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Synthetic antimicrobial agents
 Synthetic antimicrobial agents have not been modeled after
any natural product so they may not properly be called
"antibiotics."
 Some synthetics are extremely effective for treatment of
infections and are widely used.
 They are all effective against key enzymes needed for the
biosynthesis of nucleic acids.
 Because they interrupt the biosynthesis of nucleic acids
rather than attacking the finished products or substituting for
them in nucleic acids they are not genotoxic but are
comparatively safe to use.
A- Sulfonamides
 Sulfonamides were discovered in the mid 1930s following
examination of the Prontosoil rubrum dye.
 It
was
found
that;
the
active
substance
is
p-
aminobenzenesulfonic acid amide (sulfanilamid), formed by
reductive liver metabolism of the administered dye i.e.
prontosil rubrum is a pro-drug.
Sulphonamides
General Method of Synthesis
O
H
N
NH2 (CH3CO)2O
CH3 ClSO3H
H
N
H3C
S
Cl
O
O
O
O
H
N
H3C
NH3
S
O
O
O
NH2
S
H2N
O
NH2
Sulphonamides
General Method of Synthesis
O
H
N
CH3 ClSO3H
H
N
H3C
S
Cl
O
O
O
O
H
N
H3C
RH2N
S
O
O
O
S
NH-R
NaoH
H2N
O NH-R
Mechanism of Action
 Sulfonamides are bacteriosiatic, they inhibit the enzyme
dihydropteroate synthase needed for the biosynthesis of folic
acid derivatives and. ultimately, DNA, How?
 They do this by competing at the active site with paminobenzoic
acid
(PABA)
which
incorporated
into
the
developing tetrahydrofolic acid molecule by condensation
with a dihydropteroate diphosphate precursor under the
influence of dihydropteroate synthetase.
Mechanism of Action
Mechanism of Action
 Thus sulfonamides may be classified as antimetabolites
 Most susceptible bacteria are unable to take up preformed
folic acid from their environment and convert it to a
tetrahydrofolic acid but, instead, synthesize their own folates
de novo.
 As folates are essential intermediates for the preparation of
certain DNA bases, without which bacteria cannot multiply,
this inhibition is strongly bacteriostatic.
 Humans are unable to synthesize folates from component
parts,
lacking
the
necessary
enzymes
(including
dihydropteroale synthase), and folic acid is consumed as a
dietary so sulfonamides have no lethal effect upon human cell
growth.
Mechanism of Action
In a few strains of bacteria,
o
sulfonamides are attached to the dihydropteroate diphosphate in the
place of the normal PABA giving false metabolite which is not capable
of undergoing condensation with glutamic acid and inhibit the enzyme
and the net result is inability of the bacteria to multiply as soon as the
preformed folic acid in their cells is used up and further nucleic acid
biosynthesis becomes impossible.
o
Bacteria which are able to take up preformed folic acid into their cells
are resistant to sulfonamides.
Structure-activity Relationships
 The
strongly
electron
withdrawing
character
of
the
aromaticSO2 group makes the nitrogen atom to which it is
directly attached partially electropositive, thus increasing the
acidity of the hydrogen atoms attached to the nitrogen so that
this functional group is slightly acidic
 Replacement of one of the NH2 hydrogen by an electron
withdrawing heteroaromatic ring was not only consistent with
antimicrobial activity but also greatly acidified the remaining
hydrogen
and
dramatically
enhanced
potency
and
dramatically increases the water solubility under physiologic
conditions.
 The poor water solubility of the earliest sulfonamides led to
occasional
crystallization
in the urine
(crystalluria)
and
resulted in kidney damage because the molecules were
unionized at urine pH values.
Structure-activity Relationships
Therapeutic Applications
Sulfisoxazole and its pro-drug acetyl sulfisoxazole
 Its clinical use is restricted to the treatment of the primary
uncomplicated urinary tract infections.
 Sulfisoxazole is well absorbed following oral administration
distributes widely and is excreted by the kidneys.
Therapeutic Applications
 Sulfonamides are deactivated by acetylation at N-4 and
glucuronation of the aniline nitrogen in the liver.
 Allergic reactions are the most common and take the form of
rash, photosensitivity and drug fever.
 The most severe side effect is the Stevens-Johnson syndrome
characterized by sometimes-fatal erythrema multiforme and
ulceration of mucous membranes of the eye, mouth and
urethra.
Therapeutic Applications
o Other sulfonamides still in use
sulfamethizole and sulfamethoxazole.
include
sulfadiazine,
Therapeutic Applications
o Multiple
(or
triple)
sulfas
are
a
1:1:1
combination
of
sulfabenzamide, sulfacetamide and sulfathiazole which used
as a cream for carderella vaginalis vaginal infection
Therapeutic Applications
o Sulfasalazine is a pro-drug given orally and is largely not
absorbed in the gut so the majority of the dose is delivered to
the distal bowel where reductive metabolism by gut bacteria
converts the drug to sulphapyridine and 5-aminosaliclic acid
(Mesalamine).
Therapeutic Applications
o The liberation mesalamine, an anti-inflammatory agent, is the
purpose for administering this drug. This agent is used to
treat
ulcerative
colitis
and
Crohns
disease.
Direct
ad-
ministration of salicylates is otherwise irritating to the gastric
mucosa.
Mechanism of Action
 Trimethoprim inhibits the dihydrofolate reductase required for
reduction of the exogenous folic acid stepwise to dihydrofolic
acid and then to tetrahydrofolic acid an important cofactor
essential for purine biosynthesis and ultimately for DNA
synthesis.
 Endogenous produced dihydrofolate must also reduced by the
same enzyme to enter the pathway involved in DNA synthesis.
 The bacterial enzyme and the mammalian enzyme both
efficiently catalyze the conversion of dihydrofolic acid to
tetrahydrofolic acid, but the bacterial enzyme is sensitive to
inhibition by trimethoprim by up to 40,000 times lower
concentrations than is the mammalian enzyme.
 This difference explains the useful selective toxicity of
trimethoprim
Trimethopim
5-[3,4,5-Trimethoxhyphenyl)methyl]-2,4-pyrimidinediamine
H3CO
H2N
N
H3CO
NH2
N
H3CO
Synthesis
H3CO
H3CO
O
H3CO
H
+
CN
CN
C2H5O
H3CO
CH2OC2H5
H3CO
H3CO
H2N
H3CO
NH
H3CO
NH
H2N
H2N
N
H3CO
H3CO
NH
N
H
H3CO
NH2
N
NH
H3CO
Mechanism of Action
Therapeutic Application
 Trimethoprim is used as a single agent for the oral treatment
of
uncomplicated
urinary
tract
infections
caused
by
with
the
susceptible bacteria
 Most
commonly
used
in
1:5
fixed
ratio
sulfamethoxazole (Bactrim, Septra).
 This combination is not only synergistic but is less likely to
induce bacterial resistance than either agent alone.
 These agents block sequentially at two different steps in the
same essential pathway, and this combination is extremely
difficult for a naive microorganism to survive.
 Combined with sulfamethoxazole, it is used for oral treatment
of urinary tract infections, shigellosis, otitis media, traveler's
diarrhea, and bronchitis.
 The most frequent side effects of are rush, nausea and
vomiting.
Quinolones
 The quinolone antimicrobials comprise a group of synthetic
substances possessing in common an N-1-alkylated 3-carboxy
pyrid-4-one ring fused to another aromatic ring, which itself
carries other substituents.
 Nalidixic acid and cinoxacin are classified as first generation
quinolones
based
on
their
spectrum
of
activity
and
pharmacokinetic properiteis.
 They are considered minor urinary tract disinfectants that are
primarily effective against Gram (-ve) bacteria.
Quinolones
 Quinolones were of little clinical significance until the
discovery that the addition of a fluoro group at the 6-position
of the basic nucleus greatly increased the biological activity.
 Norfloxacin, the first of the second generation quinolones,
has a broad spectrum of activity and equivalent in potency to
many of the fermentation compounds.
Quinolones
 Following Norfloxacin introduction, more than a thousand
second-,
third-,
and
fourth
generation
analogues
have
introduced.
 They
include
ofloxacin,
alatrofloxacin,
levofloxacin,
norfloxacin, etc.
norfloxacin,
sparofloxacin,
ciprofloxacin,
trovofloxacin,
O
F
Ciprofloxacin
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo7-(1-piperazinyl)-3-quinolinecarboxylic
acid
COOH
N
N
HN
Synthesis
O
O
F
F
COOC2H5
O
F
COOC2H5
CH OC2H5
NH2
F
F
F
OC2H5
O
O
F
COOC2H5
F
COOC2H5 HN
Cyclization
F
F
N
H
F
O
F
N
HN
COOH
N
NH
hydrolysis
N
Quinolones
Mechanism of Action
 The quinolones are rapidly bactericidal largely as a consequence of inhibition of DNA gyrase and topoisomerase IV
key bacterial enzymes that dictate the conformation of DNA
so that it can be stored properly, unwound, replicated,
repaired, and transcribed on demand.
 Inhibition of DNA gyrase and topoisomerase I+V makes a
cell’s DNA inaccessible and leads to cell death.
 Humans shape their DNA with a topoisomerase II which does
not bind quinolones at normally achievable doses so the
quinolones do not kill host cells
Structure-Activity relationship
 The carboxy-4-pyridone nucleus is essential for activity
 The carboxylic acid and the ketone are involved in binding to the
DNA/DNA-gyrase enzyme system.
 Reduction of the 2,3-doublc bond or the 4-keto group inactivates the
molecule, and substitution at C-2 interferes with enzyme-substrate
complexation.
 Fluoro substitution at the C-6 greatly improves antimicrobial activity
by increasing the lipophilicity of the molecule, which in turn improves
the drugs penetration through the bacterial cell wall. Additionally, C-6
fluoro increases the DNA gyrase inhibitory action
Structure-Activity relationship
 Alkyl substitution on the piperazine (lomefloxacin and ofloxacin)
decrease binding to GABA, as does the addition of bulky groups at the
N-1 position (sparfloxacin).
 The cyclopropyl substitution at N-l broads activity of the quinolones
to include activity against atypical bacteria.
 The introduction of a third ring to the quinolones nucleus gives rise to
ofloxacin which has an asymmetric carbon at the C-3 position. The S(-)-isomer (levofloxacin) is twice as active as ofloxacin and 8- to 128fold more potent than the R(+)-isomer resulting from increased
binding to the DNA-gyrase.
Structure-Activity relationship
 Several of the quinolones produce mild to severe photosensitivity.
 A C-8 halogen appears to produce the highest incidence of
photosensitivity via singlet oxygen and radical induction.
 Lomefloxacin has been reported to have the highest potential for
producing phototoxicity.
 Substitution of a methoxy group at: C-8 has been reported to reduce
the photosensitivity (gatilfoxacin).
Chemical Incompatabilities
 The quinolones chelate polyvalent metal ions (Ca2+ Mg+2, Al+3, and
Fe+2)
to
form
less
water-soluble
complexes
and
thereby
lose
considerable potency.
 Thus co-administration of certain antacids, hematinics, tonics and
consumption of dairy products soon after quinolone administration is
contraindicated
Side Effects
 Among the toxicities associated with quinolones is a proconvulsant action, especially in epileptics which mainly
associated with the first generation agents.
 Other CNS problems include hallucinations, insomnia, visual
disturbances.
 Some patients also experience diarrhea, vomiting, abdominal
pain and anorexia.
 Fluoroquinolones drugs are generally much better tolerated.
Therapeutic Applications
 The second-generation quinolones are more widely used than
the first.
 Norfloxacin is mainly used for urinary tract infections
 The others, particularly ciprofloxacin, are also used for
prostatitis, upper respiratory tract infections, bone infections,
septicemia, staphylococcal and pseudomonal endocarditis,
meningitis,
sexually
transmitted
diseases
chronic
ear
infections, and purulent osteoarthritis.
 Lomefloxacin is used once daily for urinary tract and upper
respiratory
tract
microorganisms
infections
due
to
susceptible
Metronidazole
 Initially introduced for the treatment of vaginal infection caused by
amoeba, it is also useful for the treatment of trichomoniasis,
giardiasis and Gardnerella vaginalis infections.
 Metronidazole is also a component of a multidrug cocktail used to
treat Helicobacter pylori infections associated with gastric ulcers.
 Metronidazole use is associated with allergic rashes and CNS
disturbances, including convulsions in some patients.
Nitrofurans (e.g. Nitrofurantoin)
 Nitrofurantoin a widely used oral antibacterial for prophylaxis or
treatment of urinary tract infections when kidney function is not
impaired, and it inhibits kidney stone growth.
 Nausea and vomiting are common side effects. This is avoided in part
by slowing the rate of absorption of the drug through use of wax-
coated large particles (Macrodantin).
 Nitrofurantoin inhibits DNA and RNA functions
Methenamine
 A venerable drug used for the disinfection of acidic urine
 Structurally methenamine is a low molecular weight polymer of
ammonia and formaldehyde which reverts to its components under
mildly acid conditions.
 Formaldehyde is the active antimicrobial component.
 Methenamine is used for recurrent urinary tract infections
Phosphomycin
 Phosphomycin inhibits enolpyruvial transferase (an enzyme catalyzing
an early step in bacterial cell wall biosynthesis) resulting in reduced
synthesis of peptidoglycan an important component in the bacterial
cell wall.
 Phosphomycin is bactericidal against E. coli infections.
Dapsone (DDS)
Mechanism of Action
 Dapsone, a bacteriostatic agent, act through competitive
inhibition of p-aminobenzoic acid incorporation into folic acid
,it is used for treatment of leprosy.
Dapsone (DDS)
Structure-activity Relationship
 Isosteric replacement of one benzene ring resulted in the
formation of thiazolsulfone. Although still active, it is less
effective than DDS.
 Substitution on the aromatic ring, to produce acetosulfone,
reduces activity while increasing water solubility and
decreasing GI irritation.
Dapsone (DDS)
Structure-activity Relationship
 Adding methanesulfinate to DDS to give the water soluble
sulfoxone sodium which is hydrolyzed in vivo to produce DDS.
 Sulfoxone sodium is used in individuals who are unable to
tolerate DDS due to GI irritation, but it must be used in a dose
three times that of DDS because of inefficient metabolism to
DDS.
Dapsone (DDS)
Metabolism
 The major metabolic product of DDS results from Nacetylation in the liver by N-acetyltransferase