Synthesis and characterization of some new quinoline based derivatives endowed with broad spectrum antimicrobial potency

Article abstract of DOI:10.1016/j.bmcl.2012.09.039

The synthesis of a novel series of 2-(5-(2-chloro-6-fluoroquinolin-3-yl)-3- (aryl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-ones (4a-l) and N-(4-(2-chloro-6-fluoroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl) -2-morpholinoacetamides (7a-l) are described in the present paper. The chemical structures of compounds have been elucidated by IR, ¹H NMR, ¹³C NMR and mass spectral data. Antimicrobial activity was measured against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), Candida albicans (MTCC 227), Aspergillus niger (MTCC 282) and Aspergillus clavatus (MTCC 1323) by serial broth dilution. Evaluation of antimicrobial activity showed that several compounds exhibited greater activity than reference drugs and thus could be promising new lead molecules.

Full text of DOI:10.1016/j.bmcl.2012.09.039

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6871–6875
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and characterization of some new quinoline based derivatives
endowed with broad spectrum antimicrobial potency
⇑
Nisheeth C. Desai , Kiran M. Rajpara, Vivek V. Joshi
Division of Medicinal Chemistry, Department of Chemistry, Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar 364 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2012
Revised 2 September 2012
Accepted 12 September 2012
Available online 21 September 2012
The synthesis of a novel series of 2-(5-(2-chloro-6-fluoroquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H-pyrazol-
1-yl)thiazol-4(5H)-ones (4a–l) and N-(4-(2-chloro-6-fluoroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-
2-morpholinoacetamides (7a–l) are described in the present paper. The chemical structures of com-
pounds have been elucidated by IR, 1H NMR, 13C NMR and mass spectral data. Antimicrobial activity
was measured against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus
aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), Candida albicans (MTCC 227), Aspergillus niger
(MTCC 282) and Aspergillus clavatus (MTCC 1323) by serial broth dilution. Evaluation of antimicrobial
activity showed that several compounds exhibited greater activity than reference drugs and thus could
be promising new lead molecules.
Keywords:
Vilsmeier–Haack reaction
Quinoline
Pyrazoline
Thiazolidinone
Pyrimidine
Ó 2012 Elsevier Ltd. All rights reserved.
Morpholine
Antimicrobial activity
The current interest in the development of new antimicrobial
agents can be partially ascribed both to the increasing emergence
of bacterial resistance to antibiotic therapy and to newly emerging
pathogens.1,2 Over the past few years, we have been principally en-
grossed in the synthesis of quinoline incorporating structures for
antimicrobial evaluations3 on the premise that quinoline moiety
is found in a large variety of naturally occurring compounds. In
fact, introducing chloroquine into treatment of malaria more than
60 years ago triggered a new era of quickly developing antimicro-
bial drugs. In synthetic medicinal chemistry the quinoline motif
is widely exploited revealing a spectrum of activity covering
antimalarial,4 anticancer,5 antifungal, antibacterial, antiprotozoic
antibiotic,6 and anti-HIV7 effects. Moreover, 2-pyrazoline and
thiazolidinone derivatives have been reported to exhibit various
pharmacological activities such as antimicrobial,8 anti-inflamma-
tory9 and antihypertensive.10 The design concepts have been
drawn in Figure 1, which explains the structural similarity of our
new target compounds with renowned drugs.
groups such as chloro, nitro, methoxy, fluoro etc at positions 3
and 6 of pyrazoline and pyrimidine ring ‘respectively’. It has been
hoped that combination of these active groups in the new molecu-
lar design would lead to better antimicrobial agents. In continua-
tion of our research activity on quinoline derivatives, several
compounds were prepared and tested against bacteria and fungi,
potent compounds are given in Table 1.
In this communication, we report the synthesis of newly
developed two series of compounds 2-(5-(2-chloro-6-fluoroquino-
lin-3-yl)-3-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-ones
(4a–l) and N-(4-(2-chloro-6-fluoroquinolin-3-yl)-6-(aryl)pyrimi-
din-2-yl)-2-morpholinoacetamides (7a–l) starting from 2-chloro-
6-fluoroquinoline-3-carbaldehyde (1).
The Vilsmeier–Haack reaction on acetanilide provided a vital
and efficient intermediate for synthesis of several newer substi-
tuted heterocyclic compounds. The reaction was performed at
100 °C for 15–20 h, using typical Vilsmeier-Haack reagent derived
from phosphorus oxychloride-dimethylformamide.12 Although,
the reaction proceeded uneventfully, products formed were
isolated using silica gel column chromatography. The reaction se-
quences employed for synthesis of target compounds (4a–l) and
(7a–l) are illustrated in Scheme 1. Key chalcone intermediates
(2a–l) were synthesized through Claisen–Schmidt condensation
of equimolar amounts of acetophenone derivatives and 2-chloro-
6-fluoroquinoline-3-carbaldehyde (1) by stirring the reactants in
aqueous ethanolic solution containing 20% sodium hydroxide at
room temperature for 24 h.13 Newly synthesized compounds
As quinoline compounds are known to be effective antimicro-
bial compounds,11 we initiated a program to synergies the antimi-
crobial activity of quinoline and other reported heterocycles by
preparing hybrid molecules having the features of these scaffolds
in an effort to discover potent antimicrobial. To derivatize the
resulting heterocyclic system, we have used several functional
⇑
Corresponding author. Tel./fax: +91 278 2439852.
E-mail address: dnisheeth@rediffmail.com (N.C. Desai).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.09.039

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N. C. Desai et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6871–6875
Cl
N
HN
N
O
S
N
O
N
N
NH
Cl
Chloroquine
Ibipinabant
N
NH
2
N
O
NH
2
O
N
N
O
H
N
H CO
OCH
3
3
F
Br
O
Linezolid
Brodiprim
Figure 1. Structure of drugs containing reported heterocycles.
Table 1
Structures and antimicrobial activity of promising compounds
Compounds
Microorganisms
MIC,
25
lg/mL
S
O
O
N
N
N
N
4i
4j
S. pyogenes
F
N
Cl
F
S
P. aeruginosa
S. pyogenes
A. niger
12.5
25
25
N
N
NO2
F
F
A. clavatus
12.5
N
N
Cl
Cl
F
E. coli
P. aeruginosa
A. clavatus
12.5
25
25
N
N
7g
HN
O
N
O
NO2
N
Cl
N
F
N
7l
E. coli
25
HN
N
O
O
5-(2-chloro-6-fluoroquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H-pyra-
zole-1-carbothioamides (3a–l) were obtained by heating at reflux
equimolar amounts of thiosemicarbazide and the corresponding
6-(aryl)pyrimidin-2-yl)acetamides (6a–l) were synthesized by
electrophilic substitution reaction of chloroacetyl chloride with
corresponding parent 4-(2,6-dichloroquinolin-3-yl)-6-(aryl)pyrim-
idin-2-amines (5a–l) in presence of triethylamine as base and
toluene as solvent.17 Condensation of 2-chloro-N-(4-(2,6-dichloro-
a,b-unsaturated ketones (2a–l) in hot ethanolic sodium hydroxide
solution for 8 h (Scheme 1).14 Moreover, aforementioned 1-
thiocarbamoyl pyrazole derivatives (3a–l) were cyclized to (4a–l)
through their reaction with ethyl bromoacetate in hot ethanol for
1 h.15 When 3-(2-chloro-6-fluoroquinolin-3-yl)-1-(aryl)prop-2-
en-1-ones (2a–l) were refluxed with guanidine nitrate in presence
quinolin-3-yl)-6-(aryl)pyrimidin-2-yl)acetamides
(6a–l)
with
morpholine in presence of anhydrous potassium carbonate fur-
nished N-(4-(2,6-dichloroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-
2-morpholinoacetamides (7a–l).18
of
6-(aryl)pyrimidin-2-amines (5a–l) were formed.16 Various
substituted 2-chloro-N-(4-(2-chloro-6-fluoroquinolin-3-yl)-
sodium
hydroxide,
4-(2-chloro-6-fluoroquinolin-3-yl)-
All the newly synthesized compounds were evaluated against
Gram-positive bacteria (Staphylococcus aureus, Staphylococcus
pyogenes), Gram-negative bacteria (Escherichia coli, Pseudomonas

N. C. Desai et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6871–6875
6873
S
O
H2N
N
Cl
N
R
F
N
N
(a)
(c)
R
F
F
N
Cl
R
N
(2a-l)
N
Cl
NH2
(5a-l)
(3a-l)
(b)
(d)
N
R
N
Cl
N
R
N
Cl
N
(e)
S
O
F
F
N
N
N
N
F
HN
O
HN
O
R
N
(4a-l)
Cl
N
Cl
(6a-l)
O
R = -H, -2-OH, -4-OH, -4-OCH3, -2-Cl, -4-Cl,
-2-F,- 3-F, -4-F, -2-NO2, -3-NO2, -4-NO2
(7a-l)
(a) NH2CSNHNH2, Ethanol, Reflux 8 h (b) BrCH2COOC2H5, Ethanol, Reflux 1 h (c) NH2C(=NH)NH2. HNO3,
Ethanol, Reflux 10 h, NaOH (d) ClCH2COCl, Chloroform, Reflux 12 h, Et3N (e) Morpholine, Dry toluene, Reflux
8 -10 h, Anhyd. K2CO3
Scheme 1. Synthetic scheme for the title compounds 4a–l and 7a–l.
aeruginosa) and fungi (Candida albicans, Aspergillus niger and Asper-
gillus clavatus) strains. Individual minimum inhibitory concentra-
inhibition against three fungal strains. Among tested compounds,
4h (3-F) and 4j (2-NO2) from pyrazole series and compounds 7g
(2-F), 7i (4-F), 7j (2-NO2) and 7l (4-NO2) from pyrimidine series
displayed significant inhibition compared to other compounds at
tion (MIC,
lg/mL) values of tested compounds (4a–l) and (7a–l)
against the test microbes are listed in Table 2 along with MIC
values of reference compounds ciprofloxacin (for bacteria) and
griseofulvin (for fungi). Results revealed that majority of synthe-
sized compounds showed varying degrees of inhibition against
the test panel of species. The obtained antimicrobial activity of
tested compounds could be correlated to structural variations
and modifications. Key precursors, chalcones (2a–l) showed poor
antimicrobial activity. Compounds (3a–l) displayed moderate to
mild antibacterial activity. Finally, cyclized target molecules
(4a–l) showed significant to potent activity. On the other hand
pyrimidine counterparts (5a–l) and (6a–l) did not significantly af-
fect the antimicrobial potential and showed poor antibacterial
activity. Compounds (7a–l) led to a noticeable improvement in
the antimicrobial activity. Collectively, compounds (4a–l) and
(7a–l) could be considered as significant to potent active broad
spectrum antimicrobial agents identified in this study. Compounds
4g (2-F) and 4j (2-NO2) of pyrazole series and compounds 7g (2-F)
and 7l (4-NO2) of pyrimidine series showed excellent activity
against E. coli. Amongst them, compound 7g (2-F) was potent at
MIC = 100
highest inhibition at MIC = 25
pound 4j (2-NO2) showed excellent potency at MIC = 25
and MIC = 12.5 g/mL against A. niger and A. clavatus respectively
which were more potent than griseofulvin. The comparison of anti-
bacterial and antifungal activity was discussed on the basis of stan-
dard drugs ciprofloxacin and griseofulvin, ‘respectively’.
l
g/mL against C. albicans. Compound 7g (2-F) exhibited
g/mL against A. clavatus. Com-
g/mL
l
l
l
Antimicrobial activity (Table 2) revealed that target compounds
(4a–l) and (7a–l) represented broadly potent molecules. Presence
of a phenyl group (compounds 4a and 7a) did not seem to make
either a negative or a positive contribution to antimicrobial activity
against any of the analyzed microorganisms. Comparison of com-
pounds 4a–l and 7a–l with other derivatives also pointed out that
existence of electron withdrawing group at position 2 and 4 of the
benzene ring in both core structures was essential. Compounds
containing 2-NO2, 4-NO2, 2-F and 4-F exhibited pronounced activ-
ity. Presence of 2-NO2 and 2-F group caused enhancement in anti-
microbial activity against analyzed microorganisms. In fact, in case
of P. aeruginosa and A. clavatus, it even boosted antimicrobial activ-
ity. Amongst all synthesized compounds fluoro derivatives at sec-
ond and fourth position also exerted significant activity. This
attributed to smaller size of fluorine atom, which may give stability
to compound and reduce ring strain. In both serieses, compounds
containing hydrophilic substituents hydroxy and methoxy did
not lead to show potent antimicrobial effect but strongly reduced
the activity. In summary, compounds from both of these new clas-
ses of antimicrobial agents showed promising in vitro antibacterial
and antifungal activities.
MIC = 12.5
series and 7g (2-F) of pyrimidine series possessed highest inhibi-
tion against P. aeruginosa at MIC = 12.5 g/mL and MIC = 25 g/mL
respectively. Compounds 4f (4-Cl), 7g (2-F) and 7j (2-NO2) were
equipotent to ciprofloxacin at MIC = 50 g/mL against S. aureus.
Compounds 4i (4-F) and 4j (2-NO2) were more potent than stan-
dard drug at MIC = 25 g/mL, while compounds 7g (2-F) and 7j
lg/mL against E. coli. Compound 4j (2-NO2) of pyrazole
l
l
l
l
(2-NO2) were equipotent to ciprofloxacin at MIC = 50 lg/mL
against S. pyogenes.
MIC values of antifungal activity showed similar trend as anti-
bacterial activity. Intermediates exhibited poor or no activity
against all the tested panel of fungal strains. Introduction of thiazo-
lone and morpholine moiety afforded compounds to display good
In conclusion, in the present article, we have reported the syn-
thesis, characterization and antimicrobial activity of some new ser-
ies of quinoline based pyrazoline and pyrimidine derivatives.

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N. C. Desai et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6871–6875
Table 2
Results of antibacterial and antifungal screening of compounds 4a–l and 7a–l
R
N
Cl
N
S
O
F
N
N
N
N
F
HN
O
R
N
Cl
N
(4a-l)
O
(7a-l)
Comp
–R
Minimum Inhibitory Concentration (MIC) for bacteria (
lg/mL)
Minimum Inhibitory Concentration (MIC) for fungi (lg/mL)
Gram-negative
Gram-positive
E. coli
P. aeruginosa
S. aureus
S. pyogenes
C. albicans
A. niger
A. clavatus
MTCC 443
MTCC 1688
MTCC 96
MTCC 442
MTCC 227
MTCC 282
MTCC 1323
4a
4b
4c
4d
4e
4f
4g
4h
4i
–H
500
250
500
1000
50
500
25
500
50
250
500
250
1000
100
250
50
500
1000
500
500
250
50
100
500
100
100
1000
250
500
500
1000
500
100
250
50
1000
500
250
1000
50
1000
1000
1000
1000
500
500
250
100
1000
100
500
250
1000
1000
500
1000
500
250
100
250
100
100
250
100
—
1000
1000
500
500
100
50
500
1000
1000
500
50
100
500
500
100
12.5
50
100
250
500
1000
500
100
100
25
250
100
100
500
50
–2-OH
-4-OH
–4-OCH3
–2-Cl
–4-Cl
–2-F
50
100
500
25
25
500
50
250
500
1000
250
100
100
50
250
100
50
50
–3-F
–4-F
250
50
500
250
25
4j
4k
4l
–2-NO2
–3-NO2
–4-NO2
–H
–2-OH
–4-OH
–4-OCH3
–2-Cl
–4-Cl
–2-F
–3-F
–4-F
–2-NO2
–3-NO2
–4-NO2
Ciprofloxacin
Griseofulvin
25
250
50
12.5
500
100
500
500
1000
250
100
50
25
100
50
100
100
50
100
100
500
250
500
250
100
100
50
250
100
50
100
100
—
7a
7b
7c
7d
7e
7f
7g
7h
7i
250
1000
500
500
50
100
12.5
100
50
100
250
25
25
—
250
100
50
250
100
50
7j
7k
7l
100
100
50
25
—
—
100
—
—
500
100
Preliminary in vitro results of antimicrobial screening of the title
compounds, reported here, evidenced that some of the compounds
from both new series have emerged as potential lead antimicrobials
endowed with significant to potent activity. Further improvements
in activity can possibly be achieved by slight modifications in the
ring substituents. Yet, extensive additional functioning warrants
further investigations. Finally, clinical potential of these types of
compounds awaits the results of additional structure activity stud-
ies and the in vivo evaluation of their efficacies. Our findings will
have impact on medicinal chemists and pharmacists for further
investigations in this field for search of potent antimicrobial agents.
Characterization data and antimicrobial assay of all synthesized
compounds are described in supplementary data file.
References and notes
1. Cohen, M. L. Nature 2000, 406, 762.
2. Barrett, C. T.; Barrett, J. F. Curr. Opin. Biotechnol. 2003, 14, 621.
3. Desai, N. C.; Maheta, A. S.; Rajpara, K. M.; Joshi, V. V.; Vaghani, H. V.; Satodiya,
H. M. J. Saudi Chem. Soc. 2011. http://dx.doi.org/10.1016/j.jscs.2011.11.021.
4. Nasveld, P.; Kitchener, S. Trans. R. Soc. Trop. Med. Hyg. 2005, 99, 2.
5. Denny, W. A.; Wilson, W. R.; Ware, D. C.; Atwell, G. J.; Milbank, J. B.; Stevenson,
R. J. U.S. Patent 7,064,117, June 20, 2006.
6. Mahamoud, A.; Chevalier, J.; Davin-Regli, A.; Barbe, J.; Pages, J. M. Curr. Drug
Targets 2006, 7, 843.
7. Ahmed, N.; Brahmbhatt, K. G.; Sabde, S.; Mitra, D.; Singh, I. P.; Bhutani, K. K.
Bioorg. Med. Chem. Lett. 2010, 18, 2872.
8. (a) Desai, N. C.; Joshi, V. V.; Rajpara, K. M.; Vaghani, H. V.; Satodiya, H. M. J.
Fluor. Chem. 2012, 142, 67; (b) Desai, N. C.; Rajpara, K. M.; Joshi, V. V.; Vaghani,
H. V.; Satodiya, H. M. Anti-Infect. Agents 2012, 10, 75.
9. Barsoum, F. F.; Hosni, H. M.; Girgis, A. S. Bioorg. Med. Chem. Lett. 2006, 14, 3929.
10. Turan-Zitouni, G.; Chevallet, P.; Kiliç, F. S.; Erol, K. Eur. J. Med. Chem. 2000, 35,
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Acknowledgments
11. Desai, N. C.; Rajpara, K. M.; Joshi, V. V.; Vaghani, H. V.; Satodiya, H. M. Med.
Chem. Res. 2012. http://dx.doi.org/10.1007/s00044-012-0121-z.
12. Meth-Cohn, O. Heterocycles 1993, 35, 539.
We would like to express our sincere gratitude to the Depart-
ment of Chemistry, Mahatma Gandhi Campus, Maharaja Krish-
nakumarsinhji Bhavnagar University, Bhavnagar for providing
research and library facilities.
13. General procedure for preparation of 3-(2-chloro-6-fluoroquinolin-3-yl)-1-
(aryl)prop-2-en-1-ones (2a–l).
A mixture of 2-chloro-6-fluoroquinoline-3-
carbaldehyde (1) (0.01 mol) and substituted acetophenones (0.01 mol) was
stirred in ethanolic sodium hydroxide for 24 h at room temperature. The
yellow crystals formed were filtered off, washed with water and crystallized
from ethanol (95%).
Supplementary data
14. General procedure for preparation of 5-(2-chloro-6-fluoroquinolin-3-yl)-3-
(aryl)-4,5-dihydro-1H-pyrazole-1-carbothioamides (3a–l).
chalcones (0.01 mol), sodium hydroxide (0.025 mol) in ethanol (95%) (50 mL)
and thiosemicarbazide (0.01 mol) was added. Mixture was refluxed for 8 h. The
A suspension of
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
09.039.

N. C. Desai et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6871–6875
6875
product was poured into crushed ice and the solid mass which separated out
was filtered, dried and recrystallized from ethanol (95%).
17. General
procedure
for
preparation
of
2-chloro-N-(4-(2-chloro-6-
fluoroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)acetamides (6a–l). An equimolar
amount of compounds (5a–l) (0.01 mol) and chloroacetyl chloride (0.01 mol)
in chloroform was refluxed in presence of catalytic amount of triethylamine for
about 12 h. Excess of solvent was removed under reduced pressure and the
residue was stirred with water. Crude product was dried and recrystallized
from aqueous DMF.
15. General procedure for preparation of 2-(5-(2-chloro-6-fluoroquinolin-3-yl)-3-
(aryl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-ones (4a–l). To a suspension
of compounds (3a–l) (0.01 mol) in ethanol (95%), ethyl bromoacetate
(0.01 mol) was added and heated at reflux for 1 h. After cooling, the
separated product was filtered and washed. The product was crystallized
from aqueous DMF.
18. General procedure for preparation of N-(4-(2-chloro-6-fluoroquinolin-3-yl)-6-
16. General procedure for preparation of 4-(2-chloro-6-fluoroquinolin-3-yl)-6-
(aryl)pyrimidin-2-amines (5a–l). A mixture of compounds (2a–l) (0.01 mol)
(aryl)pyrimidin-2-yl)-2-morpholinoacetamides
(7a–l).
A
mixture
of
compounds (6a–l) (0.01 mol), anhydrous potassium carbonate (0.02 mol) and
morpholine (0.01 mol) in dry toluene was refluxed for about 8–10 h. After
completion of the reaction, potassium carbonate was removed by filtration and
excess of solvent was removed under reduced pressure. The obtained residues
were filtered, dried and recrystallized from aqueous DMF.
and guanidine nitrate (0.01 mol) in ethanol (95%) was refluxed, while
a
solution of sodium hydroxide (0.05 mol) in water was added portion-wise for
2 h. Refluxing was continued for a further 10 h and the mixture was poured
into ice-cold water. The formed solid was separated by filtration. Crude
product was dried and crystallized from ethanol (95%).