Reactions of oxidobis(quinolin-8-olato)vanadium(IV) with hydroxamate ligands: A route providing mixed ligand and Quinolin-8-olato-Free Vanadium(IV) Complexes

Article abstract of DOI:10.1246/bcsj.20120066

Complexes of composition [VO(Q)2-n(HL1,2)n] (IIV) (where Q: C ₉H₆NO (quinolin-8-olato ion); HL¹: [C ⁶H4- (OH)CONHO] (salicyloylhydroxamate ion); HL²: [C ₆H₃(OH)(5-Cl)CONHO] (5-chlorosalicyloylhydroxamate); n = 1 and 2) have been synthesized by the reactions of [VO(Q)₂] with predetermined molar ratios of potassium salicyloylhydroxamate and 5-chlorosalicyloylhydroxamate in THF + MeOH solvent medium. The characterization of complexes has been accomplished by elemental analyses, molar conductivity, molecular weight determinations, magnetic measurements, electrochemical and IR, electronic, mass, and ESR spectral studies. The spectroscopic studies suggested bidentate nature of hydroxamate ligands involving O,O coordination. A square-pyramidal environment around vanadium has been proposed. The antimicrobial activity of newly synthesized complexes, ligands and precursor [VO(Q)₂] have been assayed against some pathogenic bacteria E. coli, S. aureus, S. typhi, S. paratyphi, S. epidermidis, and K. pneumoniae and fungi A. niger, B. fulva, and M. circinelloides by MIC method. The complexes exhibited improved antimicrobial activity over the free ligands. Cytotoxicity of complexes was studied on mammalian transformed cell line Hep2C, a derivative of human cervix carcinoma HeLa cells by MTT assay.

Full text of DOI:10.1246/bcsj.20120066

1310 Bull. Chem. Soc. Jpn. Vol. 85, No. 12, 1310-1317 (2012)
© 2012 The Chemical Society of Japan
Reactions of Oxidobis(quinolin-8-olato)vanadium(IV) with
Hydroxamate Ligands: A Route Providing Mixed Ligand
and Quinolin-8-olato-Free Vanadium(IV) Complexes#
Neeraj Sharma,*1 Shamsher Singh Kanwar,2 Reena Gupta,2 Lata Kumari,2 and Reena Sharma1
1Department of Chemistry, Himachal Pradesh University, Summer Hill, Shimla-171005, India
2Department of Biotechnology, Himachal Pradesh University, Summer Hill, Shimla-171005, India
Received February 21, 2012; E-mail: neerajsharma_univ@yahoo.co.in
¹
Complexes of composition [VO(Q)2¹n(HL1,2)n] (I-IV) (where Q: C9H6NO (quinolin-8-olato ion); HL1: [C6H4-
¹
¹
(OH)CONHO] (salicyloylhydroxamate ion); HL2: [C6H3(OH)(5-Cl)CONHO] (5-chlorosalicyloylhydroxamate); n = 1
and 2) have been synthesized by the reactions of [VO(Q)2] with predetermined molar ratios of potassium salicyloyl-
hydroxamate and 5-chlorosalicyloylhydroxamate in THF + MeOH solvent medium. The characterization of complexes
has been accomplished by elemental analyses, molar conductivity, molecular weight determinations, magnetic mea-
surements, electrochemical and IR, electronic, mass, and ESR spectral studies. The spectroscopic studies suggested
bidentate nature of hydroxamate ligands involving O,O coordination. A square-pyramidal environment around vanadium
has been proposed. The antimicrobial activity of newly synthesized complexes, ligands and precursor [VO(Q)2] have been
assayed against some pathogenic bacteria E. coli, S. aureus, S. typhi, S. paratyphi, S. epidermidis, and K. pneumoniae
and fungi A. niger, B. fulva, and M. circinelloides by MIC method. The complexes exhibited improved antimicrobial
activity over the free ligands. Cytotoxicity of complexes was studied on mammalian transformed cell line Hep2C, a
derivative of human cervix carcinoma HeLa cells by MTT assay.
Owing to the potential applications of vanadium complexes
in diversified fields, vanadium presents a wealthy and fas-
O
O
N
cinating chemistry with versatile coordination geometry.
The pharmacological activities of vanadium complexes viz.
insulinomimetic,1 cholesterol biosynthesis,2 effective inhibitors
of human sperm mobility,3 anticancer,4,5 antimicrobial,6 and
antiamoebic agents7 have further stimulated interest in vana-
dium chemistry. Of biologically important ligands, hydroxamic
acids as organic bioligands have attracted much attention
over the years,8 wherein the hydroxamic moiety (-NHOH) is a
constituent of antibiotics, antifungal agents, food additives,
drugs, tumor inhibitors, and growth factors.9-11 The reactivity of
hydroxamic acids toward nucleic acids and sulfhydryl groups
of proteins has been established to be the reason for their
inhibitory effect on various enzymes. The naturally occurring
hydroxamic acids (siderophores) and some synthetic derivatives
also display diverse ligating behavior toward metals.12-16
The bulk of the literature on the synthesis of vanadium
complexes has shown that VOSO4¢5H2O, NH4VO3, [VCl2-
(acac)2], and [VO(acac)2]17-20 have been utilized as the starting
materials. Literature also contains voluminous reports on the
rich chemical and physiological profile of 8-hydroxyquinoline
and its derivatives whereby the heterocycle itself and its com-
plexes exhibit antiseptic, disinfectant, pesticidal, and anti-
microbial activities.21-30 In view of these observations, in the
present work, the potential of [VO(Q)2] (Figure 1) as precursor
toward its reactions with hydroxamate ligands viz. salicyloyl-
hydroxamate and 5-chlorosalicyloylhydroxamate (Figure 2)
which exhibit a broad spectrum of biological activities31-34
V
N
O
Figure 1. Structure of oxidobis(quinolin-8-olato)vanadi-
um(IV).
OH
OH
O
O
NH
NH
O-
-O
Cl
Salicyloylhydroxamate ion 5-Chlorosalicyloylhydroxamate ion
(HL1) (HL2)
Figure 2. Structures of salicyloylhydroxamate ion (HL1)
and 5-chlorosalicyloylhydroxamate ion (HL2).
has been undertaken. In order to obtain a wider insight into
the antimicrobial activities of newly synthesized complexes
we have screened these against pathogenic bacteria and fungi.
The cytotoxicity of complexes has also been studied.
Experimental
Material and Methods. Reagent-grade solvents were dried
and distilled prior to use. All other chemicals were reagent
Published on the web December 1, 2012; doi:10.1246/bcsj.20120066

N. Sharma et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012) 1311
grade. [VO(Q)2] as yellow-brown solid was prepared from
[VO(acac)2] by a reported method35 under nitrogen atmosphere
and its formation and purity was checked by C, H, and V
microanalysis and IR spectral data. The potassium salicyloyl-
hydroxamate and 5-chlorosalicyloylhydroxamate were synthe-
sized by a reported method.36 The vanadium content in
complexes was determined as V2O5. The carbon, hydrogen,
and nitrogen analysis were obtained on an Eager 300 NCH
System Elemental Analyzer. The molar conductances (10¹3 M
solutions in methanol) were obtained on an Elico Conductivity
Bridge Type CM-82T at 25 « 0.1 °C. The room-temperature
magnetic susceptibilities were measured by Gouy’s method
using Hg[Co(NCS)4] as calibrant. IR spectra of complexes
were recorded as KBr pellets on a Nicolet-5700 FTIR spectro-
photometer. The pellets were prepared in a dry box to avoid
the action of moisture. Electronic spectra of complexes were
recorded on a Varian Cary-100 Bio UV-Vis spectrophotometer
using methanol as solvent. X-band ESR spectra were recorded
on a Varian E-112 ESR spectrometer with X-band microwave
frequency (9.5 GHz) with sensitivity of 5 © 1010 ¦H spins
using powdered sample. The DART-MS of compounds were
recorded on a JEOL-AccuTOF JMS-T100LC mass spectrom-
eter having a DART (direct analysis in real time) source. The
samples were subjected as such in front of DART source.
Dry helium was used with 4 LPM flow rate for ionization. The
electrochemical studies were carried out at CH instrument
electrochemical analyzer. All voltammetry experiments were
performed in a single compartmental cell of volume 10-15 mL
containing a three-electrode system comprising of a Pt-disk
working electrode, Pt-wire as auxiliary electrode, and an Ag/
AgCl electrode as reference electrode. The supporting electro-
lyte was 0.4 M KNO3 in Milli-Q water. The redox behavior
was studied in methanol-H2O (5:95) electrolyte system by
means of cyclic voltammeter.
Synthesis. Preparation of [VO(Q)2¹n(HL1,2)n] (n = 1 and
2): To a solution of [VO(Q)2] (1 g, 2.81 mmol) in THF (20
mL) were added equi- and bimolar amounts of potassium
salicyloylhydroxamate/potassium 5-chlorosalicyloylhydroxa-
mate (0.54 g, 2.81 mmol/1.08 g, 5.63 mmol)/(0.63 g, 2.81
mmol/1.26 g, 5.60 mmol) in methanol (20 mL), in separate
experiments. The reaction mixture was stirred for 2 h and was
then refluxed for 12-16 h during which the formation of a
yellow solid anticipated as KC9H6ON was observed. It was
filtered and the filtrate was distilled off to remove excess
solvent. The concentrate was then dried under vacuum by
treating it with petroleum ether whereupon black, green, and
light brown colored complexes were obtained. These were
recrystallized from dichloromethane giving yields [VO(Q)-
(HL1)]/[VO(HL1)2] (0.92 g, 82%/0.99 g, 80%); [VO(Q)-
(HL2)]/[VO(HL2)2] (Yield: 0.91 g, 88.9%/1 g, 95.6%).
method as recommended by National Committee for Clinical
Laboratory Standard (NCCLS). MIC is the lowest concentration
of the antimicrobial agents that prevents the development of
visible growth after overnight incubation. All the samples were
tested in triplicate. The results were compared with standard
antibacterial and antifungal drugs viz. tetracycline hydro-
chloride and fluconazole (treated control), untreated control
containing both broth and fungi and the control containing only
broth (blank).
MIC Determination by Twofold Serial Dilution. The
MIC assay37 was performed in a 96-well micro-titer plate.
¹1
For MIC assay of each test drug, a stock solution of 1 mg mL
of each drug was prepared in DMSO and a row of twelve
wells was used out of which the last two wells were taken
as untreated control (no drug added). Each of the ten wells
received 100 ¯L of the Muller-Hinton broth, except the first
¹1
well that received 200 ¯L of broth containing 500 ¯g mL
concentration of the test drug. From the first well (containing
test drug), 100 ¯L broth was withdrawn with a sterile tip, and
same was added to the 100 ¯L of the broth in the second well;
contents were mixed four times. Then 100 ¯L was withdrawn
from the 2nd well and was added to the third well. This way
a range of twofold serial dilutions were prepared (500-0.98
¯g mL¹1) by performing twofold serial dilution. The broth
in each of the wells was inoculated with 2 ¯L of the bacterial
culture (K. pneumoniae, S. epidermidis, S. aureus, E. coli,
S. typhi, and S. paratyphi) and 5 ¯L of the fungal culture
(A. niger, B. fulva, and M. circinelloides) the contents were
mixed by ten clockwise and ten anticlockwise rotations on
a flat surface. The plate was incubated at 35 and 30 °C for
bacteria and fungi respectively thereafter. The observations for
growth of bacteria were recorded after 24 h and five days for
bacteria and fungi respectively.
Cell Culture. Human Cervix carcinoma (HeLa) cells were
trypsinized from a confluent monolayer culture obtained in a
25 cm2 canted neck flask. The confluent monolayer of the cells
was washed twice with phosphate-buffer saline (PBS), pH 7.2
followed by with exposure to Trypsin-EDTA (100 mg % EDTA
and 125 mg % Trypsin 1:250; Sigma Chemical Co. St. Louis,
USA) disaggregating solution for two minutes. The disaggre-
gating solution was completely removed by decantation and
the enzyme solution treated flask was incubated at 37 °C for
three minutes. The disaggregated cells were resuspended in
appropriate volume of Dulbecco’s modified Eagle’s medium
(DMEM) supplemented with fetal calf serum (FCS) (10%, v/v)
and adjusted to a cell density of 4 © 103 cells/mL.
In Vitro Cytotoxicity Assay.
The uniform volume of
Hep2C cell suspension (200 ¯L/well) was poured in the select-
ed wells of a 96-wells tissue culture plate. The columns were
marked, in wells under each of the columns the filter sterilized
drug compound prepared in DMSO (0.1 M stock) was dis-
pensed to achieve final concentration of 2, 4, 8, 20, and 28 mM.
The cells treated with drug compound were incubated in a CO2
incubator with 95% humidity at 37 °C for 16-18 h. Each of the
drug compound concentrations were tested in quadruplicate
and mean values were calculated after MTT assay (using
Antimicrobial Activity Test. The hydroxamate ligands,
vanadium precursor [VO(Q)2], and synthesized complexes were
tested in vitro for their antibacterial activity against different
bacteria Gram +ve Staphylococcus aureus and Staphylococcus
epidermidis and Gram ¹ve Escherichia coli, Salmonella typhi,
Salmonella paratyphi, and Klebsiella pneumoniae and were
also screened for antifungal activity against Aspergillus niger,
B. fulva, and M. circinelloides to obtain MIC’s at different
concentrations in DMSO (1 mg mL¹1) employing the standard
¹1
5 mg mL in PBS, 0.1 M pH 7.2 of MTT (1-(4,5-dimethyl-
thiazol-2-yl)-3,5-diphenylformazan) compound. The appropri-
ate controls with no drug compound but containing appropriate

1312 Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012)
Reactions of Oxidobis(quinolin-8-olato)vanadium(IV)
nC6H4(OH)C(O)NHOK
[VO(Q)2-n(C6H4(OH)C(O)NHO)n]
nKC9H6ON
+
THF + CH3OH
VO(Q)2
THF + CH3OH
nKC9H6ON
+
[VO(Q)2-n(C6H3(OH)(5-Cl)C(O)NHO)n]
nC6H3(OH)(5-Cl)C(O)NHOK
(n = 1 and 2)
Scheme 1. Synthesis of oxidovanadium(IV) complexes.
amount of DMSO (used to prepare stock of drug compounds)
were also incubated to see if DMSO alone has any effect on the
viability of the proliferating cells cultured in vitro.
shift in ¯(C=O) mode to lower wavenumbers and ¯(N-O) mode
to higher wave numbers are suggestive of bonding of both
the potassium salicyloylhydroxamate and potassium 5-chloro-
salicyloylhydroxamate ions via oxygen atoms of carbonyl and
hydroxyamine group. The absorption bands appeared in 985-
Results and Discussion
Complexes of composition [VO(Q)2¹n(HL1,2)n] have been
synthesized in quantitative yields by the reaction of [VO(Q)2]
with equi- and bimolar amounts of potassium salicyloylhy-
droxamate (KHL1) and potassium 5-chlorosalicyloylhydroxa-
mate (KHL2) in THF + methanol solvent medium according to
Scheme 1.
937 cm range in complexes under study have been assigned
¹1
¹1
to ¯(V=O) mode. The bands appearing at 369-350 cm in
[VO(Q)(HL1,2)] have been assigned to ¯(V-N) mode.21 The
¹1
absorption bands occurring in the 502-460 cm region have
been assigned to ¯(V-O) mode in complexes.39,40
Electronic Spectra. The electronic spectra of VO2+-oxine
complexes are known to display strong intraligand transitions
and ligand to metal charge-transfer transitions which obscure
the typical d-d transitions of the oxocation. The electronic
absorption spectra of KHL1 and KHL2 showed sharp bands
at - = 226 (¾ = 2890), 257 (2410), 221 (2990), and 256 nm
(2820) respectively attributed to intraligand ³ ¼ ³* transi-
tions. The precursor [VO(Q)2] in its spectrum is known to
exhibit a low intensity band at - = 630 nm (¾ = 390) with a
shoulder at - = 700 nm (¾ = 30). The black and deep green
solutions of complexes of composition [VO(Q)(HL1)] and
[VO(HL1)2] displayed four bands at - = 277 (¾ = 4080),
309 (1170), 573 (128), 758 nm (40) and at - = 269 (¾ = 3930),
309 (1170), 584 (137), 830 nm (80) respectively. Likewise,
the electronic spectra of black and dark brown solutions of
[VO(Q)(HL2)] and [VO(HL2)2] exhibited four bands at - =
275 (¾ = 3980), 310 (880), 588 (146), 827 nm (20) and at
- = 268 (¾ = 4040), 309 (2140), 583 (1310), 831 nm (60)
respectively, implying thereby that these two series of
complexes have shown similar features. The intense high
energy bands appearing in the 268-277 nm range and at 309
and 310 nm may be assigned to intraligand and vanadium
(d³) ¼ oxinate (³*)/hydroxamate ligand (³*) transitions
respectively. The less intense absorption bands that appeared
in 588-573 nm range may be ascribed to 2Eg ← 2T2g transition
characteristic of oxido-vanadium(IV) coordinating to good
³ donating ligands. The bands observed in the 831-758 nm
range may be assigned to be originating from a lone pair of
p orbitals on the hydroxamate/8-hydroxyquinolinate ligand
(³) into an empty d orbital of vanadium to induce strong charge
transfer to the metal center in complexes with high valence
metal ions.
The complexes are black, green, and light-brown in color and
are soluble in common organic solvents such as methanol,
chloroform, dichloromethane, and acetonitrile. The molar con-
ductance values of complexes (10¹3 M solutions) (Table 1) in
¹1
methanol in 2.62 to 4.21 S cm2 mol range suggested their
nonelectrolytic nature. The cryoscopic molecular weight deter-
minations of the complexes in water indicated these to exist
as monomers. The room-temperature magnetic moment values
of the complexes are in a 1.72-1.76 ®B range which suggest
their paramagnetic nature and +4 oxidation state for vanadium.
IR Spectra. The formation of complexes has been inferred
from a comparison of their IR spectra with those of the free
ligands (KHL1 and KHL2) and precursor [VO(Q)2] scanned
¹1
in the 4000-250 cm region. The absorption band due to
phenolic ¯(OH) mode of KHL1 and KHL2 ligands occurring
¹1
at ca. 3110 cm¹1 has been observed to appear at ca. 3180 cm
in complexes indicative of weakening of intramolecular hydro-
gen bonding of phenolic group hydrogen to the carbonyl oxygen
of the ligands upon complexation.38 The retention of ¯(OH)
mode upon complexation is thus suggestive of nonparticipation
of hydroxy group in bonding. The absorption bands occurring at
1606 and 1603 cm¹1 in KHL1 and KHL2 respectively attributed
to ¯(C=O) mode shifted to lower wavenumbers and appeared at
¹1
ca. 1576 and ca. 1580 cm in respective oxido-vanadium(IV)
complexes. The absorption band due to ¯(C-N) mode occurring
¹1
at 1392 and 1378 cm in free ligands has been found to shift
¹1
toward higher region at 1465 and 1467-1444 cm in com-
plexes derived from KHL1 and KHL2 respectively. The bands
at 3233 and 3212 cm¹1 assigned to ¯(N-H) mode in KHL1 and
KHL2 respectively did not undergo any change and appeared at
¹1
3225, 3210, 3212, and 3220 cm in respective (I), (II), (III),
and (IV) complexes, suggesting thereby that -NH group is
retained and coordination through nitrogen atom is excluded.
ESR Spectra. The room-temperature X-band ESR spectra
of [VO(Q)2¹n(HL1,2)n] (I-IV) (Figure 3 and Table 2) displayed
well-resolved typical eight lines due to the interaction of an
unpaired electron of vanadium(IV) center with its own nucleus,
I = 7/2 consistent with a single paramagnetic species of vana-
dium(IV). The g average values determined from the spectra
¹1
The sharp band occurring at 999 and 997 cm in KHL1 and
KHL2 respectively ascribed to ¯(N-O) mode has been observed
to move toward higher wave numbers and appeared at
¹1
ca. 1030 and ca. 1045, 1007 cm in respective complexes. A

N. Sharma et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012) 1313
Figure 3. ESR spectra of [VO(Q)(HL2)] (III).
Table 2. ESR Spectral Data of Oxido-Vanadium(IV)
Complexes
A««
A¦
/©10¹4 cm
Complex
g««
g¦
¹1
¹1
/©10¹4 cm
[VO(Q)(HL1)] (I) 1.924 1.952
136
139
137
142
56
59
63
64
[VO(HL1)2] (II)
1.941 1.975
[VO(Q)(HL2)] (III) 1.934 1.981
[VO(HL2)2] (IV)
1.952 1.992
are ca. 1.98 similar to the spin only values (free electron value
of 2.00) suggesting little spin-orbit coupling.
Mass Spectra. The ESI mass spectra of [VO(Q)(HL1)] (I),
[VO(HL1)2] (II), and [VO(Q)(HL2)] (III) did not show any
molecular ion peaks but structurally important fragment ions
clearly supported their formation. Complexes [VO(Q)(HL1)] (I)
and [VO(Q)(HL2)] (III) displayed the most intense peak at
m/e 146 corresponding to [C9H7NO + H]+. The mass spec-
tra of [VO(Q)(HL1)] (I) showed fragment ions at m/e 279
(66.66), 269 (86.11), 204 (80.55), 130 (88.88), and 77 (60.22)
corresponding to [C6H4(OH)C(O)NHOV(O)ONHC(O) + H]+,
[C9H6NOVO2NHC(O) + H]+,
[C6H5CONHOV(O) + H]+,
[C9H7N + H]+, and [C6H6 ¹ H] respectively. The complex
[VO(HL1)2] (II) exhibited base peak at m/e 152 corresponding
to fragment ion [C6H4(OH)C(O)NHO]+ and at m/e 279 (16.8),
138 (36.4), and 77 (30.8) corresponding to [C6H4(OH)C(O)-
NHOV(O)ONHC(O) + H]+, [C6H4(OH)C(O)NH2 + H]+, and
[C6H6 ¹ H] respectively. Complex [VO(Q)(HL2)] (III) showed
fragment ions at m/e 235 (50) and 204 (66.60) corresponding
to [C6H4(OH)C(O)NHOVO2]+ and [C6H5CONHOV(O) + H]+
respectively.
Electrochemical Studies. Electrochemical studies provide
useful information not only on the thermodynamics of redox
processes but also on the kinetics of heterogeneous electron-
transfer reactions and coupled chemical reactions. The voltam-
metric data of complexes is taken as criterion of their stability
as numerous reports describe the redox electrochemistry of
coordination compounds.41,42 Owing to the variable oxida-
tion states exhibited by vanadium, the reduction/oxidation is
known to occur between different oxidation states of vanadium
without any role played by the ligands.43
In order to probe the electrochemical properties of newly
synthesized oxido-vanadium(IV) complexes [VO(Q)2¹n
-

1314 Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012)
Reactions of Oxidobis(quinolin-8-olato)vanadium(IV)
(HL1,2)n] (I-IV) (Figure 4 and Table 3), the cyclic voltammet-
ric measurements in MeOH/H2O (5:95) at 300 mV s have
vanadyl oxygen, such reductions are usually irreversible and
no reversible reductions have been found for the vanadyl
complexes under study.45 The negative potentials of VV/VIV
couple in the complexes are indicative of their stability
suggesting thereby that oxido-vanadium(IV) complexes can
be oxidised at distinctly lower potential. It is pertinent to
mention here that the increased stability of complexes shifts the
electrochemical reduction of the central ion toward a more
negative potential. A blank CV run with the ligands in the
potential range ¹1.75 to +1.75 gave one peak at +1.0 due to
oxidation of the ligands. The nonoccurrence of this peak
in complexes suggested that the redox processes are metal
centered only.
¹1
been performed. The initial scan in the anodic direction in
¹1.75 to +1.75 V range displayed two cathodic and two anodic
peaks corresponding to the formation of the VO3+/VO2+ and
VO2+/V3+ redox couples demonstrating that these are asso-
ciated with the monoelectronic transformation. The separations
between cathodic and anodic peaks are indicative of quasi-
reversible behavior of redox couples.44 As the reduction of
vanadyl complexes to the trivalent state involves loss of the
0.006
0.004
0.002
0.000
-0.002
-0.004
The electrode process can therefore be represented as:
VIV ꢀ VV þ eꢀ1
ð1Þ
ð2Þ
VIV þ eꢀ1 ꢀ VIII
On the basis of IR, electronic, ESR and mass spectral data, a
square pyramidal geometry for the complexes has tentatively
been proposed (Figures 5-8).
-0.006
[VO(Q)2]
[VO(Q)(HL1)]
-0.008
[VO(HL1)2]
-0.010
[VO(Q)(HL2)]
Antimicrobial Activity. Antibacterial Activity: Litera-
ture contains reports that metal salts do not exhibit antimicro-
bial activity but complexation with metal leads to significant
activity.46-49 In the present work, the hydroxamate ligands,
vanadium precursor [VO(Q)2], and newly synthesized com-
plexes were tested in vitro for their antibacterial activity
(Table 4 and Figure 9) against Gram +ve bacteria Staphy-
lococcus aureus and Staphylococcus epidermidis and Gram
[VO(HL2)2]
-0.012
-0.014
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
Potential/V
Figure 4. CV of precursor [VO(Q)2] and [VO(Q)2¹n
(HL1,2)n] (I-IV).
-
Table 3. Cyclic Voltammetric Data of Oxido-Vanadium(IV) Complexes
Complex
Redox couple
Epc/V
Epa/V
¦E/mV
Ipc/mA
Ipa/mA
Ipa/Ipc
[VO(Q)2]
VO3+/VO2+
VO2+/V3+
VO3+/VO2+
VO2+/V3+
VO3+/VO2+
VO2+/V3+
VO3+/VO2+
VO2+/V3+
VO3+/VO2+
VO2+/V3+
¹0.441
0.276
¹0.384
0.272
¹0.376
0.226
¹0.380
0.234
¹0.554
0.139
¹0.674
0.015
¹0.663
¹0.044
¹0.687
¹0.064
¹0.644
¹0.032
¹113
¹137
¹290
¹257
¹286
¹269
¹306
¹298
¹272
¹221
¹4.558
¹1.506
¹3.566
1.584
¹1.595
¹1.464
¹2.223
¹1.867
¹1.251
¹5.598
2.999
6.625
4.424
6.496
4.336
8.105
4.522
8.605
4.397
8.512
¹0.688
¹4.399
¹1.24
4.10
¹2.71
¹5.536
¹2.034
¹4.608
¹3.514
¹1.520
[VO(Q)(HL1)] (I)
[VO(HL1)2] (II)
[VO(Q)(HL2)] (III)
[VO(HL2)2] (IV)
¹0.372
0.189
HO
HO
O
O
O
O
N
N
V
V
NH
O
NH
O
O
O
Cl
Figure 5. Proposed structure of [VO(Q)(HL1)] (I).
Figure 7. Proposed structure of [VO(Q)(HL2)] (III).
HO
HO
O
O
O
O
Cl
O
O
HN
HN
V
V
NH
NH
O
O
O
O
Cl
OH
OH
Figure 6. Proposed structure of [VO(HL1)2] (II).
Figure 8. Proposed structure of [VO(HL2)2] (IV).

N. Sharma et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012) 1315
¹1
Table 4. Antibacterial Activity of Ligands and Oxido-Vanadium(IV) Complexes by MIC Method Concentration (¯g mL
)
Compound
E. coli S. aureus S. epidermidis S. typhi S. paratyphi K. pneumoniae
(C6H4(OH)C(O)NHOK) (KHL1)
(C6H3(OH)(Cl)C(O)NHOK) (KHL2)
[VO(Q)2]
125
62.5
31.25
31.25
62.5
62.5
62.5
15.63
125
62.5
62.5
62.5
62.5
62.5
31.25
31.25
62.5
62.5
62.5
7.84
62.5
125
62.5
125
62.5
62.5
62.5
62.5
62.5
3.92
62.5
15.63
31.25
62.5
3.92
3.92
7.84
15.63
31.25
62.5
62.5
62.5
62.5
15.63
[VO(Q)(HL1)] (I)
[VO(HL1)2] (II)
1.96
[VO(Q)(HL2)] (III)
62.5
62.5
15.63
[VO(HL2)2] (IV)
Tetracycline hydrochloride
Table 5. Antifungal Activity of Ligands and Oxido-Vana-
E. coli
S. aureus
S. epidermidis
S. typhi
S. paratyphi
K. pneumoniae
dium(IV) Complexes by MIC Method Concentration
140
120
100
80
¹1
(¯g mL
)
M.
Compound
A. niger B. fulva
circinelloides
(C6H4(OH)C(O)NHOK)
(KHL1)
125
125
125
125
62.5
31.25
3.91
125
(C6H3(OH)(Cl)C(O)NHOK) 125
125
(KHL2)
[VO(Q)2]
[VO(Q)(HL1)] (I)
[VO(HL1)2] (II)
[VO(Q)(HL2)] (III)
[VO(HL2)2] (IV)
Fluconazole
60
125
62.5
62.5
31.25
62.5
3.91
125
62.5
62.5
62.5
62.5
3.91
40
20
31.25
3.91
0
HL1
HL2 [VO(Q)2] (I)
(II)
(III)
(IV)TetracyclinHCl
(Compound/Antibiotic)
A. niger
B. fulva
M. circinelloides
Figure 9. In vitro antibacterial spectrum of oxidobis(quino-
lin-8-olato)vanadium(IV) complexes.
140
120
100
80
¹ve bacteria Escherichia coli, Salmonella typhi, Salmonella
paratyphi, and Klebsiella pneumoniae employing MIC method
recommended by National Committee for Clinical Laboratory
Standard (NCCLS). The results were compared with treated
control, commercial antibiotic tetracycline hydrochloride
60
¹1
which inhibited bacteria under study in a 7.84-15.63 ¯g mL
40
range. The precursor [VO(Q)2] was found to inhibit the growth
of microorganisms in a concentration range of 31.25-62.5
20
¹1
¯g mL while free hydroxamate ligands inhibited in 62.5-
¹1
125 ¯g mL range.
0
[VO(Q)(HL1)] (I) and [VO(HL1)2] (II) exhibited signifi-
cantly enhanced antibacterial activity at MIC in 1.96-62.5
HL1
HL2 VO(Q)2
(I)
(II)
(III)
(IV) Fluconazole
(Compound/Antifungal)
¹1
¯g mL range. Strikingly, [VO(HL1)2] (II) showed more pro-
Figure 10. In vitro antifungal spectrum of oxidobis(quino-
lin-8-olato)vanadium(IV) complexes.
nounced activity than standard drug compound toward
S. aureus and S. typhi at MIC value 1.96 and 3.92 ¯g mL
¹1
respectively. An explanation for the observed trend of sig-
nificantly enhanced antibacterial activity of complex (II) may
be ascribed to the penetration of complex (II) into the lipid
membrane of S. aureus and thereby blocking of the metal
binding sites in the enzymes of S. aureus more as compared to
S. typhi. Complex [VO(Q)(HL2)] (III) displayed promising
activity against S. typhi and K. pneumoniae at MIC 3.92
An explanation for the observed promising antibacterial
activity of complexes can be attributed to the biological sig-
nificance associated with vanadium, hydroxamate and oxinate
ligands and efficient diffusion of the metal complexes into
bacterial cell.50,51
Antifungal Activity: The potassium salicyloylhydroxa-
mate and potassium 5-chlorosalicyloylhydroxamate ligands,
[VO(Q)2] and [VO(Q)2¹n(HL1,2)n] (I-IV) were screened
in vitro for their antifungal activity on selected fungi A. niger,
B. fulva, and M. circinelloides using MIC method (Table 5 and
Figure 10). The results were compared with standard antifungal
¹1
¯g mL while [VO(HL2)2] (IV) is more effective against
¹1
S. typhi than standard drug compound at MIC 7.84 ¯g mL
.
¹1
All other bacteria were inhibited at MIC 62.5 ¯g mL by III
and IV.

1316 Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012)
Reactions of Oxidobis(quinolin-8-olato)vanadium(IV)
Table 6. Cytotoxic Assay of Hydroxamate Ligands and Oxido-Vanadium(IV) Complexes against Hep2C Cell Line
Cell viability (%) at the selected test compound concentration
Test compound
Control
2 mM
4 mM
8 mM
20 mM
28 mM
VOSO4¢5H2O
100
100
100
100
40
35
35
30
30
(C6H4(OH)C(O)NHOK) (KHL1)
(C6H3(OH)(Cl)C(O)NHOK) (KHL2)
[VO(C9H6ON)2]
44.8
30.8
39.7
44.8
28.6
37.8
42.1
25.8
35.7
38.9
24.9
34.5
39.3
21.1
31.8
[VO(Q)2]
[VO(Q)(HL1)] (I)
100
100
100
100
55.9
83.5
38.1
33.0
55.0
83.0
28.8
31.9
51.2
83.0
27.0
25.1
50.2
48.8
21.1
24.7
42.7
45.5
19.3
24.7
[VO(HL1)2] (II)
[VO(Q)(HL2)] (III)
[VO(HL2)2] (IV)
drug fluconazole (treated control) which inhibits the fungi under
study at 3.91 ¯g mL¹1. A perusal of data has shown that both
the hydroxamate ligands and precursor [VO(Q)2] inhibited
the fungal growth at 125 ¯g mL¹1. Complex of composition
of tested drug compounds, [VO(HL1)2] (II) has shown most
encouraging results exhibiting promising antibacterial activity
toward S. aureus and S. typhi even higher than standard drug
compound. Complex [VO(Q)(HL2)] (III) has been found to
exhibit most pronounced antifungal activity toward B. fulva.
The cytotoxic study revealed I and II complexes to be more
viable.
¹1
[VO(Q)(HL1)] (I) inhibited all fungi at MIC 62.5 ¯g mL
while, [VO(HL1)2] (II) exhibited enhanced activity against
¹1
¹1
B. fulva at concentration 31.25 ¯g mL and at 62.5 ¯g mL
for A. niger and M. circinelloides. The most pronounced activ-
ity toward B. fulva has been shown by [VO(Q)(HL2)] (III) at
MIC 3.91 ¯g mL comparable to that of standard antifungal
Reena Sharma would like to thank University Grants Com-
mission, New Delhi for providing financial support in the form
of Major Research Project F. No. 33-295/2007 (SR) dated
28.02.2008. The authors would like to thank Department of
Science and Technology (DST), Government of India, New
Delhi for providing financial assistance for FT-IR and UV-vis
spectrophotometer facility to the department, Sophisticated
Analytical Instrument Facility of CDRI, Lucknow and Punjab
University Chandigarh for recording mass spectra and elemen-
tal analysis. The authors would like to thank IIT, Roorkee
for magnetic susceptibility measurements and Department
of Biotechnology, Himachal Pradesh University, Shimla for
providing laboratory facilities.
¹1
drug fluconazole while A. niger and M. circinelloides inhibited
¹1
at MIC value 31.25 and 62.50 ¯g mL respectively. Although
the exact molecular basis for the exceptional antifungal activity
exhibited by complex (III) only for B. fulva cannot be given
yet the intense cell permeable nature of the complex coupled
with intrinsic metal chelating activity may be attributed to this
observation. Complex [VO(HL2)2] (IV) inhibited B. fulva at
MIC value 31.25 ¯g mL¹1 while A. niger and M. circinelloides
were inhibited at MIC 62.5 ¯g mL¹1. The observed effective-
ness probably reflects the specificity of interaction of complexes
with fungi and easier permeability toward the microbe cells.
In Vitro Cytotoxicity Assay. Cytotoxic assays of VOSO4,
potassium salicyloylhydroxamate, potassium 5-chlorosali-
cyloylhydroxamate ligands, [VO(Q)2], and newly synthesized
complexes [VO(Q)2¹n(HL1,2)n] (I-IV) were performed at
several concentrations by means of colorimetric microculture
MTT assay (Table 6). Of four tested complexes, [VO(Q)(HL1)]
(I) and [VO(HL1)2] (II) exhibit appreciable viability of 55.9
and 83.5% respectively at 2 mM concentration. It has been
observed that with increase in concentration of test complexes,
cytotoxicity gets significantly enhanced. The cytotoxic study
has shown that complexes derived from salicyloylhydroxamate
are less toxic.
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This article is dedicated to the fond memory of our
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