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

Urinary Tract Anti-infective Agents


       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


       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


       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


       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


       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


       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


       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


       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


       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



       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


       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


       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


       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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