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IJPRD, 2011; Vol 3(4): June 2011 (164 - 171) International Standard Serial Number 0974 – 9446
Available online on www.ijprd.com 164
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A REVIEW ON DIFFERENT ACTIVITY OF QUINOLONE DERIVATIVES
Singh Smita
1
*,
Gaurav Anand
1
, Singh Ranjit
1
, Verma Vikrant
1
1
Laboratory of pharmaceutical sciences Shobhit University, Meerut U.P.
ABSTRACT
Nalidixic acid is considered to be the predecessor of all members of
the quinolone family, including the first, second, third and fourth
generations. Aim was exploring effective compounds with better
anticonvulsant activity and lower neurotoxicity; compounds were
designed and synthesized, by substituting triazone with triazolo as in
compound II. The hypothesis was that triazone compounds may have
higher affinity to the receptor due to the carbonyl group, and thus
may increase the anticonvulsant activity. The introduction of alkoxy
group to the 7th position of 1, 2, 4-triazole quinoline remarkably
increased their anticonvulsant activity. So, synthesis of a series of 8-
alkoxy-5, 6-dihydro-[1, 2, 4] triazino [4, 3- a] quinolin-1-one
derivatives was done to discuss the influence of the 8-alkoxy on
anticonvulsant activity; and found derivative as most active
compound.
Correspondence to Author
Smita Singh
Laboratory of pharmaceutical
sciences Shobhit University,
Meerut U.P.
Email
smita0082@gmail.com
Key Words
Nalidixic acid, anticonvulsant
activity, quinolone family.
International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446
Available online on www.ijprd.com 165
INTRODUCTION
1.1 History of quinolone
1
Nalidixic acid is considered to be the predecessor of all
members of the quinolone family, including the first,
second, third and fourth generations. This first
generation also included other quinolone drugs such as
pipemidic acid (1), oxolinic acid and cinoxacin (2), which
were introduced in the 1970s. They proved to be only
marginal improvements over nalidixic acid (3).
Though it is generally accepted that nalidixic acid is to
be considered the first quinolone drug, this has been
disputed over the years by a few researchers who
believe that chloroquine, from which nalidixic acid is
derived, is to be considered the first quinolone drug
rather than nalidixic acid.
1.5 Biological activity of Quinolones
Quinolone derivatives have been known to possess a
variety of biological activities such as anticonvulsant,
antibacterial, antitumor, antiplatelet, FMS kinase
inhibitors and antiHIV.
1.5.1Anticonvulsant activity
Initially a series of derivatives of 6-alkoxy-3, 4- dihydro-
2(1H) quinoline were first found by Sun et al.; among
which 6-benzyloxy-3, 4-dihydro-2(1H)-quinoline
(compound 4) showed the strongest activity with an
ED
50
value of 29.6 mg/kg in the MES test.
2
(Fig-1)
Introduction of triazolo ring to the first and second
positions of this compound I caused a remarkable
increase in the anticonvulsant activity, as seen in 7-
benzyloxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline
(compound 5),which showed ED
50
values of 17.3 mg/kg
and 24 mg/kg in the MES and the sc PTZ tests,
respectively.
2
Aim was exploring effective compounds with better
anticonvulsant activity and lower neurotoxicity;
compounds were designed and synthesized, by
substituting triazone with triazolo as in compound II.
The hypothesis was that triazone compounds may have
higher affinity to the receptor due to the carbonyl
group, and thus may increase the anticonvulsant
activity.
2
The introduction of alkoxy group to the 7th position of
1, 2, 4-triazole quinoline remarkably increased their
anticonvulsant activity. So, synthesis of a series of 8-
alkoxy-5, 6-dihydro-[1, 2, 4] triazino [4, 3- a] quinolin-1-
one derivatives was done to discuss the influence of the
8-alkoxy on anticonvulsant activity; and found (6)
derivative as most active compound.
2
R DERIVATIVES
n-C
7
H
15
6
Sun et al.; synthesized series of 8-alkoxy-5, 6-dihydro-[1,
2, 4] triazino [4, 3-a] quinolin-1-one derivatives. Their
anticonvulsant activities were evaluated by the maximal
electroshock (MES) test and their neurotoxicity were
evaluated by the rotarod neurotoxicity test. The results
showed that 8-heptyloxy- 5, 6-dihydro-[1, 2, 4] triazino
[4, 3-a] quinolin-1-one (6) was the most potent with
median effective dose (ED
50
) value of 11.4 mg/kg,
median toxicity dose (TD
50
) of 114.1 mg/kg. To explain
the possible mechanism of anticonvulsant activity, the
compound (6) was tested in chemically induced
seizures.
2
Quan et al.; design and synthesized series of substituted
quinoline-2(1H)-one and 1, 2, 4-triazolo [4, 3-a]-
quinoline derivatives that was found to meet the
International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446
Available online on www.ijprd.com 166
structural requirements essential for anticonvulsant
properties.
3
4-substituted-phenyl-3,4-dihydro-2(1H)-quinolones,5-
substituted-phenyl-4,5-dihydro-1, 2, 4-triazolo[4, 3a]
quinolones and 5-substituted-phenyl-4, 5-dihydro-1, 2,
4-triazolo-[4, 3-a]quinoline-1-(2H)-ones derivatives were
synthesized using 3-substituted-phenyl-N-phenyl-
acrylamide as a starting material.
The 4-substitued-phenyl- 3, 4-dihydro-2(1H)-quinoline
(7a-f), synthesized by introducing substituted-phenyl to
3, 4-dihydro-2(1H)-quinoline at the fourth position, had
remarkably increased anticonvulsant effects compared
to the parent compounds. The 5-substituted-phenyl-4,
5-dihydro-1, 2, 4-triazolo [4, 3-a] quinoline (8a-f),
prepared by incorporating a triazole ring into (7a-f) at
the N1-C2 positions, in turn had significantly increased
anticonvulsant activity compared to (7a-f). However, the
compounds prepared by incorporating a triazolone into
(7a-f) at the N1-C2 positions, namely, 5-substituted-
phenyl-l-4, 5-dihydro- 1,2,4-triazolo[4,3-a] quinoline-
1(2H)-ones (9a-f),exhibited no anticonvulsive effect
even under a high dose of 300 mg/kg.
Their anticonvulsant activity was evaluated by maximal
electroshock (MES) test, subcutaneous
pentylenetetrazole (ScPTZ) test, and their neurotoxic
effects were determined by the rotarod neurotoxicity
test.
4
1.5.2 Antiplatelet activity
5
Kuo et al.; synthesized some novel antiplatelet agents
having seven positional phenyl quinolone isomers.
Preliminary screening confirmed their inhibitory effects
against arachidonic acid (AA) induced platelet
aggregation.
During routine antiplatelet screening, it was discovered
that 2-phenyl-4-quinolone (10) shows aspirin- like
activity. Since physiochemical properties of (10) are
quite different from those of aspirin and the antiplatelet
activity of (10) has not previously reported, a series of
positional isomers of (10) were synthesized.
Varying the substitution position of the phenyl group
had a profound effect on the antiplatelet activity of
these isomers. 3- phenyl-4-quinolone (11) showed the
greatest potency and was superior to indomethacin.
5
Table-1 Shows the inhibitory effects of phenyl quinolone derivatives on platelet aggregation induced by (AA)
Compound IC50(uM) R
2
R
3
R
6
R
7
R
8
10 9.63 Phenyl H H H H
11 0.17 H Phenyl H H H
International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446
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12 34.99 H H H H Phenyl
13 24.90 H H H Phenyl H
14 7.04 H H Phenyl H H
15 40.00 - - - - -
16 12.19 - - - - -
17 35.00 - - - - -
Aspirin 0.25 - - - - -
Indomethacin
20.00 - - - - -
The super inhibitory effect of 3-phenyl-4-quinolone (11) against AA-induced platelet aggregation was discovered.
Antibacterial activity
Mechanism of action of quinolone as an antibacterial
activity
7
Quinolones are synthetic chemotherapeutic agents
which have a broad spectrum of antimicrobial activity as
well as a unique mechanism of action resulting in
inhibition of bacterial DNA gyrase and topoisomerase IV.
Quinolones can enter in cell easily via porins and
therefore are often used to treat intracellular pathogens
such as Legionella pneumophila and Mycoplasma
pneumoniae.
Classification
8
The quinolones are divided into generations based on
their antibacterial spectrum. The earlier-generation
agents are, in general, more narrow-spectrum than the
later ones. In general, the quinolones are grouped by
generations. But there is no standard employed to
determine which drug belongs to which generation. The
only universal standard applied is the grouping of the
non-fluorinated drugs found within this class
(quinolones) within the first-generation heading. The
first generation is rarely used today. A number of the
second-, third-, and fourth-generation drugs have been
removed from clinical practice due to severe toxicity
issues or discontinued by their manufacturers.
Chemical name of
drug
Marketed product
name
Oxolinic acid Uroxin
Piromidic acid Panacid
Pipemidic acid Dolcol
The second-generation quinolones have increased gram-
negative activity, as well as some gram-positive and
atypical pathogen coverage. Compared with first-
generation drugs and considered as a group, these
agents have broader clinical applications in the
treatment of complicated urinary tract infections and
pyelonephritis, sexually transmitted diseases, selected
pneumonias and skin infections. Second-generation
agents include ciprofloxacin, enoxacin, lomefloxacin,
norfloxacin and ofloxacin.
Third generation agents are separated in this class
because of their expanded activity against gram-positive
organisms, particularly penicillin-sensitive and penicillin-
resistant S. pneumoniae, and atypical pathogens such as
Mycoplasma pneumoniae and Chlamydia pneumoniae.
Although the third-generation quinolones retain broad
International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446
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gram-negative coverage, they are less active than
ciprofloxacin against Pseudomonas species.
Trovafloxacin, currently the only member of the fourth-
generation class, adds significant antimicrobial activity
against anaerobes while maintaining the gram-positive
and gram-negative activity of the third-generation
quinolones. It also retains activity against Pseudomonas
species comparable to that of ciprofloxacin.
Batori et al.; synthesize and evaluated N-(1-aziridino)-6-
fluoro-quinolone-3-carboxylic acids. The results of
measurements of MIC's summarized show that only two
derivatives (18, 19) of the whole series showed similar or
somewhat better activity as Nalidixic acid. These
compounds - phenyl (18) and 4-fluorophenyl (19)
substituent in the aziridine ring - are significantly more
potent against Gram-positive microorganisms than
Nalidixic acid and have similar potency against Gram-
negative ones. Introduction of a fluorine substituent in
position C-8 resulted in the loss of activity. A substituent
in the aziridine ring with enhanced electron withdrawing
property or a fused ring also led to a decrease in the
activity.
9
Foroumadi et al.; synthesized some novel N-(5-
benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benylsulfonyl-
1,3,4-thiadiazol-2-yl) piperazinyl quinolone derivatives,
evaluated them for antibacterial activity, and Identified a
series of N-substituted piperazinyl quinolones (20) and
(21) in which the N-4 hydrogen of piperazinyl group of
norfloxacin and ciprofloxacin replaced with various
nitrobenzylthio- and nitrobenzylsulfonyl-1, 3, 4-
thiadiazolyl moieties with in vitro microbiological activity
against Gram-positive organisms comparable or higher
than respective parent quinolones, ciprofloxacin, and
norfloxacin. The SAR of this series indicates that both the
structure of the benzyl unit and the S or SO
2
linker
dramatically impact antibacterial activity.
10
NN
N
N
N
S
S
R
1
F
R
O
COOH
Derivatives R R
1
20 Ethyl H
21 Cyclopropyl NO
2
Li et al.; synthesize and evaluated a series of a novel C7
non-basic substituted fluoroquinolones as antibacterial
agents. Synthesis of a series of new quinolones based on
(2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate
and(S)-pyrrolidin-2-ylmethanol has done. From in vitro
potency assay results, it was determined that 7-(5-thia-
2-aza-bicycloheptan-2-yl)-1- cyclopropyl-6- fluoro-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carboxylic acid , the
corresponding sulfoxides , and sulfone exhibited good to
excellent activities against all the Gram-positive and
Gram-negative strains tested.
11
Guo et al.; synthesized some novel fluoroquinolone
derivatives and evaluated them for antibacterial activity
in 2004. In the present work, the microwave method was
used to synthesize ethyl-7-chloro-6-fluoro-1, 4-dihydro-
4-oxoquinoline-3-carboxylate from the corresponding 3-
chloro-4fluoroaniline, It was observed that while the
yields were almost similar as that using the conventional
methods, the time of reaction was very less (only a few
minutes) in microwave method compared to the time
required for the conventional methods (6-8 hrs). Further,
microwave-assisted synthesis of quinolone nucleus could
be carried out using the reactants only, without any
solvent or any solid support which was an added
advantage over the conventional methods requiring
solvents.
12
International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446
Available online on www.ijprd.com 169
Roy et al.; synthesized a series of 5-amino-8-
methoxyquinolones derivatives and evaluated them for
their anti-bacterial activity in 2009.There was a
concomitant reduction in several of the potential side
effects (i.e., phototoxicity and clonogenicity) compared
to the most active quinolones with classic substitution at
C-8, side chains of C-7 position were only substitute
piperazine, pyrrolidine and piperidine as usual, so
interest was directed to the synthesis a series of 5-
amino-8-methoxyquinolones that have novel side chains.
The most active compounds were found to be (22), (23).
13
1.5.4 Anti HIV activity
Souza et al; synthesized several 1-[(2-hydroxy-ethoxy)
methyl]-3-carbethoxy- 4(1H) quinolones and l-[(2-
hydroxy-ethoxy) methyl]-4(1H) quinolone-3-carboxylic
acids and evaluated against herpes simplex virus type 1
(HSV-1). Compounds (24) and (25) were the most
effective anti-HSV-1 derivatives and presented a 1.5- and
1.3-fold increase in their antiviral activity in relation to
acyclovir.
14
N
COOHCl
O
O
H
O
N
COOH
O
O
H
O
F
(24) (25)
He et al; by using a structure-based approach, a series of
novel quinazoline NNRTIs was designed and synthesized.
SAR studies revealed the critical role of the cyclopropane
moiety in positioning the substituents on the quinolone
nucleus for optimal interactions with the enzyme. The
ester moiety also plays an important role for the antiviral
activity. Several of these quinolones exhibited potent
inhibitory activity against the WT virus and showed
promising activity against several NNRTI resistant
mutants. These novel quinolones could serve as
advanced leads for further optimizations, the goal of
which will be focused on overcoming the NNRTI
resistant.
15
Corelli et al; aimed at rationalizing the influence on the
anti-IN activity of the different decorating elements
introduced on the 4-quinolone-3-carboxylic acid scaffold
allowed us to highlight new aspects of structure-activity
relationships for IN inhibiting quinolones. In particular,
the substitution of the benzyl group with aryl, stryl,
aroylamino, and aniline groups results in inactive
compounds that are not able to adopt the bioactive
conformation; conversely, the phenylthio group is able
to mimic quite efficiently the benzyl group. On the other
hand, the substitution of the benzyl group with the
electron-withdrawing benzoyl moiety gives compounds
that can be accommodated in the same orientation as
the active molecules within the binding site but show a
reduced chelating ability. Finally, the replacement of the
benzene ring of the quinolone with a quinone moiety
gives compounds that, with the exception of (22), adopt
a different orientation in the binding site and likely act
through a pure ST inhibition mechanism.
16
1.5.5 FMS kinase inhibitors activity
17
Illig et al; synthesized some novel 3, 4, 6-substituted 2-
quinolones and evaluated them as FMS kinase inhibitors.
The macrophage colony-stimulating factor-1 receptor
(FMS) is the cell surface receptor for colony-stimulating
factor-1 (CSF-1), which controls growth and
differentiation of the monocytes macrophage lineage.
Macrophages are thought to play an important role in
several diseases, including cancer and inflammation. In
addition, expression of FMS in breast cancer has been
linked to poor survivability and increased size, where
presumably the receptor is involved in local invasion and
metastasis. Consequently there is significant interest in
modulating the CSF-1 pathway and several structural
classes of small-molecule inhibitors of FMS have been
synthesized. The most active compound was the 1, 7-
naphthyridine-2-one (26).
International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446
Available online on www.ijprd.com
170
NN
C
6
H
5
Cl
H
O
N
O
1.5.6 Anti tumor activity
18
You et al; synthesized a series of quinolone derivatives
containing benzimidazole, benzoxazole or benzothiazole
ring. The cytotoxocity of 12 new compounds was
evaluated in KB, Bel7402, A2780 and HT-29 cell lines.
Most of synthesized compounds showed moderate
inhibitory activity against cancer cells. The inhibitory
activities of (27), against KB and A2780 tumor cells are
comparable to that of topotecan, one of topoisomerase I
inhibitors. The inhibitory activities of (27) against KB
(IC50 = 1.31 mmol/L) and A2780 (IC50 = 0.62 mmol/L)
tumor cells are comparable to topotecan (IC50 = 0.57;
2.14 mmol/L), one of topo I inhibitors.
N
O
NO
C
2
H
5
F
(27)
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