoin
O
C
H
N N N
NH
O
O
H
HO
Metabolism
Active form
O
C
H
N N N
NH
O
O
H
H
Extended conjugation of electrons
(Brown Color à urine discoloration)
Nitrofurans For UTIs
O
C
H
O2N X
For the management of chronic prostatitis.
Can cause hepatic injury
(Hepatic drug reactions are
more common in females for
unknown reasons).
Other examples:
acetaminophen, halothane,
nitrofurantoin, diclofenac, and
sulindac.
More on nitrofurans

Synthesis of Nitrofurantoin
Ø Replacing the furan ring with other five-membered rings such as thiophene and pyrrole
are less active).
Ø Replacing nitro with other isolelectric groups (e.g., sulfo, sulfamoyl, carboxyl or cyano)
reduce the antibacterial activity.
SAR:
thiophene pyrrole
furan
O
C
H
O2N X
O
O2N R
S
O2N R NH
O2N R

Protein N C
H
H
Methenamine (Hexamethylenetetramine)
For UTIs
Can form Schiff base with protein
(Hexamine)
Acidic media
Schiff base (imine)

Fosfomycin
Ø Fosfomycin (also known as phosphomycin) inhibits enolpyruvial transferase, an
enzyme catalyzing an early step in bacterial cell wall biosynthesis. Inhibition results in
reduced synthesis of peptidoglycan, an important component in the bacterial cell
wall.
Ø Fosfomycin is bactericidal against Escherichia coli and Enterobacter faecalis infections.
Ø It is used for treatment of uncomplicated urinary tract infections by susceptible
organisms.
For UTIs

Phenazopyridine
N
N
H2 NH2
N N
UTI Analgesic (does not have antibacterial properties)
Azo dye
bright red in color
Urinary analgesic – does not heal infections
For UTIs

Faculty of Pharmacy
MedChem 3
Course #: 0201511
3 Credit Hours
Rima Hajjo, MS, PhD
r.hajjo@zuj.edu.jo
β-Lactam Antibiotics
- Penicillins

Agenda
Penicillins
What we need to know?
① Pharmacophore structure
② General Structures (highlighted in lecture)
③ SAR
④ How to improve: in vitro stability, administration route (oral is better),
stability towards β –lactamases, spectrum of activity (antibacterial activity)
⑤ Important Mechanisms of action, or reaction mechanisms.

Introduction: Antibiotics
What is an antibiotic?
1) It is a product of metabolism.
2) It is a synthetic product produced as structural analogue of naturally occurring
antibiotic.
3) It antagonizes the growth or survival of one or more species of microorganisms.
4) It is effective in low concentrations.
Modes of action:
1) Cell wall synthesis inhibitors
2) Cell membrane inhibitors
3) Protein synthesis inhibitors
4) Nucleic acids synthesis inhibitors
Major antibiotic classes that inhibit bacterial cell wall biosynthesis are:
1) β – Lactam antibiotics which include penicillins , cephalosporins and
carbapenems.
2) Monobactams.
3) Polypeptides.

Introduction: β – Lactam Antibiotics
ØAntibiotics that possess the β – Lactam ring (a
four-membered cyclic amide) such as
penicillins and cephalosporins.
ØThis group of antibiotics have:
1)Broad spectrum of antibacterial action
2)Potent and rapid bactericidal action against bacteria in the
growth phase.
3)Low frequency of toxic and other side effects in host.

Ring Types and Numberings of Clinically Available
Βeta-lactam Antibiotics
Memorize these!

The First β-Lactam Antibiotics: Penicillins
Ø Penicillins are the most widely used antibioticsin the World.
Ø Penicillins are antibacterial agents which inhibit bacterial
cell wall synthesis Discovered by Fleming from a fungal
colony (1928) shown to be non toxic and antibacterial. First
used on humans in 1942 (US, Streptococcal septicemia).
Ø The original fermentation-derived penicillins were
produced by growth of the fungus Penicillium
chrysogenum.
Penicillin G
Fermentation-derived
Active against G+ mainly

Biosynthesis of Penicillin
Two prototypes:
Memorize this structure for
6-APA in the blue box.
Benzyl penicillin: (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-
2-carboxylic acid. à IUPAC
1 2
3
4
5
7

Semisynthetic Penicillins
Then 6-APA is used to
synthesize other
“improved” penicillins
6-aminopenicillanic acid (6-APA) is
synthesized by hydrolyzing naturally
produced Penicillin G. Then 6-APA is
used to synthesize other penicillins
(semisynthetic because it relied on a
naturally-occurring precursor).
Synthesis of 6-APA from penicillin G

The 3D Shape of Penicillin
Ø Penicillin contains a highly
unstable bicyclic system
consisting of a four-membered β
–lactam ring fused to a five-
membered thiazolidine ring.
Ø The skeleton of the molecule
suggests that it is derived from
the amino acids cysteine and
valine, and this has been
established.
Ø The overall shape of the
molecule is like a half-open book,
as shown on the left.

Peptidoglycan Structure of Bacterial Cell Walls
is the Target for Penicillins
Ø β – Lactams bind at the active site of the transpeptidase enzyme that cross-links
the peptidoglycan strands at the positions indicated by arrows on the figure
above.
Ø It does this by mimicking the D-alanyl-D-alanine residues that would normally
bind to this site.

Mechanism of
Action of
Penicillins
The enzyme responsible for the cross-
linking reaction is known as the
transpeptidase enzyme .
Ø β – Lactams including
penicillin irreversibly
inhibit the enzyme
transpeptidase by
reacting with a serine
residue in the
transpeptidase à
inhibit cell wall
synthesis.
Ø Cell walls are essential
for bacteria to live.
Ø Cross-linking of
bacterial cell walls
inhibited by penicillin

Penicillin Mimics the Natural Substrate
Figure. Comparison of penicillin, 6-substituted penicillins, and acyl-d-Ala-d-Ala.

Mechanism of Transpeptidase Cross-linking and
Inhibition by Penicillins

β-Lactam Ring Acting as an Acylating Agent

Penicillin as a an Inhibitor for β-Lactamases

Penicillins: Structure Activity Relationships (SAR)
Agenda:
ØSAR Considerations
ØStructural Modifications
ØProdrugs
ØDrugs that synergize with penicillins

Major SAR Considerations, Chemical and
Biological Instabilities
1) Hydrolysis by beta-lactamases (penicllinases in case
of penicillins)
2) Instability in basic media or in presence of
nucleophiles (e.g., OH-)
3) Instability in acids

1) Deactivation by Beta-lactamases
Mechanism of β-lactamase Deactivation of Penicillin:
You need to know this!

How to Reduce Sensitivity (increase resistance) to
Beta-lactamases?
Fig. β-Lactamase resistant/sensitive structural features.

2) Instability of Βeta-lactams to Nucleophiles
Hydrolysis in basic media

3) Instability of Penicillins in Acid
Hydrolysis
involves the C-6 side
chain.
Hydrolysis in Acidic media
Skip Mechanism just
remember how it is related to
the the C-6 side chain.

Ring Opening of Penicillins Leads to Loss of
Antibiotic Activity

Comparison of Tertiary Amide and β-
Lactam Carbonyl Groups

Structural Modifications to Solve the
Main Problems of Penicillins:
1) Oral Bioavailability
2) Deactivation by beta-lactamases
3) Spectrum of activity
4) PK properties/Prodrugs
SAR Rules

Making Penicillins Orally Active (i.e., resistant
to acidic hydrolysis)

How Improve Acid Stability to Allow Oral Administration
1) Pen V
2) Amino Penicillins

Making Penicillins β-Lactamase Resistant

Orally Active, Acid and β-Lactamase Resistant

Broad Spectrum Penicillins
1) Aminopenicillins
2) Carboxypenicillins

Hydrophilic Groups on the Side Chains of R on the
6th Position of the lactam Ring
Hydrophilic groups on the side
chain have little effect
on Gram-positive activity (e.g.
penicillin T) or cause
a reduction of activity (e.g.
penicillin N).
However, they lead to an
increase in activity against
Gram-negative bacteria

Prodrugs to Aid Absorption of Ampicillin
Through the Gut Wall
Mechanism of hydrolysis of prodrugs:

Polar Extended Ester for Penicillin G

Broad-spectrum Penicillins: Ureidopenicillins
Ø Ureidopenicillins (Figure above) are the newest class of broad-spectrum penicillins
and have a urea functional group at the α-position.
Ø Generally, they have better properties than the carboxypenicillins and have largely
replaced them in the clinic.

Synergism of Penicillins with Beta Lactamse Inhibitors
Clavulanic Acid

Synergism of Penicillins with Probencid
Probencid
Ø Probenecid is a moderately lipophilic carboxylic acid that can block
facilitated transport of penicillin through the kidney tubules and slows down
the rate at which penicillin is excreted.
Ø Probenecid also competes with penicillin for binding sites on albumin. As a
result, penicillin levels in the bloodstream are enhanced and the
antibacterial activity increases—a useful tactic if faced with a particularly
resistant bacterium.

Key Points: Penicillins
① Penicillins have a bicyclic structure consisting of a β-lactam ring fused to a
thiazolidine ring.
② The strained β-lactam ring reacts irreversibly with the transpeptidase enzyme
responsible for the final cross-linking of the bacterial cell wall.
③ Penicillin analogues can be prepared by fermentation or by a semi-synthetic
synthesis from 6-aminopenicillanic acid.
④ Variation of the penicillin structure is limited to the acylside chain or -OMe on 6th
position carbon of the beta lactam ring.
⑤ Penicillins can be made more resistant to acid conditions by incorporating an
electron-withdrawing group into the acyl side chain.
⑥ Steric shields can be added to penicillins to protect them from bacterial β-lactamase
enzymes.
⑦ Broad spectrum activity is associated with the presence of an α-hydrophilic group on
the acyl side chain of penicillin.
⑧ Prodrugs of penicillins are useful in masking polar groups and improving absorption
from the gastrointestinal tract.
⑨ Extended esters are used which undergo enzyme-catalysed hydrolysis to produce a
product which degrades spontaneously to release the penicillin.
⑩ Probenecid can be administered with penicillins to hinder the excretion of
penicillins.

Faculty of Pharmacy
MedChem 3
Course #: 0201511
3 Credit Hours
Rima Hajjo, MS, PhD
r.hajjo@zuj.edu.jo
β-Lactam Antibiotics
- Cephalosporins

Agenda
ØCephalosporins
What we need to know?
① Pharmacophore structure
② General Structures (highlighted in lecture)
③ SAR
④ How to improve: in vitro stability, administration route (oral is better),
stability towards β –lactamases, spectrum of activity (antibacterial activity)
⑤ Important Mechanisms of action, or reaction mechanisms.

Cephalosporin C
Amino Adipic Acid
IUPAC NAME:
(6R,7R)-3-[(Acetyloxy)methyl]-7-{[(5R)-5-
amino-5-carboxypentanoyl]amino}-8-oxo-5-
thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid
1
2
3
4
5
6
7
8

Mechanism of Inhibition of
Transpeptidase by Cephalosporins

Biosynthesis of Cephalosporins
Building Blocks/Precursors

Positions for Possible Modification
of Cephalosporin C.
The shading indicates positions which can be varied
2
3
1
4
5
6
8

First Generation Cephalosporins
thiophene
Acetyloxy group at position 3 is
readily hydrolyzed by esterase
enzymes to give the less active
alcohol.
Metabolic Hydrolysis of Cephalothin:
Cephalothin

First Generation Cephalosporins
Ø Cephaloridine exists as a zwitterion and is soluble in water, but, like most first
generation cephalosporins, it is poorly absorbed through the gut wall and has to be
injected. Pyridinium at C3 in Cephaloridine is metabolically stable. The pyridine can
still act as a good leaving group for the inhibition mechanism, but is not cleaved by
esterases.
Ø The Me at C3 in Cefalexin increases absorption through the gut and is stable to
metabolism à orally bioavailable.
Orally absorbed
Cephaloridine Cefalexin

Other First Generation Cephalosporins
Modifications on two positions: R and X
Cefazolin Cephalexin Cefadroxil
Parenteral Oral

Second Generation Cephalosporins: Cephamycins
Ø Cephamycins contain a methoxy substituent at position 7, which has proved
advantageous. Modification of the side chain gave cefoxitin, which showed a broader
spectrum of activity than most first-generation cephalosporins. This is due to greater
resistance to β–lactamase enzymes, which may be due to the steric hindrance
provided by the methoxy group.
Ø Cefoxitin showed good metabolic stability to esterases owing to the presence of the
urethane group at position 3, rather than an ester.
Urethrane group
Urethrane group
Cephamycin C Cefoxitin

Second Generation: Oximinocephalosporins
Ø Oximinocephalosporins has been a major advance in cephalosporin research. These
structures contain an iminomethoxy group at the α –position of the acyl side chain,
which significantly increases the stability of cephalosporins against the β -lactamases
produced by some organisms (e.g. Haemophilus influenza ).
Ø Increased resistance to β -lactamases and mammalian esterases (like cefoxitin). Unlike
cefoxitin, cefuroxime retains activity against streptococci and, to a lesser extent,
against staphylococci.
Urethrane group

Examples: Second Generation
Modifications on 4 positions: R, X, Y and Z
Parenteral
Cefuroxime
Cefotetan
Cefoxitin
Cefaclor Cefprozil
Oral

Third Generation Cephalosporins
ØAminothiazolering in Ceftazidime enhances the penetration of cephalosporins
through the outer membrane of Gram-negative bacteria, and may also increase affinity
for the transpeptidase enzyme. As a result, third-generation cephalosporins containing
this ring have a marked increase in activity against these bacteria.

Ø Other 3rd generation compounds: cefotaxime, ceftizoxime, and ceftriaxone, with
different substituents at position 3 to vary the pharmacokinetic properties. They play a
major role in antimicrobial therapy because of their activity against Gram-negative
bacteria, many of which are resistant to other β –lactams.
Ø As such infections are uncommon outside hospitals, physicians are discouraged from
prescribing these drugs routinely and they are viewed as ‘reserve troops’ to be used for
troublesome infections which do not respond to the more commonly prescribed β -
lactams.
(R)
Iminomethoxy
Aminothiazole

Fourth Generation Cephalosporins
Ø They are zwitterionic compounds having a positively charged substituent at
position 3 and a negatively charged carboxylate group at position 4. This property
appears to radically enhance the ability of these compounds to penetrate the outer
membrane of Gram negative bacteria.
Ø They are also found to have a good affinity for the transpeptidase enzyme and a low
affinity for a variety of β-lactamases.
Iminomethoxy
Aminothiazole

Special Considerations for Oximes on the
7th position
Ø Z-oxime is preferred over the E-oxime
Ø Stability toward β-lactamase can be increased
around 100-fold with the addition of
methoxyoxime. Z-oxime is nearly 20,000-fold more
stable than the E-oxime

Prodrug Cephalosporins
N
S
O
H
H
HN
O OCONH2
O
NOCH3
O O
O
CH3
CH3
O
N
S
O
H
HN
O OCH3
NOCH3
H
N
S
H2N
O O
CH3
O
O
O
CH3
CH3
Cefuroxime axetil
Cefpodoxime proxetil

Another Prodrug: “Fifth-generation”
Cephalosporin
Has activity against various strains of MRSA and multi-resistant
Streptococcus pneumonia (MDRSP).
Ceftaroline fosamil
Newest Cephalosporin
The 1,3-thiazole ring is
thought to be
important for its
activity against MRSA.

Resistance to Cephalosporins
Ø The activity of a specific cephalosporin against a particular bacterial cell is
dependent on the same factors as those for penicillins. i.e. the ability to reach the
transpeptidase enzyme, stability to any β -lactamases which might be present, and
the affinity of the antibiotic for the target.
Ø For example, most cephalosporins (with the exception of cephaloridine) are stable
to the β -lactamase produced by S. aureus and can reach the transpeptidase
enzyme without difficulty. Therefore, the relative ability of cephalosporins to inhibit
S. aureus comes down to their affinity for the target transpeptidase enzyme.
Agents such as the cephamycins and ceftazidime have poor affinity, whereas other
cephalosporins have a higher affinity.
Ø The MRSA organism contains a modified transpeptidase enzyme ( PBP2a)
for which both penicillins and cephalosporins have poor affinity.

Key Points: Cephalosporins
Ø Cephalosporins contain a strained β-lactam ring fused to a dihydrothiazine ring.
Ø In general, first-generation cephalosporins offer advantages over penicillins in
that they have greater stability to acid conditions and β-lactamases, and have a
good ratio of activity against Gram-positive and Gram-negative bacteria.
However, they have poor oral availability and are generally lower in activity.
Mainly reserved for parenteral formulations.
Ø Variation of the 7-acylamino side chain alters antimicrobial activity, whereas
variation of the side chain at position 3 predominantly alters the metabolic and
pharmacokinetic properties of the compound. Introduction of a methoxy
substitution at C-7 is possible, making compounds more resistant to beta
lactamases.
Ø Semisynthetic cephalosporins can be prepared from 7-aminocephalosporanic
acid (7-ACA). 7-ACA is obtained from the chemical hydrolysis of natural
cephalosporins.

Key Points: Cephalosporins
Ø Deacetylation of acetyl groups on 3rd position of cephalosporins occurs
metabolically to produce inactive metabolites. Metabolism can be blocked
by replacing the susceptible acetoxy group with metabolically stable
groups.
Ø A methyl substituent at position 3 is good for oral absorption but bad for
activity unless a hydrophilic group is present at the α-position of the acyl
side chain.
Ø Cephamycins are cephalosporins containing a methoxy group at position 7.
Ø Oximinocephalosporins have resulted in several generations of
cephalosporins with increased potency and a broader spectrum of activity,
particularly against Gram-negative bacteria.

Faculty of Pharmacy
MedChem 3
Course #: 0201511
3 Credit Hours
Ø Aminoglycosides

Ø Aminoglycosides are irreversible inhibitors of protein
synthesis.
Ø They are active against aerobic gram negative bacilli and
staphylococci.
Ø The initial event is passive diffusion via channels across the
outer membrane. Drug is then actively transported across the
cell membrane into the cytoplasm by an oxygen- dependent
process, which is coupled to a proton pump.
Ø Low extracellular pH and anaerobic conditions inhibit
transport by reducing the gradient. Transport may be
enhanced by cell wall-active drugs, such as penicillins.

Ø They bind irreversibly to a receptor protein on the 30S ribosomal
subunit and blocks the formation of a complex that includes mRNA,
formylmethionine, and tRNA. Protein synthesis is inhibited by
aminoglycosides.
(1) They interfere with the initiation complex of peptide formation.
(2) They induce misreading of mRNA, which causes incorporation of
incorrect amino acids into the peptide, resulting in a nonfunctional
or toxic protein.

Ø They are strongly basic compounds that exist as poly cations at physiological
pH. Their inorganic acid salts are very soluble in water (as sulfates).
Ø Solutions of the aminoglycoside salts are stable to autoclaving.
Ø The high water solubility of the aminoglycosides contributes to their
pharmacokinetic properties. They distribute well into most body fluids but not
into the central nervous system, bone, fatty or connective tissues.
Ø They tend to concentrate in the kidneys and are excreted by glomerular
filtration. Metabolism of aminoglycosides in vivo apparently does not occur.
O
O
OH
NH 2
H2N
O
CH 2
OH
H2N
OH
OH
O
OH
CH 2
NH 2
HO
HO
Kanamycin C
Ø Aminoglycosides structures consist of
amino sugars linked glycosidically to
1,3-diaminoinositol.

The antibacterial spectrum (e.g. kanamycin) was limited by resistance in
many species of bacteria, this is due to the presence of R factors which
direct the synthesis of a new family of enzymes that inactivate
aminoglycoside by three separate mechanisms: acetylation, adenylation
and phosphorylation.

SAR (Ring I (A))
ØRing I (Ring A) is crucial for antibacterial activity.
ØIt is the target for enzymatic inactivation and so any change in
the substitution patterns can lead to significant changes in
antibacterial activity.
ØThe number and location of amino functions in ring I can affect
SAR.
Kanamycin B

ØKanamycin B > Kanamycin A > kanamycin C , thus indicating the greater
importance of the 6'-amino group over the the 2‘-amino group.
ØAcylation of either the 6'- or 2'- amino groups lead to a severe decrease in
potency.
Ø6'- position C- or N- methylation can lead to retention, or even improvement of
potency, 6'-N- methylation can have a beneficial effect by preventing
inactivation via 6- acetyltransferase enzymes.
O
O
OH
NH 2
OH
O NH 2
H2N
OH
OH
O
OH
HO
H2N
HO
H
H
S S
R
R
R
R
R
S
S S
R
R
R
S
S
Kanamycin A
O
O
OH
NH 2
H2N
O
CH 2
OH
H2N
OH
OH
O
OH
CH 2
NH 2
HO
HO
Kanamycin C
Kanamycin B
6’

Ø Replacement of hydroxyl groups by hydrogen can lead to an
improved potency and spectrum of action.
Ø Conversion of Kanamycin B to its 3'- deoxy or 3', 4’ dideoxy
derivative (Tobramycin or Dibekacin respectively) leads to a
substantial improvement in activity against Pseudomonas
aeurginosa and a small improvement against other species.
O
O
OH
NH 2
OH
O NH 2
H2N
OH
OH
O
NH 2
H2N
HO
H
H
S S
S
R
R
R
R
S
S S
R
R
R
S
Tobramycin
Kanamycin B

Ø Unsaturation in ring I of Kanamycin B: by replacing the 3',4'-
hydroxyl groups by a double bond diminished activity,
Ø While introduction of a 4',5'- double bond gives a potent
derivative .
NHEt
NHMe
Me
O
O
OH
OH
O
H2N
OH
O
NH 2
H2N
H
H
S
R
R
S
R
R
R
S
R
S
R
Netilmicin

SAR (Ring II (B))
Ø The most important modification to the 2-deoxystreptamine
ring has been acylation of the 1-amino with 2- hydroxyl-4-
aminobutyric acid (HABA) as in Amikacin, which improves
activity against resistant bacteria.
Ø Methylation of 1,3-diamino groups gives Spectinamine ring.
O
O
N
H
OH
HO
O
H2N
O
H2N
OH
OH
OH
O
OH
NH 2
HO
H2N
HO
H
H
S
S
R
S
R
R
R
S
S
S
S
R
R
R
S
S
Amikacin
2-deoxystreptamine ring
improves
activity against
resistant
bacteria.

SAR (Ring III (C))
Ø When ring III is a pyranose ring, removal or methylation of the 2"-
hydroxyl group has led to a considerable decrease in antibacterial
activity, although activity is retained on replacement of the 2"-
hydroxyl by an amino group, as in Seldomycin-5.
Ø The 3"-group may be a primary or secondary amino group.
Ø The 4"-hydroxyl may be axial or equatorial.
Ø Several modifications at the 6"-position have led to a retention of
antibacterial activity.

Ø When ring III is a furanose ring, the 3"-hydroxyl may be
substituted as in Neomycin and Paromomycin.
Ø Possession of a fourth ring, as in Neomycin, generally
leads to increased potency.
O
O
O
H2N
NH 2
OH
HO
O
NH 2
HO
HO
HO
O
OH
O
NH 2
OH
NH 2
OH
H
H H
R
S R
S
R
S
R
R
S
R
S
R S
R
R
R
S
R
S
Paromomycin
3
Substituted OH
With a 4th ring increases activity

Me
NHMe
OHC O
O
O
O
OH
OH
OH
OH
N
H
HO
OH
HO
NH
NH 2
N
H
NH
NH 2
H
H
R S
R
R
S
S
S
S
R
R
S
R
R
S
R
Streptomycin
Streptidine ring

Incompatibilities
With beta-lactams

Faculty of Pharmacy
MedChem 3
Course #: 0201511
3 Credit Hours
Rima Hajjo, MS, PhD
r.hajjo@zuj.edu.jo
Macrolide Antibiotics

Macrolides
Intramolecular ketal formation in
Erythromycin.
Responsible for
basic properties
of macrolides
1
6
9
2
The problem!
Macrocyclic lactone
Aglycone
Glycon
Ø Macrolides are a class of natural and
semisynthetic antibiotics.
Ø For bacterial and fungal infections.
Ø Mechanism of action: inhibit protein
synthesis.
Ø Acid sensitive
12

Mechanism of acid catalyzed intramolecular ketal
formation with Erythromycin
1
6
9
2
Just remember the simple basics:
OH on position 6 will do a
nucleophilic attack on carbonyl
carbon on position 9.
Ketal is inactive! (that’s’ bad)!

Methods for protecting erythromycin from acid
catalyzed ketal formation
1. The hydroxyl groups are changed to
methoxy groups as in clarithromycin
which has improved acid-stability and
oral absorption.
2. Increasing the member atoms of the
macrolide (e.g. 15-membered ring of
azithromycin).
3. Formation of salts with fatty acids

SAR of Macrolides EM: Erythromycin
CAM: Clarithromycin
If R1 is phenyl: carbazate
If R1 is alkyl: carbamate

Erythromycin
ØExample: isolated from Streptomyces erythreus.
ØOne of the safest antibiotics in clinical use.
ØThe structure consists of a 14-membered
macrocyclic lactone ring with a sugar and an amino
sugar attached. The sugar residues are important for
activity.
Ø Erythromycin binds to the 50S subunit of bacterial ribosomes. And, it inhibits
translocation.
Ø Erythromycin & Chloramphenicol bind to the same region of the ribosome, they
shouldn’t be administered together as they will compete with each other and be less
effective.
Ø Erythromycin is unstable to stomach acids but can be taken orally in a tablet form
(coated tablet).
Ø The acid sensitivity is due to the presence of a ketone and 2 alcohol groups which are
set up for the acid-catalyzed intramolecular formation of a ketal.

Chemical Modifications to Increase the Stability of
Macrolide Antibiotics
Ø To prevent ketal formation,
protection of hydroxyl groups was
applied in clarithromycin.
Ø The methoxy analogue is more
stable to gastric juice and has
improved oral absorption.
Ø Another method of increasing acid
stability is to increase the size of
the macrocycle ring.
Ø Azithromycin contains a 15-
membered macrocycle where an N-
methyl group is incorporated into
the macrocycle (Erythromycin has a
14-memebered macrocyclic ring)

The two hydroxyl groups that cause
the intramolecular ketal formation
in erythromycin have been masked,
one as OCH3, and the other as part
of the carbamate ring.
The cladinose sugar in
erythromycin has been
replaced with a keto-group
A carbamate ring has
been fused to the
macrocyclic ring.
Telithromycin
Telithromycin: A semi-synthetic derivative of erythromycin
3
3
6
12
9
v
v
Chemical Modifications to Increase the Stability
of Macrolide Antibiotics

Spectrum of Activity
ØThe macrolides are bacteriostatic antibiotics with a
broad spectrum of activity against many Gram positive
aerobic bacteria (Clarithro > Erythro > Azithro), and
Gram negatives aerobes (Azithro > Clarithro >
Erythro).
ØCurrently available macrolides are well tolerated, orally
available.
ØWidely used to treat mild-to-moderate infections.
ØSeveral macrolidem antibiotics have been linked to liver
injury.

Water Solubility
Ø The free bases of erythromycin and its analogs are moderately soluble in water
Ø Water solubility can be improved by salt formation with some organic acids such
as glucoheptonic and lactobionic acids to be used for parenteral administrations
Ø Water solubility can be decreased if salts are prepared with fatty acids as stearate,
estolate and laurylsulfate salts.
Ø Erythromycin stearate is a very insoluble salt form of erythromycin.
The water insolubility helps:
1) To increase stability toward acids
2) To increase oral absorption
3) To mask bitter taste

Faculty of Pharmacy
MedChem 3
Course #: 0201511
3 Credit Hours
Rima Hajjo, MS, PhD
r.hajjo@zuj.edu.jo
Antibiotics that Impair Protein Synthesis
Ø Lincosamides
Ø Chloramphenicol

Lincosamides - Introduction
Ø The lincosamides contain an unusual 8-carbon sugar, a thiomethyl amino-
octoside (O -thio-lincosamide), linked by an amide bond to an n -propyl
substituted N -methylpyrrolidylcarboxylic acid (N -methyl-n -propyltrans-
hygric acid).
Ø Lincosamides are weakly basic and form clinically useful hydrochloric acid
salts.
Ø They are chemically distinct from the macrolide antibiotics but possess
many pharmacologic similarities to them.
Ø The lincosamides are bacteriostatic, they bind to 50S ribosomal
subparticles at a site partly overlapping with the macrolide site and are
mutually cross-resistant with macrolides and work through essentially the
same molecular mechanism of action.
Ø The lincosamides undergo extensive liver metabolism resulting primarily
in N -demethylation.
Ø The N -desmethyl analog retains biologic activity.

Lincosamides
SN2 Reaction and
inversion of
stereochemistry
Methyl 6,8-dideoxy-6-(1-methyl-
trans-4-propyl-L2-
pyrolidinecarboxamido)-1-thio-D-
erythro-α-D-galactooctopyranoside

Lincomycin (Lincocin)
ØLincomycin is a natural product isolated from fermentations of
Streptomyces lincolnensis.
ØIt is active against gram-positive organisms including some
anaerobes.
ØIt is generally reserved for penicillin-allergic patients due to the
increased risk of pseudomembranous colitis.
ØIt also serves as the starting material for the synthesis of
clindamycin (by an SN-2 reaction that inverts the R
stereochemistry of the C-7 hydroxyl to a C-7 S-chloride).

Clindamycin (Cleocin)
ØThe substitution of the chloride for the
hydroxy group consequently makes
clindamycin more bioactive and lipophilic
than lincomycin, and thus, it is
betterabsorbed following oral administration.
ØIt is about 90% absorbed when taken orally.
ØClindamycin has a clinical spectrum rather
like the macrolides, although it distributes
better into bones.
ØClindamycin works well for gram-positive
coccal infections, especially in patients
allergic to β-lactams, and also has generally
better activity against anaerobes.

Clindamycin – cont.
Ø The most severe of these (black box warning) is pseudomembranous colitis caused
Clostridium difficile, an opportunistic anaerobe. Its overgrowth results from
suppression of the normal flora whose presence otherwise preserves a healthier
ecologic balance. The popularity of clindamycin in the clinic has decreased even
though pseudomembranous colitis is comparatively rare and is also associated with
several other broad-spectrum antibiotics.
Ø A less common side effect is exudative erythema multiform (Stevens-Johnson
syndrome). Clindamycin has excellent activity against Propionibacterium acnes
when applied topically.
Ø A very water-insoluble palmitate hydrochloride prodrug of clindamycin is also
available (lacks bitter taste).
Ø However, as with lincomycin, it is associated with GI complaints (nausea, vomiting,
cramps, and drug-related diarrheas).

Spectrum of Activity
Lincosamideshave an unusual antimicrobial spectrum,
being active against only Gram-positive and not Gram-
negative aerobic bacteria but widely and potently
active against anaerobic bacteria and some protozoa.

Chloramphenicol
Chloramphenicol is an antibiotic useful for the treatment of a number of
bacterial infections:
1) Eye ointment to treat conjunctivitis
2) Orally or by injection into a vein, it is used to treat meningitis, plague,
cholera, and typhoid fever.

Faculty of Pharmacy
MedChem 3
Course #: 0201511
3 Credit Hours
Rima Hajjo, MS, PhD
r.hajjo@zuj.edu.jo
Antibacterial Agents that Impair Protein Synthesis
Ø Tetracyclines and Glycylcyclines

Introduction
Ø Tetracyclines are antibiotcs isolated from Streptomyces aureofaciens (aureo
meaning golden color).
Ø They are broad spectrum, act on Gram-positive, Gram-negative, aerobic and
anerobic bacteria.
Ø most widely prescribed after penicillins.
Ø Bacteriostatic antibiotics.
Ø Inhibit protein synthesis by binding to the 30S subunit of ribosomes and
preventing aminoacyl-tRNA from binding.
Ø They inhibit protein synthesis in bacteria.
Ø Selectivity is due to the ability of bacterial cells to concentrate these agents
faster than human cells.
Ø In the case of Gram-negative bacteria, tetracyclines cross the outer
membrane by passive diffusion through the porins. Passage across the inner
membrane is dependent on a pH gradient, which suggests that a proton-
driven carrier is involved.

Introduction: Tetracyclins in Medical Use

Tetracyclins: General Structure
This family of antibiotics is characterized by a highly functionalized,
partially reduced naphthacene (four linearly fused six-membered rings)
ring system from which both the family name and numbering system are
derived.

Schematic representation of the primary binding site for a tetracycline and the sugar
phosphate groups of 16S rRNA, which also involves a magnesium ion and the critical
functional groups on the “southern” and “eastern” face of the tetracycline.
Mechanism of Action

Chemical Instabilities
I. Acid-catalyzed Instabilities of Tetracyclins
II. Base-catalyzed Instabilities of Tetracyclins
III. Chelation with metals
IV. Phototoxicity

I. Acid-catalyzed Instabilities of Tetracyclinns:
Dehydration
A tertiary and benzylic
hydroxyl group at C6 is
unstable.
This degradation product is toxic to the kidneys and produces a
Fanconi-like syndrome that, in extreme cases, has been fatal
Tetracyclines that have
no C-6-hydroxyl
groups,
such as minocycline
and doxycycline,
cannot undergo
dehydration and thus
are completely free of
this toxicity.
Secondary alcohol on
C6 is more resistant to
dehydration.

II. Base-catalyzed instabilities of Tetracyclins
Inactive lactone-derivative
Active

Metal Chelation
ØChelation is an important feature of the chemical and clinical properties of the
tetracyclines. The acidic functions of the tetracyclines are capable of forming
salts through chelation with metal ions.
ØThe salts of polyvalent metal ions, such as Fe2+, Ca2+, Mg2+, and Al3+, are all
quite insoluble at neutral pHs, insolubility is not only inconvenient for the
preparation of solutions, but also interferes with blood levels on oral
administration.
ØConsequently, the tetracyclines are incompatible with coadministered
multivalent ion-rich antacids, and concomitant consumption of food rich in
calcium (ions are contraindicated 1 hour before or 2 hours after the
tetracyclines).

Tetracyclin-Induced Teeth Discoloration
ØBones and teeth are calcium-rich structures at nearly neutral pHs and
so accumulate tetracyclines in proportion to the amount and duration
of therapy when bones and teeth are being formed. Because the
tetracyclines are yellow, this leads to a progressive and essentially
permanent discoloration in which, in advanced cases, the teeth are
even brown.
ØThis is cosmetically unattractive but does not seem to be deleterious
except in extreme cases where so much antibiotic is taken up that the
structure of bone is mechanically weakened. To avoid this,
tetracyclines are not normally given to children or pregnant women.

The keto-enol tautomerism of ring A at C1 and C3 is a
common feature to all biologically active tetracyclines,
derivatives at C1 and C3 results blocking this system and
loss of antibacterial activity
SAR of Ring A

Ø The amide is best left unsubstituted.
Ø N-monoalkylation results in prodrug which can be
hydrolyzed in vivo to parent compound.
SAR of Ring A

SAR of Ring A
Ø The α-H at C-4a position of is necessary for useful antibacterial activity.
Ø The α-C-4 dimethyl amino substituent supports the keto-enolic character of
the A-ring.
Ø Loss of activity occurs if dimethyl amino group is:
-having reversed stereochemistry
-being replaced with hydrazone (-N-N=C), oxime (-N-OH) or hydroxyl (-OH)
The basic function is the
C-4-a-dimethylamino moiety.

SAR of Ring A
Larger alkyl group àdisturb C1-C2-
C3 tautomerism àreduce
antibacterial activity e.g.
Rolitetracyline is a prodrug which
is more water soluble

SAR of Ring B: C5 and C5a
ØAll natural active tetracyclines have
unsubstituted C5 (i.e. R4=H).
ØAlkylation of the C-5 hydroxyl group (i.e.
R4=CH3) results in loss of activity.
ØSubstitution with C-5 α-hydroxyl group (i.e. R4=OH) give potent compound
(e.g. oxytetracycline).
ØCan be esterified to small alkyl esters to form semisynthetic tetracyclines
which releases oxtetracycline in vivo (prodrug).

SAR: ring C (position C6)
ØThe mostly used ring to prepare semi-synthetic
analogues.
ØUsually, natural tetracyclins have α-methyl group
and α-β-hydroxyl group at this position.
ØThe C6 methyl group contributes little to the activity of tetracycline.
ØThe C6 position is tolerant to a variety of substituents.
ØDemeclocyclin is a naturally occurring C6 α-demethylated Chlortetracycline
with an excellent activity.
ØUnstable in acidic and basic media.

SAR of Ring C: Modifications
at C6
Ø6-Deoxytetracyclines possess important chemical and
pharmacokinetic advantages 6-oxy tetracyclins. More
stable under both acidic and basic media.
Ø Unstable in strongly acidic conditions. Suffers prototropic rearrangement to
the anhydrotetracycline in acid.
Ø Stable in basic media: stable to -ketone cleavage followed by lactonization to
the isotetracycline in base.
ØReduction of the C6 hydroxyl group also dramatically changes the solubility
properties of tetracyclines. This effect is reflected in significantly higher
oil/water partition coefficients of the 6-deoxytetracyclines than of the
tetracyclins.
6

Make a secondary alcohol at
position C6
(Eliminate CH3 at C6)
Eliminate OH group at position C6
Summary: How to Increase the Stability of
Tetracyclins?
Tetracycline
Minocycline

SAR: Lipophilic Tetracyclins (6-deoxy cps.)
ØThe greater lipid solubility of the 6-deoxy compounds (such
as doxycycline and minocycline has important
pharmacokinetic consequences (absorption, distribution and
protein binding).
ØPK properties of Doxycycline and minocycline:
(1) Absorbed more completely following oral administration
(2) Exhibit higher fractions of plasma protein binding
(3) Have higher volumes of distribution and lower renal
clearance rates than the corresponding 6-oxytetracyclins.

SAR of rings C & D: Effect on Half lives (t1/2)
Derivatives have been
synthesized without
6-OH, these agents
were more stable,
lipophilic and long
lasting than those
with 6-OH group.
Long lasting
Longer t1/2

SAR of Ring D and Structure-Toxicity Relationships
ØRing D must be aromatic.
ØC7-Cl causes phototoxicity.
Ø Certain tetracyclines, most notably those with a C7-chlorine,
absorb light in the visible region, leading to free radical
generation and potentially causing severe erythema to
sensitive patients on exposure to strong sunlight.

SAR Rules:
Activity is lost by:
- Double bond between 5a and 11a
- Aromatization of ring C
Ring D must be aromatic

Spectrum of Activity and Clinical Use
ØAntimicrobial spectra of various tetracyclines are similar.
ØThey have the broadest spectrum of activity, on both gram +,
gram – and atypical bacteria.
ØDue to resistance and toxicity, penicillins replaced them in many
infections, especially the respiratory infections.
ØTetracyclines are still used in rickettsia, Chlamydia, mycoplasma
and acne infections.
ØSome of them have antiparasitic properties such as the use of
Doxycycline in the treatment and prophylaxis of malaria.
ØThey have bacteriostatic action, not recommended in life
threatening infections such as septicemia, endocarditis and
meningitis.

Mechanism of Uptake and Resistance to
Tetracyclins

Glycylcyclines
ØThese tetracycline analogues are specifically designed to
overcome two common mechanisms of tetracycline resistance: (1)
resistance mediated by acquired efflux pumps and/or (2)
ribosomal protection.
Ø Glycylcyclines are a class of
antibiotics derived from
tetracycline.
Ø Tigecycline is the only
glycylcycline approved for
antibiotic use.
Ø Broad spectrum including
MRSA.
Tigecycline
9-tert -butylglycylamido
derivative of minocycline.
Glycine

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