Urinary Tract Anti-infective Agents – Medicinal Chemistry III B. Pharma 6th Semester

Urinary Tract Anti-infective Agents

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-
important therapeutic class of antimicrobials

       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

Second-, third-, and
fourth-generation quinolones

Therapeutic Classification of Quinolones

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

       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

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

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

       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

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

       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

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

       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

       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

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

       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

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

       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

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

       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

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

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

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

       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)

       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

       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

       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

       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

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

       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

       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

       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

Nitrofurantoin- Synthesis

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