Synthesis and theoretical characterization of some new 4-substituted-1,3- diphenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazoles with potential pharmacological activity

Article abstract of DOI:10.1002/hc.20499

Synthesis of some new triazoles fused to triazoles 5a-c or thiadiazoles 6a-c and the thiolthione tautomeric equilibrium study of the title compounds are reported. The "rule of five" and complementary criteria of pharmacokinetic properties were determined

Full text of DOI:10.1002/hc.20499

Heteroatom Chemistry
Volume 19, Number 7, 2008
Synthesis and Theoretical Characterization of
Some New 4-Substituted-1,3-diphenyl-5-
thioxo-4,5-dihydro-1H-1,2,4-triazoles with
Potential Pharmacological Activity
Agata Siwek,1 Monika Wujec,1 Maria Dobosz,1 and Piotr Paneth2
1Department of Organic Chemistry, Faculty of Pharmacy, Medical University,
Staszica 6, 20-081 Lublin, Poland
2Institute of Applied Radiation Chemistry, Technical University of Lodz, Zeromskiego 116,
90-924 Lodz, Poland
Received 13 May 2008; revised 7 August 2008
thiadiazoles, are known to be antibacterially, an-
ABSTRACT: Synthesis of some new triazoles fused
tivirostatically, and CNS active [1]. For this rea-
to triazoles 5a–c or thiadiazoles 6a–c and the thiol-
son, they often appear as a building element
thione tautomeric equilibrium study of the title com-
in drug molecules [2]. The most common pro-
pounds are reported. The “rule of five” and comple-
cedure for the synthesis of 1,3,4-trisubstituted-5-
mentary criteria of pharmacokinetic properties were
thioxo-4,5-dihydro-1H-1,2,4-triazole consists of two
determined to predict whether these compounds are
steps: the first one is the intramolecular, dehydra-
orally bioavailable. Semiempirical parameterizations
tive cyclization of 1-acyl-4-disubstituted thiosemi-
have been critically benchmarked for the thiol-thione
carbazide, and the second step is the substitu-
tautomeric equilibrium against the DFT calculations.
tion of the proton at N1 of the triazole ring.
It was shown that unlike the AM1 and PM3 Hamil-
Herein, we present an alternative synthetic method,
tonians, which erroneously predict higher stability of
which uses N1-phenyl benzamidrazone hydrochlo-
the thiol tautomer, the newly developed RM1 Hamil-
ride 1 as the starting compound. Obtained prod-
tonian, on the other hand, predicts energetics of this
uct, 4-ethoxycarbonylmethyl-1,3-diphenyl-5-thioxo-
equilibrium in excellent agreement with the DFT re-
4,5-dihydro-1H-1,2,4-triazole 2, by the transforma-
ꢀ
C
sults.
2008 Wiley Periodicals, Inc. Heteroatom Chem
tion of the acetate residue located at N4 gives
triazoles fused to triazoles or thiadiazoles (com-
pounds composed of two 1,2,4-triazoles 5a–c or
1,2,4-triazole and 1,3,4-thiadiazole 6a–c, respec-
tively). Compounds 4a–c, 5a–c, and 6a–c are rea-
sonable potential candidates as bioactive substances
because they satisfy Lipinski’s rule of five [3] and
complementary criteria [4].
One of the interesting properties of mercapto-
substituted triazoles is the existence of thiol and
thione tautomeric forms. As tautomerization plays
a significant role in several processes related to
bioactivity, such as proton transfer and hydrogen
19:713–718, 2008; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20499
INTRODUCTION
Sulfur-containing compounds, such as thiosemi-
carbazides, mercapto-1,2,4-triazoles, and 1,3,4-
Correspondence to: Agata Siwek; e-mail: agata.siwek@am.lublin.
pl.
c
ꢀ
2008 Wiley Periodicals, Inc.
713

714 Siwek et al.
to NH and at 1308–1352 cm−1 attributed to C S in
agreement with our earlier calculations for both tau-
tomers [6].
The pharmacokinetic properties of 4-subs-
tituted-1,3-diphenyl-5-thioxo-4,5-dihydro-1H-1,2,4-
triazoles 5a–c and 6a–c were established for
determining whether the compounds will be orally
bioavailable. All compounds obey Lipinski’s “rule
of five” and complementary criteria as shown in
Table 3.
bonding, we became interested in the thiol-thione
tautomerism of the new title compounds. There-
fore, part of our studies has been devoted to the
tautomeric equilibrium. We have applied the DFT
level in our previous studies [5–7] of this tautomeric
equilibria because both AM1 and PM3 parameteri-
zations lead to higher stability of the thiol form in
disagreement with the DFT results and the experi-
mental data [8]. Herein, we have tested the perfor-
mance of the newly developed RM1 method [9] and
have shown that it predicts relative stability of the
tautomers in excellent agreement with the DFT re-
sults. Furthermore, calculations on oxo-analogues of
the thio-tautomers allowed us to pinpoint the prob-
lems with AM1 and PM3 calculations to the param-
eterization of the sulfur atom.
Computational Part
The title compounds are considerably large for
theoretical calculations especially when a routine
calculation is desired to evaluate a priori phar-
macokinetic parameters at the quantum level. Our
previous experience with fast semiempirical cal-
culations was, however, discouraging because the
two most robust parameterizations (AM1 and PM3)
proved inadequate in describing tautomeric equilib-
ria of the class of compounds studied here. Thus far
we have, therefore, used DFT hybrid functionals. In
the present study, we have explored the performance
of the newly developed RM1 parameterization that
is supposed to outperform both AM1 and PM3 by fix-
ing their major deficiencies. As presented in Table 4,
our calculations support this claim in the case of
compounds studied here. The data collected in this
table refer to 4-methyl-1,2,4-triazoline-5-thione (X =
S) and 4-methyl-1,2,4-triazoline-5-one (X = O) for
which DFT calculations were partly available [7].
Although AM1 and PM3 erroneously predict higher
stability of the thiol tautomer, RM1 yields this ener-
getics correctly, with very good agreement with the
results obtained at the DFT level. A comparison of
the results obtained for thio- with oxo-compounds
indicates that the RM1 method is an improvement
over the older parameterizations. Furthermore, it al-
lows us to point to parameters of the sulfur atom as
the source of the error because all three semiem-
pirical methods that were tested predicted higher
stability of the NH tautomeric form for X = O.
RESULTS AND DISCUSSION
Chemistry
The synthesis pathway leading to the title com-
pounds is given in Scheme 1. N1-phenyl ben-
zamidrazone hydrochloride, staring material 1,
4-ethoxycarbonylmethyl-1,3-diphenyl-5-thioxo-4,5-
dihydro-1H-1,2,4-triazole 2, and 1,3-diphenyl-5-
thioxo-4,5-dihydro-1H-1,2,4-triazole-4-acetic acid
hydrazide 3 were synthesized according to the
literature method [10]. The reaction of hydrazide
3 with aryl isothiocyanates afforded 4-aryl-1-[(1,3-
diphenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-4-yl)
acetyl]thiosemicarbazides 4a–c with 86%–91%
yields. Cyclization of 4a–c using 2% NaOH gave 4-
aryl-3-[(1,3-diphenyl-5-thioxo-4,5-dihydro-1H-1,2,
4-triazol-4-yl)methyl]-4,5-dihydro-1H-1,2,4-triazol-
5-thiones 5a–c in 87%–89% yields. 2-Arylamino-
5-[(1,3-diphenyl-5-thioxo-4,5-dihydro-1H-1,2,4-tri-
azol-4-yl)methyl]-1,3,4-thiadiazoles
6a–c
were
obtained with 52%–56% yields by cyclization of
4a–c in concentrated H2SO4.
The structures of all compounds were confirmed
by the results of elemental analysis as well as by
1
IR and H NMR. The characterization and spectral
In conclusion, we have presented an alterna-
tive synthetic route for 1,3,4-trisubstituted-5-thioxo-
4,5-dihydro-1H-1,2,4-triazole. Based on the calcu-
lated parameters described by Lipinski and Veber,
it was found that compounds 4a–c, 5a–c, and 6a–
c are reasonable potential candidates as bioactive
substances. In addition, we have shown that the
new semiempirical method RM1 is capable of ef-
ficiently providing energetic and geometrical infor-
mation about this class of compounds.
data of original compounds 4b, 4c, 5b, 5c and 6a–c,
are presented in Table 1 and Table 2, respectively.
Characterization data of noted compounds 4a and
5a were reported earlier in [11].
1
The H NMR spectra of 5a–c show a sharp sin-
glet at 13.8–13.9 ppm, typical for the proton linked to
N1, indicating the presence the thione tautomer. The
domination of the thione form was observed also in
the IR. The infrared spectra of 5a–c showed an ab-
sorption in the region 3306–3356 cm−1, attributed
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Theoretical Characterization of 4-Substituted-1,3-Diphenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazoles 715
N
N
+ SCNCH2COOC2H5
N
NH
S
N
C
CH2COOC2H5
NH2 HCl
1
2
+ NH2NH2
N
N
N
N
S
RNCS
N
S
N
CH2CNHNHCNHR
CH2CNHNH2
O
S
O
4a–c
3
2% NaOH
H2SO4
S
S
N
N
N
NH
N
N
N
CH2
N
NH
R
CH2
N
N
S
S
N
R
6a–c
S
N
N
N
CH2
N
N
SH
N
R
5a–c
R = C6H5 (a), 4-CH3C6H4 (b), 4-OCH3C6H4 (c)
SCHEME 1
Synthesis of the 4-aryl-1-[(1,3-diphenyl-5-thioxo-3,4-dihydro-1H-1,2,4-triazol-4-yl)acetyl]thiosemicarbazide
4a–c, 4-aryl-3-[(1,3-diphenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-4-yl)methyl]-4,5-dihydro-1H-1,2,4-triazol-5-thiones 5a–c,
and 2-arylamino-5-[(1,3-diphenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-4-yl)methyl]-1,3,4-thiadiazoles 6a–c.
Heteroatom Chemistry DOI 10.1002/hc

716 Siwek et al.
TABLE 1 Characterization Data of Compounds 4b, 4c, 5b, 5c, and 6a–c
Percent Carbonyl
Percent Hydrogen
Percent Nitrogen
Compound No.
R
Yield (%) MP (◦C) Calcd
Found
Calcd
Found
Calcd
Found
4b
4c
5b
5c
6a
6b
6c
4-CH3C6H4
4-OCH3C6H4
4-CH3C6H4
4-OCH3C6H4
C6H5
4-CH3C6H4
4-OCH3C6H4
86
91
87
89
52
55
56
196–168 60.74
223–225 58.76
251–253 63.13
233–235 61.00
220–222 62.42
170–172 63.13
253–255 61.00
60.55
58.51
63.22
60.69
62.62
63.22
60.69
4.67
4.52
4.42
4.27
4.10
4.42
4.27
4.62
4.44
4.56
4.26
3.89
4.44
4.30
17.71
17.13
18.41
17.78
18.99
18.41
17.78
17.56
16.96
18.26
17.93
19.20
18.53
17.52
TABLE 2 Spectral Data of Compounds 4b, 4c, 5b, 5c, and 6a–c
Compound No.
Spectral Data
4b
4c
5b
5c
6a
6b
6c
IR (KBr, ν in cm−1): 3356 ( NH), 2990, 1570, 807 (ArH), 2839, 1454 (Aliph.), 1686 ( C O), 1262
( C S), 751 (C S C); 1H NMR δ: 2.3 (s, 3H, CH3), 4.9 (s, 2H, CH2), 7.1–8.0 (m, 14H, ArH), 9.5, 9.8,
10.6 (3s, 3H, 3NH, D2O exchangeable)
IR (KBr, ν in cm−1): 3342 ( NH), 2996, 1568, 824 (ArH), 2830, 1460 (Aliph.), 1679 ( C O), 1259
( C S), 801 (C S C); 1H NMR δ: 3.8 (s, 3H, OCH3), 4.9 (s, 2H, CH2), 6.9–8.3 (m, 14H, ArH), 9.4,
9.8, 10.6 (3s, 3H, 3NH, D2O exchangeable)
IR (KBr, ν in cm−1): 3306 ( NH), 3040, 1567, 818 (ArH), 2831, 1467 (Aliph.), 1594 ( C N), 1352, 1276
( C S); 1H NMR δ: 2.4 (s, 3H, CH3), 5.2 (s, 2H, CH2), 7.3–8.0 (m, 14H, ArH), 13.9 (s, 1H, NH, D2O
exchangeable)
IR (KBr, ν in cm−1): 3356 ( NH), 3022, 1571, 826 (ArH), 2840, 1465 (Aliph.), 1590 ( C N), 1308, 1261
( C S); 1H NMR δ: 3.8 (s, 3H, OCH3), 5.1 (s, 2H, CH2), 7.1–8.3 (m, 14H, ArH), 13.8 (s, 1H, NH, D2O
exchangeable)
IR (KBr, ν in cm−1): 3298 ( NH), 2931, 1586, 759 (ArH), 2825, 1451 (Aliph.), 1624 ( C N), 1343, 1260
( C S), 790 (C S C); 1H NMR δ: 5.6 (s, 2H, CH2), 7.0–8.1 (m, 15H, ArH), 10.4 (s, 1H, NH, D2O
exchangeable)
IR (KBr, ν in cm−1): 3283 ( NH), 3020, 1578, 845 (ArH), 2822, 1450 (Aliph.), 1621 ( C N), 1212, 1145
( C S), 798 (C S C); 1H NMR δ: 2.3 (s, 3H, CH3), 5.6 (s, 2H, CH2), 7.1–8.1 (m, 14H, ArH), 10.3 (s,
1H, NH, D2O exchangeable)
IR (KBr, ν in cm−1): 3294 ( NH), 2995, 1564, 864 (ArH), 2819, 1455 (Aliph.), 1615 ( C N), 1293, 1156
( C S), 801 (C S C); 1H NMR δ: 3.8 (s, 3H, OCH3), 5.6 (s, 2H, CH2), 6.9–8.1 (m, 14H, ArH), 10.2 (s,
1H, NH, D2O exchangeable)
EXPERIMENTAL
Chemistry
Synthesis of 4-Aryl-3-[(1,3-diphenyl-5-thioxo-4,5-
dihydro-1H-1,2,4-triazol-4-yl)methyl]-4,5-dihydro-
1H-1,2,4-triazol-5-thiones (5a–c). The thiosemicar-
bazide derivative 4a–c (0.01 mol) was dissolved in
2% NaOH (10 mL) and refluxed for 2 h. The reaction
mixture was cooled and acidified with 3M HCl,
whereupon a solid was separated. The formed solid
was filtered, dried, and crystallized from ethanol.
Melting points were determined in a Fischer–Johns
block and are uncorrected. IR spectra (ν, cm−1) were
recorded in KBr using a Specord IR-75 spectropho-
tometer. 1H NMR spectra (δ, ppm) were recorded on
a Bruker Avance 300 in DMSO-d6 with TMS as an
internal standard.
Synthesis of 2-Arylamino-5-[(1,3-diphenyl-5-
thioxo-4,5-dihydro-1H-1,2,4-triazol-4-yl)methyl]-1,3,
Synthesis of 4-Aryl-1-[(1,3-diphenyl-5-thioxo-4,5-
dihydro-1H-1,2,4-triazol-4-yl)acetyl]thiosemicarba-
4-thiadiazoles
(6a–c). The
thiosemicarbazide
zides
(4a–c). 1,3-Diphenyl-5-thioxo-4,5-dihydro-
derivative 4a–c (0.01 mol) was dissolved in con-
centrated H2SO4 (10 mL). The solution was kept
at room temperature for 2 h and then poured
into crushed ice to precipitate a crude solid. The
product was then filtered, dried, and crystallized
from ethanol.
1H-1,2,4-triazole-4-acetic acid hydrazide 3 (0.01
mol) and appropriate isothiocyanate (0.01 mol)
were heated in an oil bath at 70◦C for 12 h. The
formed product was washed with diethyl ether, later
with hot water, dried, and crystallized from ethanol.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Theoretical Characterization of 4-Substituted-1,3-Diphenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazoles 717
TABLE 3 Pharmacokinetic and QSAR Propertiesa of 4a–c, 5a–c, and 6a–c
Compound Mw Hydratation Energy ꢀHSH -NH H-bond donors
Polarizability
Surface area
Molar refractivity
No.
4a
4b
4c
5a
5b
5c
6a
6b
6c
Log P
Volume
HOF
H-bond acceptors Rotable bonds Polar surface area Dipole moment
460.6
3.02
474.6
3.47
490.6
3.08
442.6
3.39
456.6
3.84
472.6
3.44
442.6
4.94
456.6
5.39
−14.7
1224.0
−13.5
1275.3
−16.3
1298.3
−10.9
1136.3
−9.9
–
3
7
3
7
3
8
1
6
1
6
1
7
1
6
1
6
1
7
52.4
8
54.3
8
54.9
9
51.2
5
53.0
5
53.6
6
50.6
6
52.4
6
686.1
75.9
713.5
75.9
726.8
85.1
627.1
56.4
650.4
56.4
667.3
65.6
695.9
60.6
724.9
60.6
133.6
6.6
138.7
6.5
140.1
5.3
128.4
7.4
133.4
7.5
134.8
6.5
129.9
6.7
134.9
6.8
1275.1
–
1301.0
–
1362.2
11.2
1269.2
8.7
1295.0
8.8
1356.0
–
1271.2
–
1297.9
–
1359.8
1184.3
−12.4
1213.5
−12.0
1190.5
−10.7
1242.0
−13.5
1267.2
472.6
4.99
53.1
7
740.5
69.8
136.3
7.4
a
2
3
˚
˚
Energies in kcal/mol, surfaces in A , and volumes in A .
TABLE 4 Calculated Enthalpy differences (see text)
S.-E. W. Drug Metabol Dispos 1998, 26, 838–847;
(c) Sahin, G.; Palaska, E.; Kelicen, P.; Demirdamar,
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Theory Level
AM1
X
ꢀHSH -NH (kcal/mol)
S
O
S
O
S
O
S
O
−1.3
9.5
PM3
−3.9
12.0
13.4
15.4
14.8
18.0
RM1
B3PW91/6-31G(d)
Computational Methods
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[5] Siwek, A. Ph.D. Thesis, Medical Academy, Lublin,
Poland, 2007.
[6] Siwek, A.; Wujec, M.; Dobosz, M.; Wawrzycka-
Gorczyca, I.; Paneth, P. Heteroatom Chem 2008, 19,
337–344.
[7] (a) Wujec, M.; Paneth, P. J Phys Org Chem 2007,
20, 1043–1049; (b) Wujec, M.; Paneth, P. J Phys Org
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31G(d) basis set [13] as implemented in Gaussian
[14]. Semiempirical calculations were performed us-
ing AM1, PM3, and RM1 parameterizations as imple-
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were fully optimized in the gas phase to gradients
˚
˚
of 0.3 kcal/(mol A) for DFT and 0.01 kcal/(mol A) for
semiempirical levels, respectively. Vibrational analy-
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Heteroatom Chemistry DOI 10.1002/hc