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