Synthesis and photodynamic activities of a new metronidazole-appended porphyrin and its Zn(II) complex

Article abstract of DOI:10.1142/S1088424615500868

One novel porphyrin 5,10,15-tris(phenyl)-20-[4-(2-(2-methyl-5-nitro-imidazolyl)ethoxyl)phenyl] porphyrin and its zinc(II) metalloporphyrin were synthesized and characterized by IR, UV-vis, ¹H NMR, MS and elemental analysis. The single crystal s

Full text of DOI:10.1142/S1088424615500868

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2015; 19: 1–7
DOI: 10.1142/S1088424615500868
Published at http://www.worldscinet.com/jpp/
Synthesis and photodynamic activities of a new
metronidazole-appended porphyrin and its Zn(II) complex
a
a,b
a,c
a
a
a
QiongYu , Wei-Xia Xu , Ya-HongYao , Zeng-Qi Zhang , Shu Sun and Jun Li*
a
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education,
College of Chemistry & Materials Science, Northwest University, Xi’an, Shaanxi 710069, P. R. China
b
College of Chemistry and Chemical Engineering, Xianyang Normal University, Xianyang 712000, P. R. China
College of Science, Xi’an University of Architecture and Technology, Xi’an, Shaanxi 710055, P. R. China
c
Received date 17 June 2015
Received date 7 August 2015
ABSTRACT: One novel porphyrin 5,10,15-tris(phenyl)-20-[4-(2-(2-methyl-5-nitro-imidazolyl)ethoxyl)
1
phenyl] porphyrin and its zinc(II) metalloporphyrin were synthesized and characterized by IR, UV-vis, H
NMR, MS and elemental analysis. The single crystal structure of zinc(II) porphyrin shows that the Zn(II)
ion is coordinated with four nitrogen atoms of porphyrin ring and one oxygen atom of ethanol from axial,
forming a five-coordinated square pyramidal geometry. Their cytotoxicity and photodynamic activity
against breast cancer cells were studied. The results indicate that both of the porphyrins display high
phototoxicity to the breast cancer cells with the negligible dark toxicity. In addition, the photodynamic
activity of zinc(II) porphyrin was obviously higher than that of the free porphyrin.
KEYWORDS: porphyrin, zinc(II) porphyrin, photodynamic therapy (PDT), cytotoxicity, phototoxicity,
breast cancer.
Introducing additional functional groups onto the
porphyrin skeleton has been effectively employed to
extendingthefunctionalitiesoftetrapyrrolechromophores
12]. In order to develop new porphyrin photosensitizers,
INTRODUCTION
During the past decades, there has been a growing
interest in using porphyrins as photosensitizers in the
[
photodynamic therapy (PDT) of cancer [1–7]. Compared
with conventional treatment methods, such as surgery,
chemotherapy and radiation, PDT is a promising
therapeutic modality for the treatment of a variety of
premalignant and malignant diseases, which utilizes
suitable illumination that can be replaced in the same
site if necessary [8, 9]. Because of its low cytotoxicity,
no surface damage, the capacity of highly selective,
destroying cancer cells without harming normal tissues
and relatively lower cost than surgery, PDT is a valuable
therapy method. In the process of PDT, the porphyrins
as photosensitizers generally accumulate in cancer
several modified porphyrin derivatives, like porphyrins
linked with amino acid, steroid, imidazole and nucleotide
have been employed and investigated in the treatment
of cancers in recent years [13–17]. Metronidazole
(MTZ), the Food and Drug Administration (FDA)-
approved pharmaceutical intermediate [18], which plays
a significant role in biological metabolism, particularly
against the disabled cells. Its anti-inflammation and
antibacterial function make this medicine popular and
heat-sensing among the medical domain. So introducting
metronidazole as a group into the porphyrin may further
increase the anticancer activity of porphyrin.
It has been reported that a range of metalloporphyrins
have been investigated as photosensitizers in cancer
treatment, and among those porphyrins, Zn, Ru and
Co metalloporphyrins showed dramatic and diverse
biological activities in preclinical studies [19]. In
addition, as one life essential element, Zn(II) ion plays
tissues with a relative high concertration and generate
1
the cytotoxic singlet oxygen ( O ), which can induce
2
damages to cancer cells and result in their death [10, 11].
*
Correspondence to: Jun Li, email: junli@nwu.edu.cn
Copyright © 2015 World Scientific Publishing Company

2
Q. YU ET AL.
N
HN
N
N
N
N
N
O
O
Zn
H3C
N
NH
H3C
N
N
NO2
N
NO2
H Pp
2
ZnPp
Fig. 1. The structure of porphyrins H Pp and ZnPp
2
vital roles in cellular metabolism, gene expression,
apoptosis, neurotransmission, and so forth [20, 21]. It
is also associated with physical growth retardation and
neurological disorders such as cerebral ischemia and
Alzheimer’s disease [22].
For the above reasons, in this paper, we synthesized a
new metronidazole-appended porphyrin, 5,10,15-tris
(
phenyl)-20-[4-(2-(2-methyl-5-nitro-imidazolyl)ethoxyl)
phenyl]porphyrin H Pp and its corresponding zinc(II)
2
porphyrin ZnPp (Fig. 1). Their cytotoxicities and photo-
toxicities against breast cancer cells were also studied.
RESULTS AND DISCUSSION
Synthesis of H Pp and ZnPp
2
The synthetic route of H Pp and Zn(II) porphyrin
Fig. 2. UV-vis spectra of H Pp and ZnPp
2
2
was outlined in Scheme 1. H Pp was synthesized by
2
the reaction of 5-(4-bromophenyl)-10,15,20-tri(phenyl)
porphyrin and metronidazole in DMF in the presence of
K CO at room temperature with the yield about 70%.
band can be found in the metalloporphyrin spectrum
2
3
(
418 and 420 nm for H Pp and ZnPp respectively). This
2
The ZnPp was obtained by reaction of H Pp with excess
2
is induced by the delocalized p bonds which decrease the
average electron density in metalloporphyrin.
of Zn(Ac) in a 25 mL teflon-lined stainless reactor at
2
9
0°C. The purple bulk-like single crystals were collected
In the FT-IR spectroscopy data (Table 1), the
in 72% yield.
-1
absorption peaks around 3436 and 962 cm , observed in
H Pp, are related to the stretching and bending vibrations
of the central N–H of porphyrin ring, and the two peaks
2
Characterization of H Pp and ZnPp
2
The structures of H Pp and ZnPp were characterized
are absent for ZnPp because of the coordination of
2
-1
by elemental analysis, mass spectrometry, UV-vis, FT-IR
four N atoms with Zn(II) ion. The bands at 1545 cm
1
-1
and H NMR.
and 1548 cm , found in the spectra of both H Pp and
2
From the UV-vis spectra in Fig. 2, we can find that the
metalloporphyrin, are associated with the stretching
free porphyrin H Pp exhibits the Soret band at 418 nm
vibrations of –NO ; and the bands around 1250, 1160,
1100 cm are attributed to the stretching vibrations of
2
2
-1
and four weak Q-bands in the 510–650 nm region, while
the ZnPp has the Soret band at 420 nm, and only two
weak Q-bands at 548 nm and 588 nm respectively. The
insertion of zinc(II) ion into the porphyrin ring causes
a decreasing number of Q-bands, due to the increasing
symmetry of the porphyrin ring when the H ions of N−H
are replaced by Zn(II) ion. Also a red shift of the Soret
Ph–O–C.
1
The H NMR spectrum of the porphyrin H Pp has
2
been determined in CDCl . It is showed that the chemical
3
shift of eight b-pyrrolic proton resonances is around at
d = 8.79–8.88 ppm, and the peaks at 8.21, 8.11, 7.93,
7.75 ppm are the resonance of 19 protons of the benzene
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 2–7

SYNTHESIS AND PHOTODYNAMIC ACTIVITIES OF A NEW METRONIDAZOLE-APPENDED PORPHYRIN
3
Table 1. Data of mass spectroscopy and FT-IR spectroscopy of H Pp and ZnPp
2
+
-1
Porphyrin
MS (m/z, [M + 1] )
FT-IR (U, cm )
H Pp
2
799.7
3436 (UNH), 1545 (UC-NO2), 1284 (UPh-O-C),
1
171 (UPh-O-C), 1047 (UPh-O-C), 962 (UNH
)
ZnPp
877.3
1548 (UC-NO2), 1176 (UPh-O-C), 1064 (UPh-O-C))
rings. The double peaks at d = 7.17 ppm can be ascribed
to the proton of imidazole. The multiple peaks of –CH2–
protons from –CH –CH –O– are detected at 4.42 ppm.
2
2
Then, the single peak around 2.66 ppm belongs to the
protons of the –CH . In the end, the single peak around
3
d = -2.78 ppm is from the protons of the –NH group in
porphyrinic core.
X-ray powder diffraction (PXRD)
PXRD experiment has been carried out to check the
phase purity of the complex ZnPp. The experimental and
computer-simulated PXRD patterns are shown in Fig. 3.
All the characteristic peaks are well-matched with that
of simulated one, which suggest that they are identical
samples.
Crystal structure description
The single crystal X-ray diffraction analysis illustrated
that the complex ZnPp crystallized in the triclinic crystal
system and P-1 space group. As shown in Fig. 4(a),
the Zn(II) ion inserted into the core of porphyrin by
coordinating to four pyrrole nitrogen atoms. At the same
time, an oxygen atom of ethanol coordinated to Zn(II) ion
in the axial direction to form a pyramidal geometry. The
coordinationbondlengthsofZn–Nrangedfrom2.067(12)
to 2.080(10)Å, and the bond length of Zn(2)–O(4) is
Fig. 4. The coordination environment of Zn(II) (a), and
the structural conformation of ZnPp (b)
2.108(11) Å. The angle of N(3)–Zn(2)–O(4) measured to
The porphyrin macrocycle in ZnPp displays a
distorted configuration owing to the four pyrrole rings
slightly distorted in an alternant pattern either upward
or downward with respect to the mean plane of the
porphyrin core. The angles of the two aryl rings in para-
position and the aryl ring with metronidazole ethoxy to
its para-position aryl ring were measured to be 65.66°,
be 97.6(5)°.
9
.68° respectively, shown in Fig. 4(b).
Cytotoxicity and phototoxicity
The dark cytotoxicities of H Pp and ZnPp were
2
investigated with the breast cancer cells at the
concentration of 0 mM, 0.25 mM, 0.5 mM, 1.0 mM, 5 mM,
1
0 mM, respectively, and viabilities of the breast cancer
cells were determined by using the MTT assay. As shown
in Fig. 5 orange bars, both H Pp and ZnPp exhibited
2
very low dark cytotoxicities with the survival rate above
8
0%. However, after being exposed to metal halide lamp
-2
(50 mW.cm ) for 30 min, they were found to be
Fig. 3. PXRD patterns of Zn(II) porphyrin
phototoxic towards the breast cancer cells. The results,
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 3–7

4
Q. YU ET AL.
Fig. 5. Cytotoxicity (orange bars) and phototoxicity (blue bars) of the H Pp and ZnPp in different concentrations
2
(
0 mM, 0.25 mM, 0.5 mM, 1.0 mM, 5 mM, 10 mM respectively) on breast cancer cells
represented in Fig. 5 blue bars, showed cells survival
rates decreased to 65.3% and 17.8% respectively with the
increase of porphyrins concentration, and the anti-cancer
Bruker Advance 400 MHz NMR spectrometer. The
powder X-ray diffraction (PXRD) patterns were taken with
a Bruker D8 diffractometer using graphite monochromatic
copper radiation (Cu Ka) at 40 kV, 30 mA over the 2q
range from 5 to 30°.
activity of ZnPp was obviously higher than that of H Pp.
2
As reported in Ref. [23], Vicente et al. used the Zn(II)
meso-tetra[4-(nidocarboranyl)phenyl] porphyrin to
human K562 cells, after treatment with this porphyrin in
the dark and in the presence of light, the cells survival
rates decreased to 89% and 86% respectively. Obviously,
ZnPp shows high inhibition rate to breast cancer cells
compared with one reported Zn(II) porphyrin. We likely
credit the contribution to the role of the peripherial
metronidazole group.
Synthesis
5
,10,15-Tris(phenyl)-20-[4-(2-(2-methyl-5-nitro-
imidazolyl)ethoxyl)phenyl]porphyrin (H Pp). 5,10,15-
2
tris(phenyl)-20-[4-(2-(2-methyl-5-nitro-imidazolyl)
ethoxyl)phenyl]porphyrin was synthesized by follow-
ing the two steps, shown in Scheme 1. Firstly, 4-bromo-
benzaldehyde (1.84 g, 0.01 mol), benzaldehyde (1.06 g,
0.03 mol) and pyrrole (0.04 mol, 2.5 mL) were dissolved
EXPERIMENTAL
in 150 mL propionic acid in a three-necked bottle. The
mixture was heated to reflux and was stirred for about
5
0 min. Then the solution was cooled to room temperature,
Chemicals and instruments
and two-thirds of solvent was removed under vacuum
and 40 mL C H OH was added. The mixture was cooled
4-Bromobenzaldehyde, benzaldehyde and pyrrole
2
5
were purchased from Sinopharm Chemical Reagents
Company. 1,3-Diphenylisobenzofuran (DPBF), 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
overnight in refrigerator and filtered under vacuum. Then
the crude products were purified by chromatography
on a silica-gel column with CH Cl as eluant to give
2
2
(
MTT) and other reagents were obtained from Beijing
5-(4-bromophenyl)-10,15,20-tri(phenyl)porphyrin as a
purple solid. Yield 45.1%.
chemical, reagents company. They were used without
further purification except pyrrole and N,N-dimethyl
formamide (DMF), which were distilled before use.
Dimethyl sulfoxide (DMSO) was dried using anhydrous
Na SO .Thinlayerchromatography(TLC)wasperformed
Subsequently, the desired porphyrin was obtained by
metronidazole (0.17g, 0.001mol) and 5-(4-bromophenyl)-
10,15,20-tri(phenyl)-porphyrin (0.69 g, 0.003 mol) was
mixed in 20 mL DMF and stirred in the presence of K CO
2
4
2
3
on silica gel GF254 plates. Chromatographic separations
were carried out on silica gel (100–200 mesh).
for nearly 24 h in the darkness at room temperature,
which was monitored by TLC. After the reaction was
completed, DMF was removed under vacuum. The
residue was purified by chromatography on a silica-gel
column with CH Cl as eluent, porphyrin H Pp was
Elemental analyses (C, H and N) were performed
by Vario EL-a CHNOS instrument. UV-vis spectra
were measured on a Shimadzu UV 1800 UV-vis-NIR
spectrophotometer. FT-IR spectra were recorded on a
BEQUZNDX-550 spectrometer on samples embeded
in KBr pellets. Mass spectrometry (MS) analysis were
carried out on a matrix assisted laser desorption/ionization
time of flight mass spectrometer (MALDI-TOF MS, Krato
Analytical Company of Shimadzu Biotech, Manchester,
2
2
2
obtained.Yield 25.6%. mp > 250°C, Anal. calcd. (found)
for C H N O : C 76.67 (76.61), H 4.74 (4.76), N 12.49
5
0
37
1
7
3
(12.51). H NMR (CDCl , 400 MHz): d, ppm 8.88–8.79
3
(m, 8H, b position of the pyrrol), 8.21 (d, J = 6.1 Hz, 6H,
Ar), 8.11 (d, J = 8.5 Hz, 2H, Ar), 7.93 (s, 2H, Ar), 7.75 (d,
J = 7.3 Hz, 9H, Ar), 7.17 (d, J = 8.6 Hz, 1H, imidazole),
1
Britain). The H NMR spectra were recorded using a
4.42 (dd, J = 10.6, 4.0 Hz, 4H, –CH –), 2.61 (s, 3H,
2
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 4–7

SYNTHESIS AND PHOTODYNAMIC ACTIVITIES OF A NEW METRONIDAZOLE-APPENDED PORPHYRIN
5
CHO
CHO
NH
N
N
CH3CH3COOH
+
3
+ 4
Br
N
H
HN
Br
Yield: 45.1%
N
CH3
O2N
CH3
N
N
DMF
K2CO3
N
OH
O2N
O
N
N
N
N
N
HN
N
Zn(OAC)2
Zn
O
CH2Cl2
CH3CH2OH
H3C
N
NH
N
NO2
Yield: 72.0%
Yield: 25.6%
Scheme 1. The Synthesis of H Pp and ZnPp
2
-
1
–
2
1
CH ), -2.78 (s, 2H, –NH). FT-IR (KBr): n, cm 3436,
Absorption correction was performed by using SADABS
program [24]. The structure was solved by direct method
and refined by full-matrix least-squares techniques using
the program SHELXL-97 [25]. Anisotropic thermal
parameters were assigned to all non-hydrogen atoms. The
hydrogen atoms on carbon were placed in geometrically
calculated positions with a fixed C–H distance (0.97 Å).
The crystal parameters of the complex ZnPp were given
in Table 2. Selected bonds distances and angles were
listed in Table 3.
3
921, 2359, 1641, 1601, 1544, 1499, 1465, 1397, 1336,
284, 1239, 1171, 1047, 962, 797, 736, 702, 646. UV-vis
CHCl ): l , nm 418 (Soret), 515 (QI), 550 (QII), 590
(
(
3
max
+
QIII), 645 (QIV). MS: m/z 799.7 [M + 1] amu.
Zn(II) 5,10,15-tris(phenyl)-20-[4-(2-(2-methyl-5-
nitro-imidazolyl)ethoxyl)phenyl]porphyrin (ZnPp).
To a solvent of 5 mL CH Cl and 2 mL anhydrous ethanol,
added H Pp (0.001 mol 0.78 g) and Zn(CH COO) ·2H O
2
2
2
3
2
2
(
0.003 mol, 0.65 g) with stir until their fully dissolution.
Then sealed the solution in a 25 mL teflon-lined stainless
reactor and heated slowly to 90°C in 2 h and kept for 72 h.
After that, it was cooled to the room temperature within
Study on breast cancer cells
2
4 h. The purple bulk-like single crystals were collected
Cell culture conditions. Breast cancer cells were
cultured in plastic culture flasks at 36.5 ± 0.5°C and 5%
in 72.0% yield. Anal. calcd. (found) for C H N O Zn
5
2
40
7
3
(
%): C 71.11 (71.04), H 4.49 (4.44), N (11.37). IR
CO humidified sterile incubator, by using DMEM/F-12
2
-
1
-1
spectrum (KBr): n, cm 3457, 2925, 2365, 1652, 1506,
380, 1340, 1242, 1176, 1064, 995, 799, 701, 569. MS:
medium with penicillin (100 UI.mL ), streptomycin
-1
1
(100 mg.mL ) and 10% heat-activated fetal bovine serum.
When cells were in the exponential growth phase, the
medium was removed and washed with 5 mL of phosphate
buffer saline (PBS) for three times, and treated with trypsin
+
m/z 877.7 [M + 1] amu.
Crystallographic data collection and refinement
2
mL to separate them from the flasks and collected into
The crystallographic data-set was obtained on a
Bruker SMART CCDC diffractometer with graphite-
monochromated Mo Ka radiation (l = 0.71073 Å).
a centrifuge tube containing 4 mL of the culture medium.
Cytotoxicity andphototoxicity. Duringthe cytotoxicity
test, the same concentrations of cells were suspended in
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 5–7

6
Q. YU ET AL.
Table 2. The crystal parameters of complex ZnPp
incubated for 24 h in growth medium in a humidified 5%
CO incubator at 37°C. Then, the free porphyrin and the
2
Complex
ZnPp
zinc porphyrin dissolved in DMSO were added to the
quintuplicate wells, in different concentration of 0 mM,
0.25 mM, 0.5 mM, 1.0 mM, 5 mM and 10 mM respectively.
Empirical formula
C H N O Zn
50
35
7
3
C H N Mn
56
36 12
-1
-
1
M, g.mol
q range, °
1843.16
1.16–28.25
triclinic
296
After 24 h incubation, the 20 mL MTT (5 mg.mL )
was added to each well and incubated for 4 h. The
culture medium was removed and the MTT reduzate
was dissolved by adding 150 mL DMSO. After 20
min oscilation, the absorbance was measured using an
enzyme-linked immuneoabsorbent assay plate reader
Crystal system
T, K
Space group
a, Å
P-1
(Bio-Rad) at 680 nm. The survival rate of cells was given
9.986(7)
13.628(9)
17.615(11)
94.055(14)
92.306(15)
104.930(13)
2306(3)
1
as the percentage compared to the untreated cells.
In the phototoxicity test, the breast cancer cells were
b, Å
c, Å
cultured as described above. Then, the H Pp and ZnPp
2
a, °
were dissolved in DMSO and added to the quintuplicate
wells respectively, developed for another 24 h in the
darkness. Then the cells were immediately exposed to
b, °
g, °
-1
metal halide lamp (50 mW.cm ) for 30 min and after
3
V, Å
24 h incubation. The viability of cells was measured by
the MTT assay [26, 27].
Z
-
3
Dcalc, g.cm
1.327
F(0 0 0)
916
CONCLUSION
-
1
m, mm
R /wR [I > 2q(I)]
0.580
a
1
b
In summary, a novel metronidazole-based porphyrin
derivative and its complex zinc(II) metalloporphyrin
were synthesized, then the crystal structure of ZnPp
was analyzed. Their cytotoxicities and phototoxicities
were evaluated with the MTT assay. The results
indicate that they exhibit nearly no cytotoxicity towards
breast cancer cells in the absence of light, however,
after UV irradiation for a certain period of time, they
display different degrees of phototoxicity, and the
phototoxicity of the zinc(II) porphyrin is obviously
higher than that of the free porphyrin, which may
provide some valuable reference for these porphyrin
derivatives applied in PDT for non-invasive treatment
of cancer in the future.
R = 0.1544 wR = 0.2833
1
2
2
R /wR (all reflections)
R = 0.4368 wR = 0.4353
1
2
1
2
Goodness-of-fit
1.044
-
3
Largest diff. peak and hole, eÅ
0.597 and -0.989
a
b
2
o
2
c
2
2 2 1/2
o
R = ∑(|F |-|F |)/E|F |, wR = [∑w(F - F ) /∑w(F ) ] .
1
o
c
o
2
Table 3. Selected bond lengths (Å) and angles (°) for ZnPp
Bond lengths, Å
Zn(2)-N(3)
Zn(2)-N(1)
Zn(2)-N(2)
2.067 (12) Zn(2)-N(4)
2.070 (12) Zn(2)-O(4)
2.077 (11) O(1)-C(74)
2.080 (10)
2.108 (11)
1.436 (18)
Angles,°
Acknowledgements
N(3)-Zn(2)-N(2)
N(1)-Zn(2)-N(2)
N(3)-Zn(2)-N(4)
N(1)-Zn(2)-N(4)
N(2)-Zn(2)-N(4)
161.2 (5) N(3)-Zn(2)-O(4)
89.0 (5) N(1)-Zn(2)-O(4)
97.6 (5)
97.7 (5)
The authors acknowledge the research grant provided
by the National Nature Science Foundation of China
(21271148) that resulted in this article.
89.2 (5) N(2)-Zn(2)-O(4) 101.2 (5)
163.2 (5) N(4)-Zn(2)-O(4) 99.1 (5)
87.6 (4) C(22)-N(2)-C(20) 106.8 (12)
Supporting information
Crystallographic data for Zn(II) porphyrin have
been deposited at the Cambridge Crystallographic Data
Centre (CCDC) under numbers CCDC-952593. Copies
can be obtained on request, free of charge, via www.
ccdc.cam.ac.uk/data_request/cif or from the Cambridge
Crystallographic Data Centre, 12UnionRoad, Cambridge
CB2 1EZ, UK (fax: +44 1223-336-033 or email: data_
request@ccdc.cam.ac.uk).
Dulbecco’s modified eagle medium (DMEM) and were
ultrasonicated for 30 s to prevent agglomeration. To
evaluate the toxicity of the porphyrins, the breast cancer
cells were cultured in 200 mL growth medium at a
concentration of 2 × 10 cells.well in 96-well microtiter
plates containing 200 mL culture medium per well, and
4
-1
Copyright © 2015 World Scientific Publishing Company
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SYNTHESIS AND PHOTODYNAMIC ACTIVITIES OF A NEW METRONIDAZOLE-APPENDED PORPHYRIN
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