Synthesis, characterization and antimicrobial activity of some new biquinoline derivatives containing a thiazole moiety

Article abstract of DOI:10.1016/j.cclet.2012.01.042

A series of new biquinoline derivatives containing a thiazole moiety were synthesized by a one-pot, base-catalyzed cyclocondensation reaction of 2-chloro-3-formyl quinoline, malononitrile and enaminone. All the synthesized compounds were characterized by elemental analysis, FT-IR, ¹H NMR and ¹³C NMR data. All the synthesized compounds were screened against three bacterial pathogens, namely Bacillus cereus, B. substilis and Escherichia coli and for antifungal activity against three fungal pathogens, Aspergillus niger, Fusarium oxisporum and Rhizopus using the disc diffusion method.. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Full text of DOI:10.1016/j.cclet.2012.01.042

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 454–457
www.elsevier.com/locate/cclet
Synthesis, characterization and antimicrobial activity of some new
biquinoline derivatives containing a thiazole moiety
*
Nirav K. Shah, Nimesh M. Shah , Manish P. Patel, Ranjan G. Patel
*
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120, Gujarat, India
Received 30 November 2011
Available online 3 March 2012
Abstract
A series of new biquinoline derivatives containing a thiazole moiety were synthesized by a one-pot, base-catalyzed
cyclocondensation reaction of 2-chloro-3-formyl quinoline, malononitrile and enaminone. All the synthesized compounds
were characterized by elemental analysis, FT-IR, 1H NMR and 13C NMR data. All the synthesized compounds were screened
against three bacterial pathogens, namely Bacillus cereus, B. substilis and Escherichia coli and for antifungal activity against
three fungal pathogens, Aspergillus niger, Fusarium oxisporum and Rhizopus using the disc diffusion method.
# 2012 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: Quinoline; Multicomponent reaction; Thiazole; Antimicrobial activity
Multicomponent reactions (MCRs) are of increasing importance in organic and medicinal chemistry [1]. In
times, where a premium is put on speed, diversity, and efficiency in the drug discovery process, MCR strategies
offer significant advantages over conventional linear-type syntheses [2].
Quinoline ring systems represent a major class of heterocycles in which benzene ring is fused with pyridine ring.
The derivatives of quinoline exhibit diverse biological and physiological activities such as antimicrobial [3],
antituberculosis [4], antimalarial [5], antiinflammatory [6], anticancer [7], antihypertensive [8], tyrokinase PDGF-
RTK inhibiting agents [9] and anti-HIV [10]. Recently, quinoline has been employed in the study of bioorganic and
bioorganometallic processes [11]. The quinoline skeleton is often used as a key intermediate for the design of many
pharmacologically important synthetic compounds.
Thiazoles are an important class of heterocyclic compounds, found in many potent biologically active molecules
such as fentiazac and meloxicam (both antiinflammatory agents), nizatidine (antiulcerative agent), and sulfathiazole
(antibacterial agent). Thiazoles also are frequently a vital component of novel and structurally diverse natural products
that exhibit a wide variety of biological activities. The exceptional range of antiinflammatory [12], antimicrobial [13],
antitumor [14], anticonvulsant [15], analgesic [16], and anticancer [17] properties have directed numerous synthetic
studies and new applications of thiazoles.
* Corresponding authors.
E-mail addresses: nimesh31@yahoo.com (N.M. Shah), patelmranjanben@yahoo.com (R.G. Patel).
1001-8417/$ – see front matter # 2012 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
doi:10.1016/j.cclet.2012.01.042

N.K. Shah et al. / Chinese Chemical Letters 23 (2012) 454–457
455
Based on good biological activity in novel heterocyclic systems and in continuation of our efforts in developing
heterocycles of biological interest [18,19] we undertook the synthesis of a new series of compounds incorporating the
above-mentioned biologically active moieties (quinoline and thiazole) to give biquinoline derivatives with thiazole.
1. Experimental
Solvents used were of analytical grade. All melting points were taken in open capillaries and are uncorrected. Thin-
layer chromatography (TLC, on aluminum plates precoated with silica gel, 60F254, 0.25 mm thickness) (Merck,
Darmstadt, Germany) was used for monitoring the progress of all reactions, purity and homogeneity of the synthesized
compounds; eluent-hexane:ethyl acetale 6:4. UV radiation and/or iodine were used as the visualizing agents.
Elemental analysis (% C, H, N) was carried out by a Perkin-Elmer 2400 series-II elemental analyzer (Perkin-Elmer,
USA) and all compounds were within Æ0.4% of calculation. The IR spectra were recorded in KBr on a Perkin-Elmer
Spectrum GX FT-IR Spectrophotometer (Perkin-Elmer, USA), and only the characteristic peaks were reported in
1
cmÀ1. H NMR 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 internal standard at 400 MHz and 100 MHz
respectively. Chemical shifts were reported in parts per million (ppm). Mass spectra were scanned on a Shimadzu
LCMS 2010 spectrometer (Shimadzu, Tokyo, Japan).
1.1. General procedures for the synthesis of title compounds (3a–l)
A mixture of 2-chloro-3-formylquinolines (1 mmol), malononitrile (1 mmol), and appropriate b-enaminone
(1 mmol) in ethanol (10 mL) containing catalytical amount of piperidine was slowly heated and refluxed for 3–4 h. On
completion of reaction, monitored by TLC (ethyl acetate:toluene = 3:7), the reaction mixture was cooled to room
temperature and the solid separated was filtered and washed with mixture of chloroform and methanol (1:1) to obtain
the pure compounds. Analytical and spectroscopic characterization data of the synthesized compounds are given
below: the physicochemical and spectral properties of compound 3j is presented below.
1.1.1. 2-Amino-4-(2-chloro-6-methyl(3-quinolyl))-5-oxo-1-(4-hydroxyphenylthiazol-2-yl)-1,4,5,6,7,8-hexahydro-
quinoline-3-carbonitrile (3j)
Yield: 87%; mp: 268–270 8C; Anal. Calcd. for C29H22ClN5O2S: C 64.50; H 4.11; N 12.97 (%); Found: C 64.59; H
4.25; N 13.04 (%); IR (KBr, cmÀ1): 3445 & 3345 (asym. & sym. str. of –NH2), 2202 (–CBBN str.), 1662 (–C O str.); 1H
NMR (400 MHz, DMSO-d6): d 1.85–2.29 (m, 6H, 3 Â CH2), 2.33 (s, 3H, CH3), 5.06 (s, 1H, CH), 6.10 (s, 2H, NH2),
6.87–8.22 (m, 9H, Ar-H), 9.72 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): dC 21.26 (CH3), 21.59, 27.43, 35.19,
36.42, 60.81 (C-CN), 114.15, 116.01, 116.14, 120.69, 125.31, 126.95, 127.61, 127.89, 128.10, 133.06, 137.10, 137.38,
137.79, 144.96, 149.03, 151.48, 152.81, 152.89, 153.58, 156.62 (20C, Ar-C), 195.68 (C O); MS m/z [M+H]+ 541.
2. Results and discussion
The synthetic route depicted in Scheme 1 outlines the chemistry part of the present work. The key intermediates 2-
chloro-3-formyl quinolines 1a–d were prepared according to literature method [20]. Solid phase reaction of 4-
substitutedacetophenone, thiourea and iodine for 4 h at 120 8C afford to give 2-amino-4-arylthiazole [21]. The
required b-enaminones 2a–c were prepared by the reaction b-diketone with 2-amino-4-arylthiazole by refluxing in
methanol in the presence of catalytic amount of acetic acid. The reaction occurs via an in situ initial formation of the
heterylidenenitrile, containing the electron-poor C C double bond, from the Knoevenagel condensation between 2-
chloro-3-formyl quinolines 1a–d and malononitrile by loss of water molecules. Michael addition of b-enaminone to
the ylidenic bond in forming an acyclic intermediate which cyclizes by nucleophilic attack of the NH group on the
cyano carbon, followed by tautomerisation to the final products 3a–l (Scheme 1).
The structures of the obtained compounds were fully characterized by 1H NMR, 13C NMR and FT-IR spectral data
1
and molecular weight of the compounds confirmed by mass spectrometry. H NMR (DMSO-d6) spectrum of
biquinoline derivatives 3a–l exhibited a singlet around d 5.06–5.52 for methine (H4) and 6.05–6.85 for NH2 proton
respectively. The 13C NMR spectrum of 3a is in good agreement with the structure assigned. The peaks at d 21.24,
27.46 and 36.41 are assigned to three methylene carbons, the peaks at d 35.48 are assigned to methine carbon (C4). The

456
N.K. Shah et al. / Chinese Chemical Letters 23 (2012) 454–457
R
CHO
Cl
R
1
1
CH
3
DMF
POCl
O
N
N
3
H
1a-d
O
O
R
2
R
2
O
R
2
S
I
2
N
S
N
+
o
H N
2
120 C, 4 h
NH
2
H N
2
N
H
S
O
2a-c
R
1
R
2
N
O
O
Cl
Ethanol
R
CHO
Cl
1
CN
CN
CN
N
Piperidine
N
S
N
H
N
NH
2
1a-d
2a-c
N
S
R
2
3a-l
Compd.
R1
3a
H
3b
3c
3d
Cl
H
3e
3f
3g
3h
Cl
Cl
83
3i
3j
CH3
OH
87
3k
OCH3
OH
3l
Cl
OH
82
CH3
H
OCH3
H
H
Cl
85
CH3
Cl
OCH3
Cl
H
OH
76
R2
H
Yielda%
80
79
83
78
76
81
77
aAll the yields are on isolated basis.
Scheme 1. Synthetic pathway for the title compounds biquinoline derivatives with thiazole moiety.
Table 1
Antimicrobial activity of compounds (3a-l).
Compd.
Zone of inhibition in mm
Antibacterial activity
Antifungal activity
E. coli
B. substilis
S. aureus
F. oxysporum
A. niger
R. oryzae
3a
3b
+ +
+ +
+ +
+ +
+ +
+ + +
+ +
+ +
+ +
+ +
+
+ +
+ + +
+ +
+ + +
+ + +
+ + +
+ +
+ +
+ +
+ +
3c
3d
+ + +
+ + +
+ +
+ + +
+ + +
+ +
+ + +
+ +
+ + +
+ +
3e
+ + +
+ + +
+ + +
+ + +
+ +
+ + +
+ + +
+ + +
+ +
3f
3g
+ +
+ +
+ + +
+ + +
+ + +
+ +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
NT
+ + +
+ + +
+ +
3h
3i
+
+ +
3j
3k
+ +
+ + +
+ + +
+ + +
+ + +
+ + +
NT
+ +
+ +
+
+ +
+ +
+ + +
+ + +
+ + +
+ + +
NT
+ + +
+ + +
NT
+ + +
+ +
3l
Ampicillin
Ciprofloxacin
Griseofulvin
NT
NT
+ + +
NT
NT
NT
+ + +
+ + +
(À), Inactive (inhibition zone <10 mm); (+), slightly active (inhibition zone 10–14 mm); (+ +), moderate activity (inhibition zone 15–19 mm); (+ +
+), good activity (inhibition zone ꢀ20 mm); NT, not tested; control (DMF) (À), no activity.

N.K. Shah et al. / Chinese Chemical Letters 23 (2012) 454–457
457
peak at d 60.42 is assigned to carbon attached with carbonitrile, peak at d 195.77 is assigned to carbonyl carbon. The IR
spectrum of compounds 3a–l exhibited characteristic absorption band around 3461–3318 cmÀ1 (asym. & sym. str.) for
amine, 2228–2200 cmÀ1 for cyanide (CN) and 1685–1645 cmÀ1 for carbonyl (C O) group respectively supports the
formation of 3a–l. The elemental analysis values and mass spectral data are in good agreement with theoretical data.
All the compounds were screened for their antimicrobial activities using ampicillin, ciprofloxacin and griseofulvin
as standard drugs. Reviewing the antimicrobial activity data (Table 1), it is concluded that compound 3c is the most
active among all the synthesized compounds against most of the tested organisms. Moreover, compounds 3g and 3k
displayed a good zone of inhibition against all the strains thereby exhibits interesting antimicrobial activity. It is worth
mentioning that minor change in molecular configuration of these compounds profoundly influences the activity.
Acknowledgment
The authors are grateful to the Department of Chemistry, S P University, India for providing laboratory facilities.
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