Synthesis, characterization, and biological evaluation of novel thiazole and pyrazole derivatives of quinoline-4-carboxylic acid as potential antimicrobial agents

Article abstract of DOI:10.1007/s00044-012-0333-2

A series of quinoline-based heterocycles prepared and bioevaluated for their possible antimicrobial activity against a panel of gram-positive bacteria [Staphylococcus aureus (ATCC-9144) and Bacillus subtilis (ATCC-6633)] and gram-negative bacteria [Pseudomonas aeruginosa (ATCC-25615), and Escherichia coli (MTCC-739)], and fungal strains [Candida albicans (ATCC-24433), Aspergillus niger (MTCC-872), and Aspergillus fumigatus (MTCC-343)] by the known methods. All the prepared quinoline derivatives have shown significant antimicrobial activities. Few compounds, viz. 4b, 4c and 4a, 4c proved to be active at low concentrations against Sa and Ca, respectively, while compounds 4a, 6d, and 6b showed milder inhibitory effects against other microbes. The structures of newly synthesized compounds were characterized by elemental analysis, Infrared (IR), ¹HNMR, ¹³C-NMR and Mass-spectroscopy.

Full text of DOI:10.1007/s00044-012-0333-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3527–3535
DOI 10.1007/s00044-012-0333-2
ORIGINAL RESEARCH
Synthesis, characterization, and biological evaluation of novel
thiazole and pyrazole derivatives of quinoline-4-carboxylic
acid as potential antimicrobial agents
•
Abha Bishnoi Anil Kumar Tiwari Suruchi Singh
•
•
•
Arun Sethi Chandrakant Mani Tripathi
•
Bikram Banerjee
Received: 22 March 2012 / Accepted: 6 November 2012 / Published online: 27 November 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of quinoline-based heterocycles pre-
pared and bioevaluated for their possible antimicrobial
activity against a panel of gram-positive bacteria [Staphy-
lococcus aureus (ATCC-9144) and Bacillus subtilis (ATCC-
6633)] and gram-negative bacteria [Pseudomonas aerugin-
osa (ATCC-25615), and Escherichia coli (MTCC-739)], and
fungal strains [Candida albicans (ATCC-24433), Aspergil-
lus niger (MTCC-872), and Aspergillus fumigatus (MTCC-
343)] by the known methods. All the prepared quinoline
derivatives have shown significant antimicrobial activities.
Few compounds, viz. 4b, 4c and 4a, 4c proved to be active at
low concentrations against Sa and Ca, respectively, while
compounds 4a, 6d, and 6b showed milder inhibitory effects
against other microbes. The structures of newly synthesized
compounds were characterized by elemental analysis,
Infrared (IR), 1HNMR, 13C-NMR and Mass-spectroscopy.
the human race, and a continued search for new chemo-
therapeutic agents is vital to combat this threat. Recently, a
significant amount of attention has been directed toward
the development of novel classes of biocides. To this end,
one of the best ways to design new biocidal agents is to
synthesize hybrid molecules by combining two or more
bioactive moieties in a single molecular scaffold.
Among pharmacologically active compounds, nitrogen-
containing heterocyclic molecules are significant target
owing to their wide range of applications as pharmaceuti-
cally active molecules. Quinoline derivatives have been
known to possess varied biological properties and medic-
inal uses, such as antitumor (Yamato et al., 1990, 1989;
Fujimoto, 2007), antibacterial (Parekh et al., 2011; Eswa-
ran et al. 2010a, b), antifungal (Robert et al., 2006; Ryu
et al., 2009), antihypertensive (Conklin and Hollifield,
1970; Jandhyala et al., 1967), antileishmanial (Tempone
et al., 2005; Palit et al., 2009) and antidepressant (Kumar
et al., 2011; Alhaider, 1986) agents. An important role
played by quinoline compounds was that of providing the
first photographic film sensitizer such as the cyanine dye
and ethyl red. Several quinoline derivatives as antimalarial
agents are in clinical use, since a long time (Charris et al.,
2007; Hans et al., 2010). In addition, thiosemicarbazides
can easily be cyclized to various heterocyclic ring systems
and therefore used as key intermediates in the preparation
of numerous synthetic compounds with significant bio-
logical activities. It is known that, thiazole derivatives
exhibit various biological activities such as antitubercular
(Andreani et al., 2001; Kolavi et al., 2006), antimicrobial
(Bondock et al., 2007; Vijesh et al., 2010; Mullican et al.,
1993; Song et al., 1999), anti-inflammatory (Labanauskas
et al., 2001), antiviral (El-Sabbagh et al.; 2009, Stawinska
et al., 2009), anticonvulsant (Bachir et al., 1990; Kaminski
and Obniska, 2008), antihypertensive (Adhikary et al.,
Keywords Quinoline-4-carboxylic acid ꢀ Acetophenone ꢀ
Thiosemicarbazide ꢀ Polyphosphoric acid ꢀ
Antimicrobial activity
Introduction
The increasing incidence of bacterial resistance to antibi-
otics and antimicrobial agents poses a tremendous threat to
A. Bishnoi (&) ꢀ A. K. Tiwari ꢀ S. Singh ꢀ A. Sethi
Department of Chemistry, Lucknow University,
University Road, Lucknow 226 007, India
e-mail: abhabishnoi5@gmail.com
A. K. Tiwari
e-mail: anilk.tiwari04@gmail.com
C. M. Tripathi ꢀ B. Banerjee
Division of Fermentation Technology, Central Drug Research
Institute, Lucknow 226001, India
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Med Chem Res (2013) 22:3527–3535
1976; Bakr et al., 2008), and hypoglycemic (Sohda et al.,
1992) activities among others (Messaoudi et al., 2004).
Besides, pyrazole derivatives have occupied a unique place
in the field of medicinal chemistry and have been reported
in the literature as potential biologically active pharmaco-
phores (Bondock et al., 2010; Veronique et al., 1998;
Fleming et al., 2010; Ozdemir et al., 2007). Giving atten-
tion to the biological significance of these classes of
compounds and in continuation of our research program on
the synthesis of antimicrobial agents (Bishnoi et al., 2009,
2010, 2011), we planned to synthesize a combined
molecular framework, consisting of these well-established
pharmacologically active nuclei in them.
the presence of PPA to afford the corresponding 5-(4-
substituted phenyl)-3, 4-diphenyl -1H-pyrano[4,3-c] quino-
lin-1-one 5(a–c). The IR spectra of 5 showed the shifting of
C=O stretching band from 1678 cm-1 to 1685 cm-1 and the
absence of OH stretching band region revealing the fusion
1
between 1 and benzoin. In HNMR, the signals observed
were at the expected chemical shifts with appropriate inte-
grals. Compound 5(a–c) on reaction with thiosemi/semi-
carbazides in refluxing ethanol furnished 7-(4-substituted
phenyl)-5,6-diphenyl benzo[h][1, 2, 4] triazole[3,4-a][2, 6]-
naphthyridine-3-(2H)-thione/one 6(a–f). The structures of
these compounds were well supported by their spectral data.
The IR spectra of 6 showed disappearance of absorption band
due to C=O stretching vibration, and appearance of a band at
1659–1629 cm-1 attributable to C=N vibrations and bands
at 1186–1200 and 1754–1762 cm-1attributable to C=S and
C=O, respectively, providing a strong evidence for the for-
mation of the titled compounds. The 1HNMR spectra of the
6(a–f) showed the NH proton as singlet at 12.95–13.85 ppm
region which disappeared upon deuteration.
Results and discussion
Chemistry
Two novel series of thiazole 4(a–f) and pyrazole 6(a–f)
derivatives were synthesized by the application of various
cyclization reactions (Scheme 1).The compound 1 required
for the synthesis of title compounds was prepared according
to the procedure described in the literature (Holla et al.,
2005). 4-carboxy-1-(2-oxo-2-phenylethyl)-2-(4-substituted
phenyl quinolinium iodide 2(a–c) were obtained by the
reaction of 2-(4-substituted phenyl) quinoline-4-carboxylic
acid 1(a–c) with acetophenone in the presence of iodine.The
IR spectra of 2 revealed one additional C=O stretching
vibration at 1688–1680 cm-1 region, along with C=O
stretching vibration of COOH at 1714–1700 cm-1. The
1HNMR of the compound showed signal corresponding to
CH2 attached to quinoline nitrogen at d 2.2–2.4 ppm.
Reaction of 2(a–c) with thiosemicarbazide in glacial acetic
acid afforded the thiosemicarbazones 3(a–c). The IR spectra
of the products revealed the disappearance of the C=O
absorption band at 1680–1688 cm-1 and showed symmetric
and asymmetric stretching bands at 3253–3358 cm-1 for
NH2 along with C=N stretching vibration band at
1589–1643 cm-1 and C=S stretching vibration at 1186–
1198 cm-1. A further reaction of 3(a–c) with substituted
acetophenones in glacial acetic acid in the presence of iodine
led to corresponding 4-carboxy-1-(2-phenyl-2-(4-substi-
tuted phenyl thiazol-2(5H)-ylidene)hydrazono)ethyl-2-
(p-substituted phenyl) quinolinium iodide 4(a–f) derivatives,
Experimental section
Methods and materials
All chemicals were purchased from Alfa Aesar, Sigma-
Aldrich, Merck, Sdfine, Qualigens, and Spectrochem. Sol-
vents and reagents were used without further purification,
unless otherwise specified. IR Spectra (potassium bromide)
were recorded on Perkin-Elmer FTIR spectrophotometer
(m max in cm-1); 1H- and 13C-NMR spectra were recorded on
Bruker 300 MHz instruments using CDCl3/DMSO-d6 as
solvents. Chemical shifts (d) are reported in p.p.m. using
TMS as internal standard. EI mass spectra were recorded on
a Va 70–70H mass spectrometer at 70 eV. Elemental
Analysis was performed on a Perkin-Elmer 2400 series II
elemental CHNS analyzer. Melting points were determined
in an open capillary tube and are uncorrected. The TLCs
were visualized in an iodine chamber.
General procedure for the preparation of 2-substituted
phenylquinoline-4-carboxylic acid 1(a–c)
Compounds 1 (a–c) were prepared by known method
reported in the literature (Holla et al., 2005).
1
utilizing Hantzsch synthesis. IR, HNMR, and 13CNMR
spectra of these compounds were well in agreement with
the structure assigned.The conversion of 3 to 4 involves the
cyclization of thiosemicarbazones into an azine. In the
1HNMR spectra of 3(a–c), the proton signals at 8.11–
8.26 ppm appeared for NH2 protons integrating for two
proton and the signal at 11.08–11.28 ppm for NH. On the
other hand, compound 1(a–c) were heated with benzoin in
General procedure for the preparation of 4-carboxy-2-
substituted phenyl-1-(2-oxo-2-phenylethyl)-2-phenyl
quinolinium iodide 2(a–c)
2-substituted quinoline-4-carboxylic acid 1(a–c) (0.01 mol)
were refluxed with acetophenone (0.01 mol) and iodine
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Med Chem Res (2013) 22:3527–3535
3529
Scheme 1 Synthesis of compounds 1–6. The substituent R in
compounds 1, 2, 3 & 5 are as follows: a R=H b R=Cl; c R=CH3.
The nature of substituents R and R’ in compound 4 are a R=H;
R’=NH2; b R=Cl; R’=NH2; c R=CH3; R’=NH2; d R=H; R’=H;
e R=Cl; R’=H; f R=CH3; R’=H. The nature of R and X in compounds
6 are a R=H, X=O; b R=Cl, X=O; c R=CH3, X=O; d R=H, X=S;
e R=Cl, X=S; f R=CH3, X=S. (i) PhCOCH3/I2; (ii) H2NNHCSNH2/
gla.AcOH; (iii) R’C6H5COCH3, I2/gla. AcOH; (iv) Benzoin/PPA
(v) H2NNHCXNH2/EtOH
4-Carboxy-2-(4-chloro phenyl)-1-(2-oxo-2-pheny ethyl)
quinolinium iodide (2b) Yield 81 %., light brown crys-
tals, mp 160–161 °C, Rf value, 0.70. IR (KBr) cm-1 : 3396
(OH), 1705 (C=O), 1618 (C=N), 1586 (C=C), 732 (C–Cl),
(0.5gm) in a RB flask at 100 °C for 2 h under anhydrous
reaction conditions. The crystalline mass which separated on
cooling the reaction mixture was filtered, washed repeatedly
with water, and recrystallised from ethanol. The TLCs were
checked using Benzene: Acetone (8.5:1.5 v/v) as mobile
phase.
1
1688 (C=O). HNMR (DMSO-d6) d: 7.03–8.88 (m, 14H,
Ar–H), 2.4 (s, 2H, CH2), 12.86 (s, 1H, COOH). 13CNMR
(DMSO-d6) d: 69.8 (N–CH2–CO), 115.8–147.1 (quinoline
and phenyl), 167.7 (COOH), 196.5 (COPh). EI-MS (m/z):
M? 402, 404, 385, 357, 325, 297, 291, 283, 119, 111, 77.
Anal.calcd. for C24H17ClNO3: C, 71.64; H, 4.22; N, 3.48.
Found: C, 71.73; H, 3.98; N, 3.46 %.
4-Carboxy-1-(2-oxo-2-phenylethyl)-2-phenyl quinolinium
iodide (2a) Yield 72 %., brown crystals, mp 198–200 °C,
Rf value, 0.62. IR (KBr) cm-1: 3390 (OH), 1700 (C=O),
1643 (C=N), 1580 (C=C), 1682(C=O). 1HNMR (DMSO-d6)
d: 7.24–8.72 (m, 15H, Ar–H) 2.2 (s, 2H, CH2), 12.02 (s,
1H, COOH). 13CNMR (DMSO-d6) d: 70.0 (N–CH2–CO),
118.6–139.7 (quinoline and phenyl), 167.4 (COOH), 196.2
(COPh). EI-MS (m/z): M? 367, 351, 323, 291, 263, 249,
119, 105. Anal.calcd. for C24H18NO3: C, 78.26; H, 4.89; N,
3.80. Found: C, 0.47; H, 4.63; N, 3.80 %.
4-Carboxy-1-(2-oxo-2-phenylethyl)-2-p-tolyl quinalinium
iodide (2c) Yield; 74 %., greenish crystals, mp 178–
180 °C, Rf value, 0.36. IR (KBr) cm-1: 3416 (OH),
1712(C=O), 1622 (C=N), 1580 (C=C), 1686 (C=O). 1HNMR
(DMSO-d6) d: 7.09–8.90 (m, 14H, Ar–H), 2.3 (s, 2H, CH2),
123

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Med Chem Res (2013) 22:3527–3535
2.1(s, 3H, CH3), 12.42(s, 1H, COOH). 13CNMR (DMSO-d6)
d: 21.3 (CH3 of tolyl), 70.8 (N–CH2–CO), 119.4–140.9
(quinoline and phenyl), 169.0 (COOH), 195.9 (COPh).
EI-MS (m/z): M?; 381, 365, 337, 291, 277, 263, 172, 105, 71.
Anal.calcd. for C25H20NO3: C, 78.50; H, 5.23; N, 3.66.
Found: C, 78.32; H, 5.22; N, 3.65 %.
Acetone). IR (KBr) cm-1: 3414 (OH), 1710 (C=O), 1640
(C=N), 1582 (C=C), 3312 (NH), 1192 (C=S). 1HNMR
(DMSO-d6) d: 7.08–8.62 (m, 14H, Ar–H), 1.6 (s, 2H, CH2),
2.21 (s, 3H, CH3), 8.21 (s, 2H, NH2), 11.28 (s, 1H, NH),
12.91 (s, 1H, COOH). 13CNMR (DMSO-d6) d: 22.4 (CH3
of tolyl), 50.5 (–N–CH2–CNNH–), 118.7–141.5 (quinoline
and phenyl), 154.9 (C=N), 166.0 (COOH), 180.8 (C=S).
EI-MS (m/z): M? 454, 277, 263, 192, 186, 103, 91. Ana-
l.calcd. for C26H23 N4O2S: C, 68.54; H, 5.05; N, 12.30;
Found: C, 68.72; H, 5.06; N, 12.33 %.
General procedure for the preparation of
1-(2-(-carbamothioylhydrazono)-2-phenylethyl)-4-
carboxy-2-(4-substituted phenyl)-quinolinium
iodide 3(a–c)
General procedure for the preparation of 4(a–f)
A mixture of 2(a–c) (0.01 mol) and thiosemicarbazide
(0.01 mol) was dissolved in glacial acetic acid (50 ml) by
warming gently on a water bath and was heated under reflux
for 2 h. Acetic acid was distilled off under reduced pressure,
and the residual solid mass thus obtained was washed with
water The crude products were dried in vacuum and
recrystallized from methanol. The TLCs were checked using
Benzene: Acetone (in various ratios v/v) as mobile phase.
A mixture of 3(a–c) (0.01 mol), acetophenone/substituted
acetophenone (0.01 mol) and iodine(1.3 g) in glacial acetic
acid (50 ml) was refluxed for 8–10 h. The reaction mixture
was cooled ,and the solid, which separated out, was fil-
tered, washed with water and dried in vacuum. The crude
compounds were recrystallized from a mixture of methanol
and chloroform (1:2). The TLCs were checked using
Benzene: Acetone (in various ratios v/v) as mobile phase.
1-(2-(-Carbamothioylhydrazono)-2-phenylethyl)-4-car-
boxy-2-phenyl quinolinium iodide (3a) Yield 72 %.,
yellow crystals, mp 158–164 °C, Rf value, 0.68 (8.5:1.5,
Benzene: Acetone). IR (KBr) cm-1: 3401 (O–H), 1705
(C=O), 1630 (C=N), 1578 (C=C), 3310 (N–H), 1186(C=S).
1HNMR (DMSO-d6) d: 7.12-8.59 (m, 15H, Ar–H), 1.4 (s,
2H, CH2), 8.11 (s, 2H, NH2), 11.08 (s, 1H, NH), 12.08 (s,
1H, COOH). 13CNMR (DMSO-d6) d: 50.1 (–N–CH2–
CNNH–), 119.6–139.7 (quinoline and phenyl), 154.2
(C=N), 165.3 (COOH), 180.4 (C=S). EI-MS (m/z): M?
440, 424, 396, 381, 364, 350, 263, 249, 190, 171, 103, 77.
Anal.calcd. for C25H21N4O2S: C, 68.02; H, 4.76; N, 12.69.
Found: C, 68.00; H, 4.77; N, 12.72 %.
(4-(4-Aminophenyl)thiazol-2(5H)-ylidene)hydrazono)-
2-phenylethyl)-4-carboxy-2-phenylquinolinium iodide (4a)
Yield 82 %., brown crystals, mp 132–133 °C, Rf value,
0.61 (8.5:1.5, Benzene: Acetone). IR (KBr) cm-1:3404
(OH), 1708 (C=O), 1604 (C=N), 1638 (C=N), 1578 (C=C),
1
3217 (NH). HNMR (DMSO-d6) d: 6.30–7.94 (m, 19H,
Ar–H), 1.6 (s, 2H, CH2), 2.8 (s, 2H, CH2 of thiazole), 5.26
(s, 2H, NH2), 12.78 (s, 1H, COOH). 13CNMR (DMSO-d6):
124.2–151.1 (quinoline, phenyl and aniline), 165.2 (C=O),
28.9 (C–S of thiazole), 164.1 (C=N of thiazole), 161.9
(C=N). EI-MS (m/z): M? 555, 540, 539, 511, 479, 464,
380, 366, 352, 307, 249, 204, 176, 103, 97. Anal.calcd. for
C33H26 N5O2S: C, 71.19; H, 4.67; N, 12.58. Found: C,
71.35; H, 4.68; N, 12.61 %.
1-(2-(-carbamothioylhydrazono)-2-phenylethyl)-4-car-
boxy-2-(4-chlorophenyl)-quinoliniumiodide (3b) Yield
72 %., orange crystals, mp 182–184 °C, Rf value, 0.39
(8.0:1.0, Benzene: Acetone). IR (KBr) cm-1: 3405 (OH),
1708 (C=O), 1643 (C=N), 1569 (C=C), 3327 (NH), 1198
(2-(4-(4-Aminophenyl)thiazol-2(5H)-ylidene)hydrazono)-
2-phenylethyl)-4-carboxy-2-(4-chlorophenyl) quinolinium
iodide (4b) Yield 84 %., yellow crystals, mp 160–
161 °C, Rf value, 0.54 (9.0:1.0, Benzene: Acetone). IR
(KBr) cm-1: 3402 (OH), 1708 (C=O), 1626 (C=N), 1640
(C=N), 1582 (C=C), 3226 (NH), 729 (C–Cl). 1HNMR
(DMSO-d6)d: 6.42–8.91 (m,18H,Ar–H), 1.8(s, 2H, CH2),
2.4 (s, 2H,CH2, of thiazole), 5.29 (s, 2H, NH2), 12.17
(s, 1H, COOH). 13CNMR (DMSO-d6) d: 118.4–151.7
(quinoline, phenyl and aniline), 166.1 (C=O), 29.1 (C–S of
thiazole), 161.7 (C=N of thiazole), 163.7 (C=N). EI-MS(m/
z): M?, 589, 591, 574, 573, 545, 498, 479, 414, 400, 386,
307, 297, 293, 283, 190, 176, 111, 103, 97, 92. Anal.calcd.
for C33H25ClN5O2S: C, 67.10; H, 4.23; N, 11.86. Found: C,
67.23; H, 4.25; N, 11.88 %.
1
(C=S), 729 (C–Cl). HNMR (DMSO-d6) d: 698–8.13(m,
14H, Ar–H), 1.2 (s, 2H CH2), 8.26 (s, 2H, NH2), 11.21 (s,
1H, NH), 12.41 (s, 1H, COOH). 13CNMR (DMSO-d6) d:
50.8 (–N–CH2–CNNH–), 118.9–147.1 (quinoline and
phenyl), 155.6 (C=N), 167.7 (COOH), 181.0 (C=S). EI-MS
(m/z): M? 474, 476, 459, 458, 430, 415, 400, 398, 386,
297, 283, 192, 178, 111, 103. Anal.calcd. for C25H20Cl
N4O2S: C, 63.15; H, 4.21; N, 11.78. Found: C, 63.27; H,
4.18; N, 11.81 %.
1-(2-(-Carbamothioylhydrazono)-2-phenylethyl)-4-carboxy-
2-p-tolylquinolinium iodide (3c) Yield 68 %., yellow
crystals, mp.190–195 °C, Rf value, 0.67 (8.5:1.5, Benzene:
123

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3531
(2-(4-(4-Aminophenyl)thiazol-2(5H)-ylidene)hydrazono)-
2-phenylethyl)-4-carboxy-2-p-tolyl quinolinium iodide
(4c) Yield 76 %., orange crystals, mp 210–212 °C, Rf
toluene), 27.2 (C–S of thiazole), 159.8(C=N of thiazole),
160.9 (C=N). EI-MS (m/z): M?, 554, 538, 510, 478, 464,
394, 380, 292, 278,277, 263, 186,175, 103, 97, 91, 77.
Anal.calcd for C34 H27 N4 O2 S: C, 73.48; H, 4.86; N,
10.08. Found: C, 73.77; H, 4.88; N, 10.12 %.
value, 0.57 (8.5:1.5, Benzene: Acetone). IR (KBr) cm-1
:
3418 (OH), 1714 (C=O), 1632 (C=N), 1644 (C=N), 1510
1
(C=C), 3237 (NH). HNMR (DMSO-d6)d: 6.38–8.78 (m,
18H, Ar–H), 2.24(s, 3H, CH3), 1.5 (s, 2H, CH2), 2.6 (s, 2H,
CH2 of thiazole), 5.22 (s, 2H, NH2), 12.98 (s, 1H, COOH).
13CNMR (DMSO-d6) d: 114.2–148.9 (quinoline, phenyl
and aniline), 164.8 (C=O), 18.6 (CH3 of toluene), 28.8
(C–S of thiazole), 160.0 (C=N of thiazole), 162.6 (C=N).
EI-MS (m/z): M?; 569, 554, 553, 525, 479, 478, 394, 380,
307, 293, 277, 263, 190, 176, 103. Anal.calcd. for
C34H28N5O2 S: C, 71.55; H, 4.91; N, 12.27. Found: C,
71.83; H, 4.92; N, 12.32 %.
General procedure for the preparation of 5(a–c)
A mixture of 2-substituted quinoline-4-carboxylic acid of
1(a–c) (0.05 mol), Benzoin (0.05 mol), and PPA (100 ml)
was heated in an oil bath for 4 h at 130 °C, and the reaction
mixture was poured into ice-cold water and stirred vigor-
ously for 0.5 h. The solid mass thus obtained was treated
with 5 % sodium bicarbonate solution (50 ml) to remove
any unreacted acid. The products obtained were recrystal-
lized from methanol. The TLCs were checked using Ben-
zene: Acetone (9.5: 0.5 v/v) as mobile phase.
4-Carboxy-2-phenyl-1-(2-phenyl-2-(4-phenylthiazol-2(5H)-
ylidene)hydrazono) quinoliniumiodide (4d) Yield 82 %.,
light brown crystals, mp 120–121 °C, Rf value, 0.66
(9.5:0.5 Benzene: Acetone). IR (KBr) cm-1: 3410 (OH),
1710 (C=O), 1628 (C=N), 1635 (C=N), 1588 (C=C).
1HNMR (DMSO-d6) d: 6.23–8.42 (m, 20H Ar–H), 1.2 (s,
2H, CH2), 2.7 (s, 2H, CH2 of thiazole), 12.62 (s, 1H,
COOH). 13CNMR (DMSO-d6): 114.2–152.1 (quinoline
and phenyl), 162.6 (C=O), 28.8 (C–S of thiazole), 166.3
(C=N of thiazole), 162.4 (C=N). EI-MS (m/z): M?; 540,
496, 464, 380, 366, 352, 278, 263, 249, 189, 186, 175.
Anal. calcd. for C33 H25 N4 O2 S: C, 73.17; H, 4.61; N,
10.34. Found: C, 73.06; H, 4.60; N, 10.33 %.
3,4,5-Triphenyl-1H-Pyrano[4,3-c]quinolin-1-one (5a) Yield
79 %., Chrome yellow crystals, mp 140 °C, Rf value, 0.58
(9.5:0.5 Benzene: Acetone). IR (KBr) cm-1: 1678 (C=O),
1
1650 (C=N), 1592 (C=C). HNMR (CDCl3)d: 6.86–7.95
(m, 19H, Ar–H). 13CNMR (DMSOd6)d: 110.6–146.3
(quinoline and phenyl), 150.5 (C=O). Anal. calcd for
C30H19 NO2: C, 84.71; H, 4.47; N, 3.29; Found: C, 85.52;
H, 4.52; N, 3.41 %.
5-(4-Chlorophenyl)-3,4-diphenyl-1H-Pyrana[4,3-c] quino-
lin-1-one (5b) Yield 73 %., dirty white crystals, mp
109 °C, Rf value, 0.39 (9.5:0.5 Benzene: Acetone). IR
(KBr) cm-1: 1680 (C=O), 1648(C=N), 1588(C=C), 725
(C–Cl). 1HNMR (CDCl3) d: 6.5–7.88 (m, 18H, Ar–H).
13CNMR (DMSO-d6) d: 129–130.2 (quinoline and phenyl),
155.4 (C=O). EI-MS (m/z): M? 459, 178, 126, 111, 91.
Anal. calcd. For C30H18 NO2Cl: C, 78.35; H, 3.92; N, 3.05;
Found: C, 76.73; H, 4.16; N, 2.86 %.
4-Carboxy-2-(4-chlorophenyl-1-(2-phenyl-2-(4-phenylthiazol-
2(5H)-ylidene)hydrazono)ethyl quinolinium iodide (4e)
Yield 78 %., dark brown crystals, mp 148–151 °C, Rf
value, 0.58 (9.0:1.0 Benzene: Acetone). IR (KBr) cm-1
:
3406 (OH), 1708 (C=O), 1630 (C=N), 1635 (C=N), 1589
1
(C=C), 725 (C–Cl). HNMR (DMSO-d6) d: 6.75–8.96 (m,
19H Ar–H), 1.4 (s, 2H, CH2), 2.6 (s, 2H, CH2 of thiazole),
12.71 (s, 1H, COOH). 13CNMR (DMSO-d6) d: 122–150.7
(quinoline and phenyl), 164.7 (C=O), 29.7 (C–S of thia-
zole), 163.5 (C=N of thiazole), 163.1 (C=N). EI-MS (m/z):
M?, 574, 576, 558, 530, 498, 414, 400, 386, 292, 283,189,
186, 175,111. Anal.calcd. for C33H24 ClN4 O2 S: C, 68.85;
H, 4.34; N, 9.73; Found: C, 68.98; H, 4.35; N, 9.75 %.
3,4-Diphenyl-5-p-tolyl-1H-pyrano[4,3-c]quinolin-1-one
(5c) Yield 68 %., pale yellow crystals, mp 181 °C, Rf
value, 0.41 (9.5: 0.5, Benzene: Acetone). IR (KBr) cm-1
:
1
1685 (C=O), 1652 (C=N), 1590 (C=C). HNMR (CDCl3)
d: 2.34 (s, 3H,–CH3), 6.37–7.92 (m, 18H, Ar–H). 13CNMR
(DMSO-d6) d: 21.3 (–CH3), 127–148.7 (quinoline and
phenyl), 150.4 (C=O). Anal. calcd. For C31H21 NO2: C,
84.74; H, 4.78; N, 3.19; Found: C, 85.69; H, 5.03; N,
2.93 %.
4-Carboxy-2-phenyl-2-(4-phenyl thiqzol-2(5H)-ylidene)
hydrazono) ethyl)-2-p-tolylquinolinium iodide (4f) Yield
87 %., purple crystals, mp 181–184 °C, Rf value, 0.62,
(9.0:1.0 Benzene: Acetone). IR (KBr) cm-1: 3422 (OH),
1712 (C=O), 1622 (C=N), 1638 (C=N), 1584 (C=C).
1HNMR (DMSO-d6) d: 7.08–8.29 (m, 19H Ar–H), 2.14 (s,
3H, CH3), 1.8 (s, 2H, CH2), 2.4 (s, 2H, CH2 of thiazole),
12.08 (s, 1H, COOH). 13CNMR (DMSOd6)d: 112–146.8
(quinoline and phenyl), 162.8 (C=O), 19.6 (CH3 of
General procedure for the preparation of 6(a–f)
A mixture of 5(a–c) (0.01 mol) and semicarbazide/thiose-
micarbazide (0.12 mol) in ethanol (30 ml) was heated
under reflux for 8–12 h. Ethanol was distilled off, and the
residual solid mass was washed with water. Crude products
123

3532
Med Chem Res (2013) 22:3527–3535
were dried in vacuum and recrystallized from methanol.
The TLCs were checked using Benzene: Acetone (in var-
ious ratios v/v) as mobile phase.
109.6–148 (quinoline and phenyl), 149.5(C=S), 155 (N–
C=N). EI-MS (m/z): M?, 516, 518, 419, 417, 180, 126,
111, 91. Anal.calcd for C31H20 N4 SCl: C, 72.3; H, 3.69; N,
10.88 Found: C, 71.86; H, 3.75; N, 11.29 %.
4,5,6-Triphenylbenzo[h][1, 2, 4]triazolo[3,4a][2, 6]naph-
thyridin-3(2H)-one (6a) Yield 75 %., yellow crystals, mp
172–174 °C, Rf value, 0.53 (8.5:1.5 Benzene: Acetone). IR
(KBr) cm-1: 1759 (C=O), 1569 (C=C), 1641 (C=N), 1589
5,6-Diphenyl-7-p-tolylbenzo[h][1, 2, 4]triazolo[3,4-a][2, 6]
naphthyridin-3(2H)-thione (6f) Yield 69 %., yellow crys-
tals, mp 256 °C, Rf value, 0.59 (9.0:1.0 Benzene: Acetone).
IR (KBr) cm-1: 1659 (C=N), 1579 (C=C), 1194 (C=S).
1HNMR (CDCl3) d: 1.99 (s, 3H,–CH3), 6.93–8.52 (m, 18H,
Ar–H), 13.39 (s, 1H, –NH). 13CNMR (DMSOd6)d:
110.5–150.3 (quinoline and phenyl), 150.6 (C=S), 155.2(N–
C=N). EI-MS (m/z): M?, 496, 397, 180, 126, 99, 91. Anal.
calcd. for C32H23N4S; C, 77.73; H, 4.45; N, 11.34. Found: C,
78.07; H, 4.52; N, 10.98 %.
1
(C=C). HNMR (CDCl3) d: 6.74–8.69 (m, 19H,–Ar–H),
12.95 (s, 1H,–NH). 13CNMR (DMSOd6)d: 122.4–147.0
(quinoline and phenyl), 155 (N–C=N), 159.2 (C=O).
Anal.calcd. for C31H21N4O: C, 80.17; H, 4.31; N, 12.07;
Found: C, 79.89; H, 4.26; N, 12.31 %.
7-(4-Chlorophenyl)-5,6-diphenylbenzo[h][1, 2, 4]triazolo
[3,4-a][2, 6]napthyridin-3(2H)-one (6b) Yield 75 %., grey
crystals, mp 194–195 °C, Rf value, 0.48 (8.0:2.0 Benzene:
Acetone). IR (KBr) cm-1: 1754(C=O), 1633 (C=N), 1565
(C=C), 713 (C–Cl). 1HNMR (CDCl3) d: 7.11–8.92 (m, 18H,
Ar–H), 13.83 (s, 1H,–NH). 13CNMR (DMSOd6)d:
123–150.5 (quinoline and phenyl), 154.7 (N–C=N), 159.8
(C=O). EI-MS (m/z): M?, 500, 502, 417, 419, 180, 111, 99.
Anal. calcd. for C31H20N4O: C, 74.62; H, 3.81; N, 11.23.
Found: C, 75.32; H, 4.02; N, 10.95 %.
Biological assay
In vitro antibacterial activity
The invitro antibacterial activities of compounds (4a–f and
6a–f) and standard drug (Gentamicin) were carried out
against gram-positive and gram- negative bacterial strains,
viz. Staphylococcus aureus(Sa) (ATCC-9144), Bacillus
subtilis (Bs) (ATCC-6633), Pseudomonas aeruginosa(Pa)
(ATCC-25615), and Escherichia coli(Ec) (MTCC-739)
using Disc-diffusion Method (Karaman et al., 2003) by
standard micro broth dilution as per NCCLS protocol.
Some of the compounds have shown significant activity
against the various strains. The compounds 4a, 4b, 4c, 6d,
and 6e were the most active antibacterial agents. Among
these, 4a and 4c have shown an MIC value of 3.12 lg/mL
against Sa which exceeds that of the reference drug
(MIC = 6.25 lg/mL). Compound 6e has also shown good
activity with an MIC value of 12.5 lg/mL. Compound 6d
needs to have a special mention here, as it is the only active
compound among the whole series which has shown
excellent activity against Ba with an MIC of 12.5 lg/mL.
The zone of inhibition of this compound (21 mm) is quite
comparable to Gentamicin (22 mm). Compounds 6a and 6e
have shown considerable activity against the multiresistant
bacterial strain; Pa and their structure can be further
modified to increase the antibacterial activity.
5,6-Diphenyl-7-p-tolylbenzo[h][1, 2, 4]triazolo[3,4-a]
[2, 6]naphthyridin-3(2H)-one (6c) Yield 76 %., grayish
white crystals, mp 203–205 °C, Rf value, 0.61 (8.5:1.5
Benzene: Acetone). IR (KBr) cm-1: 1762 (C=O), 1629
(C=N), 1573 (C=C). 1HNMR (CDCl3) d: 2.17 (s, 3H, CH3),
7.02–8.84 (m, 18H, ArH), 13.45 (s, 1H, NH). 13CNMR
(DMSOd6)d: 20.8 (–CH3), 121–148.9 (quinoline and phe-
nyl), 155.6 (N–C=N), 158.9 (C=O). EI-MS (m/z): M?, 480,
180, 126, 91, 83. Anal.calcd. for C32H23N4O: C, 80.33; H,
4.60; N, 11.72; Found: C, 80.65; H, 4.74; N, 11.867 %.
5,6,7-Triphenylbenzo[h][1, 2, 4]triazolo[3,4-a][2, 6]naph-
thyridin-3(2H)-thione (6d) Yield 77 %., pale white
crystals, mp 169 °C, Rf value, 0.56 (9.0:1.0 Benzene:
Acetone). IR (KBr) cm-1: 1649(C=N), 1569(C=C), 1200
1
(C=S). HNMR (CDCl3) d: 6.82–8.45 (m, 19H, Ar–H),
13.31 (s, 1H, NH). 13CNMR (DMSO-d6) d: 111–146.8
(quinoline and phenyl), 148.6 (C=S), 154.8 (N–C=N).
Anal. calcd for C31H21N4S: C, 77.5; H, 4.17; N, 11.6.
Found: C, 77.2; H, 4.29; N, 11.5 %.
In vitro antifungal activity
7-(4-Chlorophenyl)-5,6-diphenylbenzo[h][1, 2, 4]triazolo
[3,4-a][2, 6]naphthyridin-3(2H)-thione (6e) Yield 76 %.,
light yellow crystals, mp 185 °C, Rf value, 0.65 (9.0:1.0
Benzene: Acetone). IR (KBr) cm-1: 1652 (C=N), 1571 (C=C),
1186 (C=S), 719 (C–Cl). 1HNMR (CDCl3)d: 6.95–8.58 (m,
18H, Ar–H), 13.56 (s, 1H,–NH). 13CNMR (DMSO-d6)d:
Compounds 4a–f and 6a–f were also evaluated for their
antifungal activities against a variety of fungal strains viz.
Candida albicans (Ca) (ATCC-24433), Aspergillus niger
(An) (MTCC-872), and Aspergillus fumigatus(Af) (MTCC-
343) using Disc-diffusion Method (Sahm and Washington
1991) by standard micro broth dilution as per NCCLS
123

Med Chem Res (2013) 22:3527–3535
3533
protocol with a view to develop therapeutic agents having
broad spectrum of antifungal activity. As far as the anti-
fungal activity is concerned, many compounds of both the
series were found to be active, some of them with par
excellence (4a and 4b). The compounds which have shown
moderate-to-excellent antifungal activity are, 4a, 4b, 4c,
4d, 4e, and 6b. The substituted phenyl quinolinium iodides
(4a, 4b, 4d, 4e) were found to be more active against the
fungi than the benzotriazolo-naphthyridin-one/thione
derivatives (6b). The compounds also showed more
activity against the single celled Ca than the filamentous
strains of Af and An. Compounds 4a and 4c showed out-
standing activity against Ca with an MIC of 3.12 lg/mL
exceeding that of the standard drug (6.25 lg/mL). These
were followed by compounds 4e and 6b with an MIC of
12.5 lg/mL and moderate activities of 4f and 6e
(MIC = 25 lg/mL). Compound 4d proved to be the most
active against the filamentous fungi with an MIC value of
12.5 lg/mL against An followed by 4d and 6a with
MIC = 25 lg/mL against Af.
The results of preliminary in vitro antimicrobial testing
are displayed graphically in Figure 1 and in tabular form in
Table 1.
Results and discussion
The derivatives 4a–f and 6a–f were screened for their anti-
microbial activities against different bacterial and fungal
strains. Among all the assayed compounds, the substituted
phenyl quinolinium iodides have shown more potent and
universal activity as compared to the benzotriazolo–naph-
thyridin–one/thione derivatives. The compounds 4a, b, and
c showed remarkably high order of activities against the
microbes. It is very interesting to observe here that substituent
R’ plays a greater role in conferring antimicrobial activity
than the substituent R. Thus, compounds 4a, b, and c con-
taining R’=NH2 were found to be the most active against two
strains, viz. Sa and Ca, with an MIC of 3.12 lg/mL, better
than that of the reference drugs (Gentamicin and Fluconaz-
ole), while other compounds either showed moderate activi-
ties or unable to provoke any measurable degree of activity.
Fig. 1 Comparative antibacterial and antifungal study plot with
Gentamicin, Flucanozole, compounds and pathogens
Table 1 Antibacterial and Antifungal activities of newly synthesized
compounds (4a–f and 6a–f) (MIC values (lg/mL) of different strains)
by twofold serial dilution technique and diameter of zone of inhibition
(mm) of bacterial (gram ?ve and gram -ve) and fungal strains by
disc-diffusion assay
Compounds
S. aureus
B. subtilis
E. coli
P.aeruginosa
C. albicans
A. fumigatus
A. niger
4a
6.25 (24)
3.12 (34)b
3.12 (40)b
25 (18)
[100 (09‹)a
[100 (07)a
[100 (06)a
[100 (10)a
[100 (06)a
[100 (09)a
[100 (08)a
[100 (11)a
50 (18)
[100 (08)a
[100 (07)a
[100 (06)a
[100 (09)a
[100 (06)a
[100 (11)a
25 (21)
[100 (06)a
[100 (06)a
50 (18)
[100 (09)a
[100 (08)a
[100 (06)a
[100 (09)a
[100 (06)a
[100 (08)a
50 (12)
[100 (06)a
[100 (09)a
[100 (08)a
50 (13)
3.12 (36)c
[100 (07)a
3.12 (40)c
[50 (10)
12.5 (19)
25 (17)
[100 (06)a
12.5 (24)
50 (14)
[100 (08)a
25 (18)
[100 (06)a
–
[100 (06)a
[100 (09)a
[50 (10)
25 (12)
[100 (06)a
[100 (08)a
25 (12)
[100 (06)a
[100 (09)a
[100 (07)a
[100 (06)a
[100 (06)a
–
[100 (07)a
[100 (06)a
[100 (08)a
12.5 (14)
[100 (06)a
[100 (07)a
[100 (06)a
[100 (08)a
[100 (06)a
[100 (06)a
[100 (06)a
[100 (07)a
- (18)
4b
4c
4d
4e
25 (15)
4f
25 (14)
6a
[100 (08)a
[100 (09)a
50 (11)
[100 (08)a
12.5 (20)
[100 (06)a
6.25 (22)
–
6b
6c
6d
12.5 (21)
[100 (08)a
25 (19)
6e
[100 (07)a
[100 (06)a
25.0 (20)
–
6f
[100 (06)a
- (23)
Gentamicin
Fluconazole
- (22)
–
–
6.25 (21)
- (-)
–
a
No activity observed
b
c
Entries in bold font indicate better activity than reference drugs Gentamicin (Bauer et al., 1966)
Entries in bold font indicate better activity than reference drugs Fluconazole
123

3534
Med Chem Res (2013) 22:3527–3535
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Compounds 4b and 4c exhibited promising antibacterial
activity against Staphylococcus aureus (ATCC-9144).
Compounds 4a, 4b, and 4c are the lead drug candidates,
and further study is being carried out at Central Drug
Research Institute, Lucknow, India concerning their toxi-
cological evaluation. Efforts are paving ways to synthesize
more potent biologically active quinoline derivatives, uti-
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Acknowledgments The authors are thankful to the Head, Depart-
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necessary Laboratory facilities and to the Director, Central Drug
Research Institute (CDRI), Lucknow, India for providing spectral,
elemental, and biological activity data.
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