Quinolone dimers as potential antibacterial agents

Article abstract of DOI:10.2174/157017811799304322

A series of novel 6-fluoro1,4-dihydro-4-oxo-3-quinoline carboxylic acid dimers (34-37), were synthesized as potential antibacterial agents from commercially available fluoro benzoic acids.

Full text of DOI:10.2174/157017811799304322

Letters in Organic Chemistry, 2011, 8, 637-643
637
Quinolone Dimers as Potential Antibacterial Agents
Naveenkumar R. Chepyalaa, Rajashaker R. Durgia, Lakshmi K. Tatinia,
Gottumukkala V. Subbarajua, Rama M. Hindupur*,a and Muralimohan R. Dhanvadab
aAptuit Laurus Private Limited, ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad-500078, India
bDepartment of Chemistry, College of Engineering, J N T University, Kakinada-533003, India
Received December 06, 2010: Revised March 09, 2011: Accepted August 11, 2011
Abstract: A series of novel 6-fluoro1,4-dihydro-4-oxo-3-quinoline carboxylic acid dimers (34-37), were synthesized as
potential antibacterial agents from commercially available fluoro benzoic acids.
Keywords: 2,3,4,5-Tetraflurobenzoic acid, 2,4,5-Trifluoroacetophenone, anti bacterial agents, regiospecific dimeric
cyclisation, STERMOL length, quinoline carboxylic acid dimers.
INTRODUCTION
diaminocyclohexane was used as a model to restrict the free
rotation across the linker. In case of 1,2-diaminocyclo-
hexane, the carbon attached to the N-1 (either side) is a
secondary carbon as in N-1 cyclopropyl of ciprofloxacin.
Linker part of methylene groups is metabolically stable since
these two methylenes are non-benzylic as in lomefloxacin,
norfloxacin and ciprofloxacin. The details of the synthesis of
the dimers are presented below.
1,4-dihydro-4-oxo-6-fluoroquinoline-3-carboxylic acids
and its ester derivatives are of quinolone class of anti-
bacterial agents [1], which are effective against a variety of
gram-negative
microorganisms.
A
number
of
fluoroquinolone subclass of antibacterial agents such as
pefloxacin, norfloxacin, ofloxacin, ciprofloxacin, fleroxacin,
lomefloxacin, sparfloxacin are in clinical use. Since there is a
continuous
demand
of
new
antibacterial
and
fluoroquinolones, many researchers [2] have been working
on modified quinolones to potentiate them further and avoid
the resistance to currently available clinical agents [3]. We
report in this note, a general synthesis to prepare N1-
quinolone dimers (Fig. 1) as potential new antibacterial
agents.
RESULTS AND DISCUSSION
Synthesis of Fluoro Quinolone Dimers
An exploratory synthesis of N1-dimer analogues of 6-
fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid deriva-
tives starting from substituted acetophenone was
demonstrated successfully with an improvement of overall
yields by 10-20%. In general, fluoro quinolones were
prepared from commercially available substituted
fluorobenzoic acids as shown in Scheme 1. Both the methods
(where R = H) have been used to make these N1-dimers to
compare the overall yields and it has been observed that
acetophenone (Scheme 2) method is better than benzoic acid
(Scheme 1) method. In benzoic acid method the isolated
overall yields were 40 % (for tri fluorobenzoic acids, for
similar analogues in literature [7] the overall yields were
reported up to 60-70%) with the use of acetophenone method
the isolated overall yields were around 81 % until formation
of acrylates 7.
As a number of quinolone anti-bacterials contain 1,4-
dihydro-4-oxo-3-quinolinecaroboxylic acid as
a
basic
scaffold, in general most of the modifications were carried
on C-7 of quinolone and N1 of the quinolone to enhance
their activity. The literature [4] reports show that,
Quantitative Structure-Activity Relationship (QSAR) studies
of 1,4-dihydro-4-oxo-3-quinolinecaroboxylic acids will be
enhanced if N1 atom contains a substitution with an
optimum STERIMOL length of 0.42 nm, which is
approximately equivalent to an ethyl group [5]. The
Structure Activity Studies (SAR) indicate the substitution at
N-1 position is important for its bioavailability [6].
Keeping the above points in mind we have synthesized
Substituted fluorobenzoic acids 1-3 were converted into
corresponding acid chlorides 4-6 using thionyl chloride at
reflux. The corresponding acid chlorides were condensed
with ethyl 3-(dimethylamino) acrylate to produce acrylates
7-9 in about 33-35 % overall yield [7-8].
N1-quinolone dimers with
two carbon linkers.
Pharmacokinetic studies indicate that the aryl substitution at
N1 position will enhance the bioavailability of the quinolin-
3-carboxylic acids [4]. Keeping a substitution at N1-position
having a STERIMOL length of 0.42 nm as an important
parameter, the linkers such as 1,2-diaminoethane and 1,2-
diaminocyclohexane were used to prepare the dimers. 1,2-
2,4,5-trifluoroacetophenone 10 was treated with diethyl
carbonate in the presence of sodium hydride at ambient
temperature, resulted the ethyl 2,4,5 triflurobenzoyl acetate
11 with a yield of 90% [9]. Treatment of this aceto acetate
with N,N-dimethylformamide dimethylacetal (DMF-DMA)
as a neat reaction at 50-55°C gave the acrylate derivative 7
with a high yield of 90%. In general DMF-DMA reactions
*Address correspondence to this author at the Aptuit Laurus Private
Limited, ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad-
500078, India; Tel: +91-40-30413354; Fax: +91-40-23480481;
E-mail: mohan.hindupur@aptuitlaurus.com
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

638 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Chepyala et al.
O
N
O
F
ONa
R1
F
F
R1
F
N
O
ONa
O
N
N
R1 =
CH3
N
NH
N
NH
N
N
H
Fig. (1).
O
F
O
O
F
O
N
Ethyl-3-(dimethylamino)
acrylate/ TEA/ Toluene
F
F
F
F
F
F
SOCl2/ DMF/ Toluene
55-60oC, Y: 75-92%
OH
Cl
OC2H5
55-60oC, Y: 30-48%
F
R
R
R
4 R = H
5 R = F
1 R = H
2 R = F
7 R = H
8 R = F
6 R = OCH3
3 R = OCH3
9 R = OCH3
Scheme 1. Synthesis of acrylates.
O
F
O
O
O
F
O
(C2H5O)2CO,
NaH
F
DMF-DMA
F
F
F
OC2H5
OC2H5
50-55oC, 2h
Y: 91%
Y: 90%
F
N
F
F
10
Scheme 2. Synthesis of acrylates.
11
7
will be carried out in solvents, here we report at first as neat
reaction on acetoacetates, by which the yield of the reaction
has been improved to 90%.
N1-dimers
of
6,7-difluoro-1,4-dihydro-4-oxo-3-
quinolinecarboxylates 15, 16 and 17 were hydrolyzed using
aqueous sodium hydroxide in THF at reflux temperature for
4 hours to give the corresponding diacids 18, 19 and 20.
These diacid dimers are not soluble in common organic
solvents and sparingly soluble in polar solvents such as N,N-
dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).
Compound 18 was not even soluble in DMSO. The
corresponding sodium salt of compound 18 was not stable
enough, hence it was unable to record 1H-NMR for
compound 18, but characterized only by mass. Where as
Synthesis of Ethyl Linker Fluoro Quinolone N1-Dimers
Acrylates 7, 8 and 9 were treated with half equivalent of
1,2 diamino ethane in acetonitrile at ambient temperature
results in the formation of dimeric enamine ketoesters 12, 13
and 14. It has been demonstrated at first the regiospecific
dimeric cyclisation to form favored 6-membered ring to
satisfy the Baldwin rules [10] in acetonitrile in the presence
of base like cesium carbonate, which resulted in N1-dimers
of 6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylates
15, 16 and 17 (Scheme 3). It was found that cesium
carbonate resulted better yields than potassium carbonate and
triethyl amine. All the three compounds were characterized
1
compounds 19 and 20 were characterized by both H-NMR
and Mass. To minimize the polarity of compound 18,
preparation of mono-acid with compound 15 using NaOH or
aq. HCl, failed and always isolated product as diacid 18.
Compound 18 was treated with piperizine in N-methyl
pyrrolidinone (NMP) at 800C for 4h to result compound 29
which was isolated as free solid. Compound 29 is again not
soluble in DMF or in DMSO. Hence, it was converted to
1
by H-NMR and Mass. Due to poor solubility the 13C-NMR
was not recorded.

Quinolone Dimers as Potential Antibacterial Agents
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
639
O
F
O
O
O
F
F
F
F
OC2H5
OC2H5
O
F
O
N
Ethylenediamine
ACN
F
F
NH
N
O
Cs2CO3/ ACN
Reflux, 4 h, Y: 80-85%
R
R
R
R
RT, 3 h, Y: 50-65%
F
F
NH
O
F
F
N
O
R
OC2H5
OC2H5
F
O
O
7 R=H
8 R=F
9 R=OCH3
12 R=H
13 R=F
14 R=OCH3
15 R=H
16 R=F
17 R=OCH3
20% NaOH soln./ THF
Amine
N-methylpyrrolidinone
80-85oC, 5 h
Reflux, 4 h, Y: 53-66%
Y: 55-60%
O
N
O
O
O
O
N
O
F
F
F
F
OH
ONa
OC2H5
R1
N
R1
Piperazine/ N-methylpyrrolidinone
20% NaOH soln./ MeOH
R
R
R
R
R
R
80-85oC, 5 h, Y: 63%
F
F
N
O
Reflux, 5 h, Y: 54-90%
ONa
R1
N
O
R1
F
N
O
OH
OC2H5
F
O
O
O
18 R=H
19 R=F
20 R=OCH3
29
34
R=H, R1=
R=F, R1=
N
N
N
N
N
NH
NH
N
R=F, R1=
R=F, R1=
30
N
NH
N
N
N
N
CH3
31
32
33
CH3
35
R=F, R1=
NH
R=F, R1=
R=F, R1=
NH
36
37
R=F, R1=
R=F, R1=
N
H
N
H
Scheme 3. Synthesis of ethyl linker fluoro quinolone N1-dimers.
sodium salt after treating with NaOH for characterization
using D2O for 1H-NMR. The 13C-NMR recorded for
compound 29 as disodium salt in D2O was not very clear.
1, 4-dihydro-4-oxo-6-fluoro-7-subsituted amino-quinoline-3-
carboxylic acids 34-37 (Scheme 3). All the above acids were
characterized by 1H-NMR, 13C-NMR and Mass.
For further enhancement of the activity of
fluoroquinolone dimers, fluorine at C-7 position of the
quinolone was replaced with various amines as shown in
Scheme 3. Displacement of C-7 fluorine on 16 with an
excess amount of piperazine, N-methyl piperazine, 2-methyl
piperazine or azabicyclononane in N-methyl pyrrolidinone at
80-85°C yielded respective C-7 substituted dimers 30-33. All
Synthesis of Cyclohexyl Linker Fluoro Quinolone N1-
Dimers
On the other hand compounds 8 and 9 (Scheme 4) were
treated with half equivalent of cyclohexyl-1, 2-diamine in
acetonitrile at reflux temperature, unfortunately this reaction
does not proceed. When, cesium carbonate was added the
reaction goes to cyclization at reflux temperature. Hence, the
open forms 21 and 22 were not isolated. The reaction goes to
completion when catalytic amount of silica gel was added in
1
these compounds were characterized by H-NMR, 13C-NMR
and Mass. Compounds 30-33 were treated with 0.4 N
sodium hydroxide in methanol at reflux resulted in dimers of

640 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Chepyala et al.
Table 1. Chemical Structures and Yields of Fluoro Quinolone N1-Dimers (15-37).
O
O
F
R3
R1
N
R
R
R2
R1
F
N
O
R3
O
Yielda %
-R 1
-R2
Comp.
-R 3
-R
15
16
17
18
19
20
F
F
F
F
F
F
C2H4
C2H4
C2H4
C2H4
C2H4
C2H4
OC2H5
OC2H5
OC2H5
OH
H
F
85%
80%
50%
56%
66%
53%
OCH3
H
OH
F
OH
OCH3
23
24
25
26
27
28
F
F
F
F
OC2H5
OC2H5
OC2H5, OH
OH
F
OCH3
F
50%
39%
44%
55%
50%
73%
OCH3
N
NH
OC2H5
OH
F
N
NH
F
29
30
31
N
OH
H
F
F
63%
60%
60%
NH
C2H4
C2H4
C2H4
N
NH
OC2H5
OC2H5
N
N
CH3
32
OC2H5
F
55%
C2H4
N
NH

Quinolone Dimers as Potential Antibacterial Agents
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
641
(Table 1). Contd…..
Yielda %
-R 1
-R2
Comp.
-R 3
-R
N
33
C2H4
OC2H5
F
55%
N
H
34
35
N
ONa
ONa
F
F
90%
54%
NH
C2H4
C2H4
N
N
CH3
36
37
ONa
ONa
F
F
66%
80%
C2H4
C2H4
N
NH
N
N
H
aIsolated yield.
O
O
O
F
O
F
F
F
F
OC2H5
OC2H5
O
F
O
N
N
NH
F
F
Cyclohexane-1,2-diamine
Cs2CO3/ ACN
OC2H5
R
R
R
R
Reflux, 30 min,
Y: 39-50%
F
F
N
F
F
F
NH
O
R
OC2H5
OC2H5
O
O
O
8 R = F
9 R = OCH3
23 R = F
24 R = OCH3
21 R = F
22 R = OCH3
Amine/ Pyridine
80-85oC, 6 h
6N HCl sol./ EtOH or
20% aq. NaOH soln./ THF
Y: 50%
Reflux, 2 h,
Y: 55%
O
O
O
O
F
F
R3
R3
N
N
R1
F
R
R
R
R
N
N
R1
F
F
R3
OH
O
F
O
O
O
R3 = OC2H5
27 R = F, R1 =
N
NH
25 R = F,
R3 = OC2H5
26 R = OCH3, R3 = OH
20% aq. NaOH soln./ MeOH
Reflux, 5 h
Y: 73%
R3 = OH
NH
N
28 R = F, R1 =
Scheme 4. Synthesis of cyclohexyl linker fluoro quinolone N1-dimers.

642 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Chepyala et al.
this cyclization reaction, that results in compounds 23 and
24. Compound 23 was treated with aq. HCl or NaOH in
ethanol at reflux resulted in mono-acid 25 in 44% isolated
yield and rest was starting material, and it was observed that
this was not converting in to di acid. The increase in the
basicity or temperature of the reaction is leading to
decomposition. Where as compound 24 was hydrolyzed
using aq. sodium hydroxide solution in the presence of THF
gave a di acid Compound 26 (Scheme 4) charecterized by
1H-NMR and Mass. Compound 23 was treated with amines
like piperazine in NMP at 800C resulted in Compound 27.
Compound 27 was treated with aq. NaOH in methanol at
reflux resulted in Compound 28.
Compounds (15-17 and 28) were insoluble in test
solution, hence activity test was not performed and
interestingly Compounds 20 and 26 do not show any activity
towards Gram negative and do show activity over Gram
positive. Compounds 18, 25, 29-33 do show activity towards
Gram negative and do not show activity over Gram positive.
Compounds 23, 24 and 27 were shown zero activity for both
the strains. All other compounds (19, 34-37) were shown
approximately half of the activity when compared with
standard (Ciprofloxacin).
CONCLUSION
1,4-dihydro-4-oxo-7-substituted
amino-6-fluoroquino-
line-3-carboxylic acids and its ester derivatives are effective
against a variety of gram negative microorganisms. Since
fluoro quinolinones are important and high demand
antibacterial agents, here we have explored the synthesis of
N1-quinolone dimer analogues. Keeping a substitution at
N1-position having a STERIMOL length of 0.42 nm with a
2-carbon chain linker as an important parameter, we have
used linkers such as 1, 2-diaminoethane and 1, 2-
diaminocyclohexane, to satisfy steric, special and electronic
interactions. 1, 2 diamino cyclohexane, was used to restrict
the free rotation across the linker to understand the
bioavailability as well as activity. The in-vitro antibacterial
activity result shows that these dimers are having moderate
activity when compared with Ciprofloxacin.
Antibacterial Activity
The in vitro antibacterial activity of the compounds were
tested in comparison with ciprofloxacin and determined by
conventional agar dilution procedure. Dimethylsulfoxide
(DMSO) was used to control negative. Here responses (Zone
of inhibition) of microorganisms to the synthesized
compounds were measured in mm and are compared with
the standard reference drug (i.e. Ciprofloxacin). The two
microorganisms used were Escherichia coli ATCC 8739
(Gram negative) and Staphylococcus aureus ATCC 6538
(Gram positive).
Table 2. In vitro Antibacterial Activity Fluoro Quinolone N1-
Dimers (18-20, 23-27, 30-37) Tested for Gram
Negative and for Gram Positive in DMSO (50 μg/100
μL) and the “Zone of Inhibition” Values are
Measured in mm. Ciprofloxacin was Used as a
Standard
ACKNOWLEDGEMENTS
We thank Dr. Satyanarayana C. and Dr. Mani Bushan K.
for their support.
Zone of inhibition in mm
Compound No
Escherichia coli
Staphylococcus aureus
SUPPLEMENTARY MATERIAL
18
14
16
0
0
10
12
0
Supplementary material is available on the publishers
Web site along with the published article.
19
20
23
0
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