23 REVIEW ARTICLE

23
N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance
REVIEW ARTICLE
INTERNATIONL JOURNAL OF NOVEL TRENDS IN PHARMACEUTICAL SCICENCES
Available online at www.ijntps.org | ISSN: 2277 - 2782
A Focus on Quinolones and its Medicinal Importance
a
b
c
N.Saravana kumar *, D.Dhivya and B.Vijayakumar
a
Department of Pharmaceutical Chemistry, Sasikanth Reddy College of Pharmacy, North Rajupalem, Nellore, A P, India.
Department of Pharmacognosy, Sasikanth Reddy College of Pharmacy, North Rajupalem, Nellore, A P, India.
c
Department of Pharmaceutical Chemistry, Sri Venkateswara College of Pharmacy, R.V.S Nagar, Chittoor, A P, India.
b
Received for publication, September 14, 2011, and in Revised form, September 19, 2011; Published online in, October 7, 2011
ABSTRACT
Quinolones are a very important family of antibacterial agents that are widely prescribed for the treatment of infections in
humans. Quinolones comprise a relatively large, growing and most interesting group of antibacterial drugs which have made a
major impact on the field of antimicrobial chemotherapy. Since their discovery in the early 1960s, the quinolone group of
antibacterials has generated considerable clinical and scientific interest. The bacterial type II topoisomerases, DNA gyrase and
topoisomerase IV are validated targets for clinically useful quinolone antimicrobial drugs. A significant limitation to widely
utilized quinolone inhibitors is the emergence of drug-resistant bacteria due to an altered DNA gyrase. Antibiotic drug choice
will remain difficult in the presence of increasing resistance, but introduction of the new quinolones has created a new and
exciting era in antimicrobial chemotherapy.
KEY WORDS: Quinolones, antibacterial, topoisomerases, DNA gyrase.
INTRODUCTION
Development of antimicrobials for clinical use has
been most successful in targeting essential components of
5 general areas of bacterial metabolism: cell wall synthesis,
protein synthesis, RNA synthesis, DNA synthesis, and
intermediary metabolism (Table 1). The quinolones are a
family of synthetic broad-spectrum antibiotics. The term
quinolone(s) refers to potent synthetic chemotherapeutic
[1]
antibacterials . Quinolones comprise a relatively large,
growing and most interesting group of antibacterial drugs
which have made a major impact on the field of
antimicrobial chemotherapy, particularly in the past few
[2]
years .
A group of scientists in the laboratories of the
Sterling Company, while pursuing new chemical entities
based on the structure of quinine in an effort to expand the
armamentarium against malaria, discovered that derivatives
of the 1, 8-naphthyridine molecule possessed antibacterial
activity. By 1962, George Lesher and colleagues had
[3]
developed Nalidixic acid (1) . This was the first clinically
useful quinolone in the series, and by 1964 it was available
in the UK for the treatment of urinary tract infections. This
narrow clinical indication was a consequence of two factors:
the poor serum and tissue concentrations achieved after
oral administration, and the limited spectrum of activity,
Intl.J.Novel.Tr.Pharm.Sci
[4]
restricted primarily to the Enterobacteriaceae . Thereafter,
novel compounds of this family, such as pipemidic acid and
oxolinic acid, were synthesized and introduced into clinical
practice, although the clinical indication for these
quinolones still remained only for UTIs. The addition of a
fluorine atom at position 6 of the quinolone molecules
greatly enhanced their activity, facilitating their usage
beyond UTIs.
C2 H5
H 3C
N
N
OH
O
O
1
During the 1980s, a great number of
fluoroquinolones were developed. These agents showed
potent activity against Gram-negative bacteria, but not
against the Gram-positive bacteria or anaerobes. In the
1990s, further alterations of the quinolones resulted in the
To whom correspondence should be addressed:
Ms. N. Saravana Kumar,
E-mail: [email protected]
Phone: +918106105188
VOLUME 1 | NUMBER 1 | OCT | 2011
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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance
discovery of novel compounds that not only showed potent
activity against Gram-negative bacteria but also against the
[5]
Gram-positives . Fluoroquinolones as a class is now a days
one of the frequently prescribed class of antibacterial.
Fluoroquinolones have gained stupendous importance
during the last two decades because of their potent antibacterial activity against wide varieties of gram-positive and
gram-negative pathogenic bacteria with minimum toxic
side-effects and somewhat different mechanism of action
than other available antibacterial drugs. To date, many
fluoroquinolone antibacterial agents have been introduced
into clinical use (Table 2) with significant improvement in
antibacterial spectrum and activity.
A vast array of
fluoroquinolones having excellent broad-spectrum activity
forms an invaluable part of the present anti-infective
armory of the clinicians. A number of these compounds are
today's blockbusters of the antibacterial market due to their
therapeutic efficacy and tolerable side-effects even,
challenging the predominance of well established β-lactam
antibiotics which are becoming more prone to the resistant
pathogenic bacteria. The fluoroquinolones are the fastest
growing antibacterial class in terms of global revenue,
increasingly being used in both the hospital and
[6]
community sectors to treat a broad range of infection
Table 1. Bacterial targets of antimicrobial agents.
BACTERIAL TARGET
Cell wall synthesis
Protein synthesis
RNA synthesis
DNA synthesis
Intermediary
metabolism
ANTIMICROBIAL AGENT
β-Lactam antibiotics
Glycopeptides
Aminoglycosides, Macrolides,
Lincosamides, Ketolides,
Streptogramins, Tetracyclines,
Chloramphenicol
Oxazolidinones
Rifamycins
Coumarins, Naphthyridines,
Quinolones, 2-Pyridones
Sulfonamides, Trimethoprim
Clinical uses
The fluoroquinolones have been used to treat a
great variety of infections (Table 4), including gonococcal
infections, osteomyelitis, enteric infections or respiratory
[9-11]
tract infections,
and as prophylaxis in neutropenic
patients, surgery or to prevent spontaneous bacterial
[10,12]
.
peritonitis in cirrhotic patients, among others
Moreover, quinolones, along with other antibacterial
agents, have been extensively used in veterinary practice,
Intl.J.Novel.Tr.Pharm.Sci
either for medical reasons or as growth promoters. The list
of fluroquinolones with their indication, dose and duration
of therapy were shown in table 4.
BIOLOGICAL TARGET
Fluoroquinolones are a clinically important class of
antibacterial drugs that target the type II A topoisomerases
DNA gyrase and topoisomerase IV (Fig 1) , two highly
homologous enzymes that play essential roles in bacterial
[13-17]
DNA replication
. DNA gyrase is a heterotetrameric
protein consisting of two GyrA subunits and two GyrB
subunits (A2B2) encoded by the gyrA and gyrB genes,
respectively. The GyrA subunit mediates the enzymecatalyzed DNA breakage-reunion reaction and contains the
active-site tyrosine that forms a covalent complex with the
5'-labeled ends of the transiently cleaved DNA duplex. The
GyrB subunit contains an ATPase activity which facilitates
the DNA strand passing reaction of DNA gyrase.
Topoisomerase IV, a paralogue of DNA gyrase, is also a
heterotetramer, consisting of two ParC and two ParE
subunits which are homologues of the GyrA and GyrB
subunits of DNA gyrase, respectively. Fluoroquinolones
interact with the DNA breakage-reunion subunit of DNA
gyrase and topoisomerase IV, leading to the stabilization of
the covalent topoisomerase/DNA cleavable complex which
[18]
blocks DNA replication .
How do quinolones destroy bacteria without hurting
our cells?
There are many different classes of antibiotics
each exerting a different type of inhibitory effect that
specifically impacts bacteria. Bacterial cells are prokaryotic;
primitive cells that differ significantly from humans’
eukaryotic cells. Quinolones exert their bacteriocidal effect
by interfering with a bacterium’s ability to make DNA
(replication). Many quinolone antibiotics belong to a
subgroup called fluoroquinolones, which have a fluoro
functional group associated with the molecule. Both terms
are therefore used to describe antibiotics in this class.
Fig.1 Inhibition of DNA gyrase and Topoisomerase IV by
Fluoroquinolone
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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance
Table 2. Structural Formulas of Selected Quinolones and Fluoroquinolones
R
R
8
3
x
7
1
1
N
2
6
R
2
5
4
O
Compound Name
Nalidixic acid
Cinoxacin
R
1
R
-C 2 H 5
R
-H
3
X
-N-
-CH 3
[Fused dioxolo ring]
-C 2 H5
Norfloxacin
O
2
-C 2 H5
*
OH
3
Ciprofloxacin
-CH-
-F
N
NH
-CH-
-F
N
NH
-CH-
-F
N
NH
-CH-
8
C
O
Ofloxacin
CH3
Sparfloxacin
CH3
F
**
-F
N
C
NH
CH3
F
Lomefloxacin
-C 2 H5
-F
N
NH
C
CH3
F
Fleroxacin
-CH 2 -CH 2 -F
-F
N
N
CH3
C
Perfloxacin
-C 2 H 5
-F
N
N
CH3
-CH-
Levofloxacin
CH3
O
-F
(x)
CH3
O
N
N
CH3
(N 1 )
C
(N 1 )
F
Trovafloxacin
Intl.J.Novel.Tr.Pharm.Sci
F
-F
N
NH2
-N-
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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance
Table 2. (continued) Structural Formulas of Selected Quinolones and Fluoroquinolones
R
R
8
3
N1
x
7
1
2
6
R
OH
2
5
4
O
Compound Name
R
1
R
3
O
2
R
3
X
CH3
OCH 3
-F
Gatifloxacin
N
C
NH
OCH 3
-F
Moxifloxacin
N
C
N
H
*An N replaces C-2 in the basic ring structure of Cinoxacin.
Fused dioxolo
**An –NH2 group is attached to the C-5 in the basic ring
structure of Sparfloxacin.
O
C
O
Table 3 Classification on the Basis of Spectrum of Activity
Quinolone generations
First generation
Nalidixic Acid
( NegGram)
Cinoxacin
Second generation
Class I
Lomeflaxcin
Norfloxacin
Enoxacin
Class II
Ofloxacin Ciprofloxacin
Third generation
Levofloxacin
Sparfloxacin
Gatifloxacin
Moxifloxacin
Fourth generation
Intl.J.Novel.Tr.Pharm.Sci
[7, 8]
Microbiological activity
Administration and characteristics
Indications
Enterobacteriaceae
Oral administration , low serum and
tissue drug concentrations, narrow
gram-negative coverage
uncomplicated urinary tract
infections , not for use in systemic
infections
Enterobacteriaceae
Oral administration , low serum and
tissue drug concentrations , improved
gram negative coverage compared to
first generation quinolones , limited
gram positive coverage
uncomplicated urinary tract
infections , Not for use in systemic
infections
Enterobacteriaceae , atypical
pathogens ; Pseudomonas
aeruginosa
(ciprofloxacin only)
Oral and intravenous administration,
higher serum , tissue and intracellular
drug concentrations compared with
class I agents coverage of atypical
pathogens
Complicated urinary tract and
catheter-related infections,
Gastroenteritis with severe diarrhea
, Prostatitis , Nosocomial infections
, STD's
Enterobacteriaceae , atypical
pathogens , streptococci
Oral and intravenous administration ,
similar to class II second generation
quinolones but with modest
streptococcal coverage
Similar indications as for second
generation quinolones ,community
acquired pneumonia in
hospitalized patients.
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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance
Trovafloxacin
Enterobacteriaceae , atypical
pathogens ,Pseudomonas
aeruginosa , methicillinsusceptible Staphylococcus
aureus, streptococci,
anaerobes
Oral and intravenous administration,
similar to third generation quinolones
but with improved gram-positive
coverage and added anaerobic
coverage
Consider for treatment of intraabdominal infections .
Table 4 Drug, Indication, Dose, Duration of therapy chart for some Fluoroquinolones
Drug
Ciprofloxacin
Indication
Uncomplicated UTI
Complicated UTI ; Acute pyelonephritis
Uncomplicated N gonorrhea
AECB , CAP
Acute prostatitis
Infectious diarrhoea ; Typhoid Fever
Uncomplicated UTI
Uncomplicated N gonorrhea
Complicated UTI ; Acute pyelonephritis,
AECB , CAP
Uncomplicated UTI ; Acute pyelonephritis
AECB, CAP
Uncomplicated and complicated UTI ; Acute
pyelonephritis
Acute prostatitis
Uncomplicated and complicated UTI ; Acute
pyelonephritis; AECB
AECB , CAP
Gatifloxacin
Levofloxacin
Norfloxacin
Lomefloxacin
Sparfloxacin
Moxifloxacin
Ofloxacin
PO dose ( mg )
100
250-500
500
500-750
500
500
400
400
400
Interval
BID
BID
1-dose
BID
BID
BID
QD
1-dose
QD
Duration ( days )
3
7-14
1-dose
10-14
14-28
3-5
3
1-dose
7-14
250
500
400
QD
QD
BID
10
7- 14
3-10
400
400
BID
QD
14-28
3-14
400 x 1 , then
200
400
200
QD
10
AECB , CAP
QD
5-10
Uncomplicated and complicated UTI ;
BID
3-10
Chlamydia
Uncomplicated N gonorrhea
400
1-dose
1-dose
AECB , CAP
400
BID
7-10
CAP = community acquired pneumonia
AECB = acute exacerbations of chronic bronchitis
UTI = urinary tract infections
Table 5. Severity of Adverse Effects Associated with Fluoroquinolones
Quinolones
Gastrointestinal
reactions
CNS
Effects
Ofloxacin
Levofloxacin
Norfloxacin
Ciprofloxacin
Pefloxacin
Tosufloxacin
Trovafloxacin
Temafloxacin
Moxifloxacin
+
++
+
+
++
++
+++
+
+
++
++
++++
++++
+
+
Intl.J.Novel.Tr.Pharm.Sci
Photo
toxicity
++
+
Liver
toxicity
Hypogly
caemia
Tendinitis
+++
-
+++
+++
-
+++
-
Cardio
toxicity
-
Haemolitic
syndrome
+++
++++
-
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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance
Lomefloxacin
Fleroxacin
Sparfloxacin
Clinafloxacin
Grepafloxacin
+++
+++
++++
++++
++++
+
++++
+
++++
++++
++++
++++
-
-
Quinolones are bacteriocidal drugs, meaning that
they kill bacteria. These antibiotic drugs inhibit the bacterial
DNA gyrase enzyme which is necessary for DNA replication.
Since a copy of DNA must be made each time a cell divides,
interfering with replication makes it difficult for bacteria to
multiply.
How DNA is packaged is very different in bacteria
as opposed to eukaryotes. Bacteria super coil DNA using
DNA gyrase, whereas eukaryotes coil DNA around histone
proteins. Because quinolones specifically target DNA
[19]
gyrase, they do not interfere with human DNA .
STRUCTURE-ACTIVITY RELATIONSHIPS
The structure of quinolone pharmacophore was
shown in Fig. 3 The figure shows the core molecule and the
positions at which key changes are engineered. Some of
these molecular substitutions should not be altered as they
would interface with or reduce markedly the basic mode of
action of the drug. These are positions 2, 3 and 4; at
position 2, a hydrogen moiety is optimal - any larger
molecular additions may create a steric hindrance at the
adjacent positions 3 and 4 which must be a carboxyl group
and oxygen molecule, respectively. Binding to the DNA
bases occurs at these positions, which are then made
available for new hydrogen binding partners by the action
of the enzyme, DNA gyrase. The moiety at position 6
should be small, and a fluorine atom is optimal as it confers
between five- and 100-fold greater potency than any other
potential halogen moiety. The four other positions can
[4]
receive a wide range of potential substituents . SAR
studies have enabled the recognition of features that lead
to specific changes, as summarised below:-
R
R
8
7
7
1
1
x
N
R
2
++
-
+++
+++
-
+++
+++
-
It was realised that a cyclopropyl moiety (e.g., as seen
in ciprofloxacin and sparfloxacin) at this point conferred
significant activity against gram-negative bacteria. The
groups 2,4-difluorophenyl (temafloxacin)and t-butyl (BMY
40062) are slightly less potent; however, the 2,4difluorophenyl group heightens activity against anaerobes
[20]
.
Position 5
Considerable changes have been concentrated at this
position in an effort to improve the activity of the
fluoroquinolones against gram-positive bacteria. The most
advanced compounds that carry significant changes at
position 5 are sparfloxacin and PD 124816, both of which
carry an -NH2 moiety, whereas OPC 17116 (grepafloxacin)
[4]
possesses
a -CH3 molecule .
Position 7
This is one of the most influential points on the
molecule and, almost without exception, the possession of
a five or six-membered nitrogen heterocycle at this position
has improved a molecule’s activity and pharmacokinetic
profile. The most popular heterocycles employed at
position 7 are aminopyrrolidines and piperazines. Antibacterial agents that contain an aminopyrrolidine moiety
[21]
are tosufloxacin, clinafloxacin, Du6859a, Bay 3118
. In
contrast, the piperazine substituent is found on
ciprofloxacin, lomefloxacin, temafloxacin, sparfloxacin and
BMY 40062. The former moiety tends to confer better
activity against gram-positive bacteria, whereas piperazine
[20]
offers improved activity against gram-negative bacteria .
Substitution with an alkyl moiety will improve
gram positive potency and lengthen the serum half-life; this
type of change has been employed in lomefloxacin,
sparfloxacin and several other quinolones now under
development.
2
6
F
4
5
R
5
OH
3
O
O
Fig 2. The quinolone pharmacophore
Position 1
Intl.J.Novel.Tr.Pharm.Sci
Position 8
Various substituents at this position have led to
marked improvements in activity, particularly against
anaerobic bacteria; the most useful groups employed on
this position are CF, CCl and COMe.In addition to the role
that certain moieties may play in enhancing activity against
specific
groups
of
bacteria
and
altering
the
pharmacokinetic properties of a drug, these chemical
VOLUME 1 | NUMBER 1 | OCT | 2011
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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance
modifications also play a significant role in the specific
[4]
interaction of these compounds with man .
8.
ADVERSE REACTIONS
The most common adverse experience reported
for all quinolones involve the gastro-intestinal tract, skin
and CNS. Of the gastrointestinal events, nausea and
vomiting are the most common. CNS reactions vary in
severity and include dizziness, convulsions and psychoses
[22-24]
. Occasionally major events occur, which lead to
significant
tolerability
problems.
Phototoxicity,
cardiotoxicity, arthropathy and tendinitis have also been
[25-28]
observed in some patients (Table 5 )
.
9.
10.
11.
12.
13.
Conclusion
Without doubt, the newer quinolones have very
attractive properties, combining high potency, a broader
spectrum of activity, better bioavailability, oral and
intravenous formulations, high serum levels, a large volume
of distribution indicating higher concentrations in tissues
and a potentially low incidence of side-effects. From a
clinical perspective, the main problem with the quinolones
is the accumulation of resistance mutations by target
organisms. The recent demonstration that bacteria contain
two targets for the fluoroquinolones raises the hope that
new quinolones can be found that will effectively attack
both targets and thus drastically reduce the probability of
development of clinical resistance. Our present knowledge
in the topic provides wide scope for developing newer
quinolones to inhibit the highly resistant bacteria.
Therefore, we are optimistic about being able to find new,
more effective quinolones.
14.
15.
16.
17.
18.
19.
20.
21.
References
1.
2.
3.
4.
5.
6.
7.
Nelson JM, Chiller TM, Powers JH, Angulo FJ. Clin.
Infect. Dis, 2007, 44 (7): 977–80.
Saeed Emami, Abbas Shafiee and Alireza
Foroumadi. Iranian Journal of Pharmaceutical
Research, 2005, 3, 123-136.
Lesher GY, Froelich ED, Gruet MD, Bailey JH,
Brundage RP. J Med Pharm Chem, 1962, 5, 10631068.
G. S. Tillotson. J. Med. Microbiol, 1996, 44, 320-324.
Joaquim
Ruiz,
Journal
of
Antimicrobial
Chemotherapy, 2003, 51, 1109–1117.
Akhiles
Roy,
S.
M.
Sardar,
B.U.Salve,
D.D.Rishipathak. International Journal of ChemTech
Research, 2007;1: 35-46
Andriole, V. T. Drugs, 1999, 58:1.
Intl.J.Novel.Tr.Pharm.Sci
22.
23.
24.
25.
26.
27.
28.
E.M. and Reeves, D.S., "Quinolones," in Antibiotic
and Chemotherapy, Churchill Livingstone, New
York NY, 1997, 419-452 ,
Vila, J., Ruiz, J., Sanchez, F., Navarro, F., Mirelis, B.,
Jiménez de Anta, M. T. et al. Antimicrobial Agents
and Chemotherapy, 1999; 43: 161–2.
Davis, R., Markham, A. & Balfour, J. A. Drugs, 1996,
6, 1019–74.
Acar, J. F. & Goldstein, F. W. Clinical Infectious
Diseases, 1997; 24: Suppl. 1, S67– S73.
Grange, J. D., Roulot, D., Pelletier, G., Pariente, E. A.,
Denis, J., Ink, O. et al. Journal of Hepatology, 1998;
29: 430–6.
Champoux, J. J. Annu. Rev. Biochem.2001, 70,
369–413.
Drlica, K., and M. Malik., Curr. Top. Med. Chem.,
2003, 3, 249–282.
Gadelle, D., J. Filee, C. Buhler, and P. Forterre.,
Bioessays, 2003 ;25:232–242.
Levine, C., H. Hiasa, and K. J. Marians. Biochim.
Biophys. Acta,1998; 1400:29–43.
Wang, J. C. Nat. Rev. Mol. Cell Biol. ,2002, 3, 430–
440
David A. Ostrov, Jose A. Hernandez Prada, Patrick
E. Corsino et al. Antimicrobial
Agents and
Chemotherapy, 2007, 51: 3688–3698.
MOA of Quinolone Antibiotics: Mode of Action:
Ciprofloxacin
&
Other
Fluoroquinolone
Antimicrobics
Suite101.com
http://tamiport.suite101.com/moa- of-quinolone-antibiotics.
Domagala JM., J. Antimicrob Chemother, 1994, 33,
685-706.
Sanchez JP, Domagala, JM, Hagen SE et al. J Med
Chem 1988, 31, 983-991.
Christ W. J Antimicrob. Chemother., 1990, 26 suppl.
B: 219.
Lucet, I. C.; Tilly, H.; Lerebours, G.; Gres, I. L.;
Piguet,H., J. Antimicrob. Chemother. 1988, 21, 811.
Stahlmann, R; Lode, H., Drugs, 1999, 58 suppl. 2,
37.
Schaad, U. B. Pediatric Infectious Disease Journal,
1992, 11, 1043.
Schaad, U. B. Sander, E.; Wedgewood, J.; Schaffner,
T. Pediatric Infectious Disease Journal, 1992, 11,
1047.
Wilcox, M. Antibiotics Chemotherapy, 1999, 3 (3), 9.
Wolfson, J. S.; Hooper, D. C. Clinical Microbiology
Reviews, 1989, 2, 378.
VOLUME 1 | NUMBER 1 | OCT | 2011
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