Medicinal Chemistry-III

Urinary Tract Anti-
infective Agents
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Quinolones
• Synthetic substances possessing in common an N-1-alkylated 3-carboxypyrid-4-one
ring fused to another aromatic ring, which itself carries other substituents

• First quinolone to be marketed was nalidixic acid

• Spectrum of activity was limited to a small number of gram

negative organisms

• Quinolones were of little clinical significance until the discovery

that addition of a fluoro group to 6 position of basic nucleus greatly increased the
biologic activity

• Agents that contain the 6-fluoro substitution are referred to as fluoroquinolones-
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Quinolones
• Norfloxacin was approved for use in 1986 and represents the first of the second-
generation quinolones

• Broad spectrum and equivalent in potency to many of the fermentation derived
antibiotics

• Intense research ensued, and over a thousand analogs have now been made

• Ciprofloxacin, gemifloxacin, norfloxacin, ofloxacin, levofloxacin, and moxifloxacin are
currently marketed for systemic use

• In addition, ciprofloxacin, levofloxacin, moxifloxacin, and ofloxacin along with
besifloxacin and gatifloxacin are available for ophthalmic use

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Second-, third-, and fourth-generation quinolones

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Therapeutic Classification of Quinolones

Nalidixic acid
cinoxacin

Norfloxacin
Ciprofloxacin

Levofloxacin,
Gatifloxacin,
Gemifloxacin

Moxifloxacin
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Mechanism of action
• 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

• Using the energy generated by adenosine triphosphate (ATP) hydrolysis, DNA
progressively wound about itself in a positive supercoil

• In the absence of ATP, the process is reversed, relaxing the molecule

• DNA gyrase alters the conformation of DNA by catalyzing transient double-strand
cuts, passing the uncut portion of the molecule through the gap, and resealing the
molecule back together

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Mechanism of action
• DNA topoisomerase IV- unties enchained daughter DNA molecules produced through
replication of circular DNA

• Inhibition of DNA gyrase and topoisomerase IV makes a cell’s DNA inaccessible and
leads to cell death

• Different quinolones inhibit these essential enzymes to different extents

• Topoisomerase IV seems more important to some gram-positive organisms

• DNA gyrase seems more important to some gram-negative organisms

• Humans shape their DNA with topoisomerase II, an analogous enzyme to DNA gyrase

• Quinolones doesn’t bind at normally achievable doses and do not kill host cells
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Nalidixic Acid
• Pale buff crystalline powder that is sparingly soluble in water and ether, but soluble
in most polar organic solvents

• Useful in the treatment of urinary tract infections in which Gram-negative bacteria
predominate

• Particularly active against indole-positive Proteus spp. is

• Rapidly absorbed, extensively metabolized, and

rapidly excreted after oral administration

• 7-hydroxymethyl metabolite is significantly more active than the parent compound

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Norfloxacin
• Pale yellow crystalline powder that is sparingly soluble in water

• Has broad-spectrum activity against Gram-negative and Gram-positive aerobic
bacteria

• Fluorine atom provides increased potency against Gram-positive organisms

• Piperazine moiety improves antipseudomonal activity

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Norfloxacin
• Indicated for the treatment of urinary tract infections caused by E. coli, K.
pneumoniae, Enterobacter cloacae, Proteus mirabilis, indole-positive Proteus spp.,
including P. vulgaris, Providencia rettgeri, Morganella morganii, P. aeruginosa, S.
aureus, and S. epidermidis, and group-D streptococci

• Generally not effective against obligate anaerobic bacteria

• Oral absorption of norfloxacin is about 40%, 15% protein bound and is metabolized
in the liver

• Significant biliary excretion, with about 30% of the original drug appearing in the
feces

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Enoxacin
• Broad-spectrum antibacterial activity

• Used primarily for the treatment of urinary tract infections and sexually transmitted
diseases

• Approved for the treatment of uncomplicated gonococcal urethritis and has also
been shown to be effective in chancroid caused by Haemophilus ducreyi

• Also approved for the treatment of acute (uncomplicated) and chronic (complicated)
urinary tract infections

• Oral bioavailability approaches 98%

• More than 50% of the unchanged drug is excreted in the urine

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Enoxacin
• Relatively short elimination half-life of enoxacin dictates twice-a-day dosing

• Has been reported to decrease theophylline clearance, causing increased plasma
levels and increased toxicity

• Forms insoluble chelates with divalent metal ions present in antacids and hematinics,
which reduce its oral bioavailability

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Ciprofloxacin
• Higher potency against most Gram-negative bacterial species, including P.
aeruginosa, than other quinolones

• Ciprofloxacin is widely distributed to virtually all parts of the body, including the CSF

• Agent of choice for the treatment of bacterial gastroenteritis caused by Gram-
negative bacilli such as enteropathogenic E. coli, Salmonella spp. (including S. typhi),
Shigella spp., Vibrio spp., and Aeromonas hydrophilia

• It is widely used for the treatment of respiratory tract infections and is particularly
effective for controlling bronchitis and pneumonia caused by Gram-negative bacteria

• Also used for combating infections of the skin, soft tissues, bones, and joints

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Ciprofloxacin
• Both uncomplicated and complicated urinary tract infections caused by Gram-
negative bacteria can be treated effectively

• Particularly useful for the control of chronic infections characterized by renal tissue
involvement

• Has important applications in controlling venereal diseases

• A combination of ciprofloxacin with the cephalosporin antibiotic ceftriaxone is
recommended as the treatment of choice for disseminated gonorrhea

• Single-dose treatment with ciprofloxacin plus doxycycline, a tetracycline antibiotic,
can usually eradicate gonococcal urethritis

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Ciprofloxacin
• Has also been used for chancroid

• Approved for postexposure treatment of inhalational anthrax

• Injectable forms of ciprofloxacin are incompatible with drug solutions that are
alkaline because of the reduced solubility of the drug at pH 7

• May also induce crystalluria under the unusual circumstance that urinary pH above 7

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Ofloxacin
• Quinolone class of antibacterial drugs wherein the 1- and 8-positions are joined in
the form of a 1,4-oxazine ring

• Resembles ciprofloxacin in its antibacterial spectrum and potency

• Has been approved for the treatment of infections of the lower respiratory tract,
including chronic bronchitis and pneumonia, caused by Gram-negative bacilli

• Used for the treatment of pelvic inflammatory disease and is highly active against
both gonococci and chlamydia

• Not effective in the treatment of syphilis

• A single 400-mg oral dose of ofloxacin in combination with the tetracycline antibiotic
doxycycline for the outpatient treatment of acute gonococcal urethritis
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Ofloxacin
• Used for the treatment of urinary tract infections caused by Gram-negative bacilli
and for prostatitis caused by E. coli

• Infections of the skin and soft tissues caused by staphylococci, streptococci, and
Gram-negative bacilli may also be treated

• Has an asymmetric carbon atom in its structure, it is obtained and supplied
commercially as a Racemate

• 3S(–) isomer is substantially more active (8–125 times, depending on the bacterial
species) than the 3R(+) isomer and has recently been marketed as levofloxacin
(Levaquin) for the same indications as the racemate

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Ofloxacin

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Lomefloxacin
• Difluorinated quinolone with a longer elimination half-life (7–8 hours)

• Only quinolone for which once-daily oral dosing suffices

• Food slows, but does not prevent, its oral absorption

• Extent of biotransformation of lomefloxacin is only about 5%

• High concentrations of unchanged drug, ranging from 60%- 80%, excreted in urine

• Has been approved for two primary indications

• First, acute bacterial exacerbations of chronic bronchitis caused by H. influenzae or
Moraxella (Branhamella) catarrhalis, but not if Streptococcus pneumonia is the
causative organism

• Second, it is used for prophylaxis of infection following transurethral surgery
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Lomefloxacin
• Treatment of acute cystitis and chronic urinary tract infections caused by Gram-
negative bacilli

• Causes the highest incidence of phototoxicity (photosensitivity) of the currently
available quinolones

• Presence of a halogen atom (fluorine, in this case) at the 8-position has been
correlated with an increased chance of phototoxicity in the quinolones

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Sparfloxacin
• Exhibits higher potency against Grampositive bacteria, especially staphylococci and
streptococci, than the fluoroquinolones currently marketed

• More active against chlamydia and the anaerobe Bacteroides fragilis

• Activity of sparfloxacin against Gram-negative bacteria is also very impressive, and it
compares favorably with ciprofloxacin and ofloxacin in potency against Mycoplasma
spp., Legionella spp., Mycobacteria spp., and Listeria monocytogenes

• Has a long elimination half-life of 18 hours, which permits once-a-day dosing

• Recommended for the treatment of bacterial gastroenteritis and cholecystitis

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Sparfloxacin
• Incidence of phototoxicity of sparfloxacin is the lowest of the fluoroquinolones,
because of the presence of the 5-amino group, which counteracts the effect of the 8-
fluoro substituent

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Gatifloxacin

• Substitution of a methoxy group at C-8 reduces the photosensitivity

• Used in the treatment of bacterial exacerbation of chronic bronchitis and
community-acquired pneumonia

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Moxifloxacin
• Substitution of a methoxy group at C-8 reduces the photosensitivity

• Pyrrolidinyl ring represent the most signify cant antimicrobial improvement

• Have a spectrum of activity that includes Bacteroides fragilis

• Also recommended as second-line agents for tuberculosis as an off-label use

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SAR of Quinolones
• Structural features of the quinolones strongly influence the antimicrobial and
pharmacokinetic properties of this class of drugs

• Essential pharmacophore for activity is the carboxy-4-pyridone nucleus

• Apparently, the carboxylic
acid and the ketone are
involved in binding to the
DNA/DNA-gyrase enzyme
system

• Reduction of the 2,3-double bond or the 4-keto group inactivates the molecule
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SAR of Quinolones
• Substitution at C-2 interferes with enzyme–substrate complexation

• Fluoro substitution at the C-6 position greatly improves antimicrobial activity by
increasing the lipophilicity of the molecule

• Also improves the drug’s penetration through the bacterial cell wall

• C-6 fluoro also increases the DNA gyrase/topoisomerase IV inhibitory action

• An additional fl uoro group at C-8 further improves drug absorption and half-life, but
also increases drug-induced photosensitivity

• Substitution of a methoxy group at C-8 reduces the photosensitivity

• (moxifloxacin and gatifloxacin)
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SAR of Quinolones
• Heterocyclic substitution at C-7 improves the spectrum of activity especially against
gramnegative organisms

• Piperazinyl (ciprofloxacin) and pyrrolidinyl (moxifloxacin) represent the most
significant antimicrobial improvement

• Unfortunately, piperazinyl group at C-7 also increases binding to CNS γ-aminobutyric
acid (GABA) receptors, which accounts for CNS side effects

• Alkyl substitution on the piperazine nitrogen (ofloxacin and

• levofloxacin) is reported to decrease binding to GABA

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SAR of Quinolones
• Cyclopropyl substitution at N-1 appears to broaden activity of the quinolones to
include activity against atypical bacteria including Mycoplasma, Chlamydia, and
Legionella species

• Substitution of a 2,4-difluorophenyl at N-1 also improves antimicrobial potency, but
agents with this substitution (trovafloxacin and temafloxacin) have been withdrawn
from the market due to serious adverse effects

• Introduction of a third ring to the nucleus of the

quinolones gives rise to ofloxacin

• Additionally, ofloxacin has an asymmetric carbon at the C-3′ position

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SAR of Quinolones
• S -(−)-isomer (levofloxacin) is twice as active as ofloxacin and 8 to 128 times more
potent than the R-(+)-isomer resulting from increased binding to the DNA gyrase

• A chemical incompatibility common to all of the quinolones involves the ability of
these drugs to chelate polyvalent metal ions (Ca2+, Mg2+, Zn2+, Fe2+, Al3+)

• Resulting in decreased solubility and reduced drug absorption

• Chelation occurs between the metal and the 3-carboxylic acid and 4-keto groups

• Agents containing polyvalent metals should be administered separately from the
quinolones Miscellaneous
• Nitrofurans- first nitroheterocyclic compounds to be introduced into chemotherapy

• Three of these compounds- Nitrofurazone, furazolidone, and nitrofurantoin

• Have been used for the treatment of bacterial infections of various kinds for nearly
50 years

• A fourth nitrofuran, nifurtimox, is used as an antiprotozoal agent to treat
trypanosomiasis and leishmaniasis

• Another nitroheterocyclic of considerable importance is metronidazole, which is an
amebicide (a trichomonicide) and is used for the treatment of systemic infections
caused by anaerobic bacteria

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Nitrofurans

• Derivatives of 5-nitro-2-furaldehyde, formed on reaction
with the appropriate hydrazine or amine derivative

• Antimicrobial activity is present only when the nitro group
is in the 5-position

• Mechanism of antimicrobial action- not fully understood

• Known to be mutagenic and carcinogenic under certain
conditions

• It is thought that DNA damage caused by metabolic
reaction products may be involved in these cellular effects
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Furazolidine
• Yellow crystalline powder with a bitter after taste

• It is insoluble in water or alcohol

• Has bactericidal activity against a relatively broad range of intestinal pathogens,
including S. aureus, E. coli, Salmonella, Shigella, Proteus spp., Enterobacter, and
Vibrio cholera

• It is also active against the protozoan Giardia lamblia

• It is recommended for the oral treatment of bacterial or protozoal diarrhea caused
by susceptible organisms

• Only a small fraction of an orally administered dose of furazolidone is absorbed
Furazolidine
• Approximately 5% of the oral dose is detectable in the urine in the form of several
metabolites

• Some gastrointestinal distress has been reported with its use

• Alcohol should be avoided when furazolidone is being used because the drug can
inhibit aldehyde dehydrogenase

Nitrofurantoin
• Nitrofuran derivative that is suitable for oral use

• It is recommended for the treatment of urinary tract infections caused by susceptible
strains of E. coli, enterococci, S. aureus, Klebsiella, Enterobacter, and Proteus spp

• Most common side effects are gastrointestinal- anorexia, nausea, and vomiting

• Hypersensitivity reactions- pneumonitis, rashes, hepatitis, and hemolytic anemia
have occasionally been observed

Methenamine
• Activity of hexamethylenetetramine depends on the liberation of formaldehyde

• Compound is prepared by evaporating a solution of formaldehyde and strong
ammonia water to dryness

• Free base exists as odorless, white crystalline powder that sublimes at about 260°C

• It dissolves in water to form an alkaline solution and liberates formaldehyde when
warmed with mineral acids

• Weak base with a pKa of 4.9
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Methenamine

• Used internally as a urinary antiseptic for the treatment of chronic urinary tract
infections

• Free base has practically no bacteriostatic power

• Formaldehyde release at the lower pH of the kidney is required

• To optimize the antibacterial effect, an acidifying agent such as sodium biphosphate
or ammonium chloride generally accompanies the administration of methenamine

• Certain bacterial strains are resistant to the action of methenamine because they
liberate urease, an enzyme that hydrolyzes urea to form ammonia

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Methenamine

• Resultant high urinary pH prevents the activation of methenamine, rendering it
ineffective

• This problem can be overcome by the co-administration of the urease inhibitor
acetohydroxamic acid Ciprofloxacin- Synthesis

3-chloro-4-fluoroaniline ethyl ethoxymethylenmalonate

Nitrofurantoin- Synthesis

heating

potassium cyclization
hydrazine Chloroacetic acid hydrazinoacetic acid cyanate Semicarbazidoacetic acid diacetylacetal of 5-nitrofurfurol

1-aminoidantoin
Nitrofurantoin