Antioxidant evaluation of some semicarbazide, 1,2,4-triazolone and pyrazolone derivatives

Article abstract of DOI:10.2174/157018011797655188

1,2,4-Triazoles, pyrazoles and semicarbazides possessing heterocyclic ring 1-14 were synthesized as compounds with interesting pharmacological profiles. All were investigated in vitro for their antioxidant activity. Some compounds showed significant effect in the above assay. The most promising was a group of pyrazolone. The effect was dependent mainly on the substituent on the amide group. It was found that compounds 8 and 10 showed the highest antioxidant capacity comparable with the widely used reference, antioxidant 6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid (Trolox).

Full text of DOI:10.2174/157018011797655188

1004
Letters in Drug Design & Discovery, 2011, 8, 1004-1008
Antioxidant Evaluation of Some Semicarbazide, 1,2,4-Triazolone and
Pyrazolone Derivatives
Monika Pitucha*,a and Renata Nowakb
aDepartment of Organic Chemistry, Faculty of Pharmacy, Medical University, Chodꢀki 4a, 20-093 Lublin, Poland
bChair and Department of Pharmaceutical Botany, Faculty of Pharmacy, Medical University, Chodꢀki 1, 20-093 Lublin,
Poland
Received February 09, 2011: Revised July 19, 2011: Accepted August 12, 2011
Abstract: 1,2,4-Triazoles, pyrazoles and semicarbazides possessing heterocyclic ring 1-14 were synthesized as
compounds with interesting pharmacological profiles. All were investigated in vitro for their antioxidant activity. Some
compounds showed significant effect in the above assay. The most promising was a group of pyrazolone.
The effect was dependent mainly on the substituent on the amide group. It was found that compounds 8 and 10 showed
the highest antioxidant capacity comparable with the widely used reference, antioxidant 6-hydroxy-2,5,7,8-
tetramethylchroman-2-carboxylic acid (Trolox).
Keywords: Antioxidant activity, Pyrazoles, Semicarbazides, 1,2,4-Triazoles, Trolox.
1. INTRODUCTION
for their antioxidant activity. Antioxidants play a significant
role in several important biological processes such as
immunity, protection against tissue damage, reproduction
and growth or development. It is known that many human
diseases e.g. cancer, atherosclerosis and arthritis have been
correlated with oxidative damage, caused by reactive free
radicals. The literature suggests that supplementation with
antioxidants may be useful in the prevention and treatment
of Parkinson’s and Alzheimer’s disease [20,21]. Therefore,
the search for a new active antioxidant has received much
attention. The results of this search are present in this paper.
In the designing of new drugs, the development of
hybride molecules through the combination of different
pharmacophores in one frame may lead to compounds with
interesting pharmacological profiles. It is well documented
that the five membered heterocycles represent an interesting
class of compounds possessing a wide spectrum of biological
activity [1-5]. Compounds containing a pyrazole moiety are
also found to possess antitumor, anti-inflammatory and
antibacterial activities [6-8]. While a large number of 1,2,4-
triazole derivatives possess antimicrobial, anti-inflammatory
and analgesic, anticancer, anticonvulsant, antituberculosis
activities [9-11]. Many heterocycles have been reported as
antioxidant agents. For example, pyrazole derivatives
showed a good inhibitory activity and belonged to the third
generation of monoamine oxidase inhibitors and bovine
serum amine oxidase inhibitors which have the advantage of
acting through a reversible mode [12]. 1,2,4-Triazole showed
urease inhibition and antioxidant activities [13,14]. In the
literature, it is well known that several pyrroles exhibit
antioxidant properties mainly expressed by their capacity to
inhibit Fe2+- induced microsomal lipid peroxidation [15].
2. RESULTS AND DISCUSSION
The 1-[(1-methylpyrrol-2-yl)acetyl]-4-substituted-semi-
carbazide derivatives 1 and 2 were obtained upon the
reaction of carboxylic acid hydrazide with ethyl and 4-
bromophenyl isocyanate. Cyclization of these compounds in
alkaline medium led to obtain 3-[(1-methylpyrrol-2-
yl)methyl]-4-substituted-1,2,4-triazolin-5-one 3 and 4 [22].
Similarly,
1,6-bis(3-substituted-1,2,4-triazolin-5-on-4-yl)
hexanes 5-7 and 4,4’-bis(3-substituted-1,2,4-triazolin-5-on-
4-yl)diphenylmethanes 12-14 were obtained by the
intramolecular dehydrative cyclization of the respective bis-
semicarbazides [23,24] (Scheme 1). N-substituted-3-amino-
4-phenyl-pyrazolin-5-on-1-carboxamides 8-11 were synthe-
sized during the heterocyclization reaction of 1-cyanoph-
enylacetic acid hydrazide with butyl, 4-methoxyphenyl,
cyclohexyl and 1-naphtyl isocyanate [25] (Scheme 2).
On the other hand, it is known that semicarbazides are
interesting group of compounds which are valuable building
blocks for the synthesis of five-membered heterocycles
[16,17]. Many semicarbazides are reported to display
excellent biological activity [18,19].
It seemed that combination of two pharmacophore groups
in the same molecule can be an interesting challenge for the
development of new pharmacologically active compounds.
Therefore, in this paper some 1,2,4-triazoles, pyrazoles and
semicarbazides with pyrrole ring were selected and screened
All derivatives were tested for their antioxidant activity.
The DPPH radical-scavenging activity of the new
synthesized compounds 1-14 was screened using DPPH-
TLC assay [26]. TLC separation was followed by dipping
the plate in a solution of 1,1-diphenyl-2-picrylhydrazyl
(DPPH) in methanol. Recently, the DPPH radical scavenging
assay has become popular in antioxidant studies because of
its simplicity and high sensitivity. This assay is based on the
theory that a hydrogen donor is an antioxidant. The
*Address correspondence to this author at the Department of Organic
Chemistry, Faculty of Pharmacy, Medical University, Chodꢀki 4a Str., 20-
093 Lublin, Poland; Tel: 48-81-535-73-74;
E-mail: monika.pitucha@umlub.pl
1570-1808/11 $58.00+.00
© 2011 Bentham Science Publishers

Antioxidant Evaluation of Semicarbazides, Triazoles and Pyrazoles
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10 1005
H
O
O
N
b,c
a
R
C
N
R
C
+
O
C
R1NCO
HN NH
HN NH2
C
N
C
NH
R1
R
R1
O
a
3,4
1,2
O
C
O
C
H
H
N
H
H
N
N
N
R
N
C
O
X
C
O
N
R
H
H
b,c
O
H
O
C
N
H
C
N
N
N
N
C
N
X
C
R
R
5-7, 12-14
For 1,3: R= 1-methylpyrrol-2-methyl, R1= C2H5
For 2,4: R= 1-methylpyrrol-2-methyl, R1= 4-BrC6H4
For 5: R= CH3, X= (CH2)6
For 6: R = C6H5, X= (CH2)6
For 7: R= 1-methylpyrrol-2-methyl, X= (CH2)6
For 12: R= CH3, X=(C6H4)2CH2
For 13: R= 1-methylpyrrol-2-methyl, X=(C6H4)2CH2
For 14: R= CH2C6H5, X=(C6H4)2CH2
Reagents and conditions: a) diethyl ether or N,N-dimethylacetamide, room temperature; b) 2% NaOH, reflux; c) 3M HCl.
Scheme 1. Synthesis of semicarbazide and 1,2,4-triazolone derivatives.
H
O
H2N
N
C
NH
NH2
HN
C
R
a
N
N
C
CH
R
C
C
+
O
C
CN
O
O
8-11
For 8: R= C4H9
For 9: R= 4-CH3OC6H4
For 10: R= C6H11
For 11: R= 1-C10H11
Reagents and conditions: a) acetonitrile, room temperature.
Scheme 2. Synthesis of pyrazolone derivatives.
antioxidant effect is proportional to the disappearance of
DPPH (a stable and commercially available organic nitrogen
radical) in test samples. The compounds possessing radical-
scavenging activity were detected in the TLC-DPPH assay as
spectrophotometric tubing test [27,28]. The % of inhibition
of the DPPH radical solution, after the addition of each
sample solution in the same concentration, was estimated.
The results of our preliminary experiments were
incorporated into Fig. (1). Among tested compounds
pyrazolone derivatives were the most promising group. They
were evaluated for their antioxidant activity through
bright yellow bands against
a
purple background.
Compounds 6, 7, 9 and 11-14 were inactive. The active
compounds 1-5, 8 and 10 were selected and evaluated by

1006 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10
Pitucha and Nowak
80
70
60
50
40
30
20
10
0
1
2
3
4
5
8
10
Compound
Fig. (1). The comparison of DPPH radical scavenging activity of compounds 1-5, 8, 10 (selected by TLC-DPPH screening).
Table 1. The Scavenging Effects of Compounds 8 and 10 on DPPH Radical
Compound
MW
Equation
R2
EC50 [ꢀg/ml]
EC50 [ꢀM/ml]
8
10
274
300
y=4.4363x+15.326
y=3.5082x+17.558
y=14792x+ 2.3168
0.9852
0.9961
0.9968
7.8±0.2
9.25±0.3
3.2±0.1
28.5±0.1
30.8±0.2
12.9±0.2
Trolox (T)
250.3
Mean value ± SD, n=3; EC50 8/EC50 T =2.44; EC5010/ EC50T =2.89.
colorimetric scavenging activity assay against DPPH radical
with Trolox as positive controls and their activity was
expressed as EC50 values (antiradical dose required to cause
a 50% inhibition). The highest antioxidant activity in DPPH
assays of pyrazolones 8 and 10 reflects structure-activity
relationship among other compounds. N-butyl-3-amino-4-
The modification of the structure of the parent
compounds offers a promising prospect and highly active
analogs are expected to be found by further work.
3. EXPERIMENTAL
All chemicals were purchased from Merck Co. or Alfa-
Aesar and used without further purification. Melting points
(m.p.) were determined in a Fisher-Johns block and were not
corrected. IR spectra were recorded in KBr disc using a
phenyl-pyrazolin-5-on-1-carboxamide
8
showed
the
promising scavenging activity (EC50 7.9 ꢀg/ml) which was
only about 2.5 times weaker than that of strong antioxidant
Trolox (Table 1). The results of our preliminary experiments
were incorporated into Fig. (1).
1
Specord IR-75 spectrophotometer. H and 13C NMR spectra
were generally recorded at room temperature on a Bruker
AC 200F instrument (300 MHz) in DMSO-d6 with TMS as
internal standard. The mass spectra were obtained with an
AMD-604 mass spectrometer using a 70 eV electron beam.
In summary, the main aim of this study was antioxidant
activity evaluation of some semicarbazide, 1,2,4-triazolone
and pyrazolone derivatives. The conclusions that can be
drawn from the obtained results are following:
•
•
•
•
the preliminary in vitro test showed that some
pyrazolone derivatives were found to be significant
scavengers of free radicals
3.1. General Procedure for Preparation of 1-[(1-methyl-
pyrrol-2-yl)acetyl]-4-substituted Semicarbazide 1, 2
A mixture of 1-methyl-pyrrol-2-ylacetic acid hydrazide
(1.53g) and ethyl or 4-bromophenyl isocyanate in N,N-
dimethylacetamide or diethyl ether was kept at room
temperature for 24h. The precipitate was filtered and
crystallized from ethanol
the higher antioxidant activity of 8 and 10 in series of
pyrazolone reflects structure-activity relationship
among analogous compounds
the maximum activity was observed with compound
having butyl substituent in the amide group on
pyrazolone derivatives
4-Ethyl-1-[(1-methyl-pyrrol-2-yl)acetyl]semicarbazide (1)
Yield 78%, Mp = 165-167ºC [22].
N-butyl-3-amino-4-phenyl-pyrazolin-5-on-1-
carboxamide 8 showed activity (EC50 7.9 ꢀg/ml) in
comparison with strong antioxidant Trolox.
4-(4-bromophenyl)-1-[1-(metyl-pyrrol-2-yl)acetylsemicar-
bazide (2)
Yield 86%, Mp = 200-201ºC [22].

Antioxidant Evaluation of Semicarbazides, Triazoles and Pyrazoles
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10 1007
N-butyl-3-amino-4-phenyl-pyrazolin-5-on-1-carboxamide
(8)
3.2. Preparation of 3-[(1-methylpyrrol-2-yl)methyl]-4-
substituted-1,2,4-triazolin-5-one 3,4 and 1,6-bis(3-subs-
tituted-1,2,4-triazolin-5-on-4-yl)hexanes 5-7 and 4,4’-
bis[3-substituted-1,2,4-triazolin-5-on-4-yl]diphenylmeth-
anes 12-14
Yield 73%, m.p. 165-167 °C [25].
N-(4-methoxyphenyl)-3-amino-4-phenyl-pyrazolin-5-on-1-
carboxamide (9)
A mixture of 1-[(1-methyl-pyrrol-2-yl)acetyl]-4-subs-
tituted semicarbazide or 1,6-bis(1-substituted-semicarbazide-
4-yl)hexanes or 4,4’-bis(1-substituted-semicarbazide)diphen-
ylmethane and 2% aqueous solution of sodium hydroxide
was boiled for 15h. After cooling, the solution was
neutralized with dilute hydrochloric acid. The precipitate
was filtered off and crystallized from ethanol.
Yield 74%, m.p. 235-236 °C [25].
N-cyclohexyl-3-amino-4-phenyl-pyrazolin-5-on-1-
carboxamide (10)
Yield 75%, m.p. 228-230 °C [25].
N-(1-naphtyl)-3-amino-4-phenyl-pyrazolin-5-on-1-
carboxamide (11)
4-Ethyl-3-[(1-methylpyrrol-2-yl)methyl]-1,2,4-triazolin-5-
one (3)
Yield 73%, m.p. 230-232 °C [25].
Yield 90%, Mp = 150-151ºC [22].
3.4. DPPH/TLC Assay
4-Bromophenyl-3-[(1-methylpyrrol-2-yl)methyl]-1,2,4-
triazolin-5-one (4)
Preliminary assessment of the antioxidant activity of
synthesized compounds was performed by TLC method. The
solutions of analyzed compounds in concentration 0.033M
were developed on a Silica gel TLC plate Merck (Darmstadt,
Germany) using: toluene : methanol : 25% ammonia
(9:1:0.05) solvent system. After drying TLC plates were
sprayed with 0.2% 1,1-diphenyl-2-2-picrylhydrazyl (DPPH,
Fluka Co, Buchs, Switzerland) solution in methanol.
Compounds showing a yellow band on purple spot were
regarded as antioxidants [26].
Yield 89%, Mp = 180-181ºC [22].
1,6-Bis(3-methyl-1,2,4-triazolin-5-on-4-yl)hexane (5)
Yield 89%, Mp = 235-237ºC [23].
1,6-Bis(3-phenyl-1,2,4-triazolin-5-on-4-yl)hexane (6)
Yield 70%, Mp = 238-240ºC [23].
1,6-Bis{3-[(1-methylpyrrol-2-yl)methyl]-1,2,4-triazolin-5-
on-4-yl}hexane (7)
Yield 77%, Mp = 228-230ºC; H NMR (300 MHz,
DMSO) ꢀppm: 1.09-1.26 (m, 8H, CH2); 3.39-3.44 (m, 4H,
CH2); 3.49 (s, 6H, CH3); 3.89 (s, 4H, CH2); 5.69-6.64 (m,
6H, CH); 11.44 (s, 2H, NH). C NMR (300 MHz, DMSO)
3.5. Antiradical Activity
The free radical scavenging activity of compounds was
estimated according to the procedure described by Brand-
Williams [27] with some modifications. The tested
compounds, at concentrations ranging from 0.66 to 1.65
ꢂM/ml (50 ꢂl in ethanol), were mixed with 1.95 ml DPPH
solution (6 x 10-5 M in ethanol). The absorbance was
measured at 517 nm after incubating the mixture at room
temperature for 15 min in the dark. The antiradical activity
was expressed as percentage of inhibition which was
calculated by the following formula:
ꢀppm: 23.70 (CH3); 25.50; 28.09; 33.41 (CH2 ); 106.32,
107.84 (CH arom); 145.05 (C arom); 155.09 (C=O). IR
(KBr, ꢁ cm): 3067 (CH arom), 2928, 1496 (CH aliph), 1698
(C=O), 1575 (C=N), 1428 (C-N). MS (m/z) (%): 438 (54)
[M+]; 177 (47); 94 (100).
4,4’-bis(3-methyl-1,2,4-triazolin-5-on-4-yl)diphenyl-
methane (12)
[(Ablank ꢃ Asample)/Asample] ꢄ 100
Yield 83%, Mp = 308-310ºC [24].
where: Ablank is the absorbance of the DPPH radical solution
and Asample is the absorbance of the DPPH radical solution
after the addition of the sample [28,29]. EC50 (antiradical
dose required to cause a 50% inhibition) was obtained by
linear regression analysis of the dose-response curve, plotted
between % inhibition and concentration (ꢂg/ml). A UV-VIS
spectrophotometer (Nicolet Evolution 300, ThermoFisher
Scientific) was used. The absorbance of DPPH solution in
ethanol without any antioxidant (control) was also measured.
4,4’-bis[3(1-methylpyrrol-2-yl)-1,2,4-triazolin-5-on-4-
yl]diphenylmethane (13)
Yield 81%, Mp = 225-227ºC [24].
4,4’-bis(3-benzyl-1,2,4-triazolin-5-on-4-yl)diphenyl-
methane (14)
Yield 69%, Mp = 220-221ºC [24].
6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic
acid
3.3. Preparation of N-substituted-3-amino-4-phenyl-
pyrazolin-5-on-1-carboxamide 8-11
(Trolox, Fluka Co, Buchs, Switzerland) was used as a
positive control. A minimum of five different concentrations
for compound were tested in triplicate analyses.
A mixture of 1-cyanophenylacetic acid hydrazide ( 0.01
M) and butyl, 4-methoxyphenyl, cyclohexyl or 1-naphtyl
isocyanate (0.01 M) in 10 ml of acetonitryle was kept for
24h at room temperature. Then formed compound was
filtered off, washed with acetonitryle and crystallized from
mixture methanol-acetonitryle (1:1).
3.6. Statistical Analysis
All determinations of antioxidant capacity by DPPH
assay were conducted in triplicate. The reported value for
each sample was calculated as the mean of three

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