Synthesis, antiviral, cytotoxicity and antitumor evaluations of A4 type of porphyrin derivatives

Article abstract of DOI:10.1142/S1088424615500480

This manuscript describes the synthesis of a new series of porphyrin structures 4a-4m, 7, 9, 12 and 14. These structures were investigated against two types of viruses such as HIV-1 and HSV-1. Also they were screened for their antitumor activity. Among all tested compounds, it was found that compound 4b showed a high activity against HIV-1 and HSV-1 and against four different tumor cell lines. Most of the tested compounds showed a moderate degree of a potent antimicrobial activity. The structure of these compounds was confirmed on the basis of their analytical and spectral data such as UV-vis, IR, ¹³C NMR, ¹H NMR spectroscopy and mass spectral data.

Full text of DOI:10.1142/S1088424615500480

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2015; 19: 1–16
DOI: 10.1142/S1088424615500480
Published at http://www.worldscinet.com/jpp/
Synthesis, antiviral, cytotoxicity and antitumor evaluations
of A4 type of porphyrin derivatives
Ahmed A. Fadda*a and Rasha E. El-Mekawyb† and Ahmed I. El-Shafeic
a Department of Chemistry, Faculty of Science, Mansoura University, El-Gomhoria Street, Mansoura,
P.O. Box 35561, Egypt
b Department of Petrochemicals, Egyptian Petroleum Research institute, Nasr City, Cairo, Egypt
cPolymer and Color Chemistry Program, North Carolina State University, Raleigh, NC 27695, USA
Received 1 January 2015
Accepted 12 February 2015
ABSTRACT: This manuscript describes the synthesis of a new series of porphyrin structures 4a–4m,
7, 9, 12 and 14. These structures were investigated against two types of viruses such as HIV-1 and HSV-
1. Also they were screened for their antitumor activity. Among all tested compounds, it was found that
compound 4b showed a high activity against HIV-1 and HSV-1 and against four different tumor cell
lines. Most of the tested compounds showed a moderate degree of a potent antimicrobial activity. The
structure of these compounds was confirmed on the basis of their analytical and spectral data such as
UV-vis, IR, 13C NMR, 1H NMR spectroscopy and mass spectral data.
KEYWORDS: antiviral activity, antitumor activity, porphyrin structures.
having meso substituents like five-membered heterocycles
such as pyrrole, thiophene, furan etc. are scarce.
INTRODUCTION
The search for new biologically active agents is an
In recent times, there have been a few reports on meso-
important task for medicinal chemists. It has long been
tetrathienylporphyrins because of their unique energy
known that porphyrin is a representative p-functional
transfer and electrochemical properties [12]. To the best
skeleton that has been actively investigated in many
of our knowledge, there are no reports on the synthesis
research areas. [1–5]. Porphyrins have received a great
deal of interest because they show unique properties in
of porphyrins containing pyrazolyl groups at the meso
carbons. On the other hand, the chemistry of 1H-pyrazole
electronics [6], photosynthesis [7], optical memories
containing compounds is particularly interesting because
[8], photocatalysis [9], photodynamic therapy [10],
of their potential application in medicinal chemistry as
and solar cells [11]. The structural flexibility and well-
analgesic [13, 14], anti-inflammatory [15], antitumor
developed synthetic chemistry of porphyrins allow
[16, 17], antimicrobial [18–21] and therapeutic agents
their physical, biological and chemical properties to be
[22] and as potent insecticides [23] and herbicides [24]
tailored by choosing from a wide library of macrocycle
although they are scarcely found in nature [25]. Due to
substituents at the b- or meso-positions and central metal
atoms. Meso-Tetraarylporphyrins offer attractive features
many promising pharmacological, agrochemical and
analytical applications, a number of substituted pyrazoles
in this context and have been used in a wide variety of
is being used as inhibitors of heat-shock protein 90
model systems owing to their ease of synthesis and facile
(Hsp90) and as therapeutics of cancer and therefore they
functionalization. However, the reports on porphyrins
have been the focus of many synthetic targets over the past
decades [26]. 1H-Pyrazole based heterocyclic structures
have also attracted a synthetic interest for being essential
moieties in many chemotherapeutic agents with potential
antiparasitic [27], antimalarial [28] and antiviral activities
[29, 30]. As far as the anticancer activity is concerned,
literature citation revealed that a wide range of pyrazole
*Correspondence to: Ahmed A. Fadda, email: afadda50@
yahoo.com, tel: +20 502-265-636, fax: +20 502-246-781
†Current address: Department of Chemistry, Faculty of Applied
Science, Umm-Al-Qura University, Makkh, Saudi Arabia
Copyright © 2015 World Scientific Publishing Company

2
A. A. FADDA AND R. E. EL-MEKAWY AND A. I. EL-SHAFEI
Ph
derivatives was reported to contribute to a variety of
antineoplastic potentials against a wide range of cancer
cell lines [31, 32]. In this research work, we report for
the first time the synthesis and characterization of novel
meso-tetrapyrazolylporphyrins and their pharmaceutical
screening as antiviral and antitumor agents.
N-NHPh
CH3
N
N
POCl3
DMF
Ar
Ar
CHO
3a-m
2a-m
3a; Ar = Ph,3b; Ar = pyrrol-2-yl, 3c; Ar = Indol-3-yl, 3d; Ar = 4-tol-1-yl,
3e; Ar = 4-hydroxy phenyl, 3f; Ar = pyridin-2-yl, 3g; Ar = 1-biphenyl,
3h; Ar = pyridin-4-yl, 3i; Ar = 2-hydroxyphenyl, 3j; Ar = 3-hydroxyphenyl,
3k; Ar = 3-aminophenyl, 3l; Ar = 4-acetylphenyl, 3m; Ar = cyclohexen-1-yl
RESULTS AND DISCUSSION
Scheme 2. Vilsmeier–Haack reaction for the synthesis of
different formyl pyrazoles 3a–3m
Chemistry
As a continuation of our recent publishing work [33],
some new substituted 3-aryl-1-phenyl-1H-pyrazole-4-
carbaldehydes (3a–3m) were prepared by Vilsmeier–
Haack reaction of their corresponding hydrazone deriva-
tives 4a–4m [34].
1H NMR spectra have appeared very interesting due to
the anisotropic effect of porphyrin ring (Fig. 1), resulting
from circulation of electrons making up the conjugated
p-bonding system, two shielded zones were formed over
and under the macrocycle plane. The chemical shift
assigned to protons falling within the conical areas was
shielded and those falling outside the conical areas were
deshielded. In this way, it was possible to justify the
chemical shifts measured in the case of 4b were shielded
for 0.1–1.2 ppm relatively to 4b.
Moreover, porphyrin shows a broad spectrum of
biological and pharmaceutical activity. Thus, compounds
having a combination of such pyrazole and porphyrin
moities might afford less toxic and more potent drugs in the
field of medicinal chemistry. In continuation of our study on
the chemistry of heterocyclic compounds and the synthesis
of heterocyclic substituted porphyrin of pharmaceutical
importance, we report herein on the use of pyrazole
derivatives 3a–3m as a key intermediate for the synthesis
of new series of A4 type of meso-substituted porphyrin.
Thus, the arylhydrazone derivatives 2a–2m were
prepared by condensing the acetyl derivatives 1a–1m
with phenylhydrazine in the presence of a few drops
of concentrated hydrochloric acid according to the
following reaction (Scheme 1).
In addition to the above results, it was interesting to
prepare 5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-3-
carbaldehyde(6)bythereactionof3-methyl-1-phenyl-1H-
pyrazol-5(4H)-one (5) [37-41] with selenium dioxide in
dioxane to give a good yield of compound 6. When 5-oxo-
1-phenyl-4,5-dihydro-1H-pyrazole-3-carbaldehyde (6)
reacted with pyrrole, according to the above mentioned
procedure, they afforded the corresponding porphyrin 7.
Structure 7 was elucidated from its correct elemental and
spectral data. The IR spectrum showed absorption bands at
n 3418, 1675 and 1615 cm-1 corresponding to vibrational
frequencies of NH, C=O and C=N groups. Its UV-vis
Consequently, the obtained hydrazones 2a–2m were
subjected to react with Vilsmeier–Haak reagent to give
the corresponding pyrazole derivatives 3a–3m according
to the following proposed mechanism (Schemes 2 and 3).
Porphyrins 4a–4m were synthesized according to
(Scheme 4). The precursors 3a–3m were condensed with
pyrrole in the presence of p-toluenesulfonic acid and
N,N-dimethylformamide as a solvent under nitrogen gas
to obtain the free-base porphyrins 4a–4m which provided
a high yield (80–90%). We suggested that this reaction
was proceded via a capping mechanism to prevent the
formation of polymeric pyrrole [35, 36].
1
spectrum showed lmax at 423 nm (soret band). The H
NMR spectrum showed a characteristic band at d 3.8 ppm
due to CH2 protons and the absence of singlet signals at
d 9.75 ppm indicating that the CHO group was involved
in the formation of porphyrin molecule. 13C NMR gave a
more confirmation for this structure (Scheme 5).
As a continuation of the above work, the ((z)-4(4-
(dimethylamino)benzylidene)-5-oxo-1-phenyl-4,5-
dihydro-1H-pyrazole-3-carbaldehyde (8) was obtained
by the reaction of compound 6 with p-N,N-dimethyl-
1
The H NMR spectra were also consistent with the
structure of the synthesized compounds. Particularly, the
1
aminobenzaldehyde. Its H NMR spectrum showed two
singlet signals at d 3.07 and 3.12 ppm due to N-Me2
protons while the =CH proton appeared at d 7.1 ppm
and the formyl proton at d 9.85 ppm in addition to the
aromatic protons at d 7.2–7.45 ppm. When compound 8
was subjected to react with pyrrole in DMF, it afforded
the corresponding porphyrin structure 9. The IR spectrum
showed absorption bands at n 3350, 1680, 1610 and 1590
corresponding to stretching vibration of NH, C=O, C=N
O
N-NHPh
CH3
i) drops of conc. HCl
ii) Fusion at 200 °C
PhNHNH2
+
Ar
Ar
CH3
2a-m
1a-m
2a; Ar = Ph, 2b; Ar = pyrrol-2-yl, 2c; Ar = Indol-3-yl, 2d; Ar = 4-tol-1-yl,
2e; Ar = 4-hydroxy phenyl, 2f; Ar = pyridin-2-yl, 2g; Ar = 1-biphenyl,
2h; Ar = pyridin-4-yl, 2i; Ar = 2-hydroxyphenyl, 2j; Ar = 3-hydroxyphenyl,
2k; Ar = 3-aminophenyl, 2l; Ar = 4-acetylphenyl, 2m; Ar = cyclohexen-1-yl
1
and C=C functions. Its H NMR spectrum showed a
characteristic band due to =CH proton at d 7.08 ppm and
N-Me2 protons appeared at d 3.61 ppm as a singlet signal
Scheme 1. simple and convenient method for the synthesis of
different arylhydrazones 2a–2m
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 2–16

SYNTHESIS, ANTIVIRAL, CYTOTOXICITY AND ANTITUMOR EVALUATIONS OF A4 TYPE OF PORPHYRIN DERIVATIVES
3
O
O
P
H3C
H3C
H3C
H3C
H3C
H3C
N
CH
Cl
Cl2
N
CH
+
N
C
Cl
H
OPOCl2
NNHPh
Ar
Cl
H2C
NNHPh
NNHPh
Ar
NNHPh
Ar
-H+
H3O+
H3C
N
C
CH2
OHC C
OHC CH2
Ar
H2
-Me2NH
H
H3C
H3C
N
C
Cl
H
H3C
OH
NNHPh
Ar
H3O+
NNHPh
Ar
NNHPh
Ar
H3C
H3C
CHO
OHC
OHC
HC
C
N
C CH2
H
CH
-Me2NH
OHC
Ph
-H2O
N
N
Ar
CHO
3a-m
Scheme 3. Proposed mechanism of Vilsmeier–Haack reaction
Ph
N
N
Ar
Ar
Ph
NH
N
N
N
N
Ph
p-toluenesulfonic acid
N
N
N
+
N
Ar
DMF, N2 gas
N
HN
H
Ph
CHO
3a-m
Ar
Ar
N
N
Ph
4a-m
4a; Ar = Ph,4b; Ar = pyrrol-2-yl, 4c; Ar = Indol-3-yl, 4d; Ar = 4-tol-1-yl,
4e; Ar = 4-hydroxy phenyl, 4f; Ar = pyridin-2-yl, 4g; Ar = 1-biphenyl,
4h; Ar = pyridin-4-yl,4i; Ar = 2-hydroxyphenyl, 4j; Ar = 3-hydroxyphenyl,
4k; Ar = 3-aminophenyl, 4l; Ar = 4-acetylphenyl, 4m; Ar = cyclohexen-1-yl
Scheme 4. New class of porphyrin derivatives 4a–4m
plus the normal characteristic protons of a porphyrin
molecule. Its UV-vis spectrum showed lmax at 424 nm
(Scheme 6).
4-Formylphenazone (1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazole-4-carbaldehyde) (11) was obtained
by the reaction of phenazone (10) with Vilsmeier–Haak
reagent. Its IR spectrum showed stretching frequen-
cies at n 1710, 1680 and 1610 cm-1 corresponding to
formyl, amidic carbonyl and C=N function groups. The
mass spectrum showed a molecular ion peak at m/z =
216 corresponding to a molecular formula C12H12N2O2.
When compound 11 was subjected to react with pyrrole,
according to the previously mentioned procedure, it
afforded the corresponding porphyrin 12. The IR spectrum
of porphyrin 12 showed stretching vibrations due to NH,
1
C=O and C=N at n 3310, 1683 and 1610 cm-1. The H
NMR of 12 revealed four characteristic singlet signals at
d 1.77, 3.25, 3.51 and 10.56 ppm attributable to CH3, NH,
N-CH3 and NH protons, respectively. Its UV-vis spectrum
showed lmax at 425 nm (Scheme 7).
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 3–16

4
A. A. FADDA AND R. E. EL-MEKAWY AND A. I. EL-SHAFEI
13 was treated with an excess amount of pyrrole in N,N-
dimethylformamide as a solvent in an acid catalyzed
reaction, it was found that all formyl groups were
consumed in the preparation of porphyrin polymer 14
as depicted in Scheme 8. The IR spectrum showed no
absorption band at n 1709 cm-1 due to a C=O function.
+
NH
N
N
_
+
HN
The UV-vis spectrum showed an absorption band at lmax
=
420 nm. The electronic absorption data was collected in
Table 1. This data is well consistent with the molecular
structure of the synthesized porphyrins.
Fig. 1. The anisotropic effect of the porphyrin ring
In fact, one may note some slight spectral shifts by
comparing the corresponding porphyrins which contain a
heterocyclic moiety with porphyrins 4a–4m, 7, 9, 12 and
14,especiallyforboth4a,4bspecies.The4ashowedaband
centered at lmax = 423 (Soret band) after 1 h and Q-bands
absorptions, respectively at 519, 556, 593 and 649 nm
which have a strong Einstein shift compared with 4b.
The UV-vis spectrum consists of a Soret band at 419 nm
and Q-bands at 514, 548, 589 and 644 nm.
An interesting feature of the pyrrole is the possibility
for the synthesis of 2,3,5-triformylpyrrole (13) by
Vilsmeier–Haack reaction which was confirmed by
analytical tools such as the IR spectrum that revealed
absorption bands at n 3316 and 1709 cm-1 due to NH and
CHO groups. Mass spectroscopy showed a molecular
ion peak m/z = 150 ([M + 1]+, 95%). When compound
Ph
O
N
N
O
p-toluenesulfonyl chloride
OHC
H3C
N
H
N
DMF, N2 gas
N
O
Ph
SeO2
Dioxane
N
N
N
O
O
N
N
N
H
N
N
Ph
Ph
N
O
Ph
N
H
5
6
N
N
Ph
7
Scheme 5. Formyl pyrazolone 6 in porphyrin synthesis 7
CH3
N
CH3
Ph
N
CH3
O
CH3
H3C
N
C
H
CHO
N
N
OHC
CH3
CH
O
N
6
O
N
EtOH, TEA
N
NH
N
N
N
Ph
∆, 4 h
p-toluenesulfonic acid
N
N
DMF, N2 gas
Ph
N
Ph
HN
H3C
CH3
O
8
N
H
H
C
N
CH3
N
CH3
O
N
Ph
H3C
N
CH3
9
Scheme 6. Novel porphyrin structure 9
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 4–16

SYNTHESIS, ANTIVIRAL, CYTOTOXICITY AND ANTITUMOR EVALUATIONS OF A4 TYPE OF PORPHYRIN DERIVATIVES
5
H3C
Ph
N
O
N
N
CH3
NH
Ph
CH3
N
H3C
CHO
O
H3C
O
N
N
CH3
N
H
POCl3
DMF
HN
N
N
H3C
H3C
O
N
N
p-toluenesulfonic acid
DMF, N2 gas
O
Ph
Ph
O
N
N
10
11
Ph
Ph
CH3
N
N
H3C
CH3
H3C
12
Scheme 7. Antipyrin used as key intermediate for the synthesis of porphyrin 12
Biological screening
<0.1 m.M/L). However, the rest porphyrin derivatives
were found to possess the lowest cytotoxic effect (IC50
>ꢀ1.5 m.M/L) as outlined in Table 2.
Antiviral activity. Viruses with high infection rates and
rapid propagationcan cause worldwide human and animal
disease pandemics. With the emergence of previously
unknown viruses and new virus variants in recent years,
viral infection remains a major cause of human health
problems. Moreover, the existing antiviral agents mainly
target the key viral enzymes that are involved in the
process of replication. Combination therapy by drugs
with different modes of action and resistance profiles
could be beneficial for a number of viral infections. There
is a crucial need for developing new agents with novel
antiviral mechanisms and broad antiviral activities. To
this end, 17 new porphyrin compounds 4a, 4b, 4c, 4d, 4e,
4f, 4j, 4h, 4i, 4j, 4k, 4l, 4m, 7, 9, 12 and 14 were screened
and evaluated for their in vitro activity against Herpes
Simplex Virus-1 (HSV-1) and Human Immunodeficiency
Virus-1 (HIV-1). Regarding the HSV-1 which was
grown on Vero African green monkey kidney cells, the
antiviral antimitotic antibiotic Aphidicolin was used as
a positive control [42]. Antiviral activity is defined as
relatively confluent unaltered monolayers of stained
Vero cells treated with HSV-1. The cytotoxicity of the
tested porphyrin derivatives was performed using Vero
cell culture [43]. Cytotoxicity was estimated as the
concentration that caused approximately 50% inhibition
of cell proliferation or cell viability. An improved plaque
reduction assay for antiviral activity was used to test the
targeted compounds. Among the 17 tested compounds,
compound 4b revealed a marginal activity as it reduced
the number of the plaques by 45% at a minimum antiviral
concentration (MAC) of 0.03 m.M/L with cytotoxicity
(IC50 = 0.03 µ.M/L). On the other hand, compounds 4h,
4c, 4e, 4i and 4j showed a moderate activity against
HSV-1. Also, the rest of compounds exhibited from
low to no inhibitory effect against HSV-1. The obtained
results showed that the synthesized compounds showed
various levels of cytotoxicity. The highest cytotoxicity
was observed in compounds 4b, 4h, 4c, 4e, 4i and 4j (IC50
HIV-1 is a causative agent for the transmission
and development of the acquired immunodeficiency
syndrome (AIDS). Being the leading cause of death in
Africa and the fourth world wide [44], AIDS remains
one of the most urgent world health problems. Therefore,
this matter should be taken into account. Subsequently,
the procedure used to evaluate the anti-HIV-1 potency
is designed to detect agents acting at any stage of the
virus reproductive cycle [45]. The assay involves the
killing of T4 lymphocytes by HIV-1. Compounds that
interfere with viral activities will protect cells from
cytolysis. The median effective concentration (EC50) of
the tested compounds using infected cells was compared
with their cytotoxic effect (IC50) on uninfected cultures.
Infected and uninfected cultures were incubated without
test compounds to serve as controls. Zidovudine or
Azidothymidine (AZT) treated cultures were also used as
positive controls. The in vitro assessment against HIV-1
revealed that some of the tested compounds displayed a
high inhibition activity while other compounds displayed
a moderate or little activity according to the obtained
results outlined in Table 3.
Therefore, compound 4b has the most potent cytotoxic
activity against HIV-1, whereas, compounds 4h, 4g, 4c,
4e, 4j and 4i have a moderate activity. Finally, the rest of
compounds exhibited the lowest activity.
Antitumor activity. Cancer continues to present
the largest cause of mortality in the world and claims
over six million lives each year [46]. Prevention is
the sensible maneuver towards the ultimate goal of
cancer control [47]. Several methods exist for the
treatment of cancer in modern medicine. These include
chemotherapy, radiotherapy and surgery. Chemotherapy
is now considered as the most effective method of cancer
treatment. Intervention with chemopreventive agents at
the early stage in carcinogenesis is theoretically more
rational than attempting to eradicate fully developed
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 5–16

6
A. A. FADDA AND R. E. EL-MEKAWY AND A. I. EL-SHAFEI
CHO
CHO
DMF
OHC
POCl3
N
N
H
13
H
DMF
p-toluenesulfonic acid,
N2 gas, 150 °C
N
H
N
H
N
HN
N
H
N
NH
N
NH
N
H
N
H
HN
N
N
N
HN
H
NH
N
N
HN
NH
HN
HN
N
NH
N
N
N
N
H
HN
NH
NH
N
NH
N
H
HN
N
NH
N
HN
N
HN
N
N
H
NH
N
N
HN
HN
N
N
HN
H
NH
HN
HN
N
NH
HN
N
HN
H
H
N
NH
N
N
N
N
HN
N
H
HN
N
N
N
H
H
NH
NH
N
N
N
H
N
NH
H
N
HN
H
N
NH
H
N
N
N
N
HN
H
N
N
N
H
NH
HN
N
HN
N
HN
N
H
HN
NH
N
HN
NH
N
NH
N
H
N
N
N
HN
HN
N
HN
HN
NH
HN
14
Scheme 8. High functionalized porphyrin polymer 14
tumor with chemotherapeutic drugs. However, most
cancer chemotherapeutic agents severely affect the most
normal cells [48]. So, it is very important to find some
new anticancer chemical entities which have less toxicity
to host cell [49, 50]. The use of heterocyclic compounds
played an important role in the control of cancer and
its eradication program. Heterocyclic compounds are
commonly used as scaffolds on which pharmacophores
are arranged to provide potent and selective drugs. This
is especially true for five member ring heterocyclic
compounds [51], which serve as the core components
of a large number of substances that possess a wide
interesting range of the biological activity. Taking all of
the above mentioned evidence into account, the aim of
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 6–16

SYNTHESIS, ANTIVIRAL, CYTOTOXICITY AND ANTITUMOR EVALUATIONS OF A4 TYPE OF PORPHYRIN DERIVATIVES
7
Table 1. UV-vis spectra of porphyrin derivatives 4a–4m, 7, 9, 12 and 14
Compound
lmax
After 1 min (Q-bands) After 30 min (Q-bands) After 60 min (soret band)
4a
4b
4c
4d
4e
4f
649, 593, 556
644, 589, 548
526, 521
640, 556, 524
540
519
514
511
513
500
502
499
506
495
510
501
512
500
495
506
496
512
423
419
423
425
422
420
425
422
425
423
422
426
425
423
424
425
420
525, 512
536
4g
4h
4i
620, 587, 542
525
4j
630, 590, 540
554, 530
543
4k
4l
4m
7
589, 530
562
9
546, 530
632, 582
590
12
14
Table 2. The cytotoxicity, anti-HSV-1 activities of compounds 4a–4m, 7, 9, 12 and 14 and the antiviral antibiotic aphidicolin
Entry
Compound
Reduction in number in plaques, %
Minimum Antiviral Conc. (MAC), mM/L Cytotoxicity (IC50)a
1
2
Aphidicolin
100
B
0.02
C
0.58
0.32
4a
4b
4c
4d
4e
4f
3
45
29
B
0.03
0.08
C
0.03
4
0.09
5
0.15
6
28.6
30
B
0.10
0.09
C
0.08
7
0.07
8
4g
4h
4i
0.24
9
32
26
26.2
25
12
B
0.06
0.15
0.12
0.18
0.20
C
0.06
10
11
12
13
14
15
16
17
18
0.098
0.094
0.10
4j
4k
4l
0.19
4m
7
>1.74
0.128
0.125
0.199
0.15
11
B
0.23
0.31
0.24
C
9
12
14
9
B
a IC50: the concentration of drug that caused 50% loss of the monolayer present around the plaques. b B: 0% reduction in number of
viral plaques. c C: inactive compound.
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 7–16

8
A. A. FADDA AND R. E. EL-MEKAWY AND A. I. EL-SHAFEI
Table 3. The cytotoxicity, anti-HIV-1 activities of compounds 4a–4m, 7, 9, 12 and 14 and the antiviral drug
Zidovudine (AZT)
Entry Compound
Cytotoxicity (IC50), mM/La
Effective concentration (EC50), mM/Lb SI50 (IC50/EC50)c
1
2
AZT
4a
4b
4c
4d
4e
4f
35.60
C
0.70
>100
0.82
50.86
C
3
>100
>75
55.21
>75
80
>ꢀ100
>ꢀ0.75
>ꢀ0.55
>ꢀ0.75
>ꢀ0.80
>ꢀ0.35
>ꢀ0.85
>ꢀ0.70
>ꢀ0.70
>ꢀ0.69
>ꢀ0.255
C
4
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
C
5
6
7
8
4g
4h
4i
35.62
>85
>70
>70
>ꢀ69
25.5
C
9
10
11
12
13
14
15
16
17
18
4j
4k
4l
4m
7
30.25
22.5
11.00
C
>100
>100
>100
>100
>ꢀ0.30
>ꢀ0.22
>ꢀ0.11
C
9
12
14
a IC50: 50% inhibitory concentration (the molar concentration of drug that caused 50% inhibition of cell growth).
b50% effective concentration (the molar concentration of drug that caused 50% protection against HIV-1 cytopathic
effect); C: inactive compound. c SI: selectivity index: ratio IC50/EC50.
this research was to synthesize novel drugs for anticancer
evaluation as a trial to obtain new antitumor agents of a
higher activity and lower side effects. In the present work,
the selected compounds related to porphyrin derivatives
were evaluated and screened in-vitro as inhibitors of the
growth of Vero (an African green monkey kidney cell
line), WI-38 (lung fibroblast cell line), HepG2 (hepatoma
cells or human liver hepatocellular carcinoma cell line)
and MCF-7 (human breast adenocarcinoma cell line) in
comparison to the known anticancer drug: 5-fluorouracil
(5-Fu) and as a trial to get more effective and less toxic
agents. The results were expressed in the form of the
concentration of compounds that caused 50% inhibition
of cells growth.
The in vitro evaluation revealed that some of the tested
compounds revealed a high inhibition activity while
other compounds displayed a moderate or little activity
according to the obtained results outlined in Table 4.
Therefore, compounds 4b and 4h have the most potent
cytotoxic activity against HepG2 cell lines. Whereas,
compounds 4f, 4c, 4e, 4i and 4j have a moderate activity
against HepG2 cell lines. Finally, the rest of compounds
exhibited the lowest activity against HepG2 cell lines.
Additionally, compound 4b showed the highest
cytotoxic activity against WI-38 cell line while,
compounds 4f, 4c, 4e and 4j revealed a moderate
cytotoxic activity against WI-38 cell lines. On the other
hand, compounds 4k and 4l exhibited a lower activity
against WI-38 cell lines. Furthermore, compound 4b
displayed a broad spectrum of activity against MCF-7
cell lines. However, compounds 4f, 4c, 4c, 4e and 4j
revealed a moderate cytotoxic activity against MCF-7
cell lines. The rest of compounds exhibited a lower
cytotoxic activity against MCF-7 cell lines.
Structure activity relationship. From the antiviral
and antitumor activity results obtained for the selected
porphyrin derivatives, the activity of the tested
compounds could be correlated with structure variation
and modification. Therefore, it was noticed that
compound 4b has a more potent activity. This may be
attributed to the presence of five pyrrolyl rings besides a
pyrazolyl ring as a number of heterocyclic ring increase
especially a five membered ring which contains one
heteroatom and possess a high potency and activity
increase. It seems that compounds 4h, 4f, 4c exhibited a
moderate activity owing to the large size of heterocyclic
ring. Also fused heterocyclic ring decreased the activity.
On the other hand, compounds 4e, 4j and 4i revealed a
moderate activity due to the introducing of OH group
in different positions of phenyl group according to the
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 8–16

SYNTHESIS, ANTIVIRAL, CYTOTOXICITY AND ANTITUMOR EVALUATIONS OF A4 TYPE OF PORPHYRIN DERIVATIVES
9
Table 4. In vitro antitumor activities of tested compounds on different cell lines
Compound
IC50, mg/mL
HepG2
WI-38
VERO
MCF-7
4a
4b
4c
4d
4e
4f
89.20ꢀ ꢀ0.13
12.40ꢀ ꢀ0.03
29.50ꢀ ꢀ0.09
33.10ꢀ ꢀ0.06
33.02ꢀ ꢀ0.01
26.00ꢀ ꢀ0.11
89.20ꢀ ꢀ0.26
23.20ꢀ ꢀ0.03
44.10ꢀ ꢀ0.09
42.02ꢀ ꢀ0.06
88.20ꢀ ꢀ0.22
85.20ꢀ ꢀ0.09
102.00ꢀ ꢀ0.40
79.60ꢀ ꢀ0.07
79.30ꢀ ꢀ0.16
71.10ꢀ ꢀ0.15
92.00ꢀ ꢀ0.05
8.60ꢀ ꢀ0.03
79.60 0.07
20.10ꢀ ꢀ0.02
27.60ꢀ ꢀ0.19
39.80ꢀ ꢀ0.16
55.30ꢀ ꢀ0.21
40.30ꢀ ꢀ0.13
71.10ꢀ ꢀ0.15
33.70ꢀ ꢀ0.31
41.00ꢀ ꢀ0.07
46.18ꢀ ꢀ0.02
74.02ꢀ ꢀ0.06
75.32ꢀ ꢀ0.21
120.00ꢀ ꢀ0.07
65.41ꢀ ꢀ0.12
64.00ꢀ ꢀ0.02
75.00ꢀ ꢀ0.023
99.32ꢀ ꢀ0.04
3.20 ꢀ0.01
100ꢀ ꢀ0.05
9.32ꢀ ꢀ0.04
120ꢀ ꢀ0.19
12.50ꢀ ꢀ0.03
29.90ꢀ ꢀ0.14
45.60ꢀ ꢀ0.01
65.60ꢀ ꢀ0.23
45.90ꢀ ꢀ0.18
88.2ꢀ ꢀ0.22
26.1ꢀ ꢀ0.06
42.65ꢀ ꢀ0.01
42.12ꢀ ꢀ0.02
85.50ꢀ ꢀ0.04
71.60ꢀ ꢀ0.05
200.00ꢀ ꢀ0.3
88.20ꢀ ꢀ0.22
73.10ꢀ ꢀ0.11
93.85ꢀ ꢀ0.14
94.32ꢀ ꢀ0.03
2.30ꢀ ꢀ0.02
36.50ꢀ ꢀ0.33
42.60ꢀ ꢀ0.16
41.90ꢀ ꢀ0.08
38.10ꢀ ꢀ0.19
85.20ꢀ ꢀ0.07
30.3ꢀ ꢀ0.19
4g
4h
4i
49.25ꢀ ꢀ0.05
43.12ꢀ ꢀ0.01
90.01ꢀ ꢀ0.03
86.05ꢀ ꢀ0.02
100.85ꢀ ꢀ0.23
74.92ꢀ ꢀ0.20
79.12ꢀ ꢀ0.06
85.03ꢀ ꢀ0.31
75.24ꢀ ꢀ0.03
6.50ꢀ ꢀ0.04
4j
4k
4l
4m
7
9
12
14
5-Fu
a IC50 (mg/mL): 1–10 (very strong), 11–25 (strong), 26–50 (moderate), 51–100 (weak), 100–200
(very weak), 200 (noncytotoxicity).
following sequence 4e (p-OH) >ꢀ4j (m-OH) >ꢀ4i (o-OH).
recorded(KBrdisk)onaMattson5000FTIRspectrometer
at Mansoura University, Egypt. The 1H NMR spectra were
determined on a Bruker WPSY 200 M.Hz spectrometer
with tetramethylsilane and the chemical shifts are in d
ppm using (DMSO-d6) as a solvent. The mass spectra
were recorded at 70 eV with a Varian MAT 311 at the
Microanalytical Center, Cairo University. Elemental
analyses (C, H and N) were carried out at the Faculty of
Science, Cairo University. The results were found to be
in a good agreement ( 0.03) with the calculated values.
This may be attributed to a steric hindrance around
linkage between aryl substituent in meso-position and
porphyrin skeleton. It is remarkable that this variation
of activity spectrum between these derivatives indicates
the importance of one nitrogen containing a heterocyclic
ring, especially a five membered ring, as size of ring
increases, the activity decreases. Aromaticity and
steric hindrance of aryl derivatives in meso-position
of porphrin skeleton reduces conformational freedom
of the skeleton and consequently it decreases activity
and increases twist angle around linkage between aryl
substituent in meso-position and porphyrin skeleton.
Moreover, electronegativity of introducing heteroatom in
derivatives increases and stability decreased. The activity
has the following order 4b >ꢀ4h >ꢀ4f >ꢀ4c >ꢀ4e >ꢀ4j >ꢀ4i
>ꢀ4k >ꢀ4l >ꢀ7 >ꢀ12 >ꢀ9 >ꢀ4a >ꢀ4d >ꢀ4g >ꢀ14 >ꢀ4m.
Synthesis of arylhydrazone derivatives 2a–2m
General procedure. A mixture of acetyl derivatives
1a–1m (0.01 mol) and phenylhydrazine (1.08 g, 0.01
mol) was fused in silicon oil bath at 150ꢀ°C for about
5–10 min in the presence of a few drops of concentrated
HCl. The reaction mixture was washed with dil. ethanol,
filtered off, dried well, then recrystallized from dil.
ethanol.
EXPERIMENTAL
1-Phenyl-2-(1-phenylethylidene)hydrazine (2a).
Beige crystal, yield 60%, mp 170ꢀ°C. Anal. data for
C14H14N2 (210). Calcd. C; 79.97 H; 6.71 N; 13.32%.
Found C; 79.99 H; 6.72 N; 13.30%. IR (KBr): n,
General
All melting points are uncorrected and determined
on Gallenkamp electric apparatus. The IR spectra were
1
cm-1 3440 (NH), 1615 (C=N), 1608 (C=C). H NMR
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 9–16

10
A. A. FADDA AND R. E. EL-MEKAWY AND A. I. EL-SHAFEI
(DMSO-d6): d ppm 2.1 (s, 3H, CH3), 6.96–7.90 (m, 10H,
Ar-H), 10.94 (s, 1H, NH). MS: m/z 210 ([M]+, 25%), 133
(81%), 70 (100%), 156 (75%).
4-(1-(2-Phenylhydrazono)ethyl)pyridine (2h).
Orange powder, yield 65%, mp 214–216ꢀ°C. Anal.
data for C13H13N3 (211). Calcd. C; 73.91 H; 6.20 N;
19.89%. Found C; 73.99 H; 6.25 N; 19.89%. IR (KBr):
2-(1-(2-Phenylhydrazono)ethyl)-1H-pyrrole (2b).
Beige cotton crystal, yield 82%, mp 160ꢀ°C. Anal. data
for C12H13N3 (199). Calcd. C; 72.33 H; 6.58 N; 21.09%.
Found C; 72.34 H; 6.59 N; 21.09%. IR (KBr): n, cm-1
3343, 3399 (2 NH), 1625 (C=N), 1600 (C=C). 1H NMR
(DMSO-d6): d ppm 2.1 (s, 3H, CH3), 6.03 (d, 1H, pyrrolic
CH), 6.3 (d, 1H, pyrrolic CH), 6.69 (d.d, 1H, pyrrolic
CH), 7.10–7.40 (m, 5H, Ar-H), 10.64 (s, 1H, NH), 10.94
(s, 1H, NH). MS: m/z 199 ([M]+, 100%), 184 (18%), 118
(32%), 92 (75%), 80 (75.5%), 53 (45%).
3-(1-(2-Phenylhydrazono)ethyl)-1H-indole (2c).
Yellow cotton crystal, yield 86%, mp 148ꢀ°C. Anal. data
for C16H15N3 (249). Calcd. C; 77.08 H; 6.06 N; 16.85%.
Found C; 77.10 H; 6.10 N; 16.85%. IR (KBr): n, cm-1
3442, 3413 (2 NH), 1625 (C=N), 1600 (C=C).1H NMR
(DMSO-d6): d ppm 2.00 (s, 3H, CH3), 7.32 (s, 1H, CH),
6.89–8.20 (m, 9H, Ar-H), 10.64 (s, 1H, NH), 10.94 (s,
1H, NH). MS: m/z 249 ([M]+, 37%), 172 (65%), 144
(10%), 117 (35%), 90 (100%).
1-Phenyl-2-(1-p-tolylethylidene)hydrazine (2d).
Buff powder, yield 86%, mp 214ꢀ°C. Anal. data for
C15H16N2 (224). Calcd. C; 80.32 H; 7.19 N; 12.49%.
Found C; 80.30 H; 7.10 N; 12.50%. IR (KBr): n, cm-1
3455, 3439 (2 NH), 296 (CH3), 1620 (C=N), 1587 (C=C).
1H NMR (DMSO-d6): d ppm 2.1 (s, 3H, CH3), 2.3 (s,
1H,CH3), 6.91–7.56 (m, 7H, Ar-H), 7.62 (d, 2H, Ar-H),
11.01 (s, 1H, NH). MS: m/z 224 ([M]+, 25%), 208 (52%),
130 (17%), 103 (100%), 74 (52%), 49 (25%).
1
n, cm-1 3331 (NH), 1623 (C=N), 1590 (C=C). H NMR
(DMSO-d6): d ppm 1.95 (s, 3H, CH3), 7.11–7.65 (m, 9H,
Ar-H), 10.90 (s, 1H, NH); MS: m/z 211 ([M]+, 62%), 196
(54%), 143 (64%), 118 (100%), 92 (77%), 65 (74%).
MS: m/z 211 ([M]+, 62%), 196 (54%), 143 (64%), 118
(100%), 92 (77%), 65 (74%).
2-(1-(2-Phenylhydrazono)ethyl)phenol (2i). Pale
yellow cotton crystal, yield 88%, mp 233–234ꢀ°C. Anal.
data for C14H14N2O (226). Calcd. C; 74.31 H; 6.24 N;
12.38%. Found C; 74.30 H; 6.25 N; 12.37%. IR (KBr):
n, cm-1 3450 (OH), 3431 (NH), 1624 (C=N), 1587
1
(C=C). H NMR (DMSO-d6): d ppm 2.11 (s, 3H, CH3),
7.09–7.45 (m, 9H, Ar-H), 10.98 (s, 1H, NH), 11.00 (s,
1H, OH). MS: m/z 228 ([M + 2]+, 84%), 211 (36%), 132
(33%), 105 (100%), 63 (45.5%), 51 (55%).
3-(1-(2-Phenylhydrazono)ethyl)phenol (2j). Silver
cotton crystal, yield 82%, mp 230–232ꢀ°C. Anal. data for
C14H14N2O (226). Calcd. C; 74.31 H; 6.24 N; 12.38%.
Found C; 74.30 H; 6.25 N; 12.37%. IR (KBr): n, cm-1
1
3455 (OH), 3433 (NH), 1618 (C=N), 1597 (C=C). H
NMR (DMSO-d6): d ppm 1.99 (s, 3H, CH3), 7.19–7.65
(m, 9H, Ar-H), 10.65 (s, 1H, NH), 11.30 (s, 1H, OH).
MS: m/z 228 ([M + 2]+, 24%), 209 (41%), 130 (13%),
104 (100%), 63 (42%), 50 (15%).
3-(1-(2-Phenylhydrazono)ethyl)aniline (2k). Buff
cotton crystal, yield 80%, mp 220–222ꢀ°C. Anal. data
for C14H15N3 (225). Calcd. C; 74.64 H; 6.71 N; 18.65%.
Found C; 74.60 H; 6.75 N; 18.67%. IR (KBr): n, cm-1
4-(1-(2-Phenylhydrazono)ethyl)phenol (2e). Buff
powder, yield 65%, mp 220ꢀ°C. Anal. data for C14H14N2O
(226). Calcd. C; 74.31 H; 6.24 N; 12.38%. Found C; 74.30
H; 6.25 N; 12.37%. IR (KBr): n, cm-1 3451 (OH), 3431
1
3450 (NH), 3425 (NH2), 1625 (C=N), 1597 (C=C). H
NMR (DMSO-d6): d ppm 1.98 (s, 3H, CH3), 7.09–7.65
(m, 9H, Ar-H), 6.20 (s, 2H, NH2), 10.65 (s, 1H, NH). MS:
m/z 225 ([M]+, 27%), 209 (19%), 132 (62%), 104 (18%),
92 (100%), 76 (32%).
1-(4-(1-Phenylhydrazono)ethyl)phenyl)ethanone
(2l). Pale yellow crystal, yield 72%, mp 228–230ꢀ°C.Anal.
data for C16H16N2O (252). Calcd. C; 76.16 H; 6.39 N;
11.10%. Found C; 76.20 H; 6.40 N; 11.19%. IR (KBr): n,
cm-1 3433 (NH), 1725 (C=O), 1615 (C=N), 1599 (C=C).
1H NMR (DMSO-d6): d ppm 2.1 (s, 3H, CH3), 3.23 (s,
3H, CH3), 7.19–7.71 (m, 9H, Ar-H), 10.78 (s, 1H, NH).
MS: m/z 252 ([M]+, 45%), 237 (86%), 160 (100%), 145
(75%), 104 (75.5%), 64 (55%).
1-(-Cyclohexenylethylidene)-2-phenylhydrazine
(2m). Orange crystal, yield 62%, mp 171–174ꢀ°C. Anal.
data for C14H15N3 (214). Calcd. C; 78.46 H; 8.47 N;
13.07%. Found C; 78.47 H; 8.50 N; 13.10%. IR (KBr):
n, cm-1 3452 (NH), 1624 (C=N), 1597 (C=C). 1H NMR
(DMSO-d6): d ppm 2.1 (s, 3H, CH3), 1.6 (m, 4H, 2
CH2), 2.0 (m, 4H, 2 CH2), 5.3 (t, 1H, CH), 7.19–7.35
(m, 5H, Ar-H), 10.89 (s, 1H, NH). MS: m/z 215 ([M +
1]+, 37%), 199 (9%), 122 (53%), 94 (90%), 82 (100%),
58 (42%).
1
(NH), 1622 (C=N), 1587 (C=C). H NMR (DMSO-d6):
d ppm 2.1 (s, 3H, CH3), 6.93–7.45 (m, 7H, Ar-H), 7.72
(d, 2H, Ar-H), 11.21 (s, 1H, NH), 11.34 (s, 1H, OH).
MS: m/z 226 ([M]+, 73%), 210 (86%), 132 (15%), 105
(100%), 64 (45.5%), 50 (55%).
2-(1-(2-Phenylhydrazono)ethyl)pyridine (2f). Buff
powder, yield 65%, mp 216–218ꢀ°C. Anal. data for
C13H13N3 (211). Calcd. C; 73.91 H; 6.20 N; 19.89%.
Found C; 73.99 H; 6.25 N; 19.89%. IR (KBr): n,
1
cm-1 3431 (NH), 1619 (C=N), 1600 (C=C). H NMR
(DMSO-d6): d ppm 2.1 (s, 3H, CH3), 7.09–7.55 (m, 9H,
Ar-H), 11.00 (s, 1H, NH). MS: m/z 211 ([M]+, 52%), 196
(74%), 143 (66%), 118 (100%), 92 (44%), 65 (78%).
1-(1-Biphenyl-4-ylethylidene)-2-phenylhydrazine
(2g). Beige cotton crystal, yield 75%, mp 165–168ꢀ°C.
Anal. data for C20H18N2 (286). Calcd. C; 83.88 H; 6.34 N;
9.78%. Found C; 83.90 H; 6.35 N; 9.78%. IR (KBr): n,
1
cm-1 3343 (NH), 1625 (C=N), 1598 (C=C). H NMR
(DMSO-d6): d ppm 2.1 (s, 3H, CH3), 6.89–7.33 (m, 14H,
Ar-H), 10.89 (s, 1H, NH). MS: m/z 286 ([M]+, 83%), 209
(66%), 133 (74%), 106 (34%), 77 (100%), 53 (51%).
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 10–16

SYNTHESIS, ANTIVIRAL, CYTOTOXICITY AND ANTITUMOR EVALUATIONS OF A4 TYPE OF PORPHYRIN DERIVATIVES
11
Synthesis of 3-aryl-1-phenyl-1H- pyrazole-4-
carbaldehydes 3a–3m
1-Phenyl-3-(pyridin-2-yl)-1H-pyrazole-4-
carbaldehyde (3f). Green crystal, yield 88%, mp
>ꢀ300ꢀ°C. Anal. data for C15H11N3O (249). Calcd. C; 72.28
H; 4.45 N; 16.86%. Found C; 72.30 H; 4.50 N; 16.88%.
IR (KBr): n, cm-1 1676 (C=O), 1630 (C=N), 1615 (C=C).
MS: m/z 249 ([M]+, 42%), 218 (40%), 208 (40%), 185
(54%), 181 (43%), 160 (40%), 146 (51%), 117 (53%), 99
(54%), 85 (75%), 61 (85%), 55 (100%).
3-(Biphenyl-4-yl)-1-phenyl-1H-pyrazole-4-
carbaldehyde (3g). Deep yellow crystal, yield 81%,
mp 168–170ꢀ°C. Anal. data for C24H18N2O (324). Calcd.
C; 78.67 H; 4.95 N; 7.65%. Found C; 78.70 H; 4.99 N;
7.65%. IR (KBr): n, cm-1 1675 (C=O), 1620 (C=N), 1610
(C=C). MS: m/z 325 ([M + 1]+, 1.45%), 295 (8.37%), 247
(100%), 219 (7.87%), 189 (8.13%), 152 (18.33%), 104
(7.71%), 77 (38.19%).
1-Phenyl-3-(pyridin-4-yl)-1H-pyrazole-4-
carbaldehyde (3h). Pale brown crystal, yield 70%, mp
>ꢀ300ꢀ°C. Anal. data for C15H11N3O (249). Calcd. C; 72.28
H; 4.45 N; 16.86%. Found C; 72.30 H; 4.50 N; 16.88%.
IR (KBr): n, cm-1 1680 (C=O), 1632 (C=N), 1601 (C=C).
MS: m/z 250 ([M + 1]+, 18.1%), 248 (100%), 247 (70%),
246 (36.9%), 219 (17.8%), 102 (26.1%), 95 (16.3%), 76
(61.9%).
3-(2-Hydroxyphenyl)-1-phenyl-1H-pyrazole-4-
carbaldehyde (3i). Pale brown crystal, yield 88%, mp
>ꢀ300ꢀ°C. Anal. data for C16H12N2O2 (264). Calcd. C;
72.72 H; 4.58 N; 10.60%. Found C; 72.75 H; 4.60 N;
10.68%. IR (KBr): n, cm-1 3430 (OH), 1678 (C=O),
1622 (C=N), 1600 (C=C). MS: m/z 264 ([M]+, 46%), 236
(100%), 131 (45%), 104 (42%), 77 (66%).
General procedure. At 0ꢀ°C, phosphorous oxychloride
(5.37 g, 0.035 mol) was added dropwise with stirring to
DMF (1.095 g, 0.015 mol) in an ice bath during 0.5 h,
then a solution of arylhydrazone derivatives 2a–2m
(0.005 mol) in DMF (10 mL) was added to theVilsmeier–
Haak reagent and continued being stirred for about 0.5 h,
then the reaction mixture was refluxed on water bath for
1–2 h. The reaction mixture was cooled, poured onto
ice-water, then a solution of potassium carbonate was
added until effervesence ceased and the precipitated solid
material was filtered off, washed with cold water, dried
well and recrystallized from absolute ethanol.
1,3-Diphenyl-1H-pyrazole-4-carbaldehyde (3a).
Beige cotton crystal, yield 75%, mp 147–150ꢀ°C. Anal.
data for C16H12N2O (248). Calcd. C; 77.40 H; 4.87 N;
11.28%. Found C; 77.45 H; 4.88 N; 11.30%. IR (KBr):
n, cm-1 1669 (C=O), 1625 (C=N), 1698 (C=C). MS:
m/z 248 ([M]+, 45%), 247 (100%), 246 (90%), 219
(25%), 218 (75.5%), 143 (10%), 98 (11%), 94 (20%),
76 (50%).
1-Phenyl-3-(1H-pyrrol-2-yl)-1H-pyrazole-4-
carbaldehyde (3b). Black crystal, yield 75%, mp 169–
170ꢀ°C. Anal. data for C14H11N3O (237). Calcd. C; 70.87
H; 4.67 N; 17.71%. Found C; 70.88 H; 4.70 N; 17.70%.
IR (KBr): n, cm-1 3424 (NH), 1670 (C=O), 1625 (C=N),
1694 (C=C). MS: m/z 237 ([M]+, 45%), 208 (44%), 183
(36%), 161 (57%), 132 (100%), 104 (32%), 67 (26%).
3-(1H-Indol-3-yl)-1-phenyl-1H-pyrazole-4-
carbaldehyde (3c). Buff crystal, yield 72%, mp >ꢀ300ꢀ°C.
Anal.dataforC18H13N3O(287).Calcd.C;75.25H;4.56N;
14.63%. Found C; 75.26 H; 4.57 N; 14.63%. IR (KBr): n,
cm-1 3438 (NH), 1650 (C=O), 1625 (C=N), 1684 (C=C).
MS: m/z 287 ([M]+, 78%), 276 (50%), 258 (64%), 252
(48%), 211 (53%), 200 (45%), 188 (79%), 173 (53%),
156 (46%), 139 (62%), 110 (65%), 94 (60%), 78 (78%),
55 (100%).
1-Phenyl-3-p-tolyl-1H-4-carbaldehyde (3d). Bege
crystal, yield 55%, mp 110–112ꢀ°C. Anal. data for
C17H14N2O (262). Calcd. C; 77.84 H; 5.38 N; 10.68%.
Found C; 77.85 H; 5.39 N; 10.68%. IR (KBr): n, cm-1 1670
(C=O), 1635 (C=N), 1690 (C=C). 1H NMR (DMSO-d6):
d ppm 2.38 (s, 3H, CH3), 7.31–7.60 (m, 5H, Ar-H), 7.80
(d, 2H, Ar-H), 8.00 (d, 2H, Ar-H), 9.28 (s, 1H, CH), 9.98
(s, 1H, CHO). MS: m/z 262 ([M]+, 40%), 261 (100%),
260 (65%), 246 (50%), 233 (20%), 129 (10%), 76 (23%).
3-(4-Hydroxyphenyl)-1-phenyl-1H-pyrazole-4-
carbaldehyde (3e). Pale brown crystal, yield 88%, mp
>ꢀ300ꢀ°C. Anal. data for C16H12N2O2 (264). Calcd. C;
72.72 H; 4.58 N; 10.60%. Found C; 72.75 H; 4.60 N;
10.68%. IR (KBr): n, cm-1 3412 (OH), 1687 (C=O), 1622
(C=N), 1600 (C=C). MS: m/z 271 (M+ + 7, 42%), 178
(50%), 165 (36%), 149 (100%), 135 (36%), 111 (51%),
146 (51%), 97 (61%), 83 (55%).
3-(3-Hydroxyphenyl)-1-phenyl-1H-pyrazole-
4-carbaldehyde (3j). Beige crystal, yield 56%, mp
>ꢀ300ꢀ°C. Anal. data for C16H12N2O2 (264). Calcd. C;
72.72 H; 4.58 N; 10.60%. Found C; 72.75 H; 4.60 N;
10.68%. IR (KBr): n, cm-1 3422 (OH), 1678 (C=O), 1632
(C=N), 1610 (C=C). MS: m/z 265 ([M + 1]+, 17.6%), 264
(100%), 236 (32.8%), 208 (27%), 76 (32.6%).
3-(3-Aminophenyl)-1-phenyl-1H-pyrazole-4-
carbaldehyde (3k). Beige crystal, yield 66%, mp
>ꢀ300ꢀ°C. Anal. data for C16H11N2O2 (263). Calcd. C;
72.99 H; 4.98 N; 15.96%. Found C; 73.00 H; 4.90 N;
15.98%. IR (KBr): n, cm-1 3422 (NH2), 1675 (C=O),
1
1610 (C=N), 1600 (C=C). H NMR (DMSO-d6): d ppm
7.44–7.76 (m, 5H, Ar-H), 7.76 (d, 2H, 2 Ar-H), 8.02 (d,
2H, 2 Ar-H), 8.40 (s, 2H, NH2), 9.33 (s, 1H, CH), 10.01
(s, 1H, CHO). MS: m/z 263 ([M]+, 51%), 248 (28%), 170
(27%), 15 (91%), 107 (100%), 77 (32%).
3-(4-Acetylphenyl)-1-phenyl-1H-pyrazole-4-
carbaldehyde (3l). Yellow crystal, yield 60%, mp
>ꢀ300ꢀ°C. Anal. data for C16H11N2O2 (290). Calcd. C;
74.47 H; 4.86 N; 9.65%. Found C; 74.50 H; 4.88 N;
9.70%. IR (KBr): n, cm-1 1702, 1675 (2 C=O), 1623
(C=N), 1601 (C=C). MS: m/z 292 ([M + 2]+, 82%),
291(68%), 170 (88%), 153 (69%), 145 (100%), 105
(67%).
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 11–16

12
A. A. FADDA AND R. E. EL-MEKAWY AND A. I. EL-SHAFEI
3-Cyclohexenyl-1-phenyl-1H-pyrazole-4-
carbaldehyde (3m). Beige crystal, yield 52%, mp
>ꢀ300ꢀ°C;Anal. data for C16H15N2O (251). Calcd. C; 76.16
H; 6.39 N; 11.10%. Found C; 76.20 H; 6.40 N; 11.10%.
IR (KBr): n, cm-1 1755 (C=O), 1626 (C=N), 1597 (C=C).
1H NMR (DMSO-d6): d ppm 1.65 (m, 4H, 2 CH2), 1.96
(m, 4H, 2 CH2), 5.95 (t, 1H, CH), 7.44–7.76 (m, 5H,
Ar-H), 8.05 (s, 1H, CH), 10.01 (s, 1H, CHO). MS: m/z
251 ([M]+, 89%), 208 (31%), 132 (41%), 106 (100%).
NH), 5.30 (d, 2H, 2 pyrrolic CH), 5.99 (d, 2H, 2 pyrrolic
CH), 6.10 (d, 4H, 4 pyrrolic CH), 6.21 (d.d, 4H, 4
pyrrolic CH), 6.40 (d, 2H, 2 pyrrolic CH), 6.60 (d, 2H,
2 pyrrolic CH), 6.69 (d, 4H, 4 pyrrolic CH), 7.53–7.68
(m, 20H, Ar-H), 7.98 (s, 4H, 4 CH), 10.59 (s, 1H, NH),
11.01 (s, 1H, NH).
5,10,15,20-Mesotetrakis[3-(1H-indol-3-yl)-1-
phenyl-1H-pyrazole-4-yl]-21H,23H-porphyrin (4c).
Reddish brown powder, yield 90%, mp 232–234ꢀ°C.
Anal. data for C88H54N16 (1334). Calcd. C; 79.16 H;
4.04 N; 16.79%. Found C; 79.21 H; 4.06 N; 16.81%.
IR (KBr): n, cm-1 3433–3440 (NH), 1630 (C=N), 1561
Synthesis of porphyrin derivatives 4a–4m
1
General procedure. A mixture of the appropriate
aromatic aldehyde (1.44 mmol) and pyrrole (1.44 mmol,
0.0967 g) in DMF (10 mL) was placed into 100 mL
three necked round-bottom flask fitted with a magnetic
stirrer, a condenser equipped with a Dean–Stark trap,
a thermometer and a nitrogen gas bubbler inlet tube.
The reaction mixture was flushed with nitrogen gas
for 5 min and then heated to 100ꢀ°C for 10 min, then
p-toluene sulfonic acid (1.44 mmol, dissolved in 5 mL
DMF) was added to the reaction mixture using a
syringe. The clear, colorless reaction mixture turned
into various shades of red over the next 1–2 min,
was heated to 150ꢀ°C and held at this temperature for
1 h. The reaction mixture was monitored by UV.vis
spectrum. Thus, when heating was continued at
150ꢀ°C, the Soret band of porphyrins at lmax 415–430
nm started to appear with continuous disappearing
one of the Q-band intensity at 504 nm (Table 1).
After 1 h at 150ꢀ°C, the reaction mixture was cooled in an
ice bath for 20 min. The mixture was then poured onto
ice-cold water. The precipitate was collected by filtration
and dried under a vacuum at an ambient temperature and
the residue was purified by column chromatograghy
(silica gel, chloroform/hexane: 1.5/1: eluent).
(C=C). UV-vis: lmax, nm 423. H NMR (DMSO-d6): d
ppm 2.3 (s, 1H, NH), 5.20 (d, 2H, 2 pyrrolic CH), 6.19
(d, 2H, 2 pyrrolic CH), 6.44 (d, 2H, 2 pyrrolic CH), 6.69
(d, 2H, 2 pyrrolic CH), 7.32 (s, 4H, 4 CH), 7.53–7.68 (m,
36H, Ar-H), 10.09 (s, 1H, NH), 11.91 (s, 1H, NH).
5,10,15,20-Mesotetrakis[1-phenyl-3-p-tolyl-1H-
4-yl-21H,23H-porphyrin (4d). Intense reddish brown
crystal, yield 88%, mp 240–242ꢀ°C. Anal. data for
C84H62N12 (1238). Calcd. C; 81.42 H; 5.00 N; 13.57%.
Found C; 81.43 H; 54.01 N; 13.60%. IR (KBr): n, cm-1
3433 (NH), 1633 (C=N), 1567 (C=C). UV-vis: lmax, nm
425. 1H NMR (DMSO-d6): d ppm 2.17 (s, 1H, NH), 2.33
(s, 3H, CH3), 5.17 (d, 2H, 2 pyrrolic CH), 5.85 (d, 2H, 2
pyrrolic CH), 6.20 (d, 2H, 2 pyrrolic CH), 6.60 (d, 2H,
2 pyrrolic CH), 7.27 (s, 4H, 4 CH), 7.09–7.48 (m, 20H,
Ar-H), 7.70 (d, 4H, 4 CH), 7.95 (d, 41H, 4 CH), 10.79
(s, 1H, NH).
5,10,15,20-Mesotetrakis[3-(4-hydroxyphenyl)-1-
phenyl-1H-pyrazole-4-yl]-21H,23H-porphyrin (4e).
Reddish brown powder, yield 81.5%, mp >ꢀ300ꢀ°C. Anal.
data for C80H54N12O4 (1246). Calcd. C; 77.04 H; 4.33 N;
13.48%. Found C; 77.05 H; 4.33 N; 13.48%. IR (KBr): n,
cm-1 3442 (OH), 3433 (NH), 1635 (C=N), 1587 (C=C).
UV-vis: lmax, nm 422. 1H NMR (DMSO-d6): d ppm 2.23
(s, 1H, NH), 5.27 (d, 2H, 2 pyrrolic CH), 5.95 (d, 2H, 2
pyrrolic CH), 6.40 (d, 2H, 2 pyrrolic CH), 6.70 (d, 2H,
2 pyrrolic CH), 7.09–7.48 (m, 20H, Ar-H), 7.73 (d, 8H,
8 CH), 7.95 (d, 8H, 8 CH), 7.97 (s, 4H, 4 CH), 10.77 (s,
1H, NH), 11.34 (s, 1H, OH).
5,10,15,20-Mesotetrakis[1-phenyl-3-(pyridin-
2-yl)-1H-pyrazole-4-yl]-21H,23H-porphyrin (4f).
Brown powder, yield 81.5%, mp >ꢀ300ꢀ°C. Anal. data for
C80H50N16 (1074). Calcd. C; 84.91 H; 4.66 N; 10.43%.
Found C; 85.00 H; 4.63 N; 10.44%. IR (KBr): n, cm-1
3418 (NH), 1631 (C=N), 1590 (C=C). UV-vis: lmax, nm
420. 1H NMR (DMSO-d6): d ppm 2.30 (s, 1H, NH), 5.20
(d, 2H, 2 pyrrolic CH), 6.15 (d, 2H, 2 pyrrolic CH), 6.45
(d, 2H, 2 pyrrolic CH), 6.57 (d, 2H, 2 pyrrolic CH), 6.99
(d, 4H, 4 CH), 7.09–7.48 (m, 28H, Ar-H), 8.43 (d, 1H,
CH), 8.32 (s, 4H, 4 CH), 10.07 (s, 1H, NH).
5,10,15,20-Mesotetrakis[1-phenyl-3-(pyridin-4-yl)-
1H-pyrazole-4-yl]-21H,23H-porphyrin (4g). Blackish
brown powder, yield 85%, mp 224–226ꢀ°C. Anal. data
for C80H50N16 (1074). Calcd. C; 84.91 H; 4.66 N; 10.43%.
Found C; 85.00 H; 4.63 N; 10.44%. IR (KBr): n, cm-1
5,10,15,20-Mesotetrakis[1,3-diphenyl-1H-
pyrazole-4-yl]-21H,23H-porphyrin (4a). Black crystal,
yield 81%, mp 280–282ꢀ°C. Anal. data for C80H54N12
(1182). Calcd. C; 81.21 H; 4.20 N; 14.21%. Found C;
81.20 H; 4.22 N; 14.22%. IR (KBr): n, cm-1 3419 (NH),
1
1632 (C=N), 1591 (C=C). UV-vis: lmax, nm 423 nm. H
NMR (DMSO-d6): d ppm 2.28 (s, 1H, NH), 5.40 (d, 2H,
2 pyrrolic CH), 5.80 (d, 2H, 2 pyrrolic CH), 6.00 (d, 2H,
2 pyrrolic CH), 6.60 (d, 2H, 2 pyrrolic CH), 7.10–7.85
(m, 40H, Ar-H), 7.92 (s, 4H, 4 CH), 10.59 (s, 1H, NH).
13C NMR (DMSO-d6): d ppm 103.066, 106.236, 119.946,
120.587, 122.656, 123.374, 125.007, 126.303, 127.514,
128.976, 130.564, 133.130, 135.004, 136.524, 139.786,
140.723, 150.226, 157.166, 164.176.
5,10,15,20-Mesotetrakis[1-phenyl-3-(1H-pyrrol-
2-yl)-1H-pyrazole-4-yl]-21H,23H-porphyrin (4b).
Brown powder, yield 84%, mp 230–232ꢀ°C. Anal.
data for C72H50N16 (1138). Calcd. C; 75.92 H; 4.39 N;
19.66%. Found C; 75.93 H; 4.40 N; 19.69%. IR (KBr):
n, cm-1 3443 (NH), 1625 (C=N), 1561 (C=C). UV-vis:
1
l
max, nm 419. H NMR (DMSO-d6): d ppm 2.3 (s, 1H,
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 12–16

SYNTHESIS, ANTIVIRAL, CYTOTOXICITY AND ANTITUMOR EVALUATIONS OF A4 TYPE OF PORPHYRIN DERIVATIVES
13
3418 (NH), 1625 (C=N), 1590 (C=C). UV-vis: lmax, nm
420. 1H NMR (DMSO-d6): d ppm 2.31 (s, 1H, NH), 5.21
(d, 2H, 2 pyrrolic CH), 6.19 (d, 2H, 2 pyrrolic CH), 6.45
(d, 2H, 2 pyrrolic CH), 6.77 (d, 2H, 2 pyrrolic CH), 6.89
(d, 1H, CH), 7.02–7.58 (m, 20H, Ar-H).
5,10,15,20-Mesotetrakis[1-phenyl-3-(pyridin-4-
yl)-1H-pyrazole-4-yl]-21H,23H-porphyrin (4h).
Brown powder, yield 85.5%; mp >ꢀ300ꢀ°C. Anal. data for
C104H70N12 (1480). Calcd. C; 84.32 H; 4.72 N; 11.35%.
Found C; 84.33 H; 4.72 N; 11.35%. IR (KBr): n, cm-1
3418 (NH), 1635 (C=N), 1587 (C=C). UV-vis: lmax, nm
424. 1H NMR (CDCl3): d ppm 2.64 (s, 1H, NH), 5.20 (d,
2H, 2 pyrrolic CH), 5.85 (d, 2H, 2 pyrrolic CH), 6.10 (d,
2H, 2 pyrrolic CH), 6.23 (d, 2H, 2 pyrrolic CH), 6.80
(s, 4H, 4 CH), 7.26–7.97 (m, 40H, Ar-H), 8.08 (d, 8H, 8
CH), 8.53 (d, 8H, 8 CH), 10.42 (s, 1H, NH).
5,10,15,20-Mesotetrakis[3-(2-hydroxyphenyl)-1-
phenyl-1H-pyrazole-4-yl]-21H,23H-porphyrin (4i).
Brown powder, yield 89%, mp >ꢀ300ꢀ°C. Anal. data for
C80H54N12 O4 (1246). Calcd. C; 77.04 H; 4.33 N; 13.48%.
Found C; 77.05 H; 4.33 N; 13.48%. IR (KBr): n, cm-1
3440 (OH), 3423 (NH), 1626 (C=N), 1601 (C=C).
UV-vis: lmax, nm 425. 1H NMR (DMSO-d6): d ppm 2.28
(s, 1H, NH), 5.25 (d, 2H, 2 pyrrolic CH), 5.96 (d, 2H, 2
pyrrolic CH), 6.46 (d, 2H, 2 pyrrolic CH), 6.70 (d, 2H,
2 pyrrolic CH), 6.95 (d, 4H, 4 CH), 7.19–7.62 (m, 28H,
Ar-H), 7.73 (d, 1H, 4 CH), 7.97 (s, 4H, 4 CH), 10.72 (s,
1H, NH), 11.34 (s, 4H, 4 OH).
5,10,15,20-Mesotetrakis[3-(3-aminophenyl)-1-
phenyl-1H-pyrazole-4-yl]-21H,23H-porphyrin (4l).
Blackish brown powder, yield 89%, mp 247–250ꢀ°C.
Anal. data for C80H58N16 (1082). Calcd. C; 88.72 H;
5.36 N; 20.70%. Found C; 88.70 H; 5.40 N; 20.74%.
IR (KBr): n, cm-1 3418 (NH), 3385 (NH2), 1635 (C=N),
1580 (C=C). UV-vis: lmax, nm 422. 1H NMR (DMSO-d6):
d ppm 2.26 (s, 1H, NH), 5.25 (d, 2H, 2 pyrrolic CH),
5.71 (s, 1H, NH2), 5.89 (d, 2H, 2 pyrrolic CH), 6.11 (d,
2H, 2 pyrrolic CH), 6.22 (d, 2H, 2 pyrrolic CH), 6.34 (s,
4H, 4 CH), 6.4 (s, 4H, 4 CH), 6.59–6.67 (m, 20H, Ar-H),
6.78 (d.d, 4 H, 4 CH), 7.01 (d, 4H, 4 CH), 7.11 (d, 4H,
4 CH), 10.50 (s, 1H, NH).
5,10,15,20-Mesotetrakis[3-cyclohexenyl-1-phenyl-
1H-pyrazole-4-yl]-21H,23H-porphyrin (4m). Deep
violet crystal, yield 89.5%, mp 250–252ꢀ°C. Anal. data
for C80H70N16 (1254). Calcd. C; 76.55 H; 5.62 N; 17.99%.
Found C; 76.56 H; 5.60 N; 17.99%. IR (KBr): n, cm-1
3418 (NH), 1631 (C=N), 1587 (C=C). UV-vis: lmax, nm
425. 1H NMR (DMSO-d6): d ppm 1.61–2.78 (m, 24H, 12
CH2), 2.00 (t, 24H, 12 CH2), 3.37 (s, 1H, NH), 5.30 (d,
2H, 2 pyrrolic CH), 5.80 (t, 4H, 4 =CH), 6.11 (d, 2H, 2
pyrrolic CH), 6.62 (s, 4H, 4 CH), 7.11 (d, 2H, 2 pyrrolic
CH), 7.19 (d, 2H, 2 pyrrolic CH), 7.30–7.73 (m, 20H,
Ar-H), 10.58 (s, 1H, NH).
Synthesis of 6–14
5,10,15,20-Mesotetrakis[3-(3-hydroxyphenyl)-
1-phenyl-1H-pyrazole-4-yl]-21H,23H-porphyrin
(4j). Deep brown crystal, yield 89%, mp 266–268ꢀ°C.
Anal. data for C80H54N12 O4 (1246). Calcd. C; 77.04 H;
4.33 N; 13.48%. Found C; 77.05 H; 4.33 N; 13.48%.
IR (KBr): n, cm-1 3439 (OH), 3423 (NH), 1626
Synthesis of 5-oxo-1-phenyl-4,5-dihydro-1H-pyra-
zole-3-carbaldehyde (6). A pure sample of 3-methyl-
1-phenyl-1H-pyrazol-5(4H)-one (5) (0.87 g, 0.005 mol)
was refluxed in dioxane (25 mL) containing selenium
dioxide (0.56 g, 0.005 mol) for 4–5 h. The reaction
mixture was filtered while hot to remove selenium metal,
concentrated, cooled and precipitated by adding cold
water. The precipitated product 6 was filtered off, dried,
collected and recrystallized from ethanol. Brown crystal,
yield 72%, mp 153–155ꢀ°C. Anal. data for C10H8N2O2
(188). Calcd. C; 74.16 H; 4.25 N; 14.89%. Found C;
74.17 H; 4.26 N; 14.91%. IR (KBr): n, cm-1 1722 (CHO),
1650 (amidic C=O), 1610 (C=N), 1597 (C=C). 1H NMR
(CDCl3): d ppm 3.7 (s, 2H, CH2), 7.20–8.00 (m, 5H,
Ar-H), 9.75 (s, 1H, CHO). MS: m/z 188 ([M]+, 90%), 159
(42%), 131 (100%), 55 (65%).
1
(C=N), 1605 (C=C). UV-vis: lmax, nm 423. H NMR
(DMSO-d6): d ppm 2.34 (s, 1H, NH), 5.20 (d, 2H, 2
pyrrolic CH), 6.06 (d, 2H, 2 pyrrolic CH), 6.44 (d, 2H,
2 pyrrolic CH), 6.55 (d, 2H, 2 pyrrolic CH), 6.95 (d,
4H, 4 CH), 7.09–7.48 (m, 20H, Ar-H), 7.43 (d, 4H, 4
CH), 7.74 (d.d, 1H, CH), 7.89 (s, 4H, 4 CH), 8.07 (s,
4H, 4 CH), 10.51 (s, 1H, NH), 11.32 (s, 4H, 4 OH). 13C
NMR (DMSO-d6): d ppm 106.236, 111.079, 112.149,
114.719, 115.904, 119.946, 120.587, 126.303, 129.476,
130.564, 131.164, 134.430, 135.786, 139.786, 146.623,
150.226, 159.546.
5,10,15,20-Mesotetrakis[3-(4-acetylphenyl)-1-
phenyl-1H-pyrazole-4-yl]-21H,23H-porphyrin (4k).
Brown powder, yield 90%, mp >ꢀ300ꢀ°C. Anal. data for
C88H62N12O4 (1350). Calcd. C; 78.22 H; 4.59 N; 12.44%.
Found C; 78.25 H; 4.56 N; 12.48%. IR (KBr): n, cm-1
1712 (C=O), 3433 (NH), 1631 (C=N), 1587 (C=C).
UV-vis: lmax, nm 426. 1H NMR (DMSO-d6): d ppm 2.28
(s, 1H, NH), 3.01 (s, 3H, CH3), 5.40 (d, 2H, 2 pyrrolic
CH), 5.80 (d, 2H, 2 pyrrolic CH), 6.02 (d, 2H, 2 pyrrolic
CH), 6.60 (s, 4H, 4 CH), 7.12 (d, 2H, 2 pyrrolic CH),
7.19–7.50 (m, 20H, Ar-H), 7.73 (d, 8H, 8 CH), 7.82 (d,
8H, 8 CH), 10.59 (s, 1H, NH).
Synthesis of 5,10,15,20-mesotetrakis[5-oxo-1-
phenyl-4,5-dihydro-1H-pyrazole-3-yl]-21H,23H-
porphyrin (7). Dark violet crystal, yield 85.5%, mp 211–
212ꢀ°C. Anal. data for C56H38N12O4 (942). Calcd. C; 71.33
H; 4.03 N; 17.83%. Found C; 71.30 H; 4.10 N; 17.84%.
IR (KBr): n, cm-1 3418 (NH), 1675 (C=O), 1615 (C=N),
1
1587 (C=C). UV-vis: lmax, nm 423. H NMR (CDCl3):
d ppm 2.41 (s, 1H, NH), 3.80 (s, 8H, 4 CH2), 5.21 (d, 2H,
2 pyrrolic CH), 6.05 (d, 2H, 2 pyrrolic CH), 6.40 (d, 2H,
2 pyrrolic CH), 6.60 (d, 2H, 2 pyrrolic CH), 7.08–7.94
(m, 20H, Ar-H), 11.41 (s, 1H, NH). 13C NMR d (ppm):
30.297, 31.340, 109.435, 109.999, 113.843, 120.355,
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 13–16

14
A. A. FADDA AND R. E. EL-MEKAWY AND A. I. EL-SHAFEI
121.655, 122.973, 124.473, 125.073, 132.229, 137.629,
140.347, 142.262, 151.007, 155.689, 172.827.
(C=O), 1610 (C=N), 1587 (C=C). UV-vis: lmax, nm 425.
1H NMR (DMSO-d6): d ppm 1.77 (s, 12H, 4 CH3), 3.25
(s, 1H, NH), 3.51 (s, 12H, 4 CH3), 5.29 (d, 2H, 2 pyrrolic
CH), 5.90 (d, 2H, 2 pyrrolic CH), 6.04 (d, 2H, 2 pyrrolic
CH), 6.43 (d, 2H, 2 pyrrolic CH), 7.30–7.50 (m, 20H,
Ar-H), 10.56 (s, 1H, NH)
Synthesis of ((z)-4(4-(dimethylamino)benzylidene)-
5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-3-
carbaldehyde (8). A mixture of compound 6 (0.56 g,
0.003 mol) with p-N,N-dimethylaminobenzaldehyde
(0.45gm, 0.003 mol) was refluxed in 25 mL of absolute
ethanol containing a catalytic amount of triethylamine for
2 h. The reaction mixture was concentrated and cooled.
The precipitated product 10 was collected by filtration,
dried and recrystallized from ethanol.
Beige cotton crystal, yield 69%, mp 196–198ꢀ°C.
Anal. data for C19H17N3O2 (319). Calcd. C; 71.47 H;
5.32 N; 13.16%. Found C; 71.47 H; 5.33 N; 13.17%. 1H
NMR (DMSO-d6): d ppm 3.07 (s, 3H, CH3), 3.12 (s, 3H,
CH3), 7.1 (s, 1H, CH), 7.20–7.45 (m, 9H, Ar-H), 9.85
(s, 1H, CHO); IR (KBr): n, cm-1 1720, 1662 (2 C=O),
1610 (C=N), 1597 (C=C). MS: m/z 319 ([M]+, 35%), 275
(66%), 199 (19%), 145 (75%), 174 (71%), 146 (55%),
105 (65%), 77 (100%).
Synthesis of 5,10,15,20-mesotetrakis[((z)-4(4-(dim-
ethylamino)benzylidene)-5-oxo-1-phenyl-4,5-
dihydro-1H-pyrazole-3-yl]-21H,23H-porphyrin (9).
Dark red crystal, yield 82%, mp 193–195°C. Anal. data
for C92H98N16O4 (1490). Calcd. C; 74.09 H; 6.57 N;
15.03%. Found C; 74.12 H; 6.60 N; 15.06%. IR (KBr): n,
cm-1 3350 (NH), 1680 (C=O), 1610 (C=N), 1590 (C=C).
UV-vis: lmax, nm 424. 1H NMR (CDCl3): d ppm 2.29 (s,
1H, NH), 3.62 (s, 24H, 8 CH3), 5.49 (d, 2H, 2 pyrrolic
CH), 6.05 (d, 2H, 2 pyrrolic CH), 6.41 (d, 2H, 2 pyrrolic
CH), 6.56 (d, 2H, 2 pyrrolic CH), 6.77 (d, 8H, Ar-H),
7.08 (s, 4H, 4 CH), 7.08–7.94 (m, 20H, Ar-H), 8.29 (d,
8H, Ar-H), 11.41 (s, 1H, NH).
Synthesis of 1H-pyrrole-2,3,5-tricarbaldehyde (13).
At 0ꢀ°C, phosphorous oxychloride (5.37 g, 0.035 mol)
was added dropwise with stirring in DMF (1.095 g,
0.015 mol) in an ice bath for about 0.5 h then pyrrole
(0.33 g, 0.005 mol) in DMF was added to Vilsmeier–
Haack reagent and continued being stirred for about 0.5 h,
then the reaction mixture was refluxed on water bath for
1–2 h. The reaction mixture was cooled, then poured onto
ice-water, then a solution of potassium carbonate was
added until effervesence ceased and the precipitated solid
material was filtered off, washed with cold water, dried
well, then recrystallized from absolute ethanol. Beige
crystal, yield 72%, mp >ꢀ300ꢀ°C. Anal. data for C4H5NO3
(150). Calcd. C; 55.63 H; 3.33 N; 9.27 5%. Found C;
55.64 H; 3.34 N; 9.28%. IR (KBr): n, cm-1 3353 (NH),
1709 (C=O), 1612 (C=N), 1554 (C=C). 1H NMR (CDCl3):
d ppm 7.94 (d, 1H, CH), 9.62 (d, 3H, CHO), 11.23 (s, 1H,
NH). MS: m/z 150 (95%), 149 (100%), 135 (65%), 119
(82%), 105 (90%), 97 (98%), 83 (98%), 71 (45%).
Synthesis of porphyrin polymer (14). Porphyrin
polymer derivative 27 was synthesized from the reaction
of compound 13 (1.44 mmol) with an excess amount of
pyrrole by the previous capping method. Brown crystal,
yield 70%, mp >ꢀ300ꢀ°C. IR (KBr): n, cm-1 3409 (NH),
1622 (C=N), 1594 (C=C). UV-vis: lmax, nm 420.
Biological screening
Synthesis of 1,5-dimethyl-3-oxo-2-phenyl-2,3-di-
hydro-1H-pyrazole-4-carbaldehyde (11). At 0ꢀ°C,
phosphorous oxychloride (5.37 g, 0.035 mol) was added
dropwise with stirring in DMF (1.095 g, 0.015 mol) in an
ice bath for about 0.5 h, then a solution of phenazone (10)
(0.94 g, 0.005 mol) in DMF was added to the Vilsmeier–
Haack reagent and continued being stirred for further 0.5
h, then the reaction mixture was refluxed on water bath for
1–2 h. The reaction mixture was cooled, poured into ice-
water, then a solution of potassium carbonate was added
until effervesence ceased and the precipitated product 11
was filtered off, washed with cold water, dried well, then
recrystallized from absolute ethanol. Beige cotton crystal,
yield 69%, mp >ꢀ300ꢀ°C. Anal. data for C12H12N2O2 (216).
Calcd. C; 66.67 H; 5.56 N; 12.96%. Found C; 66.66 H;
5.55 N; 12.99%. IR (KBr): n, cm-1 1710, 1680 (2 C=O),
1610 (C=N), 1597 (C=C). MS: m/z 216 ([M]+, 52%), 188
(98%), 159 (15%), 121 (100%), 97 (18%), 77 (22%).
Synthesis of 5,10,15,20-mesotetrakis[1,5-dimethyl-
3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-y]-
21H,23H-porphyrin (12). Reddish brown crystal, yield
82%, mp 193–195ꢀ°C. Anal. data for C64H54N12O4 (1054).
Calcd. C; 72.86 H; 5.10 N; 15.94%. Found C; 72.88 H;
5.12 N; 15.99%. IR (KBr): n, cm-1 3310 (NH), 1683
In vitro Anti-Herpes Simplex-1 Virus (HSV-1).
Samples were prepared by dissolving in DMSO and
diluting aliquots into a sterile culture medium before
preparing a serial dilution and placed in microtiter
trays. Microtiter trays with confluent monolayer
cultures of Vero cells were inverted. The medium was
shaken out and replaced with serial dilutions of sterile
extracts in a triplicate in 100 mL medium followed
by a tittered virus in 100 mL medium containing 10%
(v/v) of calf serum in each cell. In each tray, the last
row of cells was reserved for controls that were not
treated with compounds or treated with a virus. The
trays were cultured and incubated at 37ꢀ°C in 5% CO2
atmosphere for 6 h. The trays were inverted into a pad
of paper towels. The remaining cells rinsed carefully
with a medium, and fixed with 3.7% (v/v) formaldehyde
in a saline for 20 min. The fine cells were rinsed with
water, and examined visually. Antiviral activity is
identified as relatively-confluent unaltered monolayers
of stained Vero cells treated with HSV-1. Cytotoxicity
was estimated as the concentration that caused
approximately 50% loss of the monolayer present
around the plaques caused by HSV-1 (Table 2).
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 14–16

SYNTHESIS, ANTIVIRAL, CYTOTOXICITY AND ANTITUMOR EVALUATIONS OF A4 TYPE OF PORPHYRIN DERIVATIVES
15
In vitro Anti-Human Immunodeficiency Virus-1
(HIV-1). Compounds were prepared for assay by
dissolving in DMSO then diluted 1:100 in a cell culture
medium before preparing a serial dilution and placed in
microtiter trays. T4 lymphocytes (CEM cell line) were
added and after a brief interval (1 min or more) HIV-1
was added resulting in a 1:200 final dilution of each of
the tested compounds. Cultures were incubated at 37ꢀ°C
in 5% CO2 atmosphere for six days. Tetrazolium salt XTT
was added to all cells and cultures were incubated to allow
formazan color development by virally infected cells.
Individual cells were analyzed spectrophotometrically
to a quantitative formazan production and, in addition,
were viewed microscopically for detection of viable cells.
Results were compared with controls and Zidovudine
(AZT)treatedcellsasapositivecontrolandadetermination
about activity was made as a percentage protection of T4
cells against HIV-1 cytopathic effect (Table 3).
reaction of pyrrole with different aldehydes in good to
excellent yields with hope of discovering a new structure
which leads to serving as potent antiviral and antitumor
agents. Some compounds were screened for their in
vitro biological activities showing good antiviral and
antitumor activities. Compounds 4b and 4h showed
the best antiviral and antitumor activities. The obtained
results may be related to the importance of one nitrogen
containing a heterocyclic ring, especially five membered
ring, aromaticity, steric hindrance of aryl derivatives in
meso-position of porphyrin skeleton and electronegativity
of the heteroatom.
Acknowledgements
The authors would like to express their sincere thanks
to the management of Pharmacology Department, Faculty
of Pharmacy, Mansoura University, for their support to
carry out the antiviral and antitumor activity.
Antitumor activity [52–54]. RPMI-1640 medium
(Sigma Co., St. Louis, USA), Foetal Bovine serum
(GIBCO, UK), and the cell lines from ATCC were used.
The cytotoxic activity of the synthesized compounds
was tested against human heptacellular liver carcinoma
cell line (HepG2), human lung fibroblast cell line (WI-38),
human causcasian breast adenocarcinoma cell line (MCF-
7), and normal adult African green monkey kidney cell
line (VERO). The stock samples of the compounds were
diluted with RPMI-1640 medium to desired concentrations
ranging from 10 to 1000 µg/mL. The final concentration of
DMSO in each sample did not exceed 1% v/v.
REFERENCES
1. Tidwell CP, Bharara P, Rudeseal G, Rudeseal T,
Rudeseal FH, Simmer CA, McMillan D, Lanier K,
Fondren LD, Folmar LL and Belmore K. Molecules
2007; 12: 1389–1398.
2. Wolfbeis OS. Chem. 2006; 78: 3875–3874.
3. Ozoemena K. Sensors 2006; 6: 874–891.
4. Ikeda O, Yoshinaga K and Lei J. Sensors 2005; 5:
161–170.
5. Yu J, Wang X and Zhang B. Langmuir 2004; 20:
1582–1586.
The cells were bath-cultured for 10 d, then seeded in
96 well plates of 10 × 103 cells/well in fresh complete
growth medium in 96-well microtiter plastic plates at
37ꢀ°C for 24 h. Under 5% CO2 using a water jacketed
carbon dioxide incubator (Shedon. TC2323. Carnelius,
OR, USA). The medium was added with 10% (v/v) calf
serum (Hyclone Laboratories, Ogden, UT) and cells were
incubated either alone (negative control) or with different
concentrations of sample to give a final concentrations of
(1000, 500, 200, 50, 20, 10 mg/mL). Cells were suspended
in RPMI-1640 medium, 1% antibiotic-antimycotic
mixture (104 m/mL) potassium penicillin, 104 mg/mL
streptomycin sulfate and 25 mg/mL Amphotericin B)
and 1% L-glutamin in 96-well flat bottom microplates
at 37ꢀ°C under 5% CO2. After 96 h of incubation, the
medium was again aspirated, trays were inverted onto a
pad of paper towels, the remaining cells rinsed carefully
with medium, and fixed with 3.7% (v/v) formaldehyde in
saline for at least 20 min. The fixed cells were rinsed with
water. The % viability of cells was examined visually as
described previously [55–57].
6. (a) Jiang AJ and Ng DKP. Acc. Chem. Res. 2009;
42: 4279–4289. (b) Lu G, ChenY, ZhangY, Bao M,
Bian Y, Li X and Jiang J. J. Am. Chem. Soc. 2008;
130: 11623–11630. (c) Hoang MH, Kim S-J, Kim
Y, Choi DH and Lee SJ. Chem. Eur. J. 2011; 17:
7772–7776.
7. (a) Drain CM, Varotto A and Radivojevic I. Chem.
Rev. 2009; 109: 1630–1658. (b) Vlaming SM,
Augulis R, Stuart MCA, Knoester J and Van Loos-
drecht PHM. J. Phys. Chem. B 2009; 113: 2273–
2283. (c) Wang Z, Lybarger LE, Wang W, Medforth
CJ, Miller JE and Shelnutt JA. Nanotechnology 19:
395604/1-395604/6.
8. Cho HS, Jeong DH, Cho S, Kim D, Matsuzaki Y,
Tanaka K, Tsuda A and Osuka A. J. Am. Chem. Soc.
2002; 124: 14641–1465.
9. Yu J, Wang X and Zhang B. Langmuir 2004; 20:
1582–1586.
10. Villanueva A, Stockert JC, Canete M and Acedo P.
Photochem. Photobiol. Sci. 2010; 9: 259–297.
11. (a) An Z, Odom SA, Kelley RF, Huang C, Zhang
X, Barlow S, Padilha LA, Fu J, Hagan DJ, Van
Stryland EW, Wasielewski MR and Marder SR. J.
Phys. Chem. A 2009; 113: 5585–5593. (b) Cui S,
Liu H, Gan L, Li Y and Zhu D. Adv. Mater. 2008;
CONCLUSION
A series of novel meso-tetraarylporphyrin derivatives
4a–4m, 7, 9, 12 and 14 was obtained from condensation
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 15–16

16
A. A. FADDA AND R. E. EL-MEKAWY AND A. I. EL-SHAFEI
20: 2918–2925. (c) Zhou WD, Li YL and Zhu DB.
Chem. Asian J. 2007; 2: 222–229.
34. Katritzky AR and Lagowski JM. Adv. Heterocyclic
Chem. 1963; 2: 40–44.
12. (a) Bhavana P, Varghese B and Bhyrappa P. Acta
Crystallogr. 2001; C57: 252–253; (b) Bhyrappa
P and Bhavana P. Chem. Phys. Lett. 2001; 349:
399–404.
13. Wise LD, Butler DE, Dewald HA, Lustgarten DM,
Pattison IC, Schweiss DN, Coughenour LL, Downs
DA, Heffner TG and Pugsley TA. J. Med. Chem.
1987; 30: 1807–1812.
35. Westoo G. Acta Chem. Scand. 1952; 6: 1499–1515.
36. KatritzkyAR and Maine FW. Tetrahydron 1964; 20:
299–314.
37. Bondock S, Khalifa W and Fadda AA. Eur. J. of
Med. Chem. 2007; 42: 948–954.
38. Abou-Karam M and Shier WT. J. Nat. Prod. 1990;
53: 340–344.
39. El-Emam AA, Massoud MAM, El-Bendary ER and
El-Sayed MA. Bull. Korean Chem. Soc. 2004; 25:
991–996.
14. Gursoy SA, Demirayak G and Capan K. Eur.
J. Med. Chem. 2000; 35: 359–364.
15. Badawey AM and El-Ashmawey IM. Eur. J. Med.
Chem. 1998; 35: 359–364.
40. Simon S, Ho DD and Karim QA. Lancet. 2006;
368: 489–504.
16. Daidone G, Maggio B, Plescia S, Raffa D, Musiu
C, Milia C, Perra G and Marongiu ME. Eur. J. Med.
Chem. 1998; 33: 375–382.
41. WeinslowOS, KiserOS, FineD, BaderJ, Shoemaker
RH and Boyd MR. J. Natl. Cancer Inst. 1989; 81:
577–586.
17. (a) Hilgard P and Thornes RD. Eur. J. Cancer 1976;
12: 755–762. (b) Taylor EC, Patel H and Kumar H.
Tetrahydron 1992; 48: 8089–8100.
42. Abdullaev FI. Exp. Biol. Med. 2002; 1: 20–25.
43. Geoffrey A and Cindy CK. Pure & Appl. Chem.
1994; 66: 2283–2286.
18. Nauduri D and Reddy GB. Chem. Pharm. Bull.
1998; 46: 1254–1260.
19. Foks H, Pancechowska-Ksepko DA, Kedzia and
Wolska ZZ. Farmaco 2005; 60: 513–520.
20. Dardari Z, Lemrani M, Sebban A and Bahloul A.
Arch. Pharm. Chem. Life Sci. 2006; 33: 291–296.
21. Gilbert AM, Failli A, Shumsky J and Yang Y. J.
Med. Chem. 2006; 49: 6027–6036.
44. Singh J, Kumar BA, Rajapandi R, Ghosh T, Mondal
A, Maiti BC and Maity TK. Pharmacologyonline
2010; 1: 406–416.
45. Dash DK, Nyak SS, Samanta S, Ghosh T, Jha T,
Maiti BC and Maity TK. Nat. Prod. Sci. 2007; 13:
54–60.
46. Fadda AA and El-Mekawy Rasha E. Dyes Pig.
2013; 99: 512–519.
22. (a) Jiang JB, Hesson DP, Dusak BA, Dexter DL,
Kang GJ and Hamel E. J. Med. Chem. 1990; 33:
1721–1728. (b) Anzai K, Furuse M, Yoshida A,
Matsuyama A, Moritake T and Tsuboi K. J. Radiat
Res. 2004; 45: 319–323.
47. Fadda AA and El-Mekawy Rasha E. Pharmacol.
Pharm. 2012; 3: 119–261.
48. Fadda AA, Berghot MA, Amer FA, Badawy DS and
Bayoumy Nesma M. Arch. Pharm. Chem. Life Sci.
2012; 345: 378–385.
23. ParlokJJ.J.Heterocycl.Chem.1998;35:1493–1499.
24. Frinkelstein BL and Strok CJ. J. Pestic Sci. 1997;
50: 324–328.
25. Eicher T and Hauptmann S. The chemistry of Hetero-
cycles: Structure, Reactivity, Synthesis and Applica-
tions, Thieme-Verlag: New York, 1995; pp 184–189.
26. Jolly C and Morimoto RI. J. Natl Cancer Int. 2000;
92: 1564–1572.
27. Bernardino AMR, Gomes AO, Charret KS and
Freitas ACC. Eur J. Med. Chem. 2006; 41: 80–87.
28. Katiyar SB, Srivastava K, Purib SK and Chanhana
PMS. Bioorg. Med. Chem. Lett. 2005;15:4957–4960.
29. Moukha-Chafig O, Taha ML, Lazrek HB and Vasser
JJ. Farmaco 2002; 57: 27–37.
30. Allen SH, Jhns BA, Gudmundsson KS and Freeman
GA. Bioorg. Med. Chem. 2006; 14: 944–954.
31. Gopalsamy A, Yang H, Ellingboe JW, Tsou H,
Zhang N, Honones E, Powell D, Miranda M, Mc
Ginnis JP and Rabindran SK. Bioo Med. Chem.
Lett. 2005; 15: 1591–1597.
49. El-Shafei A, Fadda AA, Khalil AM, Ameen TAE and
Badria FA. Bioorg. Med. Chem. 2009; 17: 5096–5105.
50. Fadda AA, Abdel-Rahman AA-H, El-Sayed WA,
Abdel-Dayem Tayseer A and Badria FA. Chem. of
heterocycl. Comp. 2012; 7: 1045–1054.
51. Fouad T, Nielsen C, Brunn L and Pederson EB. Sc.
J. Az. Med. Fac. (Girls) 1998; 19: 1173–1187.
52. Fadda AA, Adel A-H, Abdel-Rahman, Wael AE-S,
Zaki G and Asem AM. J. Heterocyclic Chem. 2012;
49: 93–101.
53. Kira MA, Abdel-Raeman MO and Gadalla KZ.
Tetrahydron Lett. 1969; 2: 109–110.
54. Fadda AA, Rasha E. El-Mekawy, El-Shafei AI,
Freeman HS, Hinks D and El-Fedawy M. J. Chem.
2013; 2013: 1–11.
55. Fadda AA, El-Mekawy RE, El-Shafei AI and
Freeman HS. Arch. Pharm. Chem. Life Sci. 2013;
346: 53–61.
56. Ayyad SN, Ezmirly ST, Basaif SA, Alarif WM and
Badria AF. Pharmacol. Res. 2011; 3: 160–5.
57. Abdel-Wahab BF, Awad GEA and Badria FA.
European journal of medicinal chemistry 2011; 46:
1505–11.
32. Coco MT, Congiu C, Lilliu V and Onnis V. Arch
Pharm Chem. Life Sci. 2006; 339: 7–11.
33. Knorr L. Ber. 1883; 16: 2597–2599.
Copyright © 2015 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2015; 19: 16–16