Synthesis of N-arylquinolone derivatives bearing 2-thiophenoxyquinolines and their antimicrobial evaluation

Article abstract of DOI:10.1016/j.cclet.2014.04.002

A new series of 2-thiophenoxyquinolines based trifluoromethyl substituted N-aryl quinolone derivatives 8a-f and 9a-f have been synthesized via a one-pot multicomponent reaction. In vitro antimicrobial activity of the synthesized compounds was investigated

Full text of DOI:10.1016/j.cclet.2014.04.002

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Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Synthesis of N-arylquinolone derivatives bearing
2-thiophenoxyquinolines and their antimicrobial evaluation
*
Q1 Mehul B. Kanani, Manish P. Patel
5
6
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A new series of 2-thiophenoxyquinolines based trifluoromethyl substituted N-aryl quinolone derivatives
8a–f and 9a–f have been synthesized via a one-pot multicomponent reaction. In vitro antimicrobial
activity of the synthesized compounds was investigated against a representative panel of pathogenic
strains. Compounds 8c, 9c and 9e exhibited comparable antimicrobial activity to first line drugs.
ß 2014 Manish P. Patel. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Received 3 December 2013
Received in revised form 24 March 2014
Accepted 25 March 2014
Available online xxx
Keywords:
2-Thiophenoxyquinoline
Trifluoromethyl
N-aryl quinolone
Antimicrobial activity
7
8
1. Introduction
Over the past few years, we have been principally engrossed in 31
the synthesis of quinolone-containing structures for biological 32
9
Recently, multicomponent reactions (MCRs) have been shown to
provide an efficient access to highly complex products in a single step.
They have proven to be fast, convergent, atom-efficient reactions and
often required effortless purifications through give generally high
yields of products [1]. These reactions have emerged as a valuable tool
in the synthesis of drug libraries because they have greater advantages
over conventional strategies to synthesize biologically active com-
pounds with significant structural diversity [2]. Consequently,
designing novel MCRs to generate of diverse ‘‘drug-like’’ molecules
has been the focus of many medicinal chemists.
Since the discovery of norfloxacin by Koga et al. in the early
1980s [3], fluoroquinolones have been used extensively in clinic
because of their extremely potent activity, rapid bactericidal
effects, and low incidence of resistance development [4]. These
antibiotics exhibit properties like excellent bioavailability and a
relatively low incidence of adverse and toxic effects [5]. Also a large
number of fluoroquinolone derivatives have been designed and
synthesized, and structure activity relationship (SAR) has been
accumulated. Cyclopropyl (Ciprofloxacin) and mono/difluorophe-
nyl (Difloxacin or Temafloxacin) groups are generally considered
the most favorable substituents at the N-1 position of the 4-
quinolones [6,7].
evaluations [8–11] on the fact that the quinoline moiety is found in 33
a large variety of naturally occurring compounds diverse 34
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15
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bioactivities such as antibiotic [12], antimalarial [13], antituber- 35
culosis [14], antiHIV [15], anticancer [16], antihypertensive 36
properties [17]. Additionally, some known fluoroquinolones 37
antibiotics such as Ciprofloxacin, Delafloxacin, Sparfloxacin, 38
Temafloxacin, Difloxacin and Norfloxacin are well known drugs. 39
One of the best known drugs with a trifluoromethyl-quinoline 40
nucleus, the antimalarial drug mefloquine is still being used today 41
[18]. Also, a 5-quinolone derivative, 2-(benzylthio)-7,7-dimethyl- 42
5-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile act as mGlur1 43
Modulator [19] (Fig. 1).
44
In this study, we introduce substituted 2-thiophenoxyquino- 45
lines at the C-4 position and lipophilic groups, trifluoromethyl 46
substituted aromatic ring at the N-1 position on 5-quinolone to 47
probe biological activity. The synthesis of N-aryl quinolone bearing 48
2-thiophenoxyquinolines derivatives was based on the assump- 49
tion that the incorporation of more than one bioactive moiety into 50
a single scaffold may produce novel heterocycles with good 51
antimicrobial activity.
52
2. Experimental
53
All the reagents were obtained commercially and used without 54
further purification. Solvents used were of analytical grade. All 55
melting points were taken in open capillaries and were uncorrected. 56
*
Corresponding author.
E-mail address: patelmanish1069@yahoo.com (M.P. Patel).
http://dx.doi.org/10.1016/j.cclet.2014.04.002
1001-8417/ß 2014 Manish P. Patel. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: M.B. Kanani, M.P. Patel, Synthesis of N-arylquinolone derivatives bearing 2-thiophenoxyquinolines
and their antimicrobial evaluation, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.04.002

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M.B. Kanani, M.P. Patel / Chinese Chemical Letters xxx (2014) xxx–xxx
HN
O
N
O
NH2
O
N
O
HO
O
F
H
F
H
O
O
CN
S
N
N
N
HN
N
CF3
NH
HN
F
CF3
mGlur1 Modulator
H
Ciprofloxacin
Sparfloxacin
Mefloquine
O
N
O
O
N
O
O
N
O
F
F
H
F
F
H
O
O
O
N
N
N
N
Cl
F
HO
N
H2N
F
F
F
Difloxacin
Delafloxacin
Temafloxacin
Fig. 1. Example of biologically active quinoline derivatives.
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Thin-layer chromatography (TLC, on aluminum plates coated with
silica gel 60 F254, 0.25 mm thickness) (Merck, Darmstadt, Germany)
was used for monitoring the progress of all reactions, purity and
homogeneity of the synthesized compounds. UV radiation and/or
iodine were used as the visualizing agents. Elemental analysis (% C,
H, N) was carried out using a Perkin-Elmer 2400 series-II elemental
analyzer (Perkin-Elmer, USA) and all compounds are within ꢀ0.4% of
Perkin-Elmer Spectrum GX FT-IR Spectrophotometer (Perkin-Elmer,
USA) and only the characteristic peaks are reported in cmꢁ1 1H NMR
65
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70
71
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.
and 13C NMR spectra were recorded in DMSO-d6 on a Bruker Avance
400F (MHz) spectrometer (Bruker Scientific Corporation Ltd.,
Switzerland) using solvent peak as an internal standard at 400 MHz
and 100 MHz respectively. Chemical shifts are reported in parts per
million (ppm). Mass spectra were scanned on a Shimadzu LCMS 2010
spectrometer (Shimadzu, Tokyo, Japan).
theoretical values. The IR spectra were recorded in KBr on
a
Scheme 1. General synthetic route for the title compounds 8a–f and 9a–f.
Please cite this article in press as: M.B. Kanani, M.P. Patel, Synthesis of N-arylquinolone derivatives bearing 2-thiophenoxyquinolines
and their antimicrobial evaluation, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.04.002

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M.B. Kanani, M.P. Patel / Chinese Chemical Letters xxx (2014) xxx–xxx
3
Ar
N
Ar
N
Ar
Ar
H
H
H
H
CN
NC
HN
NC
NC
N
R2
N
Ar
CN
HN
H2N
N
O
-H2O
CF3
Ar = 6-substituted-2-(4-(sub)phenylthio)quinoline-3-carbaldehyde
CF3
CF3
CF3
Scheme 2. Plausible mechanistic pathway for the synthesis of 8a–f and 9a–f biquinoline.
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100
101
102
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The synthetic approach adopted to obtain 6-(un)substituted-2-
((4-(un)substituted phenyl)thio)quinoline-3-carbaldehydes 4a–f
is shown in Scheme 1. The starting material 2-chloro-3-formyl
quinolines 2a–b were prepared by the Vilsmeier–Haack reaction
[20] from acetanilides 1a–b and were conveniently converted into
4a–f by nucleophilic displacement of chloro group at C-2 in 1a–d
with 4-(un)substituted thiophenols 3a–c in the presence of
anhydrous K2CO3 in DMF at 120 8C for 2 h.
Gram-positive and three Gram-negative bacteria as well as two 104
fungi were carried out by the broth microdilution method 105
according to National Committee for Clinical Laboratory Standards 106
(NCCLS) [21].
107
3. Results and discussion
108
The required
b
-enaminones 5 were prepared by the reaction of
The values of the MIC against microorganisms showed that 109
these compounds have significant inhibitory effects. The antibac- 110
terial data indicate that the synthesized compounds are more 111
effective against Gram-positive strains. It shows that lipophilic 112
character of the molecules plays an important role in their 113
antimicrobial effect. Among them compound 9c was found to be 114
more active than the comparator against Gram-positive bacterium 115
S. pneumoniae. Compounds 8a, 8c, 8d and 8d showed promising 116
activity against B. subtilis. Compounds 8b and 9d showed moderate 117
activity against S. pneumoniae. Compounds 8a exhibited good 118
activity toward C. tetani. Compound 8c, 9e and 9f were found to be 119
equipotent against Gram-negative bacterium S. typhi. Except 120
compounds 8b and 9b (R1 = H and R2 = CH3), all the compounds 121
displayed good to excellent inhibitory effects against C. tetani. Also, 122
compounds 8c and 9e exhibited significant potency against Gram 123
negative bacterium E. coli as benchmarked by ampicillin 124
5,5-dimethylcyclohexane-1,3-dione with trifluorinated aromatic
amines according to the literature procedures [10]. Subsequently,
the one-pot three-component cyclocondensation of a series of
4a–f,
b-enaminones 5 and malononitrile 6 or isopropyl cyanoa-
cetate 7 in ethanol containing a catalytic amount of piperidine
afforded the targeted compounds 8a–f and 9a–f in good to
excellent yields.
A plausible mechanism for the reaction is provided in Scheme
2. The heterylidenenitrile, containing an electron-poor C55C
double bond is produced, from the Knoevenagel condensation
between 4a–f and malononitrile 6 or isopropyl cyanoacetate 7
followed by dehydration. Michael addition of
b-enaminone 5 to
the ylidenic bond forms an acyclic intermediate, which cyclizes
by nucleophilic attack of the NH group on the cyano carbon. The
subsequent tautomerisation gives the final products 8a–f and
9a–f.
(MIC = 100
m
g/mL).
125
The MICs of synthesized compounds 20-amino-70,70-dimethyl-
50-oxo-2-((4-sub)phenylthio)-10-(3-(trifluoromethyl)phenyl)-
10,40,50,60,70,80-hexahydro-[3,40-biquinoline]-30-carbonitrile 8a–f
and isopropyl 20-amino-70,70-dimethyl-50-oxo-2-((4-sub)phe-
nylthio)-10-(3-(trifluoromethyl)phenyl)-10,40,50,60,70,80-hexahy-
In vitro antifungal activity of the synthesized quinolyl-quino- 126
lone derivatives are summarized in Table 1. Compound 9d was 127
endowed promising activity, while the compounds 8b and 9f 128
showed moderate activity against A. fumigatus. Unfortunately, 129
none of the synthesized compounds were found sufficiently potent 130
dro-[3,40-biquinoline]-30-carboxylate
9a–f
against
three
in inhibiting fungal pathogen C. albicans.
131
Table 1
Antimicrobial activity results of compounds 8a–f and 9a–f against various microorganisms (MIC,
mg/mL).
Compd.
R1 R2 Gram-positive bacteria
Gram-negative bacteria
Fungi
Bacillus subtilis Streptococcus pneumoniae Clostridium tetani Escherichia coli Salmonella typhi Vibrio cholerae Candida albicans Aspergillus fumigatus
MTCC 441
100
MTCC 1936
MTCC 449
MTCC 443
MTCC 98
MTCC 3906
MTCC 227
MTCC 3008
8a
H
H
250
100
250
250
250
200
200
250
62.5
100
250
250
100
10
100
500
250
500
200
250
250
500
200
200
250
500
250
50
100
250
62.5
100
100
100
200
200
500
200
62.5
125
100
10
250
250
100
200
250
200
200
250
500
250
100
100
100
10
500
500
500
500
200
250
250
250
200
200
250
500
100
10
500
1000
200
1000
500
8b
H
CH3 250
Cl 100
8c
H
>1000
>1000
>1000
500
8d
CH3
H
100
250
8e
CH3 CH3 500
CH3 Cl 250
>1000
250
8f
9a
H
H
250
500
>1000
1000
1000
250
9b
H
CH3 250
Cl 200
1000
500
9c
H
9d
CH3
H
100
>1000
500
9e
CH3 CH3 250
1000
1000
–
9f
CH3 Cl 200
>1000
–
Ampicillin
Norfloxacin
Griseofulvin
250
100
–
–
–
–
–
–
–
–
100
500
MTCC: microbial type culture collection; –: not tested.
Please cite this article in press as: M.B. Kanani, M.P. Patel, Synthesis of N-arylquinolone derivatives bearing 2-thiophenoxyquinolines
and their antimicrobial evaluation, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.04.002

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[7] (a) J.A. Makawana, M.P. Patel, R.G. Patel, Synthesis and in vitro antimicrobial
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4. Conclusion
activity of N-arylquinoline derivatives bearing 2-morpholinoquinoline moiety,
Chin. Chem. Lett. 23 (2012) 427–430;
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In conclusion, the aim of the present investigation was to design
and synthesis of 5-quinolone derivatives by introducing substi-
tuted 2-thiophenoxyquinolines at the C-4 position and diversely
trifluoromethyl substituted phenyl ring at N-1 position to probe
antimicrobial activity. Modification of substituents on both 2-
thiophenoxyquinolines ring and N-aryl quinolone ring with
various electron donatig and electron withdrawing groups
improved the activity. Compounds 8c, 9c and 9e exhibited
excellent antimicrobial activity. Finally, these compounds repre-
sent new scaffolds that could be further optimized to produce
more potent and selective antimicrobial agents.
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Acknowledgments
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The authors are thankful to Prof. H. S. Patel, Head, Department
of Chemistry, Sardar Patel University for providing 1H NMR, 13C
NMR spectroscopy and research facilities. We are also thankful to
PURSE central facility for mass spectrometry sponsored by DST,
New Delhi, Vaibhav Laboratories, Ahmedabad, Gujarat, India for
the FT-IR, SICART, Vallabh Vidyanagar, for elemental analysis and
Dhanji P. Rajani, Microcare Laboratory, Surat, Gujarat, India for
antimicrobial and antituberculosis screening of the compounds
reported herein. One of the authors (M.B. Kanani) is grateful to
UGC, New Delhi for Research Fellowship in Sciences for Meritori-
ous Students.
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Please cite this article in press as: M.B. Kanani, M.P. Patel, Synthesis of N-arylquinolone derivatives bearing 2-thiophenoxyquinolines
and their antimicrobial evaluation, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.04.002