Synthesis and biological activities of some novel aminomethyl derivatives of 4-substituted-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones

Article abstract of DOI:10.1016/j.ejmech.2013.02.025

A novel series of compounds were synthesized by cyclic condensation reaction of substituted isothiocyanate (2a-c) with 2-thiophenecarboxylic acid hydrazide (1) in the presence of ethyl alcohol, to obtain intermediate thiosemicarbazides (3a-c), which were further treated with sodium hydroxide in the presence of ethanol to obtain triazole derivatives (4a-c). The latter were refluxed with substituted secondary amines and formaldehyde for 6-10 h to afford Mannich bases (5a-k). The synthesized compounds were characterized on the basis of their spectral (IR, ¹³C and ¹H NMR) data and evaluated for biological activities. Some of the compounds were found to exhibit significant antimicrobial and antioxidant activity.

Full text of DOI:10.1016/j.ejmech.2013.02.025

European Journal of Medicinal Chemistry 63 (2013) 340e346
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and biological activities of some novel aminomethyl
derivatives of 4-substituted-5-(2-thienyl)-2,4-dihydro-3H-1,2,
4-triazole-3-thiones
Metin Koparir a, Cahit Orek a, Akif Evren Parlak b, Abdurrazak Söylemez a, Pelin Koparir c,
,
d
Mustafa Karatepe b , Sevgi Durna Dastan
*
a Firat University, Faculty of Science, Department of Chemistry, 23169 Elazig, Turkiye
b Firat University, Faculty of Science, Department of Biochemistry, 23100 Elazig, Turkiye
c Department of Chemistry, Forensic Medicine Institute, 44000 Malatya, Turkiye
d Cumhuriyet University, Faculty of Science, Department of Biology, 58140 Sivas, Turkiye
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of compounds were synthesized by cyclic condensation reaction of substituted isothio-
cyanate (2aec) with 2-thiophenecarboxylic acid hydrazide (1) in the presence of ethyl alcohol, to obtain
intermediate thiosemicarbazides (3aec), which were further treated with sodium hydroxide in the
presence of ethanol to obtain triazole derivatives (4aec). The latter were refluxed with substituted
secondary amines and formaldehyde for 6e10 h to afford Mannich bases (5aek). The synthesized
compounds were characterized on the basis of their spectral (IR, 13C and 1H NMR) data and evaluated for
biological activities. Some of the compounds were found to exhibit significant antimicrobial and anti-
oxidant activity.
Received 15 November 2012
Received in revised form
19 February 2013
Accepted 21 February 2013
Available online 1 March 2013
Keywords:
4-Substituted-5-(2-thienyl)-2,4-dihydro-
3H-1,2,4-triazole-3-thiones
Mannich bases
Ó 2013 Elsevier Masson SAS. All rights reserved.
Biological activity
1. Introduction
properties [8e11]. Few Mannich bases derived from 1,2,4-triazoles
carrying N-methylpiperazine substituent were biologically active
The ring-closure reactions of carbohydrazides are well-known
and have been thoroughly studied. In these reactions five-
membered heterocycles with three heteroatoms such as are
formed, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, and 1,2,4-triazoles.
1,3,4-oxadiazole, 1,3,4-thiadiazole, and 1,2,4-triazole ring systems
[12,13]. 4,5-Substituted products containing 1,2,4-triazole in their
molecules seem to be suitable candidates for further chemical
modifications and might be of interest as pharmacologically active
compounds and ligands useful in coordination chemistry [14].
Derivatives of 4,5-substituted 1,2,4-triazole were synthesized by
intramolecular cyclization of 1,4-disubstituted thiosemicarbazides
[15]. In addition there are some studies on electronic structures and
thiolethione tautomeric equilibrium of heterocyclic thione de-
rivatives [16e19].
In view of these findings, we report on the synthesis, charac-
terization and antibacterial, antifungal and antioxidant activities
some of 4-substituted-5-(2-thienyl)-1,2,4-triazole 3-thione and
their Mannich bases.
are typical planar six-p-electron partially aromatic systems, and are
used, along with their derivatives, as starting materials for the
synthesis of many heterocycles. The 1,2,4-triazole and its de-
rivatives were reported to exhibit various pharmacological activ-
ities such as antimicrobial, analgesic, anti-inflammatory, anticancer
and antioxidant properties [1e4]. Some present day drugs such as
Ribavirin (antiviral agent), Rizatriptan (antimigraine agent), Al-
prazolam (anxiolytic agent), Fluconazole and Itraconazole (anti-
fungal agents) are examples of potent molecules possessing a
triazole nucleus [5e7]. Many studies have shown that Mannich
bases have possess potent biological characteristics such as anti-
bacterial, antifungal, anti-inflammatory, antimalarial and pesticide
2. Results and discussion
2.1. Chemistry
The reaction sequences employed for synthesis of title com-
pounds are shown in Scheme 1. In the present work,
* Corresponding author. Tel.: þ90 424 237 00 00x3528; fax: þ90 424 237 00 10.
E-mail address: mkaratepe23@hotmail.com (M. Karatepe).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.02.025

M. Koparir et al. / European Journal of Medicinal Chemistry 63 (2013) 340e346
341
O
O
S
C
C
Et-OH
RNCS
NH
NH
+
2
NH NH
NH
R
S
S
1
2a-c
3a-c
NaOH
H
N
N
N
N
SH
N
R
S
S
N
R
S
4a-c
O
N
5a
N
N
HN
O
S
N
HCHO
S
CF
O
N
3
N
N
H C
3
HN
O
N
N
5f
S
CF3
N
N
N
HCHO
S
5b
HN
N
S
N
N
S
HCHO
H C
3
H
N
CH
3
N
CH
N
N
3
N
H
N
N
N
N
5c
N
N
HN
CH3
HN
CH3
5g
S
N
S
+
S
N
S
+
S
S
HCHO
S
N
N
N
HCHO
S
S
S
H C
H C
3
CH
3
3
4a
N
4b
N
N
HN
N
N
N
NH
5h
5d
H3
C
CH
3
CH3
HCHO
S
HCHO
N
S
H C
3
N
N
N
N
N
HN
5e
S
N
S
HCHO
H C
3
N
O
N
N
5i
HN
O
S
HCHO
N
S
CH
2
CH
N
3
H
N
N
N
5j
N
HN
CH3
S
N
S
+
HCHO
S
N
S
CH
2
CH
2
4c
N
N
5k
N
N
N
HN
S
N
S
HCHO
CH
2
Scheme 1. Synthesis and the structures of the compounds.
thiosemicarbazides (3aec) were synthesized by reacting 2-
thiophenecarboxylic acid hydrazide (1) with substituted isothio-
cyanate (2aec) in the presence of ethanol at reflux temperature
by condensation method. The synthesized thiosemicarbazides
were reacted with sodium hydroxide in the presence of ethanol to
obtain 4-substituted-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-
3-thiones (4aec). The syntheses of triazoles were reacted with
formaldehyde and secondary amines to afford Mannich bases (5ae

342
M. Koparir et al. / European Journal of Medicinal Chemistry 63 (2013) 340e346
k). All compounds displayed IR, 1H and 13C NMR spectra and
elemental analyzes consistent with the assigned structures. In the
1H NMR spectrum of compounds (4aec), the signal due to eSH
group appeared at 13.98e14.08 ppm. The aromatic protons
appeared as a multiplet at 6.71e7.85 ppm. Moreover, the C]S
group resonated at 167.3e169.6 ppm in the 13C NMR spectra of
compounds (4aec). In the IR spectrum of (4aec) the most char-
acteristic absorptions are at 3015 and 3109 cmꢀ1 aromatic bands,
1577 and 1645 cmꢀ1 (C]N), 1261 and 1277 cmꢀ1, (C]S) and (CeSe
C) stretching bands at 713e736 cmꢀ1. When compounds (4aec)
were converted to Mannich bases of 4-substituted-5-(2-thienyl)-
2,4-dihydro-3H-1,2,4-triazole-3-thiones in acidic media, eNH
peaks disappeared, while new signals due to the eNeCH2eNe
group were observed at 5.04e5.21 ppm in the 1H NMR spectra of
compounds (5aek). In the 1H NMR spectrum of compounds (5aee),
signal due to AreH appeared at 6.73e7.92 ppm. The NeCH2eCH3
drug. Compounds 5b, 5d, 5e and 5k exhibited good antifungal
activity almost equivalent to that of the standard. Antifungal
screening revealed that compounds, 5a, 5f and 5i showed
excellent activity against all the tested fungal strains, namely P.
marneffei, T. mentagrophytes, A. flavus and A. fumigatus at 1.56e
3.12
mg/mL concentration. The remaining compounds were found
to be active at higher concentrations, e.g., 6.25 and 25
mg/mL. It was
therefore concluded that the presence of morpholine and pipera-
zine moiety, in addition to thienyl, phenyl, ethyl and benzyl groups,
was found to be essential for their high antifungal activity of these
compounds. The results of antifungal screening of newly com-
pounds 1,2,4-triazole (4aec) and Mannich bases (5aek) as the MIC
values, are summarized in Table 1.
Compounds 4aec showed moderate activity against all the
bacterial strains. All the synthesized derivatives, compounds 5d,
5e, 5h and 5k showed comparatively good activity against all the
bacterial strains. Compounds 5a, 5f and 5i exhibited good
antibacterial activity almost equivalent to that of the standard
drug. The antibacterial screening revealed that of the tested
compounds, 5b, 5c, 5g and 5j showed excellent activity against
all the tested bacterial strains, S. aureus, K. pneumoniae, E. coli and
appeared as
a quartet at 4.24e4.30 ppm and NeCH2eCH3
appeared as a triplet at 1.25e1.41 ppm. Moreover, the C]S group
resonated at 168.1e168.7 ppm in the 13C NMR spectra of com-
pounds (5aee). In the IR spectrum of (5aee), the most character-
istic absorptions are at 3022 and 3107 cmꢀ1 aromatic bands, 1572
and 1612 cmꢀ1 (C]N), 1276 and 1285 cmꢀ1, and (C]S) and (CeSe
C) stretching bands at 740e782 cmꢀ1. In the 1H NMR spectrum of
compounds (5feh), signal due to AreH appeared at 6.66e7.72 ppm.
P. aeruginosa at 3.12e1.56
compounds found to be active at higher concentrations, e.g., 6.25
and 25 g/mL. Compounds 5b, 5c, 5g and 5j were also the most
mg/mL concentration. The remaining
m
Moreover, the C]S group resonated at 169.6e169.8 ppm in the 13
C
active against the investigated strains as compared to the standard
drug. It was therefore concluded that the presence of 4-methyl
piperidine and trifluoromethylphenylpiperazine moiety were
essential for their high antibacterial activity of these compounds.
The results of antibacterial screening of newly prepared com-
pounds 5aek expressed as the MIC values, compared with the
starting triazoles (4aec), and control (ciprofloxacin), are summa-
rized in Table 2.
NMR spectra of compounds (5feh). In the IR spectrum of (5feh)
the most characteristic absorptions are at 3040 and 3114 cmꢀ1 ar-
omatic bands, 1578 and 1593 cmꢀ1 (C]N), 1277 and 1280 cmꢀ1
,
and (C]S) and (CeSeC) stretching bands at 710e783 cmꢀ1 1H
.
NMR spectrum of compounds (5iek), a signal due to AreH
appeared at 6.83e7.88 ppm. The NeCH2eCH]CH2 appeared as a
twelve peaks at 5.90e6.04 ppm, NeCH2eCH]CH2 and trans pro-
tons of CH2 in the allyl group appeared as a multiple signals at
4.85e4.92 ppm; and NeCH2eCH]CH2 cis protons of CH2 in the
allyl group appeared as a doublet at 5.20 ppm. Moreover, the C]S
group resonated at 168.9e169.3 ppm in the 13C NMR spectra of
compounds (5iek). In the IR spectrum of (5iek) the most charac-
teristic absorptions are at 3073 and 3090 cmꢀ1 aromatic bands,
1506 and 1665 cmꢀ1 (C]N), 1268 and 1271 cmꢀ1, and (C]S) and
(CeSeC) stretching bands at 721e729 cmꢀ1. The data for all com-
pounds are given in the Experimental section.
2.2.2. Antioxidant activity
Since antioxidants are gaining attention as a potential means of
treating a large number of lifestyle diseases like aging, cancer,
diabetes, cardiovascular and other degenerative diseases, it is of
immense significance to establish some new antioxidants via a
convenient synthetic methodology. Although a number of methods
are available, including ORAC, ABTS, DMPD, FRAP, TRAP, TBA, su-
peroxide radical scavenging, hydroxyl radical scavenging, nitric
oxide radical scavenging, xanthine oxidase, cytochrome C, reducing
power method, etc. DPPH method is very common and has been
shown to be the most appropriate method [20].
2.2. Biological evaluation
2.2.1. Antibacterial and antifungal activity
The new synthesized compounds were evaluated for their
antibacterial and antifungal activities against the Gram-positive
bacteria: Staphylococcus aureus (ATCC 25923) the Gram negative
bacteria: Escherichia coli (ATCC 25922), Pseudomonas aeruginosa
(ATCC 27853) and Klebsiella pneumoniae (recultured) and four
fungal strains Aspergillus flavus (NCIM No. 524), Aspergillus fumi-
gatus (NCIM No. 902), Penicillium marneffei (recultured) and Tri-
chophyton mentagrophytes (recultured). Both microbial studies
were assessed by minimum inhibitory concentration (MIC) by se-
rial plate dilution method. MIC is the highest dilution of the com-
pound, which shows clear fluid with no development of turbidity.
Antibacterial and antifungal screening revealed that some of the
Table 1
Antifungal activity of compounds (4aec) and (5aek).
Compound
MIC in
mg/mL
P. marneffei T. mentagrophytes A. flavus A. fumigatus
4a
4b
4c
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
25
25
25
12
12
12
12
12
12
25
25
25
3.12
6.25
12
6.25
6.25
3.12
12
12
3.12
12
1.56
3.12
6.25
3.12
3.12
1.56
6.25
6.25
1.56
6.25
3.12
3.12
0
1.56
3.12
6.25
3.12
3.12
1.56
6.25
6.25
1.56
6.25
3.12
3.12
0
3.12
6.25
12
6.25
6.25
3.12
12
12
3.12
12
tested compounds showed good inhibition at 1.56e25
mg/mL in
DMSO. The compounds 4aec showed moderate activity against all
the fungal strains. Among the screened compounds, 5c, 5g, 5h and
5j showed comparatively good activity against all the fungal strains.
Compounds 5a, 5b, 5def, 5i and 5k showed good antifungal
activity against all the fungal strains. Of all the synthesized
derivatives, compounds 5a, 5b, 5def, 5i and 5k were the most
active against the investigated strains, compared to the standard
6.25
6.25
6.25
0
Ciclopiroxolaminea 6.25
DMSO (control)
0
The MIC values were evaluated at concentration range, 1.56e25
m
g/mL.
a
Ciclopiroxolamine was used as a standard.

M. Koparir et al. / European Journal of Medicinal Chemistry 63 (2013) 340e346
343
Table 2
thienyl moiety. The antimicrobial activity study revealed that all the
compounds tested showed good antibacterial and antifungal ac-
tivities against pathogenic strains. The structure and biological
activity relationship of title compounds showed that the presence
of thienyl groups and biologically active groups like morpholine, 4-
benzylpiperazine, N-methylpiperidine and trifluoromethylphenyl-
piperazine groups attached to the triazole ring of the title com-
pounds are responsible for good antimicrobial activity. A similar
correlation was observed for antioxidant activity. All compounds
greatly improved their activity compared to precursors. Therefore,
the significant antifungal, antibacterial and antioxidant activity of
compounds may be due to the presence of morpholine, N-meth-
ylpiperidine and piperazine moiety in addition to thienyl, phenyl,
methyl, ethyl and allyl group. Finally, our biological activity results
agree with the results reported in literature, take into 1,2,4-triazole,
phenyl, piperazine, morpholine and benzyl the groups [21e26].
Hence it is concluded that there is ample scope for further study.
Antibacterial activity of compounds (4aec) and (5aek).
Compound
MIC in
m
g/mL
E. coli
K. pneumoniae
P. aeruginosa
S. aureus
4a
4b
4c
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
12
12
12
6.25
3.12
3.12
12
12
12
25
12
12
12
6.25
3.12
3.12
12
12
12
25
6.25
3.12
3.12
6.25
6.25
6.25
3.12
6.25
6.25
3.12
6.25
6.25
0
3.12
1.56
1.56
6.25
6.25
12
1.56
6.25
3.12
1.56
6.25
3.12
0
12
12
6.25
3.12
12
6.25
3.12
12
6.25
3.12
12
6.25
3.12
12
Ciprofloxacina
DMSO (control)
6.25
0
6.25
0
The MIC values were evaluated at concentration range, 1.56e25
m
g/mL.
4. Experimental
a
Ciprofloxacin was used as a standard.
4.1. Chemistry assays
Compounds 4aec showed moderate antioxidant activity. Of all
the synthesized derivatives, compounds 5b, 5d, 5e, 5h and 5k
showed very good activities which were similar to reference anti-
oxidant compound. In addition compounds 5c, 5g and 5j showed
good scavenging activities. From all the synthesized derivatives,
compounds 5a, 5f and 5i exhibited the highest radical scavenging
activities which were better than the reference antioxidant
compound.
Compounds 5a, 5f and 5i with morpholine moiety showed the
best DPPH radical scavenging activity at all concentration, followed
by compound 5d, 5e and 5k with piperazine moiety, 5h with
dipropylamine and 5b with having trifluoromethyl phenyl moiety.
As shown in Table 3, the title compounds have scavenging ac-
tivity between 36.1% and 95.0% within the investigated concen-
tration range. The antioxidant activity of the title compounds are
obvious that the scavenging activity increases with increasing
sample concentration in the range tested.
Melting points were determined on a Thomas Hoover melting
point apparatus and uncorrected, but checked by differential
scanning calorimeter (DSC). The IR spectra were measured with
PerkineElmer spectrum one FTeIR spectrophotometer. Electronic
spectral studies were conducted on a Shimadzu model UV-1700
spectrophotometer in the wavelength 1100e200 nm. The 1H and
13C spectra were taken on Bruker AC-400 NMR spectrometer
operating at 400 MHz for 1H, 100 MHz for 13C NMR. Compounds
were dissolved in DMSO and chemical shifts were referenced to
TMS (1H and 13C NMR). Starting chemicals were obtained from
Merck or Aldrich.
4.1.1. General procedure for the synthesis of 4aec
A mixture of 2-thienyl thiosemicarbazides (3aec) (0.01 mol)
and 10% potassium hydroxide solution (10 mL) was refluxed for 3 h.
The mixture was then cooled to room temperature and filtered. The
filtrate was neutralized by the gradual addition of glacial acetic
acid. The resulting solid was collected by filtration, dried and
recrystallized from ethyl alcohol.
3. Conclusions
The research study reports the successful synthesis and anti-
microbial activity of new 1,2,4-triazole and Mannich bases bearing
4.1.1.1. 4-Ethyl-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione
(4a). This compound was obtained as shining white solid, yield:
85%; mp: 256e257 ꢁC; IR (KBr, cmꢀ1) 3015e3102 (AreH), 2868e
2938 (CH str.), 1577 (C]N), 1277 (C]S), 713 (CeSeC); 1H NMR
Table 3
Antioxidant scavenging activity of compounds (4aec) and (5aek) on DPPHꢂ free
radical at different concentrations.
(DMSO-d6)
d
: 1.23 (t, 3H, NeCH2eCH3, J ¼ 7.2 Hz), 4.21 (q, 2H, eNe
Tested
Compound
DPPH scavenging activity (%)
62.5 125 187.5
CH2eCH3, J ¼ 7.2 Hz), 7.26 (dd,1H, AreH, J ¼ 4.0, 4.8 Hz), 7.67 (d, 1H,
AreH, J ¼ 3.2 Hz) 7.85 (d, 1H, AreH, J ¼ 4.8 Hz), 14.0 (s, 1H, SH); 13
C
m
M
m
M
mM
250
m
M
312.5 mM
4a
4b
4c
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
36.4 ꢃ 0.7 47.1 ꢃ 0.1 49.6 ꢃ 0.1 53.3 ꢃ 0.5
36.1 ꢃ 0.6 45.7 ꢃ 0.6 47.9 ꢃ 0.1 51.2 ꢃ 0.6
40.7 ꢃ 0.3 45.2 ꢃ 0.4 47.4 ꢃ 0.3 55.5 ꢃ 0.1
60.4 ꢃ 0.6 69.8 ꢃ 0.2 82.8 ꢃ 0.4 88.6 ꢃ 0.5
52.0 ꢃ 0.1 61.1 ꢃ 0.4 71.3 ꢃ 0.3 80.2 ꢃ 0.2
49.2 ꢃ 0.2 52.5 ꢃ 0.4 65.2 ꢃ 0.4 67.6 ꢃ 0.6
53.5 ꢃ 0.4 63.2 ꢃ 0.6 74.5 ꢃ 0.2 83.1 ꢃ 0.2
52.2 ꢃ 0.1 63.1 ꢃ 0.2 72.7 ꢃ 0.2 82.5 ꢃ 0.3
62.1 ꢃ 0.2
65.1 ꢃ 1.0
68.8 ꢃ 0.5
93.6 ꢃ 0.3
81.6 ꢃ 0.2
71.3 ꢃ 0.4
90.9 ꢃ 0.2
90.2 ꢃ 0.1
NMR (DMSO-d6) d: 13.6, 39.6, 126.7, 128.7, 129.4, 130.1, 146.1, 167.3.
MW: C8H9N3S2 (211). Elemental analysis: calcd C, 45.47; H, 4.29; N,
19.89; S, 30.35; found, C, 45.43; H, 4.26; N, 19.90; S, 30.33.
4.1.1.2. 4-Phenyl-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-
thione (4b). This compound was obtained as shining white solid,
yield: 79%; mp: 164e165 ꢁC; IR (KBr, cmꢀ1) 3065e3109 (AreH),
59.1 ꢃ 0.2 68.4 ꢃ 0.2 79.2 ꢃ 0.1 87.2 ꢃ 0.1 92 0.7 ꢃ 0.2
44.7 ꢃ 0.4 51.1 ꢃ 0.8 61.1 ꢃ 0.4 66.9 ꢃ 0.3 70 0.7 ꢃ 0.5
52.1 ꢃ 0.6 62.6 ꢃ 0.2 72.1 ꢃ 0.1 81.4 ꢃ 0.4 89 0.2 ꢃ 0.2
1579 (C]N), 1267 (C]S), 715 (CeSeC); 1H NMR (DMSO-d6)
d
:
:
6.66e7.70 (m, 8H, AreH), 13.98 (s, 1H, SH); 13C NMR (DMSO-d6)
d
62.3 ꢃ 0.1 71.2 ꢃ 0.2 83.1 ꢃ 0.2 89.9 ꢃ 0.2
50.1 ꢃ 0.3 53.5 ꢃ 0.4 68.1 ꢃ 0.3 69.7 ꢃ 0.2
54.0 ꢃ 0.1 64.4 ꢃ 0.3 75.0 ꢃ 0.1 84.1 ꢃ 0.2
55.1 ꢃ 0.2 65.0 ꢃ 0.2 75.2 ꢃ 0.2 85.8 ꢃ 0.4
95.0 ꢃ 0.1
72.4 ꢃ 0.2
91.6 ꢃ 0.2
91.7 ꢃ 0.2
126.6, 128.1, 129.2, 129.4, 130.1, 130.3,130.6, 135.0, 144.7, 169.6. MW:
12H9N3S2 (259). Elemental analysis: calcd C, 55.57; H, 3.50; N,
C
5k
16.20; S, 24.73; found, C, 55.56; H, 3.49; N, 16.19; S, 24.74.
Ascorbic
acida
4.1.1.3. 4-Allyl-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione
(4c). This compound was obtained as shining claret red solid, yield:
75%; mp: 157e158 ꢁC; IR (KBr, cmꢀ1) 3070e3086 (AreH), 2967 (CH
a
Ascorbic acid (reference antioxidant compounds) was used as a standard. The
scavenging capacities were represented as percentage inhibition and values were
the means of three replicates (mean ꢃ SD, n ¼ 3).

344
M. Koparir et al. / European Journal of Medicinal Chemistry 63 (2013) 340e346
str.), 1645 (C]N), 1261 (C]S), 736 (CeSeC); 1H NMR (DMSO-d6)
d:
C15H22N4S2 (322). Elemental analysis: calcd C, 55.86; H, 6.88; N,
4.83e4.89 (m, 3H, NeCH2eCH]CH2 and NeCH2eCH]CH2,
(trans)), 5.17 (d, 1H, NeCH2eCHeCH2, Jcis ¼ 10.4 Hz), 5.87e5.95
17.37; S, 19.89; found, C, 55.84; H, 6.89; N, 17.35; S, 19.87.
(ddt, 1H, NeCH2eCHeCH2, Jtrans
¼
17.1 Hz, Jcis
¼
10.5 Hz
4.2.4. 2-[(4-Benzylpiperazin-1-yl)methyl]-4-ethyl-5-(2-thienyl)-
2,4-dihydro-3H-1,2,4-triazole-3-thione (5d)
JCH2 ¼ 4.8 Hz), 7.21 (dd, 1H, AreH, J ¼ 2.7, 3.0 Hz), 7.58 (d, 1H, AreH,
J ¼ 1.8 Hz) 7.81 (d, 1H, AreH, J ¼ 3.9 Hz), 14.08 (s, 1H, SH); 13C NMR
This compound was obtained as shining white solid, yield: 68%;
(DMSO-d6) d: 46.1, 117.0, 126.6, 128.6, 129.1, 130.1, 131.8, 146.5, 167.9.
mp: 92e93 ꢁC; IR (KBr, cmꢀ1) 3022e3083 (AreH), 2812e2937 (CH
MW: C9H9N3S2 (223). Elemental analysis: calcd C, 48.40; H, 4.06; N,
18.82; S, 28.72; found, C, 48.38; H, 4.09; N, 18.80; S, 28.74.
str.), 1574 (C]N), 1285 (C]S), 740 (CeSeC); 1H NMR (DMSO-d6)
d:
1.41 (t, 3H, NeCH2eCH3, J ¼ 9.6 Hz), 2.50 (t, 4H, eCH2eNeCH2
piperazine ring), 2.90 (t, 4H, NeCH2 piperazine ring), 3.48 (s, 2H,
NeCH2eAr), 4.30 (q, 2H, NeCH2eCH3, J ¼ 9.6 Hz), 5.21 (s, 2H, Ne
4.2. General procedure for the synthesis of 5aek
CH2eN) 7.18e7.56 (m, 8H, ArH); 13C NMR (DMSO-d6)
d: 13.6, 30.9,
A solution of appropriate triazoles (4aec) (0.01 mol), formal-
dehyde (40%, 1,5 mL) and suitably substituted secondary amines
(0.01 mol) in ethanol (20 mL) was stirred for an hour and left
overnight at room temperature. The solid mass thus separated was
collected by filtration, dried and recrystallized from ethyl alcohol.
40.9, 50.4, 53.0, 63.1, 67.1, 69.4,126.4,127.1,127.9,128.2,128.8,129.3,
144.9, 168.7. MW: C20H25N5S2 (399). Elemental analysis: calcd C,
60.12; H, 6.31; N, 17.53; S, 16.05; found, C, 60.09; H, 6.29; N, 17.50; S,
16.02.
4.2.5. 4-Ethyl-2-[(4-phenylpiperazin-1-yl)methyl]-5-(2-thienyl)-
2,4-dihydro-3H-1,2,4-triazole-3-thione (5e)
Hc
Ha
N
This compound was obtained as shining white solid, yield: 69%;
Hc
Ha
mp: 126e127 ꢁC; IR (KBr, cmꢀ1) 3083 (AreH), 2826e2961 (CH str.),
Hd
Hb
1599 (C]N), 1279 (C]S), 761 (CeSeC); 1H NMR (DMSO-d6)
d: 1.27
N
N
Hd
Hb
(t, 3H, NeCH2eCH3), 2.85 (t, 4H, eCH2eNeCH2 piperazine ring),
3.11 (t, 4H, NeCH2 piperazine ring), 4.25 (q, 2H, NeCH2eCH3), 5.16
CH
3
S
N
R
He
S
(s, 2H, NeCH2eN), 6.73e7.91 (m, 8H, ArH); 13C NMR (DMSO-d6)
d:
13.5, 40.9, 48.7, 50.3, 69.0, 116.1, 119.4, 126.7, 129.0, 129.3, 129.9,
130.6, 145.1, 151.5, 168.4. MW: C19H23N5S2 (385). Elemental anal-
ysis: calcd C, 59.19; H, 6.01; N, 18.16; S, 16.63; found, C, 59.21; H,
6.03; N, 18.14; S, 16.65.
Note: the structure for NMR (5c, 5g and 5j).
4.2.1. 4-Ethyl-2-(morpholin-4-ylmethyl)-5-(2-thienyl)-2,4-
dihydro-3H-1,2,4-triazole-3-thione (5a)
4.2.6. 2-(Morpholin-4-ylmethyl)-4-phenyl-5-(2-thienyl)-2,4-
dihydro-3H-1,2,4-triazole-3-thione (5f)
This compound was obtained as shining yellow solid, yield: 66%;
mp: 197e198 ꢁC; IR (KBr, cmꢀ1) 3040e3114 (AreH), 2852e2961
(CH str.), 1579 (C]N), 1278 (C]S), 783 (CeSeC); 1H NMR
This compound was obtained as shining white solid, yield: 69%;
mp: 96e97 ꢁC; IR (KBr, cmꢀ1) 3070 (AreH), 2839e2962 (CH str.),
1574 (C]N), 1279 (C]S), 779 (CeSeC); 1H NMR (DMSO-d6)
d: 1.25
(t, 3H, NeCH2eCH3, J ¼ 7.2 Hz), 2.66 (t, 4H, NeCH2 morpholine),
3.54 (t, 4H, OCH2 morpholine), 4.24 (q, 2H, NeCH2eCH3, J ¼ 7.2 Hz),
5.06 (s 2H, NeCH2eN), 7.28e7.89 (m, 3H, ArH); 13C NMR (DMSO-d6)
(DMSO-d6)
morpholine), 5.13 (s, 2H, NeCH2eN), 6.71e7.72 (m, 8H, AreH);
13C NMR (DMSO-d6)
: 50.4, 66.3, 69.2, 126.6, 128.1, 129.2, 129.4,
d: 3.34 (t, 4H, NeCH2 morpholine), 3.58 (t, 4H, OeCH2
d: 13.5, 40.7, 50.5, 66.4, 69.2, 126.6, 128.7, 129.1, 130.1, 146.0, 167.3.
d
MW: C13H18N4OS2 (310). Elemental analysis: calcd C, 50.30; H, 5.84;
N, 18.05; S, 20.66; found, C, 50.29; H, 5.79; N, 18.03; S, 20.68.
130.1, 130.3, 130.6, 135.0, 144.9, 169.8. MW: C17H18N4OS2 (358).
Elemental analysis: calcd C, 56.96; H, 5.06; N, 15.63; S, 17.89; found,
C, 56.94; H, 5.09; N, 15.61; S, 17.88.
4.2.2. 4-Ethyl-5-(2-thienyl)-2-({4-[3-(trifluoromethyl)phenyl]
piperazin-1-yl}methyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5b)
This compound was obtained as shining white solid, yield: 70%;
mp: 80e81 ꢁC; IR (KBr, cmꢀ1) 3105 (AreH), 2840e2948 (CH str.),
4.2.7. 2-[(4-Methylpiperidin-1-yl)methyl]-4-phenyl-5-(2-thienyl)-
2,4-dihydro-3H-1,2,4-triazole-3-thione (5g)
This compound was obtained as shining white solid, yield: 65%;
mp: 153e154 ꢁC; IR (KBr, cmꢀ1) 3051e3106 (AreH), 2818e2943
(CH), 1593 (C]N), 1277 (C]S), 712 (CeSeC); 1H NMR (DMSO-d6)
1612 (C]N), 1282 (C]S), 782 (CeSeC); 1H NMR (DMSO-d6)
d: 1.27
(t, 3H, NeCH2eCH3, J ¼ 7.2 Hz), 2.86 (t, 4H, NeCH2 piperazine ring),
3.22 (t, 4H, ArN CH2 piperazine ring), 4.26 (q, 2H, NeCH2eCH3,
J ¼ 7.2 Hz), 5.17 (s 2H, NCH2N), 7.03e7.92 (m, 7H, ArH); 13C NMR
d
: 0.85 (d, 3H, eCHeCH3, J ¼ 6.0 Hz), 1.03e1.25 (m, 3H, He and Hd),
1.57 (d, 2H, Hc, J ¼ 12 Hz), 2.41 (t, 2H, Hb, J ¼ 11.6 Hz), 3.05 (d, 2H, Ha,
(DMSO-d6) d: 13.5, 48.1, 50.1, 51.2, 68.9, 111.4, 111.6, 115.0, 123.7,
J ¼ 11.2 Hz), 5.10 (s, 2H, NeCH2eN), 6.68e7.70 (m, 8H, AreH); 13C
126.6, 129.0, 129.6, 130.1, 130.4, 130.6, 145.1, 151.7, 168.4. MW:
20H22F3N5S2 (453). Elemental analysis: calcd C, 52.96; H, 4.89; N,
NMR (DMSO-d6) d: 22.2, 30.0, 34.2, 50.8, 69.9, 126.6, 128.1, 129.2,
C
129.4, 130.1, 130.3, 130.6, 135.0, 144.7, 169.6. MW: C19H22N4S2 (370).
Elemental analysis: calcd C, 61.59; H, 5.98; N, 15.12; S, 17.31; found,
C, 61.62; H, 6.01; N, 15.11; S, 17.29.
15.44; S, 14.14; found, C, 52.94; H, 4.86; N, 15.46; S, 14.12.
4.2.3. 4-Ethyl-2-[(4-methylpiperidin-1-yl)methyl]-5-(2-thienyl)-
2,4-dihydro-3H-1,2,4-triazole-3-thione (5c)
4.2.8. 2-[(Dipropylamino)methyl]-4-phenyl-5-(2-thienyl)-2,4-
dihydro-3H-1,2,4-triazole-3-thione (5h)
This compound was obtained as shining white solid, yield: 62%;
mp: 128e129 ꢁC; IR (KBr, cmꢀ1) 3043e3098 (AreH), 2870e2955
(CH str.), 1578 (C]N), 1280 (C]S), 710 (AreH); 1H NMR (DMSO-
This compound was obtained as shining white solid, yield: 69%;
mp: 77e78 ꢁC; IR (KBr, cmꢀ1) 3069e3107 (AreH), 2819e2941 (CH
str.), 1572 (C]N), 1276 (C]S), 770 (CeSeC); 1H NMR (DMSO-d6)
d:
0.82 (d, 3H, eCHeCH3, J ¼ 6.4 Hz), 1.02e1.07 (ddt, 2H, Hd,
J ¼ 7.2 Hz), 1.08e1.25 (m, 4H, NeCH2eCH3 and He), 1.53 (d, 2H, Hc,
J ¼ 12 Hz), 2.28 (t, 2H, Hb, J ¼ 11.6 Hz), 3.00 (d, 2H, Ha, J ¼ 11.2 Hz)
4.24 (q, 2H, NeCH2eCH3, J ¼ 6.8 Hz), 5.04 (s, 2H, NeCH2eN), 7.26e
d6)
d
: 0.87 (t, 6H, NeCH2eCH2eCH3, J ¼ 7.2 Hz), 1.50e1.56 (m, 4H,
NeCH2eCH2CH3, J ¼ 7.2 Hz), 2.68 (t, 4H, NeCH2eCH2eCH3,
J ¼ 6.8 Hz), 5.17 (s, 2H, NeCH2eN), 6.66e7.70 (m, 8H, AreH); 13C
7.88 (m, 3H, AreH); 13C NMR (DMSO-d6)
d
: 13.4, 22.1, 29.9, 34.1,
NMR (DMSO-d6) d: 13.19, 25.3, 50.2, 69.7, 126.7, 128.0, 129.1, 129.4,
40.7, 50.7, 69.6, 126.1, 128.8, 129.6, 130.4, 144.7, 168.1. MW:
130.1, 130.3, 130.6, 135.1, 144.7, 169.6. MW: C19H24N4S2 (372).

M. Koparir et al. / European Journal of Medicinal Chemistry 63 (2013) 340e346
345
Elemental analysis: calcd C, 61.25; H, 6.49; N, 15.04; S, 17.21; found,
C, 61.22; H, 6.46; N, 15.06; S, 17.19.
were prepared in triplicate and maintained at 37 ꢁC for 3e4 days.
Antibacterial activity was determined by measuring the mini-
mum inhibitory concentration (MIC) values. The activity of each
compound was compared with ciprofloxacin as standard [29,30].
4.2.9. 4-Allyl-2-(morpholin-4-ylmethyl)-5-(2-thienyl)-2,4-dihydro-
3H-1,2,4-triazole-3-thione (5i)
This compound was obtained as shining orange solid, yield:
55%; mp: 78e79 ꢁC; IR (KBr, cmꢀ1) 3085e3090 (AreH), 2853e2966
(CH str.), 1665 (C]N), 1270 (C]S), 721 (CeSeC); 1H NMR (DMSO-
4.3.2. Antifungal activity
Newly prepared compounds were screened for their antifungal
activity against A. flavus [NCIM No. 524], A. fumigatus [NCIM No. 902],
P. marneffei [recultured] and T. mentagrophytes [recultured] in DMSO
by serial plate dilution method [31,32]. Agar media were prepared by
d6)
d
: 2.69 (t, 4H, NeCH2 morpholine, J ¼ 4.8 Hz), 3.56 (t, 4H, OeCH2
morpholine, J ¼ 4.5 Hz), 4.87e4.92 (m, 3H, NeCH2eCH]CH2 and
NeCH2eCH]CH2 (trans H)), 5.12 (s, 2H, NeCH2eN), 5.20 (d,1H, Ne
CH2eCH]CH2, Jcis ¼ 10.2 Hz), 5.90e6.03 (ddt, 1H, CH2eCH]CH2),
dissolving peptone (1 g), D-glucose (4 g) and agar (2 g) in distilled
water (100 mL) and adjusting the pH to 5.7. Normal salinewas used to
make a suspension of the spores of fungal strains for lawning. A
loopful of particular fungal strain was transferred to 3 mL of saline to
obtain a suspension of corresponding species. Agar media of 20 mL
were poured into each Petri dish. Excess suspension was decanted
and plates were dried by placing in an incubator at 37 ꢁC for 1 h. An
agar punch was used to produce wells on these seeded agar plates
and minimum inhibitory concentrations of the test compounds in
dimethylsulfoxide (DMSO) were added into each labeled well. A
control was also prepared for the plates in thesameway using solvent
DMSO. Petri dishes were prepared in triplicate and maintained at
37 ꢁC for 3e4 days. Antifungal activity was determined by measuring
the minimum inhibitory concentration (MIC) values. The activity of
each compound was compared with ciclopiroxolamine as standard.
7.25e7.88 (m, 3H, AreH); 13C NMR (DMSO-d6)
d: 47.4, 50.7, 66.5,
69.4, 117.3, 126.2, 128.8, 130.0, 130.7, 131.9, 145.5, 169.2. MW:
14H18N4OS2 (322). Elemental analysis: calcd C, 52.15; H, 5.63; N,
C
17.38; S, 19.89; found, C, 52.13; H, 5.61; N, 17.40; S, 19.94.
4.2.10. 4-Allyl-2-[(4-methylpiperidin-1-yl)methyl]-5-(2-thienyl)-
2,4-dihydro-3H-1,2,4-triazole-3-thione (5j)
This compound was obtained as shining pink solid, yield: 50%;
mp: 60e61 ꢁC; IR (KBr, cmꢀ1) 3073 (AreH), 2838e2919 (CH str.),
1506 (C]N), 1268 (C]S), 729 (CeSeC); 1H NMR (DMSO-d6)
d: 0.86
(d, 3H, CHCH3), 1.03e1.24 (m, 3H, Hd and He), 1.56 (d, 2H, Hc,
J ¼ 10.5 Hz) 2.33 (t, 2H, Hb, J ¼ 11.7 Hz), 3.03 (d, 2H, Ha, J ¼ 11.7 Hz),
4.85e4.91 (m, 3H, NeCH2eCH]CH2 and NeCH2eCH]CH2 (trans
H)), 5.10 (s, 2H, NeCH2eN), 5.20 (d, 1H, NeCH2eCH]CH2,
Jcis ¼ 10.5 Hz), 5.90e6.00 (ddt, 1H, NeCH2eCH]CH2), 7.24e7.87
4.3.3. DPPH free radical scavenging activity
(m, 3H, AreH); 13C NMR (DMS-d6)
d: 22.3, 30.1, 34.3, 47.3, 50.9,
The free radical-scavenging activity of the title compound was
determined by spectrophotometric measurement of the change in
the absorbance of DPPHꢂ (1,1-diphenyl-2-picrylhydrazylradical) at
70.2, 117.1, 126.3, 128.8, 129.9, 130.6, 131.9, 145.3, 168.9. MW:
16H22N4S2 (334). Elemental analysis: calcd C, 57.45; H, 6.63; N,
C
16.75; S, 19.17; found, C, 57.43; H, 6.61; N, 16.72; S, 19.18.
517 nm. Stock solutions (500
were prepared in DMSO. DPPHꢂ solution (400
sample solution at different concentrations (500, 1000, 1500, 2000
and 2500 L) and appropriately diluted with DMSO to a total vol-
ume of 4.0 mL. A control was produced by diluting 400 L from
m
M) of the tested sample and DPPHꢂ
M) was added to the
m
4.2.11. 4-Allyl-2-[(4-phenylpiperazin-1-yl)methyl]-5-(2-thienyl)-
2,4-dihydro-3H-1,2,4-triazole-3-thione (5k)
m
This compound was obtained as shining pink solid, yield: 54%;
m
mp: 143e144 ꢁC; IR (KBr, cmꢀ1) 3084 (AreH), 2821e2947 (CH str.),
DPPHꢂ stock solution was also diluted to 4.0 mL using DMSO sol-
vent. For the control, only solvent was added. Ascorbic acid was
used as a standard (using the reference antioxidant) for this test.
For the standard, the sample was replaced with the same amount of
ascorbic acid. The DPPH (1,1-diphenyl-2-picrylhydrazyl) radical
scavenging method was chosen to assess the antioxidant potential
of the target compounds in comparison with the commercially
available antioxidant ascorbic acid at the same concentrations. The
reaction mixtures were thoroughly mixed by shaking the test tubes
vigorously and incubated at 25 ꢁC for 60 min in a water bath in the
dark. Absorbance at 517 nm was measured and the solvent was
corrected throughout. The scavenging effect was calculated using
the following equation [33]:
1648 (C]N), 1271 (C]S), 721 (CeSeC); 1H NMR (DMSO-d6)
d: 3.03
(t, 4H, eCH2eNeCH2 piperazine ring), 3.20 (t, 4H, NeCH2 piperazine
ring), 4.87e4.89 (m, 2H, NeCH2eCH]CH2), 5.11 (d, 2H, NeCH2e
CH]CH2 (trans H)), 5.29e5.30 (m, 3H, NeCH2eN and NeCH2e
CH]CH2 (cis H)), 5.97e6.04 (ddt, 1H, NeCH2eCH]CH2), 6.83e
7.54 (m, 8H, AreH); 13C NMR (DMS-d6)
d: 47.6, 49.4, 50.4, 69.5,
116.3, 118.2, 119.9, 126.1, 128.0, 129.1, 129.3, 129.4, 130.6, 145.4, 151.3,
168.9. MW: C20H23N5S2 (397). Elemental analysis: calcd C, 60.42; H,
5.83; N, 17.62; S, 16.13; found, C, 60.44; H, 5.85; N, 17.65; S, 16.15.
4.3. Biological assays
4.3.1. Antibacterial activity
A0 ꢀ As
The newly synthesized compounds were screened for antibac-
terial activity against E. coli (ATTC 25922), S. aureus (ATTC 25923),
P. aeruginosa (ATCC 27853) and K. pneumoniae (recultured) bacte-
rial strains by serial plate dilution method [27,28]. Serial dilutions
of the drug in Mullere-Hinton broth were taken in tubes and their
pH was adjusted to 5.0 using phosphate buffer. Standardized sus-
pension of the test bacterium was inoculated and incubated for 16e
18 h at 37 ꢁC. The minimum inhibitory concentration (MIC) was
noted by observing the lowest concentration of the drug at which
there was no visible growth. Agar media were poured into each
Petri dish. Excess suspension was decanted and plates were dried
by placing in incubator at 37 ꢁC for 1 h using an agar punch, wells
were made on these seeded agar plates and minimum inhibitory
concentrations of the test compounds in dimethylsulfoxide (DMSO)
were added into each labeled well. A control was also prepared for
the plates in the same way using solvent DMSO. The Petri dishes
Scavenging activityð%Þ ¼
ꢄ 100
A0
where As is the absorbance of the DPPHꢂ in the presence of the tested
compounds and standard and A0 is the absorbance of the DPPHꢂ in
the absence of the tested compound and standard (control).
Acknowledgments
This study was supported by FUBAP (grant number FF.11.38),
Elazig, Turkey.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.02.025.

346
M. Koparir et al. / European Journal of Medicinal Chemistry 63 (2013) 340e346
[17] S. Ozturk, M. Akkurt, A. Cansiz, M. Koparir, M. Sekerci, F.W. Heinemann, Acta
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