Synthesis and evaluation of antibacterial activity of water-soluble copper, nickel and zinc tetra (n-carbonylacrylic) aminephthalocyanines

Article abstract of DOI:10.1007/s00044-012-0427-x

Water-soluble copper, nickel, and zinc tetra (n-carbonylacrylic) aminephthalocyanines were synthesized with an aim to evaluate their role as therapeutic materials. They were characterized by UV-Vis spectrophotometer, infra-red spectra, elemental analysis, nuclear magnetic resonance, and thermogravimetry. Efforts were made to optimize the synthesis of intermediates and final products. Photoluminescence studies were carried out on these compounds. The investigation of antibacterial activity of these aqueous soluble phthalocyanines was carried out on Staphylococcus citreus, Serratia marcescens, Proteus vulgaris, Bacillus subtilis, and Pseudomonas fluorescence, showed good inhibitory activity.

Full text of DOI:10.1007/s00044-012-0427-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4300–4307
DOI 10.1007/s00044-012-0427-x
ORIGINAL RESEARCH
Synthesis and evaluation of antibacterial activity of water-soluble
copper, nickel and zinc tetra (n-carbonylacrylic)
aminephthalocyanines
•
•
•
P. A. Pavaskar S. S. Patil I. Furtado
A. V. Salker
Received: 16 March 2012 / Accepted: 15 December 2012 / Published online: 6 January 2013
Ó Springer Science+Business Media New York 2013
Abstract Water-soluble copper, nickel, and zinc tetra
(n-carbonylacrylic) aminephthalocyanines were synthe-
sized with an aim to evaluate their role as therapeutic
materials. They were characterized by UV–Vis spectro-
photometer, infra-red spectra, elemental analysis, nuclear
magnetic resonance, and thermogravimetry. Efforts were
made to optimize the synthesis of intermediates and final
products. Photoluminescence studies were carried out on
these compounds. The investigation of antibacterial activ-
ity of these aqueous soluble phthalocyanines was carried
out on Staphylococcus citreus, Serratia marcescens, Pro-
teus vulgaris, Bacillus subtilis, and Pseudomonas fluores-
cence, showed good inhibitory activity.
more thermal stability than many other metal organic
compounds. Pcs have multifunctional applications in oxi-
dation–reduction reactions (Pan et al., 2005; Liu et al.,
2007), in photoreduction processes (Premkumar and
Ramaraj, 1997), the light harvesting property of Pcs is used
for the degradation of organic molecules, dyes etc. in the
presence of light (Xia et al., 2008; Borkar and Salker,
2006), and the property of Pcs is also being studied for their
use in photodynamic therapy (PDT) and other similar
applications (Brasseau and Lier, 1987; Sharman and Lier,
2005). Use of Pcs in PDT is, however, restricted due to
their very low solubility in aqueous media. Synthesis of Pcs
and that of tetra-nitro and tetra-amino Pc using melt and
microwave assisted reactions (Kantra et al., 2008; Chen
et al., 2006) and other reactions (Reddy and Keshavayya,
2002), respectively, are well-documented. Methods repor-
ted for synthesizing more water-soluble Pcs involve sul-
fonation at peripheral position (Shaabani et al., 2003) or
attack on the phosphate moieties (Boyle and Lier, 1995).
This communication details synthesis of novel, water-
soluble copper, nickel, and zinc n-carbonylacrylic amine-
substituted Pcs using easily available chemicals, minimum
organic solvents, less time, and ambient condition, so that
the product formed can be evaluated in aqueous solution
for different therapeutic applications such as antimicrobial
activities (Nas et al., 2011) and others. Analysis of pho-
toluminescence is also presented and discussed herein.
Keywords
Copper tetra (n-carbonylacrylic) aminophthalocyanine Á
Nickel tetra (n-carbonylacrylic) aminophthalocyanine Á
Zinc tetra (n-carbonylacrylic) aminophthalocyanine Á
Photoluminescence Á Antibacterial activity
Introduction
Phthalocyanines (Pcs) are the class of compounds known
as tetrapyrolic macromolecules and have comparatively
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-012-0427-x) contains supplementary
material, which is available to authorized users.
Materials and methods
P. A. Pavaskar Á A. V. Salker (&)
Department of Chemistry, Goa University, Goa 403206, India
e-mail: sal_arun@rediffmail.com
4-Nitrophthalimide was synthesized from phthalic anhy-
dride as per the reported method (Young and Onyebuagu,
1990). Urea, NiCl2Á6H2O, CuCl2Á2H2O, ZnCl2, Ammo-
nium molybdate, maleic anhydride, and DMF of pure
S. S. Patil Á I. Furtado
Department of Microbiology, Goa University, Goa 403206, India
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Med Chem Res (2013) 22:4300–4307
4301
analytical grade chemicals were used without further
purification.
ethanol followed by diethyl ether, and finally dried in
vacuum.
Water-soluble copper and zinc tetra (n-carbonylacrylic)
Pcs (CuTCPc and ZnTCPc) were prepared using the above
procedure. Salts of CuCl2Á2H2O and ZnCl2 were used for
the preparation of CuTCPc and ZnTCPc for the central
metal atoms.
Synthesis of metal phthalocyanine
The route adopted for the synthesis of metal tetra (n-car-
bonylacrylic) aminephthalocyanine is given in Scheme 1.
Synthesis of nickel tetranitro-phthalocyanine (NiTNPc)
Characterization of synthesized Pcs
Finely ground, 4-nitrophthalimide 9.75 g (0.05 mol), 15 g
(0.25 mol) urea, 2.97 g of NiCl2Á6H2O (0.0125 mol), and
0.15 g of ammonium molybdate were taken in a 250 ml
beaker and heated between 180 and 200 °C, for 1 h. The
solid product was treated with HCl (1 M) followed by
NaOH (1 M). The product was filtered out, washed to
neutralization with water, and dried in vacuum. The yield
was 76 %, and kmax in DMF gave 635 and 272 nm
absorptions, respectively. Copper tetranitro-phthalocyanine
(CuTNPc) and zinc tetranitro-phthalocyanine (ZnTNPc)
were also prepared following the above procedure.
Elucidation of chemical structure was characterized with
FTIR spectrophotometer employing Shimadzu IR prestige
21 spectrometer using KBr Pellets; the UV–Vis spectra for
each Pc was obtained using Shimadzu spectrophotometer in
DMF and in 0.1 N NaOH for aqueous soluble Pc. Elemental
analysis of each of the synthesized Pcs was carried out
employing Prostar Varian C, H, N analyzer. NMR was
recorded in DMSO using Bruker 400 MHz spectrometer.
The thermal stability of individual Pcs was checked using
TG (model NETZSCH STA 409PC). Photoluminescence
studies were done by loading sample on powder holder, and
measurements were done using Shimadzu RF-530IPC
spectrofluorophotometer with a xenon flash lamp, and a UV-
35 filter was used at the emission slit to avoid harmonic
effects from the grating. The Gouy method was used to
measure magnetic susceptibility at ambient temperature with
a field of 8,500 G using mercury tetrathiocyanatocobaltate as
a standard.
Synthesis of nickel tetraamino-phthalocyanine
(NiTAPc)
The above prepared NiTNPc (7 g) was transferred into a
500 ml beaker with approximately 100 ml water and kept
boiling on water bath, for 20 min; similarly, 21 g of Na2S
was dissolved in a separate 250 ml beaker and kept boiling
on water bath, for 20 min. After 20 min, both the beakers
were removed from the water bath, and Na2S solution was
slowly transferred to 500 ml beaker containing NiTNPc
solution while still warm. The resulting mixture was
allowed to stand at ambient temperature for 15 min. Fur-
ther, the solid residue thus obtained was washed with HCl
(1 M) followed by NaOH (1 M). The filtered out product
was washed to neutralization with water and dried in
vacuum. The yield was 80 %, and kmax in DMF gave 713
and 310 nm absorptions, respectively. Copper tetraamino-
phthalocyanine (CuTNPc) and zinc tetraamino-phthalo-
cyanine (ZnTNPc) were prepared as above.
Effect of phthalocyanines on bacterial cultures
Phthalocyanine conjugates of copper, nickel, and zinc
(CuTCPc, NiTCPc, and ZnTCPc) were individually dis-
solved in alkaline buffer (pH 8) to obtain a corresponding
solution, having a final concentration of 100 lg/ml and
2 mg/ml, respectively. Antibacterial activity by each of
these Pcs was tested against five emerging opportunistic
bacterial pathogens obtained from the Department of
Microbiology, Goa Medical College, Goa. Twenty-four
hour old seed cultures of Staphylococcus citreus/Serratia
marcescens/Bacillus subtilis/Proteus vulgaris and Pseu-
domonas fluorescence pre-grown in nutrient broth, were
plated on to separate nutrient agar, for matt growth. Sub-
sequently, wells were bored into the agar with a sterile
10-mm diameter cork borer, aseptically for agar well dif-
fusion assay (Cooper, 1955). Different concentrations of
individual phthalocyanines in the range of 0.2 lg to a
maximum of 1 mg were added into separate wells. All
plates were incubated at appropriate temperature and
monitored for growth, zones of inhibition of growth, and/
exhibition around the well, if any, periodically.
Synthesis of nickel tetra (n-carbonylacrylic)
aminephthalocyanine (NiTCPc)
One mole of 4 g of nickel tetraamino phthalocyanine
(NiTAPc) was dissolved in 75 ml DMF, to which 2.5 g
(4 mol) of maleic anhydride was added, and the reaction
mixture was kept at 50 °C for 3 h. Later, the entire solution
was poured into 1 l distilled water, filtered, and the residue
dissolved in 0.1 M NaOH and precipitated with addition of
0.1 M HCl. The precipitate, thus obtained, was firstly
washed with water till free from chloride ions, then with
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Med Chem Res (2013) 22:4300–4307
Melt
O
O
O
NH
H2N
NH2
O
+
O
O
O
O2N
O
H2SO4/HNO3
NH
NH
O
NO2
O
Ammonium molybdate
Metal salt
O
O2N
O
N
N
N
N
M
N
N
N
N
+
NH
H2N
NH2
O2N
O
NO2
O2N
Na2S
NHCOCH=CHCOOH
NH2
N
N
N
N
M
N
N
N
N
N
N
N
N
M
N
N
N
N
Maleic anhydride
H2N
HOOCHC=HCOCHN
NHCOCH=CHCOOH
NH2
HOOCHC=HCOCHN
H2N
M=Cu, Ni and Zn
Scheme 1 Mechanistic reaction path ways
Results and discussion
in between 1,712 and 1,713 cm-1 corresponds to the
presence of carbonyl group. The characteristic FTIR peaks
of different functional groups are observed with change in
substitution on the ring in case of (1) NiTNPc, (2) NiTAPc,
and (3) NiTCPc (Fig. 1).
FTIR peaks around 1,525–1,532 cm-1 correspond to the
presence of nitro group, those around 3,300–3,200 cm-1
indicate the presence of primary amino group, and the one
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Med Chem Res (2013) 22:4300–4307
4303
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
(3)
(a)
(3)
(2)
(2)
(4)
(1)
(1)
300
400
400
400
500
600
700
800
Wavelength (nm)
4000
3500
3000
2500
2000
1500
1000
500
(b)
2.0
1.5
1.0
0.5
0.0
Wavenumber (cm-1)
Fig. 1 IR spectra of (1) NiTNPc, (2) NiTAPc, and (3) NiTCPc
(3)
UV–Vis measurements were done to observe the shift in
Q and B band with change in substitution on the ring and
change in solvent in case of water-soluble Pc. The
appearance of Q band in the visible region is responsible
for the color of the compound. Figure 2a shows represen-
tative UV–Vis spectra of (1) CuTNPc, (2) CuTAPc,
(3) CuTCPc in DMF, and (4) CuTCPc in 0.1 N NaOH.
Figure 2b shows representative UV–Vis spectra of (1)
NiTNPc, (2) NiTAPc, (3) NiTCPc in DMF, and (4) NiT-
CPc in 0.1 N NaOH. Figure 2c shows representative UV–
Vis spectra of (1) ZnTNPc, (2) ZnTAPc, (3) ZnTCPc in
DMF, and (4) ZnTCPc in 0.1 N NaOH, respectively.
The yield of the NiTCPc was 85 %, and kmax obtained in
DMF were 692 and 311 nm, respectively, whereas the kmax
in 0.1 M NaOH were 632 and 293 nm, respectively. Anal:
Calc. for C48H28N12O12Ni. 2H2O: C 54.41, H 3.04, N
15.86 % and found C 53.63, H 2.99, N 16.91 %. The
magnetic susceptibility study indicated that the compound
NiTCPc was diamagnetic. The NMR signals due to aro-
matic protons were observed from 6.63 to 7.23 ppm, sig-
nals due to amido proton were seen at 6.03 ppm and that
due to aliphatic protons at 2.09 ppm.
(2)
(4)
(1)
300
500
600
700
800
Wavelength (nm)
2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
-0.2
(c)
(2)
(3)
(4)
(1)
The yield of copper tetra (n-carbonylacrylic) ami-
nephthalocyanine (CuTCPc) was 87 %, and kmax in DMF
were 696 and 344 nm absorptions, respectively, whereas
kmax in 0.1 M NaOH were 612 and 297 nm, respectively.
Anal: calc. for C48H28N12O12CuÁ1H2O: C 55.10, H 2.89, N
16.06 % and found C 55.95, H 3.11, N 15.64 %. As copper
exists in ?2 oxidation state in the compound, it is para-
magnetic in nature due to which NMR signals were not
observed.
300
500
600
700
800
Wavelength(nm)
Fig. 2 a UV–Vis spectra of (1) CuTNPc, (2) CuTAPc, (3) CuTCPc
in DMF, and (4) CuTCPc in 0.1 N NaOH. b UV–Vis spectra of (1)
NiTNPc, (2) NiTAPc, (3) NiTCPc in DMF, and (4) NiTCPc in 0.1 N
NaOH. c UV–Vis spectra of (1) ZnTNPc, (2) ZnTAPc, (3) ZnTCPc in
DMF, and (4) ZnTCPc in 0.1 N NaOH
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Med Chem Res (2013) 22:4300–4307
The yield of zinc tetra (n-carbonylacrylic) aminepht-
higher temperature till 300 °C without undergoing any
decomposition or compositional change.
halocyanine (ZnTCPc) was 88 %, and kmax in DMF were
690 and 353 nm, respectively, whereas kmax in 0.1 M
NaOH were 661 and 341 nm, respectively. Anal: Calc. For
C48H28N12O12ZnÁ3H2O: C 53.17, H 3.16, N 15.50 % and
found C 52.95, H 3.01, N 16.40 %. The magnetic suscep-
tibility study indicated that this compound was diamag-
netic. NMR signals obtained in the case of ZnTCPc were
almost similar to those obtained in the case of NiTCPc.
The impact of substitution at peripheral position on the
stability of the compound studied using TG revealed that
these compounds have good thermal stability up to 400 °C
as seen for n-carbonylacrylic amine-substituted Pc in
Fig. 3. These compounds can be conveniently used at
Photoluminescence data recorded in Fig. 4 show emis-
sion maximum at 468 nm for n-carbonyl acrylic amine-
substituted Pc, on excitation at 220 nm, Fig. 5 indicates the
excitation spectra. Figure 6 shows up-conversion at
450–480 nm with maximum at 468 nm, for the same
compounds, after excitation at lower energy wavelength at
625 nm. Interestingly, excitation of the compounds either
with higher energy at 220 nm and or lower energy at
625 nm resulted in emissions in the range 450–470 nm.
ZnTCPc showed maximum intensity as compared to that of
CuTCPc and NiTCPc. The up-conversion was observed in
160
140
120
(1)
Excitation at 220 nm
100
80
60
40
20
0
(3)
(2)
300
400
Wavelength (nm)
Fig. 5 Excitation at 220 nm (1) CuTCPc, (2) ZnTCPc, and (3)
NiTCPc
Fig. 3 TG curves of (1) CuTCPc, (2) ZnTCPc, and (3) NiTCPc
320
300
Upconversion at 468 nm
280
260
240
220
200
180
160
140
120
100
160
(3)
140
(3)
120
Emission at 468 nm
(1)
100
(1)
(2)
80
60
40
20
0
(2)
400
500
400
500
600
700
800
Wavelength (nm)
Wavelength (nm)
Fig. 6 Up-conversion at 468 nm (1) CuTCPc, (2) ZnTCPc, and (3)
NiTCPc
Fig. 4 Emission at 468 nm (1) CuTCPc, (2) ZnTCPc, and (3)
NiTCPc
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Med Chem Res (2013) 22:4300–4307
4305
all the samples by keeping the slit width same. Sample was
excited at different wavelengths in the range 580–650 nm,
of which 625 nm showed the up-conversion. The up-con-
version pattern was similar to that of excitation at 220 nm
indicating that in both the cases, emission centers were the
same. The up-conversion process may be explained by anti
stokes two photon theory ,i.e., when the samples were
irradiated at 625 nm, the first photon pumps the electron
from the conduction band to the intermediate level, and the
second photon ionizes the electrons to the conduction band.
When the electrons are recaptured or transfer energy in the
valence band, intrinsic emission occurs, while the recom-
bination or transfer of energy in the intermediate level
gives the emission at lower wavelength.
Images depicted in Fig. 7 showed absence of growth of
S. citreus, S. marcecans, and B. subtilis around wells
containing the phthalocyanine conjugates of copper, nickel,
and zinc. In Fig. 8, different higher concentrations of
ZnTCPc showed activity against P. vulgaris, thus sug-
gesting that the conjugates affected growth adversely. As
observed in Fig. 9a, b, inhibition of growth with copper
and nickel conjugates occurred at minimum of 10 and
20 lg in case of S. citreus, S. marcescens, P. vulgaris, P.
fluorescence; S. citreus, S. marcescens, B. subtilis, and P.
vulgaris, respectively. The adverse effect of Cu and Ni
conjugates, in terms of size of growth inhibition zone
was in the order of: P. fluorescence = S. citreus [
S. marcescens = P. vulgaris and S. marcescens [ B. sub-
tilis [ S. citreus, respectively. Further, as evident in
Fig. 9c, Zn conjugates at 200, 400, and 600 lg affected
growth of S. citreus [ S. marcescens, P. vulgaris, and B.
subtilis, respectively. It is noteworthy that the growth of P.
fluorescence was inhibited only by Cu conjugate. The Cu
and Ni conjugates are potent at a tenfold lower concen-
tration than that of Zn conjugate. The observation is,
therefore, an evidence of antimicrobiocity/antibiocity of
metal phthalocyanines against S. citreus, S. marcescens, P.
vulgaris, B. subtilis, and P. fluorescence, which is dose-
Fig. 7 Zones of inhibition of growth by CuTCPc, NiTCPc, and
ZnTCPc: a Bacillus subtilis; b Serratia marcecans; c Staphylococcus
citreus
Fig. 8 Zones of inhibition of growth on Proteus vulgaris by ZnTCPc
at (i) 200; (ii) 400; (iii) 600; (iv) 800; and (v) 1,000 lg of
concentration (DC diluent control)
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Hospital and also because: S. citreus is recommended to be
pyogenic and involved in nosocomial infections (Chang
and Chen, 2003); S. marcecans (Sunenshine et al., 2007),
P. vulgaris are involved in emerging UTI infections
(Trevejo et al., 2005); and B. subtilis is often encountered
as a laboratory contaminant or in casual handling of food
and food poisoning thereof (Parisi, 1985). The inhibition of
growth of P. fluorescence by Cu conjugates is of special
significance as the organism is known to be resistant to
many frontline antibiotics (Pitt et al., 2003).
These compounds, therefore, have an excellent property
to provide or make available oxygen species for the oxi-
dation, and there is every chance that such reactions may
be more effective in the presence of light. Further, these
properties of light harvesting and photoluminescence
property including up-conversion may be playing a vital
role in the antibacterial activity of Pcs. It is also note
worthy that the phthalocyanine compounds in solution
have potency to generate reactive oxygen species in the
presence of dissolved oxygen and light. Thus, the activity
may be increased by taking oxygen-enriched solution. The
PDT may also work based on a similar phenomenon
wherein oxygen species like singlet oxygen may be
involved in killing bacteria present around.
Conclusion
A novel aqueous soluble metal phthalocyanines of copper,
nickel, and zinc were synthesized, starting from easily
available phthalic anhydride. The conditions required for
synthesis of intermediate products were optimized. This
method developed for the synthesis of water-soluble Pcs is
important and can be used further as therapeutic materials.
The up-conversion study indicates that the molecule may
show some application in laser technology and also for
PDT. The preliminary results clearly indicate that the
phthalocyanine conjugates are potent ‘bacteriocides’ and
that their potency can be affixed in terms of minimum
inhibitory concentration (MIC) against the bacterial cul-
tures used in the study.
Fig. 9 Inhibition of growth of: Staphylococcus citreus, filled square;
Serratia marcescens, filled circle; Proteus vulgaris, filled triangle;
Bacillus subtilis, open square; and Pseudomonas fluorescence, open
circle. By Phthalocyanine conjugates of: a CuTCPc, b NiTCPc, and
c ZnTCPc
Acknowledgments Authors are grateful to the Department of
Science & Technology, New Delhi, for the financial assistance and
the Department of Microbiology (Bacterial Pathogens), Goa Medical
College, Goa, for providing microbial cultures.
dependent, bacteria- and metal-specific. Such inhibition of
growth, seen with antibiotics, is termed as antimicrobial
effect and is taken as the criteria for evaluating potency of
antibiotics (Cooper and Woodman, 1946). The results are
of significance as the bacterial pathogens under study were
obtained as emerging pathogenic status from the State
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