Synthesis and Investigation of the Antibacterial Activity of New Tris-Thiourea Derivatives

Article abstract of DOI:10.1007/s11094-021-02372-6

An efficient procedure for the preparation of symmetrical tris-thiourea derivatives (5a – 5h) by means of one-pot condensation reaction between available benzoyl chlorides (1a –1h) with potassium thiocyanate (2) and melamine (4) under reflux conditions is

Full text of DOI:10.1007/s11094-021-02372-6

DOI 10.1007/s11094-021-02372-6
Pharmaceutical Chemistry Journal, Vol. 55, No. 1, April, 2021 (Russian Original Vol. 55, No. 1, January, 2021)
SYNTHESIS AND INVESTIGATION
OF THE ANTIBACTERIAL ACTIVITY
OF NEW TRIS-THIOUREA DERIVATIVES
Saghi Shiroud Ghorbani,1 Naser Montazeri,1,*
Masoud Mohammadi Zeydi,1 and Masood Ghane2
Original article submitted January 23, 2020.
An efficient procedure for the preparation of symmetrical tris-thiourea derivatives (5a – 5h) by means of
one-pot condensation reaction between available benzoyl chlorides (1a –1h) with potassium thiocyanate (2)
and melamine (4) under reflux conditions is presented. All the synthesized tris-thioureas were evaluated for
their biological activities against a group of Gram-positive (Staphylococcus aureus and Bacillus cereus) and
Gram-negative (Escherichia coli) bacteria. The synthesized compounds showed no activity against P.
aeruginosa. All compounds exhibited excellent antibacterial activity against indicated bacterial strains. The
new products were characterized using FT-IR, 1H and 13C NMR spectra, and elemental analysis.
Keywords: symmetrical tris-thioureas, benzoyl chlorides, potassium thiocyanate, melamine, antibacterial ac-
tivity.
1. INTRODUCTION
bial [2] and herbicidal [3]. Some triazine derivatives showed
anti-oxidant [4], anticoccidial [5], and herbicidal [6] activi-
ties. They were also used as potential therapeutic agents for
diseases related to HIV infection [7], bacteria [8, 9], tumors
[10, 11], cancer [12], and malaria [13, 14]. Furthermore,
thiourea and its derivatives are the topic of significant inter-
est because of their productivity in medicinal chemistry due
to their biological activity as herbicides, fungicides [15],
phosphodiesterase enzyme inhibitor [16], and antiprolife-
rative agents [17]. Thiourea derivatives exhibit antimicrobial
[18], anti-inflammatory [19], anti-hepatitis [20], and antican-
cer [21] activities. These compounds are noteworthy build-
ing blocks for the synthesis of guanidines, amides, and some
types of heterocycles [22]. For these reasons, several meth-
ods have been reported for the preparation of thioureas.
Among these procedures, condensation of amines with iso-
thiocyanate or its derivatives constitutes the most widely ac-
cepted general procedure [23]. Notwithstanding their toxic-
ity, the use of these materials remains inevitable because of
the importance of thioureas and its derivatives in medicinal
field [24]. Thus, new nontoxic and safer methods to synthe-
size thioureas are yet to be developed. Consequently, combi-
nation of the two cores in one molecule may lead to increase
in all useful biological properties.
The identification of heterocyclic rings as effective struc-
tures in drug exploration is, undoubtedly, one of the attrac-
tive fields in pharmaceutical chemistry. These special struc-
tures represent a group of compounds that act as ligands for
various biological receptors with a vast degree of binding af-
finity. Infections caused by multi-drug resistant microorgan-
isms pose a profound challenge to the medical community
and the need for a serious therapy has led to a search for new
antimicrobial agents. Utilization of these compounds should
allow us to quickly discover new biologically active mole-
cules possessing a wide range of therapeutic activities on a
shorter time scale [1].
In this article, we report the synthesis and biological ac-
tivity of some tris-thiourea derivatives containing triazine
core as a class of privileged molecules that have a broad
range of biological properties. Among the structures having
high antimicrobial activities, triazine derivatives constitute a
valuable group of heterocycles possessing various pharma-
cological properties including broadly active as antimicro-
1
Department of Chemistry, Faculty of Sciences, Islamic Azad University,
Tonekabon Branch, Tonekabon, Iran.
2
Department of Microbiology, Islamic Azad University, Tonekabon
Branch, Tonekabon, Iran.
*
e-mail: montazer1350@gmail.com
60
0091-150X/21/5501-0060 © 2021 Springer Science+Business Media, LLC

Synthesis and Investigation of the Antibacterial Activity
61
2. EXPERIMENTAL
N,N¢,N²-(((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris-
(carbonothioyl))tris(4-ethylbenzamide) (5c). Yield: 89%;
M.P. 241 – 243°C; FT-IR (KBr): n 3431, 3325 (N-H, str.),
2.1. Materials and Methods
3093 (C-H
str.), 2982 (C-H
str.), 1668 (C=O str.),
aliph
All materials used for the preparation of thioureas were
obtained from Merck and Fluka Company, and used without
purification. The product structures were identified by their
FT-IR, 1H and 13C NMR, and elemental analyses. The melt-
ing points were measured on Electrothermal Type 9100 melt-
ing points apparatus and remained uncorrected. FT-IR spec-
tra (n, cm-1) were recorded on Shimadzu IR-470
arom
1604 (C=N str.), 1555, 1527 (C=C str.), 1309 (C=S str.),
1151 (C-N Str.) cm-1. H NMR (250 MHz, DMSO-d ): d
1
6
1.24 (3H, t, J = 8.0 Hz, CH ), 2.30 (2H, q, J = 6.7 Hz, CH ),
3
2
7.30 (6H, d, J = 8.0 Hz, 6CH), 7.39 (3H, s, 3NH), 7.78 (6H,
d, J = 8.0 Hz, 6CH), 11.09 (3H, s, 3NH) ppm. 13C NMR
(63 MHz, DMSO-d ): d 173.5, 167.9, 162.3, 143.3, 131.4,
6
1
spectrophotometer using KBr pellets. The H and 13C NMR
129.3, 129.1, 23.0, 12.9 ppm. Anal. calcd. for
C H N O S : C, 56.63; H, 4.75; N, 18.01. Found: C, 56.65;
spectra were recorded on Bruker DRX 250 MHz spectrome-
33 33
9
3 3
H, 4.72; N, 18.04.
ter using DMSO-d as a solvent and TMS as an internal stan-
6
N,N¢,N²-(((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris-
(carbonothioyl))tris(4-nitrobenzamide) (5d). Yield: 88%;
M. M. 196 – 198°C; FT-IR (KBr): n 3451, 3301 (N-H, str.),
dard, and the chemical shifts were expressed as ä, ppm. Ele-
mental analyses were obtained using Carlo–Erba EA1110
CHNO-S analyzer and agreed with the calculated values.
3118 (C-H
str.), 1713 (C=O str.), 1665 (C=N str.), 1593,
arom
2.2. General Procedure for the Synthesis of tris-Thioureas
(5a –5h)
1568 (C=C str.), 1533, 1328 (NO str.), 1243 (C=S str.), 1097
2
(C-N str.) cm-1. 1H NMR (250 MHz, DMSO-d ): d 7.10 (3H,
6
s, 3NH), 8.26 (6H, d, J = 8.2 Hz, 6CH), 8.13 (6H, d,
J = 8.2 Hz, 6CH), 11.11 (3H, s, 3NH) ppm. 13C NMR
Benzoyl chlorides (15 mmol) in dry acetone (10 mL)
was added dropwise into a stirred solution of potassium
thiocyanate (15 mmol) in dry acetone (5 mL). The mixture
was stirred under reflux conditions for 1 h to form compound
3. The solvent was evaporated in vacuum to form a yellowish
powder. The compound 3 was added to melamine (5 mmol)
in DMSO (15 mL) and heated under reflux conditions for
16 h, the progress of reaction was monitored by TLC
(63 MHz, DMSO-d ): d 174.6, 167.0, 163.7, 150.0, 138.6,
6
131.0, 123.9 ppm. Anal. calcd. for C H N O S : C, 43.20;
27 18 12
9 3
H, 2.42; N, 22.39. Found: C, 43.23; H, 2.45; N, 22.36.
N,N¢,N²-(((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris-
(carbonothioyl))tris(4-methylbenzamide) (5e). Yield:
83%; M. P. 177 – 179°C; FT-IR (KBr): n 3435, 3256 (N-H,
(CHCl :MeOH (4:1)). After completion of the reaction, the
str.), 3131 (C-H
str.), 1717 (C=O str.), 1668 (C=N str.),
3
arom
1610, 1515 (C=C str.), 1230 (C=S str.), 1117 (C-N str.) cm-1.
reaction mixture was evaporated slowly and the product
powder were obtained. The white powder was filtered,
washed with EtOH 96%, and dried to afford the pure com-
pounds 5a – 5h.
1H NMR (250 MHz, DMSO-d ): d 2.35 (3H, s, CH ), 7.10
6
3
(3H, s, 3NH), 7.29 (6H, d, J = 7.5 Hz, 6CH), 7.79 (6H, d,
J = 7.5 Hz, 6CH), 11.15 (3H, s, 3NH) ppm. 13C NMR
N,N¢,N²-(((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris-
(carbonothioyl))tribenzamid (5a). Yield: 79%; M.P.
218 – 220°C; FT-IR (KBr): n 3466, 3289 (N-H, str.), 3026
(63 MHz, DMSO-d ): d 173.8, 167.9, 163.2, 143.3, 131.4,
6
129.3, 129.1, 21.5 ppm. Anal. calcd. for C H N O S : C,
30 27
9
3 3
54.78; H, 4.14; N, 19.16. Found: C, 54.75; H, 4.16; N, 19.13.
N,N¢,N²-(((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris-
(carbonothioyl))tris(2-methylbenzamide) (5f). Yield: 71%;
M. P. 193 – 195°C; FT-IR (KBr): n 3435, 3288 (N-H, str.),
1726 (C=O str.), 1665 (C=N str.), 1591, 1560 (C=C str.),
(C-H str.), 1670 (C=O str.), 1594 (C=N str.), 1556, 1533
arom
1
(C=C str.), 1313 (C=S str.), 1159 (C-N str.) cm-1. H NMR
(250 MHz, DMSO-d ): d 7.08 (3H, s, 3NH), 7.47 – 7.64 (9H,
6
m, 9CH), 7.89 (6H, d, J = 8.0 Hz, 6CH), 11.31 (3H, s, 3NH)
ppm. 13C NMR (63 MHz, DMSO-d ): d 174.1, 168.1, 162.7,
1
1261 (C=S str.), 1112 (C-N str.) cm-1. H NMR (250 MHz,
6
134.2, 133.0, 129.0, 128.8 ppm. Anal. calcd. for
C H F N O S : C, 52.67; H, 3.44; N, 20.47. Found: C,
DMSO-d ): d 2.34 (3H, s, CH ), 7.08 – 7.70 (15H, m, 12CH,
3NH), 11.41 (3H, s, 3NH) ppm. 13C NMR (63 MHz,
6
3
27 18
3
9
3 3
52.69; H, 3.42; N, 20.44.
DMSO-d ): d 174.0, 167.7, 162.7, 145.6, 135.8, 131.0,
6
N,N¢,N²-(((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris-
(carbonothioyl))tris(4-chlorobenzamide) (5b). Yield:
87%; M.P. 269 – 270°C; FT-IR (KBr): n 3492, 3420 (N-H,
130.8, 128.1, 127.2, 20.5 ppm. Anal. calcd. for
C H N O S : C, 54.78; H, 4.14; N, 19.16. Found: C, 54.75;
30 27
9
3 3
H, 4.11; N, 19.19.
str.), 3118 (C-H
1633, 1541 (C=C str.), 1239 (C=S str.), 1131 (C-N str.) cm-1.
1H NMR (250 MHz, DMSO-d ): d 6.87 (3H, s, 3NH), 7.57
str.), 1728 (C=O str.), 1663 (C=N str.),
N,N¢,N²-(((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris-
(carbonothioyl))tris(2-chlorobenzamide) (5g). Yield: 75%;
M. P. 212 – 214°C; FT-IR (KBr): n 3470, 3300 (N-H, str.),
1713 (C=O str.), 1665 (C=N str.), 1593, 1559 (C=C str.),
arom
6
(6H, d, J = 8.4 Hz, 6CH), 7.90 (6H, d, J = 8.4 Hz, 6CH),
11.43 (3H, s, 3NH) ppm. 13C NMR (63 MHz, DMSO-d ): d
1
1308 (C=S str.), 1096 (C-N str.) cm-1. H NMR (250 MHz,
6
174.3, 167.2, 163.6, 137.9, 132.9, 131.0, 128.9 ppm. Anal.
calcd. for C H Cl N O S : C, 45.10; H, 2.52; Cl, 14.79; N,
DMSO-d ): d 6.95 (3H, s, 3NH), 7.08 (3H, d, J = 7.7 Hz,
6
3CH), 7.51 (3H, d, J = 7.5 Hz, 6CH), 7.62 – 7.84 (6H, m,
6CH), 11.28 (3H, s, 3NH) ppm. 13C NMR (63 MHz,
27 18
3
9
3 3
17.53. Found: C, 45.14; H, 2.50; Cl, 14.77; N, 17.56.

62
Saghi Shiroud Ghorbani et al.
Scheme 1. Synthesis of tris-thiourea derivatives from melamine.
used as references to anti-bacterial drugs and placed on the
medium. All the plates incubated in 37°C for 24 h. The disc
strengths and the zone size interpretation were determined in
accordance with Clinical Laboratory Standard Institute
(CLSI 2017) guidelines.
DMSO-d ): d 173.3, 167.0, 163.1, 145.8, 132.1, 130.0,
6
129.3, 127.1, 126.5 ppm. Anal. calcd. for C H Cl N O S :
27 18
3
9
3 3
C, 45.10; H, 2.52; Cl, 14.79; N, 17.53. Found: C, 45.13; H,
2.54; Cl, 11.79; N, 17.55.
N,N¢,N²-(((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris-
(carbonothioyl))tris(4-fluorobenzamide) (5h). Yield: 73%;
M. P. 189 – 191°C; FT-IR (KBr): n 3454, 3278 (N-H, str.),
1732 (C=O str.), 1677 (C=N str.), 1591, 1503 (C=C str.),
3. RESULTS AND DISCUSSION
1223 (C=S str.), 1090 (C-N str.) cm-1. H NMR (250 MHz,
1
We have developed the synthesis of novel tris-thiourea
derivatives (5a – 5h) using melamine as central core at suit-
able conditions (Scheme 1) and examined their biological ac-
tivity against Gram-positive and Gram-negative bacteria (see
Table 1 and Fig. 1 – 3). This report describes the synthesis,
spectroscopic characterization, and antibacterial activity of
several new tris-thiourea derivatives against S. aureus, B. ce-
reus, and E. coli bacterial strains. For the preparation of the
tris-thiourea derivatives, benzoyl chloride 1 was converted to
DMSO-d ): d 7.09 (3H, s, 3NH), 7.27 (6H, t, J = 6.2 Hz,
6
6CH), 7.49 (6H, dd, J = 6.0, 4.0 Hz, 6CH), 11.42 (3H, s,
3NH) ppm. 13C NMR (63 MHz, DMSO-d ): d 175.0, 169.7,
6
162.1, 147.4 (1J = 227.0 Hz), 135.8, 127.2, 126.2
(2J = 39.6 Hz) ppm. Anal. calcd. for C H F N O S : C,
27 18
3
9
3 3
48.43; H, 2.71; F, 8.51; N, 18.82. Found: C, 48.45; H, 2.73;
F, 8.54; N, 18.85.
2.3. Antibacterial Activity Assay
isothiocyanate
3
through reaction with potassium
Antibacterial activity was determined using the disc dif-
fusion procedure and principles of the Clinical and Labora-
tory Standards Institute (CLSI 2017). The antibacterial prop-
erties of each compound were tested against standard bacte-
rial strains including S. aureus (ATCC 25923), B. cereus
(ATCC 14579) and E. coli (ATCC 25922). To perform the
test, each strain was added into the sterile phosphate buffer
saline and its turbidity was adjusted to 0.5 McFarland tube
(1.5 ´ 108 cells mL-1). Then 100 mL of the suspension was
full streaked on the Muller-Hinton agar medium (Merck-
Germany) and each of the synthesized tris-thioureas was
placed on a medium after being impregnated with a paper
disk. Antibiotic discs (Padtan Teb-Iran), viz., nitrofurantoin
(300 mg), penicillin (10 mg), imipenem (10 mg), cefalexin
(30 mg), co-amoxyclav (20 mg), trimethoprim sulfamethox-
azole (1.2 mg), gentamicin (10 mg), tetracycline (30 mg),
azithromycin (15 mg) and chloramphenicol (30 mg) were
thiocyanate 2 in dry acetone under reflux conditions. The last
step was the reaction of isothiocyanate 3 with melamine 4,
generating tris-thiourea derivatives (5a – 5h) as shown in
Scheme 1.
The target products were obtained via an efficient and
simple synthetic route without minimal purification, with
yields ranging from 71 to 89%. A noteworthy factor in the
synthesis of tris-thiourea derivatives is the low solubility of
melamine in acetone. To fix this problem, after completion of
the reaction at the first stage, which is increases of benzoyl
chlorides to potassium thiocyanate, acetone was evaporated
and dimethyl sulfoxide was replaced.
The formation of all the synthesized compounds
(5a – 5h) was fully characterized by FT-IR, 1H and 13C NMR
spectroscopy. and elemental analysis. FT-IR spectroscopy
data for compound 5b reveal the presence of NH stretching
at 3492 and 3420 cm-1, C=O stretching at 1728 cm-1, C=N

Synthesis and Investigation of the Antibacterial Activity
63
Fig. 1. Comparison of the germicidal effect of synthesized compounds and various antibiotics against E. coli.
Fig. 2. Comparison of the germicidal effect of synthesized compounds and various antibiotics against S. aureus.
1
stretching at 1680 cm-1, C=C stretching at 1633 and
1541 cm-1, and C=S stretching at 1239 cm-1. Furthermore,
determined by examining the FT-IR, H, 13C NMR spectra
and elemental analysis. The antibacterial activities of
tris-thiourea derivatives were appraised against four bacterial
1H NMR spectra of compound 5b in DMSO-d showed two
6
singlet at d 6.87 and 11.43 ppm for –NH proton that con-
firmed the formation of this compound. Also, the 13C NMR
spectrum of compound 5b in DMSO-d showed seven sig-
6
TABLE 1. Results of One-Way Analysis of Variance to Compare
the Growth Rate of E. coli, S. aureus and B. cereus Bacteria in the
Presence of Compounds Studied
nals in agreement with the proposed structure.
According to Table 1 and Fig. 1 – 3, all bacteria showed
a significant difference between the germicide rate under the
action of various compounds (P < 0.05). For E. coli, the
highest germicide rate was observed for compound 5a and
the lowest rate, for compound 5e; for S. aureus, the highest
microbicide rate was observed for compound 5g and the low-
est for compounds 5a and 5b; for B. cereus, the highest ger-
micide rate was observed for compounds 5c, 5d, 5f, 5g and
5h and the lowest, for compounds 5b and 5e.
Compound
E. coli (cm)
S. aureus (cm)
0.68e ± 0.75
B. cereus (cm)
2.10b ± 0.235
1.50c ± 0.115
3.41a ± 0.145
3.40a ± 0.075
1.28c ± 0.085
3.59a ± 0.145
3.40a ± 0.095
3.41a ± 0.120
3.61a ± 0.110
5a
5b
5c
5d
5e
5f
0.59e ± 0.085
3.20b ± 0.070
1.60d ± 0.125
1.80c ± 0.140
3.20b ± 0.060
3.63a ± 0.098
3.17b ± 0.085
0
3.18c ± 0.140
3.19c ± 0.050
3.09d ± 0.095
3.38b ± 0.120
3.30b ± 0.050
3.19c ± 0.145
In concluding, we reported an efficient protocol for syn-
thesis of tris-thiourea derivatives (5a – 5h) in good to excel-
lent yields from one-pot condensation reaction between
available benzoyl chlorides (1a – 1h) with potassium
thiocyanate (2) and melamine (4) under reflux conditions.
The chemical structure of all synthesized compounds was
5g
5h
One-way analysis F = 404.763
of variance P = 0.001
F = 483.274
P = 0.001
F = 152.961
P = 0.001

64
Saghi Shiroud Ghorbani et al.
Fig. 3. Comparison the germicidal effect of synthesized compounds and various antibiotics against B. cereus.
12. S. Cascioferro, B. Parrino, V. Spanò, et al., Eur. J. Med. Chem.,
strains, including S. aureus, B. cereus, E. coli and P. aeru-
ginosa. The synthesized tris-thioureas showed excellent anti-
bacterial activity against Gram-positive bacteria (S. aureus
and B. cereus) as well as against some Gram-negative bacte-
ria (E. coli). The synthesized compounds exhibited no activ-
ity against P. aeruginosa.
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