Synthesis of New N-Benzoyl-N'-Triazine Thiourea Derivatives and Their Antibacterial Activity

Article abstract of DOI:10.1134/S106816201905008X

Abstract: A series of new N-benzoyl-N'-triazine thiourea derivatives have been synthesized via the reaction of 4-amino-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one with benzoyl chloride derivatives and ammonium thiocyanate in acetone under reflux conditions. 4-Amino-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one was prepared from the reaction of two equivalents of hydrazine hydrate with carbon disulfide and sodium pyruvate. The chemical structure of thioureas was confirmed using FT-IR, ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry, and elemental analysis. The synthesized thioureas were assayed for their antibacterial activity against both gram-positive (Micrococcusluteus and Bacilluscereus) and gram-negative (Pseudomonasaeruginosa and Escherichiacoli) bacteria using the agar well diffusion method.

Full text of DOI:10.1134/S106816201905008X

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2019, Vol. 45, No. 5, pp. 391–397. © Pleiades Publishing, Ltd., 2019.
Synthesis of New N-Benzoyl-N'-Triazine Thiourea Derivatives
and Their Antibacterial Activity
M. Marzia, K. Pourshamsiana, 1, F. Hatamjafaria, A. Shiroudib, 1, and A. R. Oliaeya
aDepartment of Chemistry, Faculty of Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, 46841-61167 Iran
bYoung Researchers and Elite Club, East Tehran Branch, Islamic Azad University, Tehran, 15847-43311 Iran
Received February 6, 2019; revised April 17, 2019; accepted May 11, 2019
Abstract—A series of new N-benzoyl-N'-triazine thiourea derivatives have been synthesized via the reaction
of 4-amino-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one with benzoyl chloride derivatives and
ammonium thiocyanate in acetone under reflux conditions. 4-Amino-6-methyl-3-thioxo-3,4-dihydro-
1,2,4-triazin-5(2H)-one was prepared from the reaction of two equivalents of hydrazine hydrate with carbon
disulfide and sodium pyruvate. The chemical structure of thioureas was confirmed using FT-IR, 1H NMR,
13C NMR, and high-resolution mass spectrometry, and elemental analysis. The synthesized thioureas were
assayed for their antibacterial activity against both gram-positive (Micrococcus luteus and Bacillus cereus) and
gram-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria using the agar well diffusion method.
Keywords: thiourea, triazin, hydrazine hydrate, sodium pyruvate, antibacterial
DOI: 10.1134/S106816201905008X
INTRODUCTION
In recent decades, there has been notable interest
in the studying of Schiff base compounds. Schiff
bases, containing various donor atoms, also find use in
metal coordination and analytical applications. Since
most compounds containing nitrogen and sulfur
atoms have biological activity, preparation of the cor-
responding compounds could be of interest from the
opinion of biological activity and chemical reactivity
[28–30]. 1,2,4-Triazines are well known as heterocy-
clic thiones derived from thiocarbohydrazide. A
number of their derivatives display biological activity
and have been used for different objectives, such as
Compounds containing carbonyl and thiocarbonyl
groups have an important role among organic reagents
as potential donor ligands [1–4]. There is significant
interest in the chemistry of nitrogen- and sulfur-con-
taining heterocyclic substances due to the fact that
they are multifunctional donors with nitrogen or sulfur
atoms. Thiourea and its derivatives are nitrogen- and
sulfur-containing compounds that display important
pharmaceutical and biological activities, therefore
they are useful materials in drug research [5, 6]. The
potential activities shown by this cores include anti-
convulsant [7], antitumor [8], insecticidal [9], fungi-
cidal [10], antimicrobials [11], anti-inflammatory [12], neutral antibiotics, antibacterials, herbicides, etc.
anti-hepatitis C [13], antidepressant [14], phosphodi-
esterases enzyme inhibitor [15], β-lactamase inhibitor
[16], and aromatase inhibitor [17] activities. In addi-
tion, some of the thiourea derivatives are highly active
in inhibiting formation of micelles, and denature pro-
teins [18, 19]. Most of thioureas that contain heterocy-
clic cores, such as thiadiazoles, triazoles, oxadiazoles,
and pyrazoles, in their structure indicate potent bio-
logical activities [20, 21]. A number of thioureas, as
1,2,4-Thiotriazines are well known compounds
derived from thiosemicarbazide and thiocarbohydra-
zide, some of which exhibit biological activity [31–
33]. In continuation of our previous research on
preparation of catalysts, organic compounds, and het-
erocycles and study of their biological activity [34–
38], herein we report synthesis of several new N-ben-
zoyl-N'-triazine thiourea derivatives. Products (Xa–g)
fungicides, have attracted widespread attention from were prepared through reaction of 4-amino-6-methyl-
researchers for decades [22]. Various studies have
shown that these compounds exhibit significant anti-
cancer activity against prostate cancer, lung cancer,
breast cancer, liver cancer, etc. [23–27].
3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (VI)
with benzoyl chloride derivatives (VIIa−g) and
ammonium thiocyanate (VIII) in good yield. In addi-
tion, antibacterial activity of N-benzoyl-N'-triazin
thiourea derivatives was evaluated against a set of
gram-positive and gram-negative bacteria.
1 Corresponding
(Kh. Pourshamsian); abolfazl.shiroudi@iauet.ac.ir (A. Shiroudi).
author:
e-mail:
Kshams49@gmail.com
391

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MARZI et al.
100
95
90
85
80
75
70
65
60
55
50
45
H
S
N
O
S
N
N–H
N
N
H
N
H
O
C=S
C=O
4000
3500
3000
2500
2000
1500
1000
500
Wavenumbers, cm–1
Fig. 1. FT-IR spectrum of thiourea (Xa).
ing vibration bands at υ 3447−3056 cm–1 for N−H, two
absorption bands in the regions of υ 1663−1728 cm–1
related to C=O and two stretching bands in the regions
of υ 1482−1608 cm–1 related to C=C bond; peaks in
the regions of 1236−1379 cm–1 suggest the presence of
the C=S group.
The 1H NMR spectra of triazine thioureas (Xb−g)
show a sharp singlet at δ 2.04–2.40 ppm due to the
protons of CH3 triazine rings and multiple signals in
the regions of δ 7.31−8.35 ppm due to the aromatic
protons. Amino protons appear as three single signals
at δ 9.92–13.79 ppm, while for compounds (Xc) and
(Xe), phenyl CH3 protons appear as a singlet signal at
RESULTS AND DISCUSSION
Synthesis of several N-benzoyl-N'-triazine thiourea
derivatives was carried out by treating benzoyl chlo-
ride (VII) with an equivalent of ammonium thiocya-
nate (VIII) in dry acetone followed by reaction with an
equivalent of 4-amino-6-methyl-3-thioxo-3,4-dihy-
dro-1,2,4-triazin-5(2H)-one (VI) to furnish the
thiourea derivatives (Xa−g) in good yields and excel-
lent purity. The product structures were confirmed
1
13
using FT-IR, H NMR, C NMR, and high-resolu-
tion mass spectrometry, and elemental analysis. The
Fourier transform infrared (FT-IR) spectra of synthe-
sized compounds showed similar trend of stretching
frequency modes. FT-IR spectrum of compound (Xa)
reveals the presence of three bands at 3327, 3166, and
3076 cm–1 for the N−H groups. Also, presence of two
peaks at 1713 and 1697 cm–1 indicates the existence of
C=O moiety and two peaks at 1296 and 1270 cm–1
indicate the C=S moiety (Fig. 1).
δ 2.36 and 2.49 ppm, respectively. The 13C NMR spec-
tra of triazine thioureas (Xb−g) show 10 to 13 signals
which are in agreement with the proposed structure of
compounds. High-resolution mass spectra of all the
thioureas showed molecular ion peaks. Also, elemen-
tal analysis data match with the theoretical values.
Intermediate (IX) was prepared from the reaction of
one equivalents of NH4SCN (VIII) with one equiva-
lent of benzoyl chloride (VII); color of reaction mix-
ture turned pale yellow. Later (IX) underwent an addi-
tion reaction with 4-amino-6-methyl-3-thioxo-3,4-
dihydro-1,2,4-triazin-5(2H)-one (VI) to produce
(Xa−g) with a color change of the reaction to orange.
1
The H NMR spectrum of compound (Xa) in
DMSO-d6 showed a singlet for CH3 (δ 2.18 ppm) and
a multiple singlet (δ 7.52–7.66 ppm), along with a
doublet (δ 7.9) for the aromatic protons and three
characteristic N–H protons at δ 12.11, 12.48, and
13
13.80 ppm (Fig. 2). The C NMR spectrum of com-
pound (Xa) showed ten signals in agreement with the
proposed structure. In this spectrum, the methyl car-
bon appeared at 17.0 and two C=O groups resonated at
δ 181.6 and 174.3 ppm, while two C=S resonated at
δ 168.2 and 141.0 ppm, respectively.
The novel N-benzoyl-N'-triazine thiourea deriva-
tives (Xa−g) were appraised for their in vitro antibac-
terial activity against two gram-positive (Micrococcus
luteus, ATCC 9341, and Bacillus cereus, ATCC 11778)
and two gram-negative (Pseudomonas aeruginosa,
Adhami et al. [39] have synthesized triazine ATCC 27853, and Escherichia coli, ATCC 25922) bac-
thioureas (Xa). The FT-IR spectra of triazine thiourea terial strains using the zone inhibition method [40].
derivatives (Xb−g) reveal the presence of three stretch- Penicillin and DMSO were used as positive and nega-
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SYNTHESIS OF NEW N-BENZOYL-N'-TRIAZINE THIOUREA DERIVATIVES
393
H
S
N
O
S
N
N
N
H
N
H
O
8.0
7.5
15 14 13 12 11 10
9
8
7
6
5
4
3
2
1
ppm
Fig. 2. 1H NMR spectrum of thiourea (Xa).
tive controls, respectively. DMSO showed no activity sized thioureas showed reasonable antibacterial activity
against gram-negative and gram-positive bacteria.
against afore-mentioned bacterial strains, while peni-
cillin showed the highest antibacterial activity against
all bacterial strains (Table 1). Antibacterial activity of
N-benzoyl-N'-triazine thiourea derivatives (Xa−g)
was measured at a concentration of 1000 g/mL in
DMSO. Each of the experiments was performed in trip-
licate. All data are reported as mean standard devia-
Thiourea derivatives with the electron withdrawing
substituents such as F, Cl, and NO2 showed better
antibacterial activity than the unsubstituted com-
pounds or those with electron donating substituents.
Compound (Xf) showed excellent activity against
M. luteus, while compound (Xg) showed good activity
tion in millimeter and shown in Table 1. All the synthe- against B. cereus. Lipophilicity is a very important
Table 1. Antimicrobial activity of N-benzoyl-N'-triazine thiourea derivatives (Xa–g)
Antimicrobial activity (zone of inhibition), mm
Entry
Product
gram-positive
gram-negative
P. aeruginosa
B. cereus
M. luteus
E. coli
1
2
3
4
5
6
7
8
9
(Xa)
(Xb)
11
27
17
25
18
26
28
−
12
15
14
19
13
32
21
−
9
16
11
14
12
21
14
−
8
9
(Xc)
8
(Xd)
11
16
21
12
−
(Xe)
(Xf)
(Xg)
DMSO
Penicillin
33
49
21
47
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 45 No. 5 2019

394
MARZI et al.
molecular descriptor, which is well suited to biochem- possess higher activity against gram-positive than
gram-negative bacteria.
ical activity, and the behavior of various lipophilic
compounds plays an important role in their biological
activity mechanisms.
EXPERIMENTAL
Chemicals and Reagents
CONCLUSIONS
All chemicals were obtained from Fluka and Merck
companies and used without additional purification.
Thin-layer chromatography HF254 fluorescent sil-
ica gel plates were examined under ultraviolet light at
254 nm. All melting points were recorded on an Elec-
trothermal-type 9100 melting points apparatus and are
uncorrected. FT-IR spectra (υ, cm–1) were obtained
We report a simple and efficient protocol for syn-
thesis of N-benzoyl-N'-triazine thiourea derivatives
(Xa−g) in good yields and excellent purity from reac-
tion of 4-amino-6-methyl-3-thioxo-3,4-dihydro-
1,2,4-triazin-5(2H)-one (VI) with benzoyl chloride
derivatives (VIIa−g) and ammonium thiocyanate (VIII)
under reflux conditions in dry acetone. The chemical
on a Shimadzu IR-470 spectrophotometer using KBr
structure of thioureas was characterized by FT-IR, disks. H and 13C NMR spectra (δ, ppm) were
1
1H NMR, 13C NMR, and high-resolution mass spec-
trometry, and elemental analysis. The antibacterial
recorded using Bruker DRX 250, 300 MHz spec-
trometer in acetone or DMSO-d6. High-resolution
activities of N-benzoyl-N'-triazine thiourea deriva- mass spectra (HRMS) were recorded by Agilent 6520
tives were estimated against four bacterial strains, (QTOF) ESI-HRMS machine. Elemental analyses
including M. luteus, B. cereus, P. aeruginosa, and were carried out on a Carlo-Erba EA1110 CNNO-S
E. coli. The results show that the thioureas derivatives analyzer and agreed with calculated values.
(II)
NH2NH2
H2O
S
S
EtOH
0−5oC
CS2
NH2NH2
+
H2NHN
O
SH
H2NHN
NHNH2
(IV)
NH2
N
(I)
(II)
(III)
S
S
O
H2O
H2NHN
NHNH2 + H3C
COO-Na+
reflux
HN
(V)
N
CH3
(IV)
(VI)
Scheme 1. Synthetic route for preparation of 4-amino-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one.
H
O
S
N
O
N
O
S
Cl
N
(VI)
Acetone
reflux
N
Acetone
reflux
CH3
C
N
H
N
NH4SCN
+
R
R
S
H
R
O
(VII)
(VIII)
(IX)
(X)
a) R = H
a) R = H
b) R = 4-NO2
c) R = 4-CH3
d) R = 2-Cl
e) R = 2-CH3
f) R = 4-Cl
b) R = 4-NO2
c) R = 4-CH3
d) R = 2-Cl
e) R = 2-CH3
f) R = 4-Cl
g) R = 4-F
g) R = 4-F
Scheme 2. Preparation of novel N-benzoyl-N'-triazine thioureas.
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SYNTHESIS OF NEW N-BENZOYL-N'-TRIAZINE THIOUREA DERIVATIVES
395
13
General Procedure for Preparation
of 4-Amino-6-Methyl-3-Thioxo-3,4-Dihydro-1,2,4-
Triazin-5(2H)One (VI)
10.46 (1H, s, N−H), 10.95 (1H, s, N−H). C NMR
(62.89 MHz, acetone-d6): 172.0 (C=O), 168.2 (C=O),
166.0 (C=S), 157.4 (C=S), 156.0 (C=N), 150.2 (C),
139.5 (C), 129.8 (C), 123.5 (C), 17.1 (CH3). HRMS
((+)-ESI): m/z = 366.0202 (calcd. 366.0205 for
C12H10N6O4S2). Anal. Calcd. for: C, 39.34; H, 2.75;
N, 22.94. Found: C, 39.37; H, 2.72; N, 22.91.
4-Amino-6-methyl-3-thioxo-3,4-dihydro-1,2,4-tri-
azin-5(2H)-one (VI) was prepared by reported chemi-
cal technique [41]. In a round-bottomed flask, thio-
carbohydrazide (IV) (1 mmol) was dissolved in 5 mL
distilled water at 60°C. To the resulting solution,
sodium pyruvate (V) (1 mmol) was added, and then
the reaction mixture was stirred for 30 min at reflux
conditions. The reaction progress was monitored using
thin-layer chromatography (CHCl3 : MeOH, 4 : 1).
After reaction completion, the resulting mixture was
cooled and neutralized with 2 N HCl. Finally, the
resultant precipitate was filtered, dried, and purified
using recrystallization in distilled water (Scheme 1).
4-Methyl-N-((6-methyl-5-oxo-3-thioxo-2,5-dihy-
dro-1,2,4-triazin-4(3H)-yl)carbamothioyl)benzamide (Xc).
Yellow powder, yield 85%, mp 192−194°C, FT-IR:
3321, 3160, 3082 (N−H), 2968 (C−Harom), 1727, 1713
(C=O), 1608, 1571 (C=C), 1378, 1236 (C=S).
1H NMR (250.13 MHz, DMSO-d6): 2.17 (3H, s,
CH3), 2.36 (3H, s, CH3), 7.31 (2H, d, J = 7.5 Hz,
Ar−H), 7.88 (2H, d, J = 7.5 Hz, Ar−H), 12.01 (1H, s,
N−H), 12.50 (1H, s, N−H), 13.79 (1H, s, N−H).
13C NMR (62.89 MHz, DMSO-d6): 181.7 (C=O),
174.3 (C=O), 168.0 (C=S), 151.0 (C=S), 147.6
(C=N), 143.9 (C), 129.6 (C), 129.4 (C), 129.1 (C),
21.6 (CH3), 17.0 (CH3). HRMS ((+)-ESI): m/z =
335.0509 (calcd. 335.0511 for C13H13N5O2S2). Anal.
Calcd. for: C, 46.55; H, 3.91; N, 20.88. Found: C,
46.51; H, 3.94; N, 20.85.
General Procedure for Preparation
of N-Benzoyl-N'-Triazine Thioureas (Xa−g)
Benzoyl chlorides (5 mmol) were added drop-wise
into a rotating solution of ammonium thiocyanate
(10 mmol) in dry acetone (10 mL). The reaction mix-
ture was stirred for 1 h under reflux conditions and
then cooled in ice bath. At the next step, a solution of
4-amino-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-
5(2H)-one (1 mmol) in dry acetone (5 mL) was added
to the reaction vessel and was stirred under reflux con-
ditions for another 4 h. After cooling, the reaction
mixture was poured into ice and water dish. Finally,
the resulting solid was filtered, washed with CHCl3,
recrystallized from EtOH (96%), and dried to afford
pure compounds (Xa−g) in good yield with high
purity (Scheme 2).
N-((6-Methyl-5-oxo-3-thioxo-2,5-dihydro-1,2,4-
triazin-4(3H)-yl)carbamothioyl)benzamide (Xa). Yel-
low powder, yield 85%, mp 320−323°C, FT-IR: 3327,
3166, 3076 (N−H), 2954 (C−Harom), 1713, 1697
(C=O), 1518, 1490 (C=C), 1296, 1270 (C=S).
1H NMR (250.13 MHz, DMSO-d6): 2.18 (3H, s, CH3),
7.52−7.66 (3H, m, Ar−H), 7.97 (2H, d, J = 6.7 Hz,
Ar–H), 12.11 (1H, s, N−H), 12.48 (1H, s, N−H),
13.80 (1H, s, N−H). 13C NMR (62.89 MHz, DMSO-d6):
181.6 (C=O), 174.3 (C=O), 168.2 (C=S), 151.0
(C=S), 147.6 (C=N), 133.9 (C), 132.0 (C), 129.3 (C),
129.0 (C), 17.0 (CH3). HRMS ((+)-ESI): m/z =
321.0350 (calcd. 321.0354 for C12H11N5O2S2). Anal.
Calcd. for: C, 44.85; H, 3.45; N, 21.79. Found: C,
44.81; H, 3.48; N, 21.75.
2-Chloro-N-((6-methyl-5-oxo-3-thioxo-2,5-dihy-
dro-1,2,4-triazin-4(3H)-yl)carbamothioyl)benzamide (Xd).
Pale yellow powder, yield 79%, mp 226−228°C, FT-IR:
3332, 3164, 3089 (N−H), 2972 (C−Harom), 1727, 1687
1
(C=O), 1515, 1498 (C=C), 1377, 1281 (C=S). H
NMR (250.13 MHz, acetone-d6): 2.26 (3H, s, CH3),
7.49−7.56 (3H, m, Ar−H), 7.73 (1H, d, J = 7.2 Hz,
Ar–H), 11.20 (1H, s, N−H), 12.36 (1H, s, N−H),
12.74 (1H, s, N−H). 13C NMR (62.89 MHz, acetone-d6):
180.9 (C=O), 174.4 (C=O), 167.1 (C=S), 150.6
(C=S), 147.3 (C=N), 133.7 (C), 132.6 (C), 130.8 (C),
130.0 (C) 129.5 (C), 127.2 (C), 16.0 (CH3). HRMS
((+)-ESI): m/z = 354.9961 (calcd. 354.9964 for
C12H10ClN5O2S2). Anal. Calcd. for: C, 40.51; H, 2.83;
N, 19.68. Found: C, 40.54; H, 2.80; N, 19.65.
2-Methyl-N-((6-methyl-5-oxo-3-thioxo-2,5-dihy-
dro-1,2,4-triazin-4(3H)-yl)carbamothioyl)benzamide (Xe).
Yellow powder, yield 87%, mp 212−213°C, FT-IR:
3328, 3138, 3074 (N−H), 2961 (C−Harom), 1711, 1689
1
(C=O), 1507 (C=C), 1379, 1316 (C=S). H NMR
(300.13 MHz, acetone-d6): 2.27 (3H, s, CH3), 2.49
(3H, s, CH3), 7.31−7.36 (2H, m, Ar−H), 7.48 (1H, t,
J = 7.5 Hz, Ar−H), 7.63 (1H, d, J = 7.5 Hz, Ar−H),
11.05 (1H, s, N−H), 12.54 (1H, s, N−H), 12.81 (1H, s,
N−H). 13C NMR (75.56 MHz, acetone-d6): 181.5
(C=O), 174.6 (C=O), 170.0 (C=S), 150.7 (C=S),
N-((6-Methyl-5-oxo-3-thioxo-2,5-dihydro-1,2,4-
triazin-4(3H)-yl)carbamothioyl)-4-nitrobenzamide (Xb). 147.3 (C=N), 136.9 (C), 133.4 (C), 131.5 (C), 131.1
Yellow powder, yield 75%, mp 232−234°C, FT-IR: (C), 127.8 (C), 125.8 (C), 19.0 (CH3), 16.0 (CH3).
3390, 3320, 3265 (N−H), 3156 (C−Harom), 1724, 1691
HRMS ((+)-ESI): m/z = 335.0508 (calcd. 335.0511
(C=O), 1600, 1482 (C=C), 1523, 1350 (NO2), 1322, for C13H13N5O2S2). Anal. Calcd. for: 46.55; H, 3.91;
1
N, 20.88. Found: 46.58; H, 3.88; N, 20.84.
1236 (C=S). H NMR (250.13 MHz, acetone-d6):
2.04 (3H, s, CH3), 8.20 (2H, d, J = 6.7 Hz, Ar−H),
4-Chloro-N-((6-methyl-5-oxo-3-thioxo-2,5-dihy-
8.35 (2H, d, J = 6.7 Hz, Ar−H), 9.92 (1H, s, N−H), dro-1,2,4-triazin-4(3H)-yl)carbamothioyl)benzamide (Xf).
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MARZI et al.
Yellow powder, yield 81%, mp 183−185°C, FT-IR:
3334, 3254, 3056 (N−H), 2923 (C−Harom), 1726, 1663
(C=O), 1520, 1483 (C=C), 1375, 1255 (C=S).
1H NMR (250.13 MHz, DMSO-d6): 2.40 (3H, s,
CH3), 7.64 (2H, d, J = 8.0 Hz, Ar−H), 8.11 (2H, d,
J = 8.0 Hz, Ar−H), 11.82 (1H, s, N−H), 12.69 (1H, s,
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COMPLIANCE WITH ETHICAL STANDARDS
This article does not contain any studies involving
human participants performed by any of the authors and
does not contain any studies involving animals performed
by any of the authors.
Conflict of Interests
The authors declare that they have no conflicts of interest.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 45
No. 5
2019

SYNTHESIS OF NEW N-BENZOYL-N'-TRIAZINE THIOUREA DERIVATIVES
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