Cu(II) and Ni(II) complexes of coumarin derivatives with fourth generation flouroquinolone: Synthesis, characterization, microbicidal and antioxidant assay

Article abstract of DOI:10.1007/s00044-014-0943-y

New Cu(II) and Ni(II) complexes of acetyl coumarin derivatives with gatifloxacin were synthesized. Characterization of the complexes was carried out by elemental analysis, FT-IR, FAB-MS, electronic spectra and magnetic measurement alongwith thermo gravimetric studies. Thermal study reveals the absence of coordinated water molecule in case of Cu(II) complexes. All the Cu(II) complexes were found more potent antibacterial activity compared to Ni(II) complexes. The antituberculosis data have shown that copper conjugation may be advantageous in designing highly effective drugs for antitubercular therapy. These complexes were also found to be potent antioxidizing agents comprising radical scavenging capability and ferric reducing abilities. Springer Science+Business Media 2014.

Full text of DOI:10.1007/s00044-014-0943-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-0943-y
ORIGINAL RESEARCH
Cu(II) and Ni(II) complexes of coumarin derivatives with fourth
generation flouroquinolone: synthesis, characterization,
microbicidal and antioxidant assay
•
Jiten Patel Hitesh Dholariya Ketan Patel
•
•
•
Jaimin Bhatt Kanuprasad Patel
Received: 16 September 2013 / Accepted: 7 February 2014
Ó Springer Science+Business Media New York 2014
Abstract New Cu(II) and Ni(II) complexes of acetyl cou-
marin derivatives with gatifloxacin were synthesized. Char-
acterization of the complexes was carried out by elemental
analysis, FT-IR, FAB-MS, electronic spectra and magnetic
measurement along with thermo gravimetric studies. Thermal
study reveals the absence of coordinated water molecule in
case of Cu(II) complexes. All the Cu(II) complexes were
found more potent antibacterial activity compared to Ni(II)
complexes. The antituberculosis data have shown that copper
conjugation may be advantageous in designing highly effec-
tive drugs for antitubercular therapy. These complexes were
also found to be potent antioxidizing agents comprising rad-
ical scavenging capability and ferric reducing abilities.
antibacterial, antitubercular and antioxidant agents (Beraldo
and Gambinob, 2004; Sandbhor et al., 2002; De Souza and
De Giovani, 2004). Coumarin containing compounds have
found important uses as ligand for the synthesis of coordi-
nation compounds (Kapoor et al., 2012; Creaven et al.,
2006). We were particularly attracted to the transition metal
complexes of coumarin derivatives because such compounds
have been reported to function as not only superior thermal
stability and optical properties, but also they have the
promising biological and medical applications including
anti-inflammatory, antitubercular, chemotherapeutic, anti-
coagulant, antibacterial, cycotoxicity and antioxidant (Fy-
laktakidou et al., 2004; Egan et al., 1997; Finn et al., 2002;
Appendino et al., 2004; Patonay et al., 1984; Lin et al., 2008;
Koshy et al., 2000; Kidane et al., 2004). There has been a
tremendous growth of drugs from flouroquinolone family,
since the exponential growth of this family has produced
thousands of analogues (Da Silva et al., 2003; De Souza,
2005). The coordination compounds of these drugs with
metal ions of biological and pharmaceutical importance are
of considerable interest. There have been several reports
about the synthesis, crystal structure and biological evalua-
tion of metal complexes with flouroquinolones (Sadeek and
El-Shwiniy, 2010; Turel et al., 2003; Sousa et al., 2012).
Fluoroquinolones generally act as bidentate ligands binding
to the metallic ion through the carboxylate and carbonyl
oxygens. Usually, distorted octahedral geometry was pre-
ferred for most trantisition metal complexes (Chulvi et al.,
1991). Coordination of the fluoroquinolones with metal ions
having geometry other then octahedral is much lesscommon.
Gatifloxacin (GTF) is a novel 6-fluoro- 8-methoxy quinolone
with important structural modification which expands their
spectrum of activity beyond its antibacterial organisms, and
reduced adverse effects as compared with earlier fluoro-
quinolones (Blondeau et al., 2000; Bauernfeind, 1997).
Keywords Antibacterial Á Antitubercular Á
Radical scavenging activity Á FRAP assay Á Gatifloxacin
Introduction
Metal ions play a vital role in many biologically applications
(Sigel et al., 2006). Transition metal complexes are associ-
ated with various biomolecules related to essential physio-
logical activities in human organism. Our effort is focused on
these metal-ion complexes because of they are promising
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-014-0943-y) contains supplementary
material, which is available to authorized users.
J. Patel Á H. Dholariya Á K. Patel Á J. Bhatt Á K. Patel (&)
V. P. & R. P. T. P. Science College, Sardar Patel University,
Vallabh Vidyanagar 388 120, Gujarat, India
e-mail: drkdpatel64@yahoo.co.in
J. Patel
e-mail: jitenpatel87@gmail.com
123

Med Chem Res
Oxidation is highly imperative for many living organ-
isms to produce their metabolic energy by using biological
processes. Atherosclerosis, diabetes, cancer etc. may be
related to oxidative damage, that are continuously pro-
duced in cell result death and tissue damage (Gomes et al.,
2001; Kang et al., 2003; Babbs, 1990). The coumarins
were found as potent ROS scavengers, and they were also
effective inhibitors against XO’s reduction (Kontogiorgis
et al., 2006; Lien et al., 1999). As transition metal ions play
a vital role in the initiation of free radical processes, metal
chelating compounds of coumarins extensively considered
as potent antioxidant agents. The interaction of coumarins
with metal ions may increase the antioxidant properties and
some other biological effects (Ji and Zhang, 2004; Datta
et al., 2011), besides this some marketed drugs also found
beneficial as antitubercular and antioxidant agent (Vincenzi
and Thomas, 1999; Ahirrao, 2008).
the complexes was recorded at SAIF, CDRI, Lucknow with
JEOL SX-102/DA-6000 mass spectrometer at room tem-
perature using Argon/Xenon as the FAB gas. The elec-
tronic spectra (200–1,200 nm) were collected using
LAMBDA 19 UV/Vis/NIR spectrophotometer. Thermal
stability and decomposition of the complexes were deter-
mined using a model 5000/2960 SDT, TA instrument,
U.S.A. The experiments were performed in N2 atmosphere
at a heating rate of 20 °C min-1 in the temperature range
20–800 °C. The magnetic susceptibility measurement were
obtained by the Gouy’s method using mercury tetrathio-
cyanato cobaltate(II) as a calibrant (v = 16.44 9 10-6
c.g.s. units at 20 °C). Diamagnetic corrections were made
using Pascal’s constant.
Preparation of ligands
Our interest in the activity of transition metals com-
plexes with combination of pharmacophores having two
diverse biologically active compounds. On this backdrop,
we synthesized series of transition metal complexes of
GTF with acetyl coumarin derivatives. The characteriza-
tion of complexes are carried out on the basis of FT-IR,
ESI–MS, elemental, TG, electronic spectral analysis and
magnetic measurement. Also the diverse biological appli-
cations including antibacterial, antifungal, antituberculosis
and antioxidant are carried out.
All the neutral bidentate ligands were synthesized from
reaction of 3-acetyl coumarin and various substituted aro-
matic aldehydes by Claisen-Schmidt condensation using
reported method (Lin et al., 2008). An ethanolic (50 mL)
solution of 3-acetyl coumarin (0.01 M) and appropriate
aromatic aldehyde (0.01 M) were taken in 3-neck round
bottom flask, catalytic amount of piperidine (1.0 mL) was
added in reaction mass and it was stirred for 10 min at
room temperature. After a clear solution was obtained
reaction mixture was refluxed in water bath for 6 h. The
completion of reaction was monitored by TLC using
mobile phase ethyl acetate:hexane (7:3). After the com-
pletion of reaction mixture was allowed to come at room
temperature. A solid product separated out was filtered off,
washed with cold ethanol and dried in air. It was recrys-
tallized from ethanol.
Experimental
Material
All chemicals were purchased from the following com-
mercial sources: Spectrochem Pvt. Ltd., Mumbai, E. Merck
Pvt. Ltd., Mumbai, s.d. fine-chem Ltd., Mumbai. All
chemicals were of reagent grade and solvents of analytical
grade were distilled, purified and dried using appropriate
methods. All reactions were monitored by thin-layer
chromatography (TLC on alluminium plates coated with
silica gel 60 F254, 0.25 mm thickness, Merck) and detection
of the components were done under UV light or explore in
iodine chamber. The metal nitrates were used in hydrated
form.
General procedure for synthesis of ligands is shown in
Scheme 1.
3-(3-phenyl-acryloyl)-2H-chromen-2-one (L1)
3-(3-phenyl-acryloyl)-2H-chromen-2-one was synthesized
by reported method (Lin et al., 2008) using 3-acetyl cou-
marin and benzaldehyde; C18H12O3; Yield, 77 %; m.p.
142–146 °C; FTIR (KBr. cm-1): 1610, m(C=O, a, b-
unsaturated ketone); 1740, m(C=O, lactone carbonyl of
coumarin); 1530, m(C=C, aromatic stretching); 3028, m(C–
H, aromatic stretching); 1H NMR (DMSO-d6 400 MHz): d
6.80 (1H, m, C6-H), d 7.11–7.63 (8H, m, aromatic protons),
d 7.77 (1H, d, J = 7.6, CH=CH– protons), d 7.83 (1H, d,
J = 7.6 CH=CH– protons), d 8.49 (1H, s, C4-H).; 13C
NMR (DMSO-d6 100 MHz): d 113.6 (C-4a), 117.1 (C-8),
118.9 (C-10, –CO–CH =), 124.7, 125.3, 126.0, 127.4,
128.8, 129.7, 133.6, 134.2 (8, Ar–C(C-3,C-5,C-6,C-7,
C-12,C-13,17,C-14,16,C-15)), 146.9(C-11, –CH=CH–),
147.3(C-4), 152.2(C-8a), 159.3 (C=O, lactone carbonyl of
Physical measurement
Elemental analysis (C, H, N) was performed using the
PerkinElmer, USA 2400-II CHN analyzer. The melting
point of all metal complexes was measured using open
capillary tube method. FT-IR spectra (4,000–400 cm-1
)
were recorded with Spectrum GX-PerkinElmer spectro-
photometer using KBr pellets. The FAB-Mass spectrum of
123

Med Chem Res
Scheme 1 General synthetic route of complexes (1–8)
coumarin(C-2)), 189.5 (C=O, a, b-unsaturated ketone(C-
9)) ESI–MS (m/z): 276.7 [M] ? . Found (%); C, 78.20, H,
4.32. calculated: C, 78.25, H, 4.38.
292.4 [M] ? . Found (%); C, 73.86, H, 4.05. calculated: C,
73.97, H, 4.14.
3-(3-(4-hydroxyphenyl)acryloyl)-2H-chromen-2-one (L3)
3-(3-(3-hydroxyphenyl)acryloyl)-2H-chromen-2-one (L2)
3-(3-(4-hydroxyphenyl)acryloyl)-2H-chromen-2-one was
synthesized by same method as L1 using 3-acetyl coumarin
and 4- hydroxybenzaldehyde; C18H12O4; Yield, 72 %; m.p.
210–212 °C; FTIR (KBr. cm-1): 3484, m(O–H, stretching);
1622, m(C=O, a, b-unsaturated ketone); 1745, m(C=O, lac-
tone carbonyl of coumarin); 1484, m(C=C, aromatic
3-(3-(3-hydroxyphenyl)acryloyl)-2H-chromen-2-one was
synthesized by same method as L1 using 3-acetyl coumarin
and 3- hydroxybenzaldehyde; C18H12O4; Yield, 70 %; m.p.
201–205 °C; FTIR (KBr. cm-1): 3479, m(O–H, stretching);
1615, m(C=O, a, b-unsaturated ketone); 1735, m(C=O, lac-
tone carbonyl of coumarin); 1555, m(C=C, aromatic
1
stretching); 3018, m(C–H, aromatic stretching); H NMR
1
stretching); 3040, m(C–H, aromatic stretching); H NMR
(DMSO-d6 400 MHz): d 6.86 (2H, d, J = 7.8, p-substi-
tuted phenyl ring), d 6.88 (1H, d, J = 16, CH=CH– pro-
tons), d 7.23 (1H, m, aromatic protons), d 7.40 (2H, d,
J = 7.8, p-substituted phenyl ring), d 7.63–7.74 (3H, m,
three aromatic protons), d 7.90 (1H, d, J = 16, CH=CH–
protons), d 8.53 (1H, s, C4-H), d 9.58 (1H, s, –OH); 13C
NMR (DMSO-d6 100 MHz): d 114.4 (C-4a), 116.7 (C-8),
118.3 (C-10, –CO–CH =), 124.5, 125.0, 127.0, 127.5,
129.9, 130.2, 134.4 (7, Ar–C(C-3,C-5,C-6,C-7,C-12,C-
13,17,C-14,16)), 147.1 (C-11, –CH=CH–), 147.5 (C-4),
151.7 (C-15, carbon attach to phenolic OH), 155.3 (C-8a),
159.2 (C=O, lactone carbonyl of coumarin(C-2)), 190.8
(DMSO-d6 400 MHz): d 6.87 (1H, m, C6-H), d 7.20–7.86
(7H, m, aromatic protons), d 7.94 (1H, d, J = 7.8,
CH=CH– protons), d 8.04 (1H, d, J = 8.0 CH=CH– pro-
tons), d 8.48 (1H, s, C4-H). 9.48 (1H, s, –OH); 13C NMR
(DMSO-d6 100 MHz): d 114.8 (C-4a), 116.9 (C-8), 118.6
(C-10, –CO–CH =), 119.9, 120.0, 124.2, 124.8, 126.9,
127.6, 129.7, 130.0, 133.9 (9, Ar–C(C-3,C-5,C-6,C-7,C-
12,C-13,C-15,C-16,C-17)), 146.6 (C-11, –CH=CH–), 147.2
(C-4), 152.8 (C-14, carbon attached to phenolic OH), 155.7
(C-8a), 159.6 (C=O, lactone carbonyl of coumarin(C-2)),
188.8 (C=O, a, b-unsaturated ketone(C-9)); ESI–MS (m/z):
123

Med Chem Res
(C=O, a, b-unsaturated ketone(C-9)); ESI–MS (m/z);
292.7[M]?. Found (%): C, 73.90, H, 4.02. calculated: C,
73.97, H, 4.14.
178–182 °C; FTIR (KBr. cm-1): 1610, m(C=O, a, b-
unsaturated ketone); 1744, m(C=O, lactone carbonyl of
coumarin); 1528 (ArNO2, asymmetric); 1344 (ArNO2,
symmetric); 1535, m(C=C, aromatic stretching); 3034, m(C–
3-(3-(3-chlorophenyl)acryloyl)-2H-chromen-2-one (L4)
H, aromatic stretching); H NMR (DMSO-d6 400 MHz):):
1
d 6.88 (1H, m, C6-H), d 7.23–7.71 (7H, m, aromatic pro-
tons), d 7.79 (1H, d, J = 7.8, CH=CH– protons), d 7.80
(1H, d, J = 7.8 CH=CH– protons), d 8.52 (1H, s, C4-H);
13C NMR (DMSO-d6 100 MHz): d 113.8 (C-4a), 116.1 (C-
8), 118.5 (C-10, –CO–CH =), 123.2, 124.4, 125.5, 127.1,
127.7, 128.4, 129.6, 130.5, 134.5 (9, Ar–C(C-3,C-5,C-6,C-
7,C-12,C-13,C-15,C-16,C-17)), 147.2 (C-11, –CH=CH–),
147.9 (C-4), 149.7 (C-14, carbon attach to phenolic NO2),
156.0 (C-8a), 159.7 (C=O, lactone carbonyl of couma-
rin(C-2)), 188.2 (C=O, a, b-unsaturated ketone(C-9)); ESI–
MS (m/z): 321.2 [M]?; Found (%): C, 67.21, H, 3.27,N,
4.31. calculated: C, 67.34, H, 3.45, N, 4.39.
3-(3-(3-chlorophenyl)acryloyl)-2H-chromen-2-one was syn-
thesized by same method as L1 using 3-acetyl coumarin and
3-cholorobenzaldehyde; C18H11ClO3; Yield, 78 %; m.p.
215–217 °C; FTIR (KBr. cm-1): 1615, m(C=O, a, b-
unsaturated ketone); 1739, m(C=O, lactone carbonyl of
coumarin); 1523, m(C=C, aromatic stretching); 3045, m(C–
H, aromatic stretching); 1H NMR (DMSO-d6 400 MHz): d
6.78 (1H, m, C6-H), d 7.18–7.65 (7H, m, aromatic protons),
d 7.72 (1H, d, J = 8.0, CH=CH– protons), d 7.89 (1H, d,
J=7.6 CH=CH– protons), d 8.37 (1H, s, C4-H); 13C NMR
(DMSO-d6 100 MHz): d 114.2 (C-4a), 116.5 (C-8), 118.2
(C-10, –CO–CH =), 124.7, 125.2, 126.9, 127.6, 128.4,
129.8, 130.4, 133.5, 134.0, 136.1 (10, Ar–C(C-3,C-5,C-
6,C-7,C-12,C-13,C-14,C-15,C-16,C-17)), 146.8 (C-11,
–CH=CH–), 147.7 (C-4), 155.7 (C-8a), 158.2 (C=O, lac-
tone carbonyl of coumarin(C-2)), 187.6 (C=O, a, b-unsat-
urated ketone(C-9)); ESI–MS (m/z): 310.5, 312.7 [M]?;
Found (%): C, 69.46, H, 3.57. calculated: C, 69.58, H, 3.49.
3-(3-(4-nitrophenyl)acryloyl)-2H-chromen-2-one (L7)
3-(3-(4-nitrophenyl)acryloyl)-2H-chromen-2-one was syn-
thesized by same method as L1 using 3-acetyl coumarin
and 4-nitrobenzaldehyde; C18H11NO5; Yield, 68 %; m.p.
171–175 °C; FTIR (KBr. cm-1): 1614, m(C=O, a, b-
unsaturated ketone); 1738, m(C=O, lactone carbonyl of
coumarin); 1523 (ArNO2, asymmetric); 1347 (ArNO2,
symmetric); 1543, m(C=C, aromatic stretching); 3037, m(C–
H, aromatic stretching); 1H NMR (DMSO-d6 400 MHz): d
6.90 (1H, m, C6-H), d 7.14 (2H, d, J = 7.2, p-substituted
phenyl ring), d 7.25 (1H, m, aromatic protons), d 7.45 (2H,
m, aromatic proton), d 7.78 (2H, d, J = 7.2, p-substituted
phenyl ring), d 7.86 (1H, d, J = 7.2, CH=CH– protons), d
7.91 (1H, d, J = 7.2, CH=CH– protons), d 8.53 (1H, s, C4-
H); 13C NMR (DMSO-d6 100 MHz): d 114.1 (C-4a), 116.3
(C-8), 118.5 (C-10, –CO–CH =), 124.9, 125.7, 126.9,
127.1, 129.5, 130.6, 134.8 (7, Ar–C(C-3,C-5,C-6,C-7,C-
12,C-13,17,C-14,16)), 146.8 (C-11, –CH=CH–), 147.2 (C-
4), 148.7 (C-15, carbon attach to phenolic NO2), 154.7 (C-
8a), 159.6 (C=O, lactone carbonyl of coumarin(C-2)),
189.7 (C=O, a, b-unsaturated ketone(C-9)); ESI–MS (m/z):
321.4 [M] ? ; Found (%): C, 67.29, H, 3.37, N, 4.36.
calculated: C, 67.34, H, 3.45, N, 4.39.
3-(3-(4-chlorophenyl)acryloyl)-2H-chromen-2-one (L5)
3-(3-(4-chlorophenyl)acryloyl)-2H-chromen-2-one was syn-
thesized by same method as L1 using 3-acetyl coumarin and
4- cholorobenzaldehyde; C18H11ClO3; Yield, 70 %; m.p.
223–226 °C; FTIR (KBr. cm-1): 1618, m(C=O, a, b-
unsaturated ketone); 1742, m(C=O, lactone carbonyl of
coumarin); 1591, m(C=C, aromatic stretching); 3062, m(C–
H, aromatic stretching); 1H NMR (DMSO-d6 400 MHz): d
6.86 (1H, m, C6-H), d 7.12 (2H, d, J = 7.2, p-substituted
phenyl ring), d 7.23 (1H, m, aromatic protons), d 7.39 (2H,
m, aromatic proton), d 7.63 (2H, d, J = 7.2, p-substituted
phenyl ring), d 7.88 (1H, d, J = 7.8, CH=CH– protons), d
7.90 (1H, d, J = 7.8, CH=CH– protons), d 8.52 (1H, s,
C4-H); 13C NMR (DMSO-d6 100 MHz): d 114.8 (C-4a),
116.5 (C-8), 118.6 (C-10, –CO–CH =), 124.2, 125.1,
126.2, 127.9, 129.8, 130.0, 133.5, 134.6 (8, Ar–C(C-3,C-
5,C-6,C-7,C-12,C-13,17,C-14,16,C-15)), 147.1 (C-11,
–CH=CH–), 147.6 (C-4), 151.5 (C-8a), 159.7 (C=O, lac-
tone carbonyl of coumarin(C-2)), 190.2 (C=O, a, b-unsat-
urated ketone(C-9)); ESI–MS (m/z): 310.6, 312.7 [M]?;
Found (%): C, 69.40, H, 3.66. calculated: C, 69.58, H, 3.57.
3-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-2H-chromen-
2-one (L8)
3-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-2H-chromen-
2-one was synthesized by same method as L1 using
3-acetyl coumarin and 4-hydroxy-3-methoxybenzaldehyde;
C19H14O5; Yield, 79 %; m.p. 230–234 °C; FTIR (KBr.
cm-1): 3475, m(O–H, stretching); 1620, m(C=O, a, b-
unsaturated ketone); 1743, m(C=O, lactone carbonyl of
coumarin); 1241 (C–O–C, asymmetric); 1039 (C–O–C,
3-(3-(3-nitrophenyl)acryloyl)-2H-chromen-2-one (L6)
3-(3-(3-nitrophenyl)acryloyl)-2H-chromen-2-one was syn-
thesized by same method as L1 using 3-acetyl coumarin
and 3- nitrobenzaldehyde; C18H11NO5; Yield, 64 %; m.p.
123

Med Chem Res
symmetric); 1H NMR (DMSO-d6 400 MHz):): d 3.86 (3H,
s, –OCH3), d 6.91(1H, m, C6-H), 7.12–7.79 (6H, m, aro-
matic protons), d 7.89 (1H, d, J = 7.6, CH=CH– protons),
d 7.93 (1H, d, J = 7.6, CH=CH– protons), d 8.56 (1H, s,
C4-H), d 9.67 (1H, s, -OH); 13C NMR (DMSO-d6
100 MHz):): d 34.9 (C-18, OCH3), 111.5 (C-13), 114.6 (C-
16), 115.1 (C-4a), 116.4 (C-8), 118.0 (C-10, –CO–CH=),
124.2, 125.8, 127.6, 129.4, 130.4, 134.5 (6 different types
of aromatic carbons(C-3,C-5,C-6,C-7,C-12,C-17)), 147.2
(C-11, –CH=CH–), 147.4 (C-4), 148.8 (C-14), 151.7 (C-15,
carbon attach to phenolic OH), 155.6 (C-8a), 158.8 (C=O,
lactone carbonyl of coumarin(C-2)), 190.4 (C=O, a, b-
unsaturated ketone(C-9)); ESI–MS (m/z): 322.1 [M]?;
Found (%): C, 78.77, H, 4.31. calculated: C, 78.80, H, 4.38.
resistance to antibiotics and their metal complexes through
biochemical and morphological modifications. The anti-
bacterial activity was determined as minimum inhibitory
concentration (MIC) by following method (Trommel and
Marzilli, 2001). Antibacterial activity of complexes were
compared with respect to second (CPF), third (LVF) and
fourth (GTF) generation quinolones. The in vitro antibac-
terial activity of all the synthesized compounds was carried
out against 24 h old cultures of microorganisms by broth
dilution method. Serial broth micro dilution method was
adopted as a reference method. 10 ml Luria broth solution
was prepared in distilled water, while pH of the solution
was adjusted to 7.4 0.2 at room temperature and steril-
ized by autoclaving at 15 lb pressure for 20 min. The tested
microorganism strains were made in the Luria broth and
incubated at 37 °C for overnight. Sample and standard
solutions were prepared in DMSO. Serial dilutions of test
compounds were inoculated in broth; to this a standardized
microorganism suspension was added. Each test tube
incubated at 37 °C for 24 h. At the end of the incubation
period tubes were examined for the turbidity. Turbidity in
the test tubes indicated that microorganism growth has not
inhibited by the antibiotic contained in the medium at the
test concentration.
Synthesis of complexes (C1–C8)
All the metal complexes (1–8) were synthesized according
to (Scheme 1) using the following general method. An
aqueous solution of appropriate divalent metals
CuCl2.2H2O/NiCl2.6H2O (10 mmol, 10 mL) was added to
methanolic solution of appropriate ligand (L) (10 mmol,
50 mL) followed by addition of an ethanolic solution of
GTF (10 mmol, 50 mL), the pH was adjusted to 6.0 with
diluted CH3ONa solution. The resulting solution was
refluxed for 5–8 h and then heated over a steam bath to
evaporate up to half of the volume. The reaction mixture
was kept overnight at room temperature. A fine coloured
powder was obtained was washed with ether and dried over
vacuum desiccators. The analytical and physiochemical
data of the ligands and complexes are summarized in
(Table 1).
Antituberculosis activity
The activity of Cu (1–4) and Ni (5–8) complexes against
Mycobacterium tuberculosis strain H37Rv (MTCC200)
was determined by following method (Rattan, 2000). The
resulted antituberculosis activity was expressed as minimal
inhibition concentration (MIC) as well as % inhibition of
growth was measured at MIC are summarized in con-
cluding part. Isoniazid and Rifampicin were used as stan-
dard drugs for comparison purpose were as GTF used as
control. All the synthesized complexes were examined for
antituberculosis activity against Mycobacterium tubercu-
losis H37Rv strain using Lowenstein-Jensen medium
method. Isoniazid and Rifampicin was used as the standard
Method of antimicrobial assay
The biological activity of metal complexes were tested
against variety of bacteria such as B. subtilis, S. aureus, S.
pneumonia (Gram positive), E. coli, P. aeruginosa, S. typhi
(Gram negative), because these microorganisms can get
Table 1 Analytical and physiochemical parameters of synthesized compounds
Compounds/Empirical formula
Elemental analyses, % found (required)
m.p. Yield Molecular leff/
(°C) (%)
mass
B.M.
C
H
N
Cu(II)
[Cu(GTF)(L1)(Cl)]5H2O C37H43ClCuFN3O12/(1)
[Cu(GTF)(L2)(Cl)]5H2O C37H42Cl2CuFN3O12/(2)
[Cu(GTF)(L3)(Cl)]5H2O C37H42ClCuFN4O14/(3)
[Cu(GTF)(L4)(Cl)]5H2O C37H43ClCuFN3O13/(4)
[Ni(GTF)(L1)(Cl)(H2O)]3H2O C37H41ClFN3NiO11/(5) 54.36 (54.40) 5.09 (5.06) 5.20 (5.14) 7.15 (7.19) [300 48
[Ni(GTF)(L2)(Cl)(H2O)]3H2O C37H40Cl2FN3NiO11/(6) 52.14 (52.20) 4.72 (4.74) 4.91 (4.94) 6.92 (6.89) [300 55
[Ni(GTF)(L3)(Cl)(H2O)]3H2O C37H40ClFN4NiO13/(7) 51.50 (51.56) 4.63 (4.68) 6.45 (6.50) 6.78 (6.81) [300 52
[Ni(GTF)(L4)(Cl)(H2O)]3H2O C37H41ClFN3NiO12/(8) 53.39 (53.36) 4.91 (4.96) 4.99 (5.05) 7.01 (7.05) [300 59
52.88 (52.92) 5.14 (5.16) 4.97 (5.00) 7.55 (7.57) [300 60
50.82 (50.84) 4.86 (4.84) 4.76 (4.81) 7.32 (7.27) [300 62
50.27 (50.23) 4.75 (4.78) 6.40 (6.33) 7.12 (7.18) [300 58
51.88 (51.93) 5.01 (5.06) 4.87 (4.91) 7.40 (7.43) [300 65
839.75
874.19
884.75
855.75
816.88
851.13
861.88
831.17
1.82
1.78
1.75
1.80
3.10
3.17
2.98
3.05
123

Med Chem Res
drug, whereas GTF used as control. The dilutions of
standard drugs were prepared in DMSO to get different
concentrations of 0.1–2 lg mL-1. Stock solutions of syn-
thesized compounds were prepared in DMSO. Further
dilutions were prepared in DMSO to get different con-
centrations. 1.0 mL of each concentration was used for the
study, to this 9.0 mL of Lowenstein- Jensen medium was
added. A sweep from M. tuberculosis H37RV strain culture
was discharged with the help of nichrome wire loop having
3 mm external diameter into a vial containing 4 mL of
sterile distilled water. The vial was shaken for 5 min. The
suspension was inoculated on the surface test compounds
containing Lowenstein–Jensen medium. Further test media
was incubated for 2 weeks at 37 °C. Readings were taken
after incubation period of 2 weeks.
ligands and metal chloride solution. The metal content in
the complex was determined spectrophotometrically. All
the coloured metal complexes are stable in atmospheric
conditions for extended periods and soluble in DMSO,
while insoluble in water and in most organic solvents.
Elemental data found by analysis (Table 1) were in good
agreement with proposed structures as per (Scheme 1). The
coordination was confirmed by FAB-Mass, electronic
spectra, FT-IR spectra, thermal study and magnetic
measurement.
IR spectra
The important infrared spectral bands and their assign-
ments for compounds (Table 2) were showed that couma-
rin derivatives coordinate to the metal ions in a bidentate
behaviour via the a, b-unsaturated ketone and the lactone
carbonyl oxygens. IR spectral data of the coumarin deriv-
atives shows 1,610–1,625 and 1,740–1,750 cm-1 bands
corresponding to a, b-unsaturated ketone and lactone
carbonyl ketone, respectively, on complexation these
peaks shifted to a lower frequency 1,595–1,608 and
1,728–1,735 cm-1 due to complex formation which is
good indication that coumarin is coordinated to the metal
ions. Spectra of the mixed-ligand Ni(II) complexes reveals
that a broad band in the region 3,300–3,450 cm-1 due to
the OH stretching of the water molecule which indicates
formation of complexes (Anacona and Toledo, 2001).
Absent of this OH band indicates no coordinated water
molecule present in case of Cu complexes. Besides this
according to the elemental analysis and thermogravimetric
studies, all the complexes contain water of crystallization.
The IR spectra showed characteristic absorption bands
around *3,430, *1,615, *1,336 cm-1 were attributed to
the stretching vibration m(H–O), m(COO)asym, m(COO)-
sym, respectively. These bands of carboxylic group of GTF
have been replaced by two strong bands in the range
1,553–1,573 cm-1 [masym(C=O)] and 1,360–1,370 cm-1
[msym(C=O)] due to the coordination with metal ion (S. Jain
et al., 2002). The monodentate coordination mode of car-
boxylato ligand was characterized by D value falling in the
range 192–212 cm-1 (Nakamoto, 1986; Deacon and Phi-
lips, 1980). The valence vibration of the carboxylic stretch
for free GTF was found at *1,730 cm-1 which disappears
due to the complexation. Peak in range 1,615–1,630 cm-1
found in case of complexes were for pyridone m(C=O)
atom which appeared at *1,720 cm-1 in GTF; this shift in
band towards lower energy suggests coordination via
pyridone oxygen atom (Turel et al., 1997). The coordina-
tion is also supported by the appearance of IR bands due to
m(Cu–O) and m(Ni–O) vibrations in the range 505–525 and
545–558 cm-1, respectively (Kharadi and Patel, 2010;
Singh et al., 2012).
FRAP assay and radical scavenging activity
Ferric reducing antioxidant power (FRAP) as well as 1,1-
diphenyl-2-picryl-hydrazil (DPPH) radical scavenging
activity of all compounds were determined according to the
reported methods (Patel et al., 2012a, b; Blois, 1958). In
FRAP assay, reducing power of the TPTZ-Fe(III) complex
to TPTZ-Fe(II) complex for the total antioxidant capacity
of tested samples was measured. The total antioxidant
capacities of a compound consider as a significant indicator
of its potential antioxidant activity and compared to the
standard antioxidant compound ascorbic acid. For DPPH
radical activity, tests were run in triplicate for all com-
pounds, and the results were obtained for fix concentration
at which each compound showed approximately 50 %
activity (IC50). The DPPH free radical scavenging capa-
bility was determined by following formula, % activ-
ity = [(A0 - Ac)/A0] 9 100 where A0 and Ac represent the
absorbance in the absence and presence of the tested
complex, respectively.
Results and discussion
Synthesis and structural determination
3-(3-phenyl-acryloyl)-2H-chromen-2-one (L1), 3-(3-(4-
chlorophenyl)acryloyl)-2H-chromen-2-one (L2), 3-(3-(4-
nitrophenyl)acryloyl)-2H-chromen-2-one (L3) and 3-(3-(4-
hydroxyphenyl)acryloyl)-2H-chromen-2-one (L4) were
used for the preparation of M (II) (M = Cu, Ni) complexes
(Scheme 1). These neutral bidentate ligands using Claisen-
Schmidt condensation method were previously reported by
us (Patel et al., 2012a, b). 3-acetyl coumarin is reacted with
equimolar respective aromatic aldehyde in presence of
piperidine catalyst. M (II) complexes were obtained by
refluxing the equimolar reaction mass of two bidentate
123

Med Chem Res
Table 2 FT-IR data of synthesized compounds in cm-1
Complexes (1–8)
m(O–H)br a, b-unsaturated lactone carbonyl m(C = O) of m(COO)asym m(COO)sym m(M–O)w
pyridone
m(C = O)s
m(C = O)s
[Cu(GTF)(L1)(Cl)]5H2O/(1)
[Cu(GTF)(L2)(Cl)]5H2O/(2)
[Cu(GTF)(L3)(Cl)]5H2O/(3)
[Cu(GTF)(L4)(Cl)]5H2O/(4)
[Ni(GTF)(L1)(Cl)(H2O)]3H2O/(5) 3,335
[Ni(GTF)(L2)(Cl)(H2O)]3H2O/(6) 3,340
[Ni(GTF)(L3)(Cl)(H2O)]3H2O/(7) 3,342
[Ni(GTF)(L4)(Cl)(H2O)]3H2O/(8) 3,340
–
–
–
–
1,595
1,603
1,600
1,608
1,597
1,604
1,600
1,608
1,732
1,730
1,728
1,735
1,730
1,728
1,730
1,734
1,615
1,618
1,630
1,624
1,619
1,624
1,628
1,622
1,553
1,557
1,562
1,558
1,556
1,562
1,573
1,567
1,361
1,363
1,368
1,363
1,364
1,366
1,370
1,360
518
525
520
505
545
552
558
550
s strong, w weak, br broad
Electronic spectra and magnetic measurement
water (calc. 10.71 %, obs. 10.86 %), This low temperature
loss confirms that the water molecules do not participate in
coordination and considered as crystalline water. In second
step, weight loss occurs between 180 and 390 °C due to
decomposition of bidentate ligand (calc. 32.90 %, obs.
33.20 %) where as third weight loss between 430 and 650°
corresponds to decomposition of GTF (calc. 44.67 %, obs.
42.90 %). Thermogravimetric curve of Ni(II) complex (5)
provides similar three step decomposition as Cu(II) com-
plex with varies in temperature and mass loses. First weight
loss occurs between 50 and 120 °C due to loss of three
crystalline water molecules (calc. 6.61 %, obs. 6.68 %), in
second step between 160 and 410 °C corresponds to
decomposition of bidentate ligand and one coordinated
molecule of each (Cl and H2O) (calc. 40.36 %, obs.
40.10 %) where as third loss between 440 and 690 °C
corresponds to decomposition of GTF (calc. 45.93 %, obs.
44.86 %). Rest of the compound in both complexes con-
siders as metal oxides e.g. CuO and NiO.
Electronic spectral data together with magnetic suscepti-
bility measurements gave enough support to discover the
geometry of metal complexes. Copper(II) complexes that
is, d9 system with a simple ligand at low temperature
exhibit an absorption band with a large width make them
very difficult to interpret. Cu(II) complexes with different
coordination numbers resulted in different geometry.
However, many copper compounds show temperature
dependent geometric distortions, and single copper ions in
a host lattice of regular symmetry may exhibit interesting
spectroscopic properties (Weber et al., 2009). In our case
of copper(II) complexes, bands observed in the regions
*9,550(m1), *13,500(m2) and *18,800(m3) cm-1 have
been ascribed to the transitions 2B1 ? 2A1, 2B1 ? 2B2
and 2B1 ? 2E, respectively, which was further ascertained
by its magnetic moment of 1.75–1.82 BM falls within the
range normally observed for square pyramidal Cu(II)
complexes (1–4) (Figgis and Lewis, 1960; Carballo et al.,
2004). The absorption spectra of nickel complexes display
three d–d transition bands with D4h symmetry in the range
*10,800(m1), *14,600(m2) and *21,180(m3) cm-1. The
transitions correspond to the 3A2g (F) ? 3T2g (F), 3A2g
(F) ? 3T1g (F) and 3A2g (F) ? 3T2g (P), respectively.
These transitions reveal that the Ni(II) complexes possess
octahedral geometry, which was further supported by the
observed magnetic moment values between 2.98 and 3.17
B.M. (Balhausen, 1962; Al-Resayes et al., 2012).The
observed magnetic moments of Ni(II) complexes are in the
range expected for spin-free d8 systems.
FAB-mass spectra
FAB-Mass spectra of all complexes were obtained using
m-nitrobenzyl alcohol as matrix. Figure 1 represents the
FAB-MS of complex [Cu(GTF)(L1)(Cl)]5H2O (1) and
[Ni(GTF)(L1)(Cl)(H2O)]3H2O (5). The [M?2H]? frag-
ments without water of crystallization are observed at 748,
750 and 763, 761 m/z in case of complex 1 and complex 5,
respectively. There also exists a fragment of complex 1 (at
m/z = 708) and 5 (at m/z = 713) indicates the presence of
Cl atom in respective complexes. The peaks at 615 m/z and
610 m/z correspond to removal of piperazine ring,
respectively, in complex 1 and 5. Also, the peak at 743 m/z
corresponds to loss of coordinated water molecule was
found in case of complex 5, apart from it several peaks
found at 136, 137, 154, 289 and 307 m/z are due to usage
of matrix in both the complexes.
Thermal study
Thermal decomposition occurs in three steps for Cu(II)
complex (1) (Psomas et al., 1998). First weight loss occurs
between 70 and 140 °C due to loss of five molecules of
123

Med Chem Res
Antibacterial activity
2. Gram negative bacteria
E. coli: In this case, none of the complex found
more potent than any standard drug.
Activity data from (Table 3) indicate that all the Cu(II)
complexes (1–4) found more potent then Ni(II) complexes
(5–8), beyond which Cu(II) complex (4) with hydroxyl
molecule at pera position found most potent against all the
bacteria. The result indicates that substitution of the
hydroxyl groups on the phenyl ring of the coumarin ligand
play vital for improved the antibacterial activity of Cu(II)
complexes. Comparison between the gram positive and
gram negative strains indicates enhanced potency of all
complexes (1–8) for gram positive bacteria, particularly S.
aureus and S. Pneumonia. in gram negative bacteria.
aeruginosa found to be more potent than other two bacteria
E. coli and S. typhi along with it, P. aeruginosa was only
the gram negative bacteria which found more potent then
gram positive bacteria B. subtilis.
P. aeruginosa: Complexes 2, 4 and 8 are found
active against all standard drug, beyond which 4 is
found most potent, where as all the remaining
complexes found less potent against all standard
drugs.
S. Pneumonia: In this case, only single complex i.e.
4 found equipotent with GTF, where as remaining
complexes found less potent compare to standard
drugs.
Reviewing the activity data, these rationales are con-
sidered for increased in activity of all complexes,
(I) bidentate nature of the ligand (II) chelating affect in
which bidentate coordination of quinolone with metal ion
(III) on the basis of Overtone’s and Tweed’s chelation
theory (IV) dinuclear centres are usually more active than
mononuclear ones. In general, the in vitro evaluation of all
complexes revealed improved therapeutic effectiveness of
GTF when it binds with metal and bidentate ligands, as
compared to the standard antibiotics including GTF itself.
Further developmental studies to acquire more information
about structure–activity relationships are in progress in our
laboratories.
1. Gram positive bacteria
B. subtilis: In this case, complex 4 is only
compound, which found more potent than all the
standard drugs and complexes 1 and 2 found more
potent then GTF, where as complex 8 found
equipotent compared to GTF.
S. aureus: Complexes 2, 4 and 8 are found active
against all standard drug, beyond which 4 is found
most potent, where as all the remaining complexes
excluding 7 are found active against LVF and CPF.
S. Pneumonia: In this case, all the complexes
excluding 7 are found more potent against all
standard drugs, beyond which 4 is found most
potent.
Antituberculosis activity
The encouraging results from the antibacterial studies
prompted us to go for preliminary screening of complexes
Fig. 1 FAB-Mass spectra of
Cu(II) and Ni (II) complex
123

Med Chem Res
Table 3 Antibacterial activity of complexes
Compound
M
R
Minimum inhibitory concentration (lg/mL)
Gram positive bacteria
Gram negative bacteria
B. s. MTCC-441 S. a. MTCC-96 S. pn. MTCC-2672 E. c. MTCC-443 P. a. MTCC-1688 S. ty. MTCC-98
CuCl2Á2H2O
2620
3.0
2,510
2.1
2,550
1.5
2,890
15.0
10.0
[20.0
6.8
2,430
3.8
2,760
7.0
1
Cu
Ni
H
2
Cl
2.8
0.9
0.6
1.5
10.0
[20.0
4.5
3
NO2 5.0
OH 1.2
3.5
1.8
4.8
4
0.6
0.3
1.0
NiCl2Á6H2O
5
3,450
5.2
5.0
3,040
3.0
2,920
1.5
3,680
15.0
15.0
[20.0
8.0
3,150
4.6
3,290
10.0
10.0
[20.0
7.0
H
6
Cl
2.5
0.9
4.2
7
NO2 7.0
OH 3.5
3.5
5.8
2.2
6.8
8
1.4
0.6
2.0
Gatifloxacin
Levofloxacin
Ciprofloxacin
2.0
2.0
5.0
2.7
4.5
2.5
3.8
3.6
3.1
2.7
4.0
1.8
6.0
4.5
1.3
3.0
2.5
B.s.: B. subtilis (MTCC-441), S.a.: S. aureus (MTCC-96), S. pn.: S. pneumonia (MTCC-2672), E.c.: E. coli (MTCC-443), P.a.: P. aeruginosa
(MTCC-1688), S.ty.: S. typhi (MTCC-98), M metal, R variables
for their in vitro antituberculosis activity. Antituberculosis
activity data (Table 4) of the complexes clearly indicate
that most complexes provide excellent % inhibition (C90).
Reviewing the MIC data, Both Cu(II) and Ni(II) complexes
(4 and 8) with GTF containing hydroxyl group were most
active within each series inhibiting bacterial growth at 0.25
and 0.35 mg/mL, respectively. On the other hand, the least
active complexes (3 and 7) of the series were Cu(II) and
Ni(II) complex with GTF containing nitro group which
exhibited MIC value of 1.15 and 1.50 mg/mL, respec-
tively. Rest of the complexes containing Cl and H has
shown significant activity between 0.30 and 0.80. The
activity data show advantages of copper coordination over
nickel complexes. In general, all the complexes exhibited
superior activity then marketed drug Rifampicin except
complex 3 and 7.
FRAP assay and radical scavenging activity
The FRAP assay data from Fig. 2 indicate that metal
complexes exhibit higher antioxidant activity then its free
ligands. The internal comparison of complexes clearly
indicates the higher antioxidant potency of Cu(II) com-
plexes. DPPH scavenging activity amongst the all com-
pounds, the complexes (1–4) show higher antioxidant
potency due to presence of Cu(II) ion as shown in Fig. 3. In
particular, all the compounds have been found potent ferric
Table 4 Antituberculosis activity of complexes
Compound
MIC lg/mL M. tuberculosis
(MTCC 200)
% Inhibition
1
0.78
0.31
1.15
0.25
0.69
0.40
1.50
0.35
0.1
85
95
60
99
90
98
45
98
99
98
95
2
3
4
5
6
7
8
Gatifloxacin
Isoniazid
Rifampicin
0.20
1.0
Fig. 2 Frap assay of compounds
123

Med Chem Res
Delhi, India for providing financial support to one of the author (JDB)
in the form of INSPIRE fellowship. We are thankful to the Director,
SICART, Vallabh Vidyanagar for spectral analysis facility. Authors
are also grateful to the Microcare laboratory, Surat for providing bio-
analysis facility.
References
Ahirrao P (2008) Recent developments in antitubercular drug. Mini
Rev Med Chem 8:1441–1451
Al-Resayes SI, Shakir M, Abbasi A, Amin KMY, Lateef A (2012)
Synthesis, spectroscopic characterization and biological activi-
ties of N4O2 Schiff base ligand and its metal complexes of
Co(II), Ni(II), Cu(II) and Zn(II), Spectrochim. Acta Part A
93:86–94
Anacona JR, Toledo C (2001) Synthesis and antitubercular activity of
palladium and platinum complexes with fluoroquinolones. Trans
Met Chem 26:228–231
Appendino G, Mercalli E, Fuzzati N, Arnoldi L, Stavri M, Gibbons S,
Ballero M, Maxia A (2004) Chemical composition and in vitro
activity of plant extracts from ferula communis and Dittrichia
viscosa against postharvest fungi. J Nat Prod 67:2108–2110
Babbs CF (1990) Oxygen radicals in ulcerative colitis. Free Radic
Biol Med 8:191–200
Fig. 3 DPPH radical scavenging activity of compounds
reducing capacity and radical scavenging capability com-
pared to standard drug (ascorbic acid). The antioxidant
activity of the ligand and its M(II) complexes (where
M = Ni and Cu) against the DDPH radical and FRAP
assay was found to increase in the order of L \ Ni(II) \
Cu(II).
Balhausen CJ (1962) Introduction to ligand fields. McGraw Hill, New
York
Bauernfeind A (1997) Comparison of the antibacterial activities of the
quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin,
Conclusion
clinafloxacin, levofloxacin and ciprofloxacin.
Chemother 40:639–651
Beraldo H, Gambinob D (2004) The wide pharmacological versatility
of semicarbazones, thiosemicarbazones and their metal com-
plexes. Mini Rev Med Chem 4:31–39
J Antimicrob
The neutral bidentate ligands were prepared with 1:1 molar
ratio of 3-acetyl coumarin and various aromatic aldehydes
using piperidine as catalyst in ethanol. All the complexes
(C) were obtained by the reaction of ligands and GTF with
metal chloride having 1:1:1 molar ratio in ethanol and the
yields were good to moderate. In all the metal–GTF
complexes, metal ions coordinated by four oxygen atoms
amongst which two from GTF and two ketone groups
(lactone carbonyl oxygen and a,b-unsaturated carbonyl
oxygen) from coumarin chalcone. GTF acts as a bidentate
ligand through the ring carbonyl group at position-4 and
through one of the oxygen atom of carboxylate group at
position-3.The different geometry was assigned for Cu(II)
and Ni(II)complexes on the basis of electronic, magnetic
moment value and thermogravimetric analysis. Also, FAB-
Mass fragments support the different coordinated mole-
cules for Cu(II) and Ni(II) complexes. All the complexes
found excellent antibacterial and antituberculosis activity.
They have been also found as potent antioxidant agents
comprising radical scavenging capability and ferric
reducing abilities. In general, metal interaction with two
distinct biological compounds is beneficial to prepare
biologically potent agents against infectious diseases.
Blois MS (1958) Antioxidant determinations by the use of stable free
radical. Nature 26:1199–1200
Blondeau JM, Laskowski R, Bjarnason J, Stewart C (2000) Compar-
ative in vitro activity of gatifloxacin, grepafloxacin, levofloxacin,
moxifloxacin and trovafloxacin against 4151 Gram-negative and
Gram-positive organisms. Int J Antimicrob Agents 14:45–50
Carballo R, Castineiras A, Covelo B, Garcia-Martinez E, Niclos J,
Vazquez-Lopez EM (2004) Solid state coordination chemistry of
mononuclear mixed-ligand complexes of Ni (II), Cu (II) and Zn
(II) with a-hydroxycarboxylic acids and imidazole. Polyhedron
23:1505–1518
Chulvi C, Munoz MC, Perello L, Ortiz R, Arriortua MI, Via J, Urtiaga
K, Amigo JM, Ochando LE (1991) Coordination behavior of
cinoxacine: synthesis and crystal structure of tris (cinoxacinate)
cobaltate(II) of sodium hexahydrate (HCx = 1-ethyl-4(1H)-oxo-
(1,3) dioxolo-(4,5g) cinnoline-3-carboxylic acid). J Inorg Bio-
chem 42:133–138
Creaven BS, Egan DA, Kavanagh K, McCann M, Noble A, Thati B,
Walsh M (2006) Synthesis, characterization and antimicro-
bial activity of
a
series of substituted coumarin-3-
carboxylatosilver(I) complexes. Inorg Chim Acta 359:3976–3984
Da Silva AD, De Almeida MV, De Souza MVN, Couri MRC (2003)
Biological activity and synthetic metodologies for the prepara-
tion of fluoroquinolones, a class of potent antibacterial agents.
Curr Med Chem 10:21–39
Datta P, Mukhopadhyay AP, Manna P, Tiekink ERT, Sil PC, Sinha
CJ (2011) Structure, photophysics, electrochemistry, DFT cal-
culation, and in vitro antioxidant activity of coumarin Schiff
base complexes of Group 6 metal carbonyls. Inorg Biochem
105:577–588
Acknowledgments We articulate our appreciation to authorities of
V. P. & R. P. T. P. Science College, Sardar Patel University, Vallabh
Vidyanagar, India for providing infrastructural & chemical facilities.
We are greatful to Department of Science and Technology (DST)
123

Med Chem Res
De Souza MVN (2005) New fluoroquinolones: a class of potent
antibiotics. Mini Rev Med Chem 5:1009–1017
Lin HC, Tsai SH, Chen CS, Chang YC, Lee CM, Lai ZY, Lin CM
(2008) Structure-activity relationship of coumarin derivatives on
xanthine oxidase-inhibiting and free radical-scavenging activi-
ties. Biochem Pharmacol 75:1416–1425
De Souza RFV, De Giovani WF (2004) Antioxidant properties of
complexes of flavonoids with metal ions. Redox Rep 9:97–104
Deacon GB, Philips RJ (1980) Carboxylate as the protonation site in
(Peroxo)diiron(III) model complexes of soluble methane monoox-
ygenase and related diiron proteins. Coord Chem Rev 33:227–250
Egan DA, James P, Cooke D, O’Kennedy R (1997) Cytotoxic activity
of new acetoxycoumarin derivatives in cancer cell lines. Cancer
Lett 118:201–211
Figgis BN, Lewis J (1960) Modern coordination chemistry. In: Lewis
J, Wilkins RG (eds) Principles and methods. Interscience, New
York
Finn GJ, Kenealy E, Creaven BS, Egan DA (2002) 7,8-Dihydroxy-
coumarin inhibits A549 human lung adenocarcinoma cell
proliferation by inducing apoptosis via suppression of Akt/NF-
jB signaling. Cancer Lett 183:61–68
Fylaktakidou KC, Hadjipavlou-Litina DJ, Litinas KE, Nicolaides DN
(2004) Cytotoxic activity of new acetoxycoumarin derivatives in
cancer cell lines. Curr Pharm Des 10:3813–3833
Gomes AJ, Lunardi CN, Gonzalez S, Tedesco AC (2001) The
antioxidant action of Polypodium leucotomos extract and kojic
acid: reactions with reactive oxygen species. Braz J Med Biol
Res 34:1487–1494
Nakamoto K (1986) Infrared and Raman spectra of inorganic and
coordination compounds, 4th edn. Wiley Interscience, New York
Patel JC, Dholariya HR, Patel KS, Patel KD (2012a) Spectral,
thermal, biological and multi-heating rate kinetic properties of
Cu(II) complexes containing N2O2 donor ligands: 1,10-phenan-
throline and acyl coumarins. Appl Organomet Chem 24:332–337
Patel KS, Patel JC, Dholariya HR, Patel KD (2012b) Multiple heating
rate kinetic parameters, thermal, X-ray diffraction studies of
newly synthesized octahedral copper complexes based on
bromo-coumarins along with their antioxidant, anti-tubercular
and antimicrobial activity evaluation, Spectrochim. Acta Part A
96:468–479
Patonay T, Litkei G, Bognar R, Eredi J, Miszti C (1984) Synthesis,
antibacterial and antifungal activity of 4-hydroxycoumarin
derivatives, analogues of novobiocin. Pharmazie 39:86–91
Psomas G, Dendrinou-Samara C, Philippakopoulos P, Tangoulis V,
Raptopoulou CP, Samaras EL, Kessissoglou DP (1998) CuII-
herbicide complexes: structure and bioactivity. Inorg Chim Acta
272:24–32
Rattan A (2000) In: Churchill BI (ed) Antimicrobials in laboratory
medicine. Livingstone, New Delhi
Jain S, Jain NK, Pitre KS (2002) Bio-inorganic studies on the Fe(II)
sparfloxacin complex. Met Based Drugs 9:1–8
Sadeek AS, El-Shwiniy WH (2010) Metal complexes of the fourth
generation quinolone antimicrobial drug gatifloxacin: synthesis,
structure and biological evaluation. J Mol Struct 977:243–253
Sandbhor U, Padhye S, Billington D, Rathbone D, Franzblau S,
Anson CE, Powell AKJ (2002) Inorg Biochem 90:127–136
Sigel A, Sigel H, Sigel RKO (2006) Metal ions in life sciences.
Wiley, Chichester
Ji HF, Zhang HY (2004) A new strategy to combat Alzheimer’s disease.
Combining radical-scavenging potential with metal-protein-attenu-
ating ability in one molecule. Chem Res Toxicol 17:471–475
Kang DG, Yun CK, Lee HSJ (2003) Identification and characteriza-
tion of antioxidants from Sophora flavescens. Ethnopharmacol.
87:231–236
Kapoor P, Singh RV, Fahmi NJ (2012) Preparation, spectroscopic
characterization and biological evaluation of metal complexes
with schiff base derived from benzofuran and coumarin moieties.
Coord Chem 65:262–277
Kharadi GJ, Patel KD (2010) In-vitro antimicrobial, thermal and spectral
studies of mixed ligand Cu(II) heterochelates of clioquinol and
coumarin derivatives. Appl Organomet Chem 24:332–337
Kidane AG, Salacinski H, Tiwari A, Bruckdorfer KR, Seifalian AM
(2004) Anticoagulant and antiplatelet agents: their clinical and
device application(s) together with usages to engineer surfaces.
Biomacromolecules 5:798–813
Singh K, Kumar Y, Puri P, Kumar M, Sharma C (2012) Cobalt, nickel,
copper and zinc complexes with 1,3-diphenyl-1H-pyrazole-4-
carboxaldehyde Schiff bases: antimicrobial, spectroscopic, ther-
mal and fluorescence studies. Eur J Med Chem 52:313–321
Sousa I, Claro V, Pereira JL, Amaral AL, Silva LC, De Castro B, Feio
MJ, Pereira E, Gameiro PJ (2012) Synthesis, characterization
and antibacterial studies of a copper(II) levofloxacin ternary
complex. Inorg Biochem 110:64–71
Trommel JS, Marzilli LG (2001) Synthesis and DNA Binding of
novel water-soluble cationic methylcobalt porphyrins. Inorg
Chem 40:4374–4384
Kontogiorgis CA, Savvoglou K, Hadjipavlou LDJ (2006) Evaluation
of natural substances from Evolvulus alsinoides L. with the
purpose of determining their antioxidant potency. J Enzyme
Inhib Med Chem 21:21–29
Turel I, Leban I, Bukovec N (1997) Crystal structures and charac-
terization of the Bismuth (III) compound with quinolone family
member (Ciprofloxacin). Antibacterial study. J Inorg Biochem
66:241–245
Koshy J, Das VGK, Balabaskaran S, Ng SW, Wahab N (2000) High
in-vitro antitumour activity of triphenyltin coumarin 3-carbox-
ylate and its coordination complexes with monodentate oxygen
donor ligands against the epstein barr virus (EBV)-DNA positive
Raji and the P-388 murine leukaemia cell lines, and evidence for
the suppression by organotin of the early antigen complex in the
EBV lytic cycle. Met Based Drugs 7:245–251
Lien EJ, Ren S, Bui HH, Wang R (1999) Flavonoid B-ring chemistry
and antioxidant activity: fast reaction kinetics. Free Radic Biol
Med 14:285–294
Turel I, Golobic A, Klavzar A, Pihlar B, Buglyo P, Tolis E, Rehder D,
Sepcic KJ (2003) Interactions of oxovanadium(IV) and the quinolone
family member—ciprofloxacin. Inorg Biochem 95:199–207
Vincenzi FF, Thomas HR (1999) Stobadine: bellwether of a broader
view of drug actions. Life Sci 65:1857–1864
Weber E, Marten J, Seichter W (2009) Synthesis and crystal
structures of the chelating ligand 3-[(2,6-dimethylphenyl)hy-
drazono]-1,1,1-trifluoropentane-2,4-dione and its complex with
copper(II). J Coord Chim 62:3401–3410
123