Quinolones:Thequinolonescompriseaseriesofsyntheticantibacterialagentspatternedafternalidixicacid,anaphthyridinederivativeintroducedforthetreatmentofurinarytractinfectionsin1963.

1. QUINOLONES AND FLUOROQUINOLONES
Series of Synthetic Antibacterial Agents
Dr. Aejaz Ahmed
HOD & Associate Professor
Department of Pharmaceutical Chemistry
ALI-ALLANA COLLEGE OF PHARMACY, AKKALKUWA
MEDICINAL CHEMISTRY –III
Unit III
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2. Introductions: Quinolones are potent, broad-spectrum
antibacterial agents. Several organic compounds obtained by
chemical synthesis on the basis of model compounds have useful
antibacterial activity for the treatment of local, systemic, and/or
urinary tract infections
Quinolones: The quinolones comprise a series of synthetic
antibacterial agents patterned after nalidixic acid, a naphthyridine
derivative introduced for the treatment of urinary tract infections in
1963.
2

3. Classification of Quinolones
Isosteric heterocyclic groupings in this class include the
• The Naphthyridines (e.g., Nalidixic acid, enoxacin), and the cinnolines
(e.g., cinoxacin).
• Quinolones & Fluoroquinolones examples : Norfloxacin, Ciprofloxacin,
ofloxacin, Levofloxacin, Lomefloxacine, Moxifloxacin, Gatifloxacine,
Sparfloxacine, Pefloxacine, Balofloxacine,
Up to the present time, the clinical usefulness of the quinolones has been
largely confined to the treatment of urinary tract infections. good oral
absorption, activity against common Gram-negative urinary pathogens, and
comparatively higher urinary (compared with plasma and tissue)
concentrations are the key useful properties. 3

4. The key features Includes…….
• Extensive structure–activity investigations leading to compounds
with
•Enhanced potency,
•Extended spectrum of activity, and
•Improved absorption and distribution properties.
•The class has evolved to the point that certain newer members
are useful for the treatment of various serious systemic infections.
In fact, these more potent analogs are sometimes classified
separately (from the urinary tract-specific agents) as the
fluoroquinolones, because all members of the group have a 6-fluoro
substituent in common at 6 positions. 4

5. Generation Drug Names Spectrum
1st
Nalidixic Acid
Cinoxacin
Gram- but not Pseudomonas
species
2nd
Norfloxacin
Ciprofloxacin
Enoxacin
Ofloxacin
Gram- (including Pseudomonas
species), some Gram+ (S.
aureus) and some atypicals
3rd
Levofloxacin
Sparfloxacin
Moxifloxacin
Gemifloxacin
Same as 2nd generation with
extended Gram+ and atypical
coverage
4th
*Trovafloxacin
Balofloxacine
Same as 3rd generation with
broad anaerobic coverage
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6. Mechanism of Action
All the quinolones and fluroquinoones are having similar Mode of action
• Bactericidal. Inhibit DNA gyrase (topoisomerase II).Inhibition of
topoisomerase IV (newer FQ’s).
• DNA gyrase is the primary target. It is responsible for the
continuous introduction of negative supercoils into DNA. This is an
ATP-dependent enzyme requiring that both strands of the DNA be
cut to permit passage of a segment of DNA thru a break, which is
then resealed.
6

7. Inhibit DNA gyrase (topoisomerase II).
Inhibition of topoisomerase IV (newer FQ’s). 7

8. STRUCTURES OF FLUOROQUINOLONES
1. Substituent at N-1 position: A compilation of active
N-1 quinolone substituents is shown below with
an emphasis on overall in vitro potency
2. The simple replacement of C-2 hydrogen has generally to be disadvantageous - e.g., C-2
methyl or hydroxyl groups. However, some derivatives containing a suitable C-1, C-2 ring
have been shown to possess notable activity.
3. Without doubt, the C-3 carboxylic acid moiety is most commonly encountered. Other acidic
groups such as sulphonic acid, phosphonic acid, tetrazole, as well as derivatization as an
ester results in a loss of antibacterial activity.
4. The C-4-oxo group of the quinolone nucleus appears to be essential for antibacterial
activity. Replacement with 4-thioxo or sulphonyl group leads to a loss of activity.
5. The incorporation of an amino group at the C-5 position has proven beneficial in terms of
antibacterial activity. The order of activity at R5: NH2, CH3 > F, H > OH, OR, SH, SR.
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9. 7. A hydrogen atom at the C-8 or a nitrogen atom (a naphthyridone) is the most common. In
general, a C-8 fluoro substituent offers good potency against gramnegative pathogens, while
a C-8 methoxy moiety is active against gram-positive bacteria.
8. The order of activity at R8: F, Cl, OCH3 > H, CF3 > methyl, vinyl, propargyl.
9. A halogen (F or Cl) at the 8- position improves oral absorption.
10. The joining of N1-group to the C-8 position with oxazine ring leads to active ofloxacin.
6. The incorporation of a fluorine atom at the C-6 position of the quinolone is monumental
The order of activity at R6: F > Cl, Br, CH3 > CN. 7. The introduction of a piperazine moiety at
C-7 was a landmark development. Other aminopyrrolidines also are compatible for activity.
R 1 = N1
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10. 10

11. USES: Fluoroquinolones are used to treat upper and lower respiratory
infections, gonorrhoea, bacterial gastroenteritis, skin and soft tissue
infections, urinary tract infections, and bone and joint infections, and against
tuberculosis. 11

12. • Parent drug: Nalidixic acid
• Nalidixic acid is useful in the treatment of urinary tract infections in which Gram-
negative bacteria predominate.
• The activity against indole-positive Proteus spp. is particularly noteworthy, and
nalidixic acid and its congeners represent important alternatives for the treatment of
urinary tract infections caused by strains of these bacteria resistant to other agents.
1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-
carboxylic acid
• Nalidixic acid possesses a t1/2 Time of 6 to 7 hours. It is eliminated, in part,
unchanged in the urine and 80% as metabolites.
• The 7-hydroxymethyl metabolite is significantly more active than the parent
compound.
12

13. Norfloxacine
• 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
quinolinecarboxylic acid
• This quinoline has broad-spectrum activity against Gram-negative and Gram-
positive aerobic bacteria. The fluorine atom provides increased potency against
Gram-positive organisms, whereas the piperazine moiety improves antipseudomonal
activity.
• Norfloxacin is 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.
• It is generally not effective against obligate anaerobic bacteria.
•Norfloxacin in a single 800-mg oral dose has also been approved for the treatment
of uncomplicated gonorrhea. The oral absorption of norfloxacin is about 40%.
•The drug is 15% protein bound and is metabolized in the liver. The t1/2elim is 4 to 8
hours. Approximately 30% of a dose is eliminated in the urine and feces. 13

14. Ciprofloxacin
• Administration [Usual Dosage]: IV, PO [500 – 750 mg q 8-12h]
• Spectrum: Gram- aerobic rods, and Legionella pneumophila, and other atypicals. Poor
activity against Strep. pneumoniae.
• Indications:
-- Nosocomial pneumonia
-- Intra-abdominal infections
– Uncomplicated/complicated UTI
– Anthrax exposure and prophylaxis
• Unique Qualities:
– Binds divalent cations (i.e. Ca & Mg) which decreases absorption
-- Increased effects of warfarin
• ADRs
– QTC prolongation, torsades de pointes, arrhythmias
– Nausea, GI upset
– Interstitial nephritis
1-Cyclopropyl0-6-fluoro-1,4-dihydro-4-oxo-7-(1-
piperazinyl)-3-quinolinecarboxylicacid
14

15. Levofloxacin
• Spectrum: Gram-, Gram+ (S. aureus including MRSA & S. pneumoniae) and Legionella
pneumophila, atypical resp. pathogens,
Mycobacterium tuberculosis
• Indications:
--Chronic bronchitis and CAP ---- Nosocomial pneumonia
--SSTIs ---Intra-abdominal infections
• Unique Qualities:
– Binds divalent cations (i.e. Ca & Mg) which decreases absorption
ADRs
– Blood glucose disturbances in DM patients
– QTC prolongation, torsades de pointes, arrhythmias
– Nausea, GI upset
– Interstitial nephritis
Sparfloxacin, (cis)-5-amino-1-cyclopropyl-7-(3,5-
dimethyl)- 1-piperazinyl)-6,8-difluoro-1,4-dihydro-
4-oxo-3-quinolinecarboxylic acid,
15

16. Moxifloxacin
• Administration [Usual Dosage]: IV, PO and ophthalmic [400mg q24h]
• Spectrum: Gram-, Gram+ (S. aureus including MRSA & S. pneumoniae) & atypicals
• (L. pneumophila, C pneumonia & M. pneumoniae), Mycobacterium tuberculosis, gram-
negative anaerobes
• Indications:
– Chronic bronchitis
– CAP
– Bacterial conjuctivitis
– Sinusitis
• Unique Qualities:
– Binds divalent cations (i.e. Ca & Mg) which decreases absorption
– Safety and efficacy not established in patients <18 y.o.
• ADRs
– Blood glucose disturbances in DM patients
– QTC prolongation, torsades de pointes, arrhythmias
– Nausea, GI upset
– Interstitial nephritis
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17. 17
Nitrofurans
The first nitroheterocyclic compounds to be introduced into chemotherapy
were the nitrofurans.
Three of these compounds are……….
1. Nitrofurazone,
2. Furazolidone, and
3. Nitrofurantoin
These compounds 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.

18. 18
The nitrofurans are 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.
5-nitro-2-furaldehyde

19. Mode of Action
• The mechanism of antimicrobial action of the nitrofurans has been
extensively studied, but it still is not fully understood.
• In addition to their antimicrobial actions, the nitrofurans are 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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20. 20
5-Nitro-2-furaldehyde semicarbazone (Furacin) occurs as a lemon-yellow crystalline
solid that is sparingly soluble in water and practically insoluble in organic solvents.
Nitrofurazone is chemically stable, but moderately light sensitive. It is used topically in
the treatment of burns, especially when bacterial resistance to other agents may be a
concern.
 It may also be used to prevent bacterial infection associated with skin grafts.
Nitrofurazone has a broad spectrum of activity against Gram-positive and Gram-negative
bacteria, but it is not active against fungi.
 It is bactericidal against most bacteria commonly causing surface infections, including
S. aureus, Streptococcus spp., E. coli, Clostridium perfringens, Enterobacter (Aerobacter)
aerogenes, and Proteus spp.; however, P. aeruginosa strains are resistant.
Nitrofurazone is marketed in solutions, ointments, and suppositories in a usual
concentration of 0.2%.
Nitrofurazone

21. 21
3-[(5-Nitrofurylidene)amino]-2-oxazolidinone (Furoxone) occurs as a yellow crystalline
powder with a bitter aftertaste.
It is insoluble in water or alcohol. Furazolidone has bactericidal activity against a
relatively broad range of intestinal pathogens, including S. aureus, E. coli, Salmonella,
Shigella, Proteus spp., Enterobacter, and Vibrio cholerae.
 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. The usual adult dosage is 100 mg 4 times daily.
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.
Furazolidone

22. 22
Nitrofurantoin, 1-(5-nitro-2-furfurylidene)-1-aminohydantoin (Furadantin,
Macrodantin), is a 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.
The most common side effects are gastrointestinal (anorexia, nausea, and
vomiting); however, hypersensitivity reactions (pneumonitis, rashes, hepatitis, and
hemolytic anemia) have occasionally been observed.
 A macrocrystalline form (Macrodantin) is claimed to improve gastrointestinal
tolerance without interfering with oral absorption.
Nitrofurantoin

23. Thank you
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