Chemical and pharmacological properties of 3-(thiophen-2-yl)-4-substituted- Δ2-1,2,4-triazoline-5-thiones

Article abstract of DOI:10.1080/10426500801968136

Three 3-(thiophen-2-yl)-4-substituted-Δ2-1,2,4-triazoline-5-thiones were synthesized by intramolecular cyclization of 1-(thiophen-2-ylcarbonyl)-4- substituted thiosemicarbazides in alkaline medium. Their effects on the central nervous system (CNS) of mice

Full text of DOI:10.1080/10426500801968136

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Chemical and Pharmacological
Properties of 3-(Thiophen-2-
2
yl)-4-substituted-Δ -1,2,4-
triazoline-5-thiones
Agata Siwek a , Monika Wujec a , Maria Dobosz a ,
Ewa Jagiełło-Wójtowicz b , Agnieszka Kleinrok b ,
Anna Chodkowska b & Piotr Paneth c
a Department of Organic Chemistry, Faculty of
Pharmacy , Medical University , Lublin, Poland
b Department of Toxicology , Medical University ,
Lublin, Poland
c Institute of Applied Radiation Chemistry, Technical
University of Lodz , Lodz, Poland
Published online: 07 Oct 2008.
To cite this article: Agata Siwek , Monika Wujec , Maria Dobosz , Ewa Jagiełło-
Wójtowicz , Agnieszka Kleinrok , Anna Chodkowska & Piotr Paneth (2008) Chemical
2
and Pharmacological Properties of 3-(Thiophen-2-yl)-4-substituted-Δ -1,2,4-
triazoline-5-thiones, Phosphorus, Sulfur, and Silicon and the Related Elements,
183:11, 2669-2677
To link to this article: http://dx.doi.org/10.1080/10426500801968136
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Phosphorus, Sulfur, and Silicon, 183:2669–2677, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500801968136
Chemical and Pharmacological Properties of 3-(Thiophen-
2-yl)-4-substituted-∆2-1,2,4-triazoline-5-thiones
Agata Siwek,1 Monika Wujec,1 Maria Dobosz,1
2
2
´
Ewa Jagiello-Wojtowicz, Agnieszka Kleinrok,
ꢀꢀ
Anna Chodkowska,2 and Piotr Paneth3
1Department of Organic Chemistry, Faculty of Pharmacy, Medical
University, Lublin, Poland
2Department of Toxicology, Medical University, Lublin, Poland
3Institute of Applied Radiation Chemistry, Technical University of Lodz,
Lodz, Poland
2
Three 3-(thiophen-2-yl)-4-substituted-ꢀ -1,2,4-triazoline-5-thiones were synthe-
sized by intramolecular cyclization of 1-(thiophen-2-ylcarbonyl)-4-substituted
thiosemicarbazides in alkaline medium. Their effects on the central nervous sys-
tem (CNS) of mice in some behavioral tests were investigated. All investigated com-
pounds displayed antinociceptive activity. The correlation between the structural
features and bioactivity has been discussed.
Keywords ꢀ2-1,2,4-Triazoline-5-thione; CHELPG; CNS-activity; DFT
INTRODUCTION
Organic compounds containing five-membered aromatic heterocyclic
rings are widely distributed in nature and often play an important role
in various biochemical processes. Thiophene and 1,2,4-triazole deriva-
tives belong to aromatic heterocyclic group, which constitutes an im-
portant structural fragment in many pharmaceutical and chemical
compounds. Thiophene and 1,2,4-triazole compounds have been found
to show nematocidal, insecticidal, antifungal, antiviral, antibacterial,
antitumor activity.1Apart from wide practical applications of these
compounds,2 they exhibit also interesting chemistry, including unre-
solved problem thiol-thione equilibrium.3 We have recently examined
a series of three 3-(2-methylfuran-3-yl)-1,2,4-triazoles with different
Received 9 January 2008; accepted 30 January 2008.
Address correspondence to Agata Siwek, Department of Organic Chemistry, Fac-
ulty of Pharmacy, Medical University, 6 Staszica Str., 20-081 Lublin, Poland. E-mail:
agata.siwek@am.lublin.pl
2669

2670
A. Siwek et al.
substituents at the N4 atom.4 Studies of antinociceptive and antide-
pressive activity indicated that the best effects were obtained with
phenyl substituent while the weakest influence was observed for 2-
methoxy-phenyl substituent at N4. In the literature, the influence of an
aromatic ring conjugated with the triazole ring has been analyzed, and
it has been postulated that the relative positions of these rings plays a
role in the strength of biological activity—the strongest effect has been
postulated for the rings being positioned perpendicularly. In an attempt
to further explore this suggestion, herein, we present studies of a se-
ries of three compounds with the same substituents at N4 as reported
earlier but with thiophen rather than 4-methylfuran as the second
substituent.
RESULTS AND DISCUSSION
Chemistry
The synthesis of the title compounds 2a−2c is illustrated in Scheme 1.
The preparation of the intermediate thiosemicarbazides 1a−1c was car-
ried out with the reaction of thiophen-2-carboxylic acid hydrazide with
isothiocyanates. The 1-(thiophen-2-ylcarbonyl)-4-substituted tiosemi-
carbazides 1a−1c, when subjected to reaction with 2% NaOH, un-
derwent intramolecular cyclization to furnish the corresponding 3-
(thiophen-2-yl)-4-substituted-ꢀ2-1,2,4-triazoline-5-thiones 2a−2c. The
structures of all compounds were confirmed by the results of elemental
analysis as well as by IR and 1H NMR. The characterization data and
the spectral data of original compounds, 1a−1c, 2b and 2c, are pre-
sented in Table I and Table II, respectively. Characterization data of
noted compound 2a were reported previously.4
SCHEME 1 Synthesis of the 1-(thiophen-2-ylcarbonyl)-4-substituted
thiosemicarbazides 1a−1c and 3-(thiophen-2-yl)-4-substituted-ꢀ2-1,2,4-
triazoline-5-thiones 2a−2c.

2
3-(Thiophen-2-yl)-4-substituted-ꢀ -1,2,4-triazoline-5-thiones
2671
TABLE I Characterization Data of Compounds 1a−1c and 2b, 2c
% Carbonyl % Hydrogen % Nitrogen
M.p. ◦
C Found Calcd. Found Calcd. Found Calcd.
Compound
no.
Yield
%
R
1a
1b
1c
2b
2c
C6H5
91 198−200 52.02 51.96 4.25
4.00 14.89 15.15
4.26 13.98 13.67
6.05 14.52 14.83
3.83 14.78 14.52
5.70 15.78 15.83
2-OCH3C6H4 89 167−169 50.45 50.79 4.12
C6H11
93 198−200 50.88 50.85 6.17
2-OCH3C6H4 87 253−255 53.87 53.96 3.64
C6H11
89 162−164 54.36 54.31 5.89
TABLE II Spectral Data of Compounds 1a−1c and 2b, 2c
Compound no.
1a
1b
1c
IR(KBr, ν in cm−1): 3319 ( NH), 3101, 1498 (ArH), 1661 (
C O),
1240 (
C
S), 756 (C
S
C); 1H-NMR: δ 7.13−7.46 (m, 6H,
thiophene 1H & 5ArH), 7.84−7.88 (m, 2H, thiophene H), 9.72,
9.88, 10.56 (3s, 3H, 3NH, D2O exchangeable).
IR(KBr, ν in cm−1): 3550 ( NH), 3030, 1497 (ArH), 2835, 1466, 1436
(
OCH3), 1670 ( C O), 1243 ( C S), 808 (C S
C); 1H-NMR: δ
3.75 (s, 3H, OCH3), 6.93−7.90 (m, 7H, thiophene 3H & 4ArH),
9.26, 9.82, 10.64 (3s, 3H, 3NH, D2O exchangeable).
IR(KBr, ν in cm−1): 3313 ( NH), 2933, 2855, 1447, 721 (Aliph.),
1642 (
C O), 1549, 1255 ( C S), 747 (C S
C); 1H-NMR: δ
1.03−1.77 (m, 10H, cyclohexane H), 4.13 (s, 1H, cyclohexane H),
7.17–7.20 (t(J=4.3), 1H, thiophene H), 7.83−7.85 (m, 2H, thiophene
H), 7.70, 9.21, 10.27 (3s, 3H, 3NH, D2O exchangeable).
2b
2c
IR(KBr, ν in cm−1): 3398 ( NH), 3071, 1600 (ArH), 2834, 1466
(
3.67 (s, 3H, OCH3), 6.83−6.85 (dd(J=1.2,3.8), 1H, thiophene H),
6.99−7.02 (dd(J=3.8,5.1), 1H, thiophene H), 7.13−7.18 (m, 1H,
ArH), ), 7.25−7.29 (dd(J=1.0,8.4), 1H, ArH), 7.40−7.43 (dd(J=1.8,7.8)
1H, ArH), 7.56−7.62 (m, 1H, ArH), 7.66−7.68 (dd(J=1.2,5.1), 1H,
thiophene H), 14.06 (s, 1H, NH, D2O exchangeable).
CH3), 1577 ( C N), 1259 ( C S), 794 (C S
C); 1H-NMR: δ
,
IR(KBr, ν in cm−1): 3313 ( NH), 2933, 2855, (Aliph.), 1577 (
C
N),
1270 (
C
S), 791 (C
S
C); 1H-NMR: δ 1.08−1.80 (m, 10H,
cyclohexane H), 4.14 (s, 1H, cyclohexane H), 7.17−7.22 (t(J=4.3)
,
1H, thiophene H), ), 7.80-7.86 (m, 2H, thiophene H), 14.30 (s, 1H,
NH, D2O exchangeable).

2672
A. Siwek et al.
Pharmacological Part
Preliminary behavioral study showed that 3-(thiophen-2-yl)-4-
substituted-ꢀ2-1,2,4-triazoline-5-thiones 2a−2c prolonged the
thiopental sleeping time. In the test of pentetrazole seizures compounds
2a and 2c showed weak antiepileptic action; they were active only in
the dose of 0.1 their LD50. Compounds 2a−2c displayed significantly
antinociceptive effect in the “writhing syndrome” test. Compound 2b
produced strong antinociceptive properties in a wide range of doses. Of
the three examined compounds, only 2b produced weak antidepressive
and antiserotoninergic activity in mice. In the remaining tests all
compounds were inactive.
Computational
Structures of molecules 2a−2c were optimized at the DFT level in the
gas phase and in water using continuum solvent model. No significant
differences between geometries obtained in both phases were observed.
Selected geometrical parameters are collected in Table III. Atom num-
bering is provided in Table I. Flatness of the rings was calculated as
the average of the five (thiophene, triazole) or six (phenyl, 2-methoxy-
phenyl) dihedral angles, in which each bond of the rings defined the
ledge of the angle. Several parameters that are frequently used in QSAR
studies on pharmacologically active compounds are collected in Table
IV. As can be seen, the volumes and surface areas of all three compounds
are similar, excluding the possibility that differentiation of the biolog-
ical activity originates in the molecular shape. The major differences
are geometries, in particular the angle between triazole and thiophene
rings.
Dipoles moments for 2a−2c are substantially higher than when 2-
methylfuran instead of thiophene is connected with the triazole ring.
However, they are in the same order, with the dipole moment of 2b
being the largest indicating that the electrostatic distribution in 2b dif-
fers from that in the other two molecules. These differences are illus-
trated graphically in Figure 1, in which electrostatic potential has been
mapped onto the electron density surface. Color coding of this figure
indicates electron rich space with red and electron deficient space with
blue. Color intensity corresponds to the magnitude of partial charge
in a given volume. Comparison of these three surfaces confirms higher
polarity of 2b and indicates that the major difference is in the vicin-
ity of the sulfur atom. This supports our previous conclusion that the
triazole moiety plays dominant role in the biological activity of these
molecules. It is worth noticing that these differences are not apparent

2
3-(Thiophen-2-yl)-4-substituted-ꢀ -1,2,4-triazoline-5-thiones
2673
◦
˚
TABLE III Selected Geometric Parameters (A, ) of
Molecules 2a−2c at B3PW91/6-31G(d)
2a
2b
2c
Bond distances
N1-N2
N2-C3
C3-N4
N4-C5
C5-N1
C5-C7
C7-S8
S8-C9
C9-C10
C10-C11
C11-C7
N4-C(R)
1.355
1.345
1.380
1.386
—
1.450
1.742
1.722
1.370
1.418
1.379
1.433
1.687
1.355
1.344
1.381
1.386
1.313
1.450
1.742
1.722
1.370
1.417
1.380
1.427
1.686
1.352
1.348
1.376
1.386
—
1.458
1.744
1.722
1.369
1.422
1.375
1.476
1.693
C3-S6
Valence angles
N1-N2-C3
N2-C3-S6
C3-N4-C(R)
N4-C5-C7
C7-S8-C9
Dihedral angles
N1-C5-C7-S8
Ring flatness
Thiophene
Triazole
114.3
128.1
124.6
127.1
91.5
114.3
128.1
124.3
127.3
91.6
114.3
125.7
127.3
126.5
91.6
155.9
174.6
120.5
0.0 0.1
0.0 0.7
0.0 0.4
0.00 0.03
0.0 0.4
0.0 0.5
0.0 0.8
0.0 0.9
—
R
Angles between rings
Triazole - R
Triazole - thiophene
82.3
24.0
87.6
5.4
—
59.5
TABLE IV Selected Properties of Molecules 2a−2c
2a
2b
2c
Dipole moment [D]
8.0
2.68
709
8.5
2.43
778
7.9
2.58
747
logP
Volume [A ]
3
˚
2
˚
Surface area [A ]
435
468
450
Hydration energy [kJ/mol]
Partial atomic charges
−60.0
−44.2
−35.7
S6
S8
−0.45
0.33
−0.45
0.33
−0.44
0.32
H(N2)
0.46
0.46
0.46

2674
A. Siwek et al.
FIGURE 1 CHELPG electrostatic potential of compounds 2a−2c (from left to
right) mapped on the electron density surfaces.
from the Mulliken partial charge analysis (see last 3 entries in Table
IV), indicating that the partial charges are frequently confusing and
not very informative.
In conclusion, we have found that CNS effects of investigated deriva-
tives 2a−2c are weak and only their antinociceptive properties could
be worth examining in more detail. Although at present the number of
biologically active compounds that we have characterized is too small
to launch full statistical analysis, our previous results5 obtained for an
analogous series of compounds seem to indicate that their bioactivity
is correlated with the charge distribution of the triazole ring. On the
other hand, we did not find a correlation with the conformation of the
auxiliary aromatic ring(s).
EXPERIMENTAL
Chemistry
Melting points were determined in a Fischer–Johns block and are un-
corrected. IR spectra (ν, cm−1) were recorded in KBr using a Specord
IR-75 spectrophotometer. 1H NMR spectra (δ, ppm) were recorded on a
Bruker Avance 300 in DMSO-d6 with TMS as internal standard.
1-(Thiophen-2-ylcarbonyl)-4-substituted Thiosemicarbazides
1a−1c
The thiophene-2-carboxylic acid hydrazide (0.01 mol) and appropri-
ate isothiocyanate (0.01 mol) were heated in an oil bath at 80◦C for 12
h. The formed product was washed with diethyl ether, next with hot
water, dried, and crystallized from ethanol.
3-(Thiophen-2-yl)-4-substituted-∆2-1,2,4-triazoline-5-thiones
2a−2c
The thiosemicarbazide derivative 1a−1c (0.01 mol) was dissolved in
2% NaOH (10 mL) and refluxed for 2 h. The reaction mixture was cooled

2
3-(Thiophen-2-yl)-4-substituted-ꢀ -1,2,4-triazoline-5-thiones
2675
and acidified with 3M HCl, whereupon a solid separated out. The solid
formed was filtered, dried, and crystallized from ethanol.
Pharmacology
The study was carried on Albino Swiss male mice (23−25 g). Compounds
2a−2c were administered intraperitoneally (ip) as a suspensions in a
1% solution of Tween 80. Control animals received the same volumes
(0.1 cm3/10 g to mice of the solvent). In all experiments compounds
were used in doses starting from 0.1 LD50 and decreasing gradually
until there were no further pharmacological activity. Each experimental
group consisted of 10 animals. This work has been approved by the
Ethics Committee of Medical University in Lublin.
The screening of CNS activity in mice was performed 30 min after
the administration of the derivatives in the tests described below. The
results obtained were presented as means and evaluated statistically
using Studentꢀs t-test or the exact Fischer test.
Motor coordination was quantified with the “chimney test.”6 The rec-
tal body temperature was measured by Ellab thermometer. Anxiolytic
properties were assessed by the “four plate” test.7 Antidepressive activ-
ity was measured by the “forced swimming” test.8 The thiopental (60
mg/kg ip) sleeping time of mice (from disappearance to return of the
righting reflex) was measured. Pain reactivity was measured in mice
by the “writhing syndrome” test.9 Antiepileptic activity was observed
in the pentetrazole (90 mg/kg sc)-induced seizures. Antiserotoninergic
effects were measured according to Corn et al.10
Computational Methods
All calculations were carried out at the DFT level using the hybrid
B3PW91 functional11 and the 6-31G(d) basis set12 as implemented
in Gaussian.13 Molecular geometries were fully optimized in the gas
phase. Vibrational analysis has been carried out to confirm identity of
the stationary points (3n-6 real vibrations). The default PCM implicit
solvent model14 with parameters corresponding to water was used. Par-
tial atomic charges were obtained using CHELPG electrostatic fitting
method.15 Electrostatic mapping on the density surface was performed
using GaussView program16 with default settings. QSAR module of
HyperChem17 was used in calculations of logP values.
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