Antituberculosis and antifungal activities of synthesized benzoylthiourea derivatives

Article abstract of DOI:10.14233/ajchem.2013.15157a

A series of benzoylthiourea derivatives have been synthesized from benzoyl isothiocyanate and phenyleneamine in CH₂Cl₂ medium under solid-liquid phase transfer catalysis conditions. Structures of these compounds have been characteriz

Full text of DOI:10.14233/ajchem.2013.15157a

Asian Journal of Chemistry; Vol. 25, No. 13 (2013), 7551-7553
http://dx.doi.org/10.14233/ajchem.2013.15157A
Antibacterial and Antifungal Activities of Bisbenzoylthiourea
Compounds from Benzoyl Isothiocyanate and Diamines
*
MENG-MENG ZHAO , XIU-YAN DONG, GANG LI, YU-HUA YANG, YU-JIE ZHANG and XIAO-QIN YANG
School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou 730070, P.R. China
*Corresponding author: E-mail: zhaomm80@163.com
(Received: 15 January 2013;
Accepted: 1 July 2013)
AJC-13749
Five bisbenzoylthiourea compounds have been synthesized from benzoyl isothiocyanate and different diamines in CH2Cl2 medium under
solid-liquid phase transfer catalysis conditions. Structures of these compounds have been characterized by elemental analyses as well as
IR and 1H NMR spectroscopy. These compounds were tested for their antibacterial and antifungal activities. The results indicated most of
the compounds have good antimicrobial activities, especially in against agriculture disease fungal.
Key Words: Bisbenzoylthiourea, Synthesis, Antibacterial and antifungal activity.
IR spectrophotometer using KBr pellets. The 1H NMR spectra
INTRODUCTION
were recorded on a Mercury-400BB spectrometer at room tempe-
As we know, thiourea compounds, especially acylthiourea
rature using CDCl3 as solvent. Melting points was measured
compounds, are of great interest because of their varied biolo-
by the use of a microscopic melting point apparatus made in
gical activities such as herbicides, insecticides, plant-growth
Beijing Taike Instrument Limited Company and the thermo-
regulators, antifungal and pharmacodynamics1-4. Some
meter was uncorrected.
thiourea compounds are prominent organic reaction catalyst
The antimicrobial activity was determined using agar disc
in the metal-catalyzed asymmetric reduction of carbonyl
diffusion method by measuring the inhibition zone in mm.
compounds and carbonylative cyclization of o-hydroxyaryl-
The microbiology stains were obtained from China Center of
Industrial Culture Collection, including 4 species of bacteria:
Pseudomonas aeruginosa NKCCMRNK10.PAO1∆rhlI and
Escherichia coliACCC11864 as gram-negative Obligate aerobes
bacteria, Corynebacterium diphtheriae CCTCCAB2010172
and Staphylococcus aureus ACCC01331 as gram-positive
facultative aerobic bacteria. 3 species of fungi: Gibberella sp.
CICIMF0137, Pythium aphanidermatum ACCC36125 and
Cochliobolus sativus ACCC30139 as against agricultural
disease fungal.Ampicillin and nystatin were served as standard
antibacterial and antifungal agents, respectively.
acetylenes5-7. In recent years, with the rapid development of
coordination chemistry and supramolecular chemistry,
thiourea compounds are one of many important neutral
receptors and their tendency to coordinate with metal ions8-13
.
Herein, in a novel series of bisbenzoylthioureas (3a-3e) have
been synthesized and characterized by elemental analyses, IR
and 1H NMR spectroscopy, their antibacterial activities have
also been studied.
EXPERIMENTAL
Benzoyl chloride, o-chlorobenzoyl chloride, 1,2-dibromo-
ethane, 1,3-dibromopropane and polyethylene glycol-400 were
purchased from Alfa Aesar and used without further purifi-
cation. The other reagents and solvents were analytical grade
reagents from Tianjin Chemical Reagent Factory. 1,2-
Bis(phthalimidooxy)ethane and 1,3-bis(phthalimidooxy)-
propane were synthesized according to a literature method14-
16. C, H and N analyses were carried out with a GmbH
VariuoEL V3.00 automatic elemental analyzer. IR spectra in
the range 4000-400 cm-1 were recorded on a VERTEX70 FT-
General procedure: Benzoyl chloride and its derivatives
was treated with ammonium thiocyanate under the condition
of solid-liquid phase transfer catalysis using PEG-400 as the
catalyst to give the corresponding benzoyl isothiocyanates,
without isolation, the obtained benzoyl isothiocyanates were
treated with differet diamines to afford the title compounds
3a-3e in good-to-excellent yield17,18. Synthetic route to benzoyl-
thiourea derivatives 3a-3d is shown in Fig. 1. All the synthe-
sized compounds have been characterized by elemental analyses
as well as IR and 1H NMR spectroscopy (Tables 1 and 2).

7552 Zhao et al.
Asian J. Chem.
R1
S
O
O
O
NH4SCN
N
NH2RNH2/CH2Cl2
r.t.
H
HN
S
R
NH
PEG-400/CH2Cl2 , r.t.
N=C=S
Cl
HN
O
R1
R1
R1
2
1
3
3a: R1=H, R=-CH2-CH2-;
3b: R1=H, R=-CH2-CH2-CH2-CH2-;
3c: R1=2-Cl, R=-CH2-CH2-CH2-CH2-CH2-CH2-;
3d: R1=H, R=-O-CH2-CH2-O-;
3e: R1=H, R=-O-CH2-CH2-CH2-O-;
Fig. 1. Synthetic route to benzoylthiourea derivatives 3a-3e
TABLE-1
COLOUR, YIELDS, MELTING POINTS AND ANALYTICAL DATA OF SYNTHESIZED COMPOUNDS 3a-3e
Elemental analysis (%): Found (calcd.)
Compound
Colour
m.p. (ºC)
Yield (%)
m.f. (m.w.)
C
H
N
Colourless
Colourless
Colourless
Colourless
Colourless
214-215
196-198
176-178
122-123
117-118
82.3
81.8
90.6
65.6
51.8
C18H18N4O2S2 (386.49)
C20H22N4O2S2 (414.54)
C22H26N4O2S2 (442.6)
C18H18N4O4S2 (418.49)
C19H20N4O4S2 (432.52)
55.90 (55.94)
57.91 (57.95)
59. 86 (59.70)
51.43 (51.66)
52.62 (52.76)
4.59 (4.69)
5.47 (5.35)
5. 90 (5.92)
4.60 (4.34)
4.95 (4.66)
14.28 (14.50)
13.36 (13.52)
12.39 (12.66)
13.71 (13.39)
13.23 (12.95)
3a
3b
3c
3d
3e
TABLE-2
IR AND 1H-NMR SPECTRAL DATA OF SYNTHESIZED COMPOUNDS3a-3e
IR (ν, cm–1)
1HNMR (DMSO-d6, δ/ppm)
Compound
3422,3234(NH); 1668(C=O); 1158(C=S)
3416,3222(NH); 1672(C=O); 1146(C=S)
3.98 (t, 4H, CH2); 7.36-7.98 (m, 10H, C6H5);10.95 (s, 2H, NH); 11.31 (s, 2H, NH).
1.70 (t, 4H, CH2); 3.68 (t, 4H, CH2);7.45-7.92 (m, 10H, C6H5); 10.91 (s, 1H, NH);
11.02 (s, 1H, NH).
3a
3b
3243(NH); 1668(C=O); 1153(C=S)
3329,3175(NH); 1680(C=O); 1178(C=S)
3203(NH); 1677(C=O); 1177(C=S)
1.45 (t, 4H, CH2); 1.65 (t, 4H, CH2);3.60 (t, 4H, CH2); 7.45-7.93 (m, 10H,
C6H5);10.89 (s, 2H, NH); 11.01 (s, 2H, NH).
4.50 (s, 4H, CH2); 7.51 (t, J = 10.2 Hz, 4H, ArH);7.61(d, J = 10.2 Hz, 2H, ArH); 7.83
(d, J = 10.8 Hz, 4H, ArH);8.93 (s, 2H, HN); 12.90 (s, 2H, HN).
2.18 (d, J = 8.8 Hz, 2H, CH2); 4.40 (t, J = 8.2Hz, 4H, CH2); 7.52(t, J = 10.2 Hz, 4H,
ArH); 7.62 (d, J = 9.2 Hz, 2H, ArH);7.85 (d, J = 9.2 Hz, 4H, ArH); 8.90 (s, 2H, HN);
12.78 (s, 2H, HN).
3c
3d
3e
Synthesis of N,N'-(1,4-tetramethylene)bisbenzoyl-
thiourea (3a), N,N'-(1,4-tetramethylene)bisbenzoylthiourea
(3b) and N, N'-(1,6-hexamethylene)bisbenzoylthiourea (3c):
1.41 g (0.01 mol) of benzoyl chloride was reacted with 1.15 g
(0.015 mol) of ammonium thiocyanate in 25 mL of CH2Cl2
under solid-liquid phase transfer catalysis conditions, using
0.18 g of 3 % polyethylene glycol-400 as the catalyst, to give
the corresponding benzoyl isothiocyanate after stirring for 1 h
at the room temperature, a white pricipatate was formed and
the white solution turned to yellow, filtered and washed with
CH2Cl2, which was reacted with a CH2Cl2 (15 mL) solution of
0.0045 mol of diamines (ethanediamine/1,4-butanediamine/
1,6-hexamethylendiamine) at the room temperature, after stir-
ring for 2.5 h. The solid isolated was separated from the liquid
phase by filtration, washed successively with CH2Cl2 and H2O,
respectively, the product was dried under reduced pressure
and purified with recrystallization from DMF to obtain the
title compound 3a-3c.
Synthesis of N,N'-(ethylenedioxy)bisbenzoylthiourea
(3d) and N,N'-(1,3- propylenedioxy)bisbenzoylthiourea
(3e): Benzoyl chloride (0.72 g, 0.005 mol) was reacted with
ammonium thiocyanate (0.57 g, 0.0075 mol) in CH2Cl2 (15 mL)
solution under soild-liquid phase transfer catalysis, using
polyethylene glycol-400 (0.09 g) as the catalyst, to give a
CH2Cl2 solution of benzoyl isothiocyanate, which was reacted
with a CH2Cl2 (15 mL) solution of 0.0025 mol of diamines
(1,2-bis(amineoxy)ethane19-22/1,3-bis(amineoxy)propane22-24
)
at the room temperature, after stirring for 4 h. The solid isolated
was separated from the liquid phase by filtration, washed
successively with H2O and CH2Cl2, respectively, the product
was dried under reduced pressure to obtain the title compounds
(3d and 3e).
Antimicrobial activity: All the synthesized compounds
were evaluated in vitro for their antibacterial and antifungal
activities. nutrient agar and sabourd's medium were used to
culture bacteria and fungal, respectively. The hot nutrient agar

Vol. 25, No. 13 (2013)
Antibacterial and Antifungal Activities of Bisbenzoylthiourea Compounds 7553
TABLE-3
RESULTS OF ANTIMICROBIAL ACTIVITY OF SYNTHESIZED COMPOUNDS 3a-3e
Diameter of zone of inhibition (mm)
Corynebacterium Staphylococcus
Gibberella
Compound
Pseudomonas
aeruginosa
Escherichia
coli
Pythium
Cochliobolus
sativus
diphtheriae
6.8 0.25
4.3 0.2
7.7 0.15
15.1 0.5
11.2 0.5
13.7 0.4
–
aureus
5.9 0.2
5.6 0.15
6.2 0.2
12.1 0.3
8.6 0.4
sp.
aphanidermatum
3.1 0.1
–
5.4 0.15
–
6.9 0.25
11.9 0.45
8.9 0.3
8.1 0.3
7.9 0.3
8.8 0.2
17.6 0.7
13.1 0.4
–
6.3 0.2
–
9.3 0.4
16.8 0.5
15.6 0.3
–
8.2 0.1
8.4 0.35
8.9 0.1
17.5 0.6
14.3 0.6
–
3a
3b
5.4 0.15
14.8 0.6
10.4 0.35
16 0.25
–
3c
3d
3e
Ampicillin
Nystatin
15.9
0.7
13.6
0.5
–
–
15.4 0.3
18.1 0.6
17.3 0.5
–: Indicates no activity.
and sabourd's medium solution was poured into sterilized
petridishes and allowed to attain room temperature. Seed layer
medium which contains the previously grown subculture was
lawned into the Petri dishes. Cups were made using sterile
borer of 5 mm diameter. To these cups 0.5 mL of the drug
solution (50 µg/mL), standard solution were added and allowed
to cool for 1 h to facilitate diffusion. The plate was incubated
at 37 ºC for 48 h. Zone of inhibition around wells were measured.
All tests were repeated three times to confirm the results. The
results are showed in Table-3.
standard drugs, but the antifungal activity is more prominent.
So the bright prospects of the compounds synthesized above
in against agricultural disease fungal and the potential of anti-
microbial have been brought out.
REFERENCES
1. A. Jurasek, P. Safer and V. Zvak, Chem. Pap., 41, 693 (1987).
2. S.G. Teoh, S.H. Ang, H.K. Fun and C.-W. Ong, J. Organomet. Chem.,
580, 17 (1999).
3. H. Arslan, N. Duran, N.O. Sahin and N. Kulcu, Asian J. Chem., 18,
1710 (2006).
4. R. Campo, J.J. Criado, E. Garcia, M.R. Hermosa, A. Jiménez-Sánchez,
J.L. Manzano, E. Monte, E. Rodríguez-Fernández and F. Sanz, J. Inorg.
Biochem., 89, 74 (2002).
RESULTS AND DISCUSSION
5. Y. Nan, H. Miao and Z. Yang, Org. Lett., 2, 297 (2000).
6. J.A.J. Breuzard, M.L. Tommasino, F. Toucard, M. Lemaire and M.C.
Bonnet, J. Mol. Catal. A: Chem., 156, 223 (2000).
7. F. Touchard, F. Fache and M. Lemaire, Tetrahedron: Asymm., 8, 3319
(1997).
8. P. Buhlmann, S. Nishizawa, K.P. Xiao and Y. Umezawa, Tetrahedon,
53, 1647 (1997).
9. Y.M. Zhang, W.X. Xu, Y.Q. Zhou, H. Yao and T.-B. Wei, Acta Chim.
Sin., 64, 79 (2006).
10. J. Valdés-Martínez, S. Hernández-Ortega, M. Rubio, D.T. Li, J.K.
Swearingen, W. Kaminsky, D.R. Kelman and D.X. West, J. Chem.
Crystallogr., 34, 533 (2004).
11. Y.M. Zhang, T.B. Wei, L, Xian and L.M. Gao, Phosphorus, Sulfur
Silicon Rel. Elem., 179, 2007 (2004).
12. Y.M. Zhang, L. Xian, T.B. Wei and K.B.Yu, J. Chem. Res., 798 (2003).
13. E. Guillon, I. DeÂchamps-Olivier and J.P. Barbier, Polyhedron, 17,
3255 (1998).
14. W.K. Dong,Y.X. Sun, S.J. Xing,Y. Wang and X.H. Gao, Z. Naturforsch.,
67b, 197 (2012).
15. W.K. Dong, J.F. Tong, Y.X. Sun, S.S. Gong and L. Li, Synth. React.
Inorg. Met.-Org. Nano-Met. Chem., 41, 155 (2011).
16. W.K. Dong and J.G. Duan, J. Coord. Chem., 61, 781 (2007).
17. Y.M. Zhang, L. Xian and T.B. Wei, Acta Cryst., C59, m473 (2003).
18. W.K. Dong, X.Q. Yang. L.Q. Chai, Y.Q. Tian and J.H. Feng, Phosphorus,
Sulfur Silicon Rel. Elem., 183, 1181 (2008).
19. S. Akine, T. Taniguchi and T. Nabeshima, Angew. Chem., Int. Ed., 41,
4670 (2002).
20. W.K. Dong, G. Wang, S.S. Gong, J.F. Tong, Y.X. Sun and X.H. Gao,
Transition Met. Chem., 37, 271 (2012).
21. W.K. Dong, Y.X. Sun, X.N. He J.F. Tong and J.C. Wu, Spectrochim.
Acta A, 76, 476 (2010).
22. W.K. Dong,Y.X. Sun,Y.P. Zhang, L. Li, X.N. He and X.L. Tang, Inorg.
Chim. Acta, 362, 117 (2009).
23. W.K. Dong, X.N. He, H.B.Yan, Z.W. Lv, X. Chen, C.Y. Zhao and X.L.
Tang, Polyhedron, 28, 1419 (2009).
24. W.K. Dong, J.G. Duan, Y.H. Guan, J.Y. Shi and C.Y. Zhao, Inorg.
A series of bisbenzoylthiourea compounds 3a-3e have
been synthesized with good yields and the structures are
confirmed by elemental analyses, IR spectra and 1H NMR data.
All the synthesized compounds were tested for their anti-
microbial activities and 7 species of microbial have been
choosen. Because two classes of the compounds synthesized
above (3d and 3e) were oxime compounds and they were
reported as oxygen eliminating agent, so they were tested by
two obligate aerobes bacteria and two facultative aerobic
bacteria to prove their oxygen eliminating activities.Acylthio-
urea compounds also reported varied biological activities
especially in the aspect of agricultural disease prevention and
treatment, so they were tested by 3 species of commom agricul-
tural disease fungal to prove their antifungal activities. The
results presented: compound 3d showed the highest antibac-
terial and antifungal activities and close to the standard drug.
For some bacteria and fungal, compound 3d even have higher
antimicrobial activities than the standard drugs like the
experiment of Corynebacterium diphtheria, Gibberella sp and
Cochliobolus sativus. Compounds 3e and 3c also possess
higher antibacterial and antifungal activities. Compounds 3d
and 3e were shown higher inhibition on the two Obligate
aerobes bacteria and lower inhibition on the two facultative
aerobic bacteria because of their oxygen eliminating activities.
At the concentration of 50 µg/mL, compound 3b have no
inhibition on gram-negative bacteria like the experiment of
Pseudomonas aeruginosa and Escherichia coli, it possess the
lowest antibacterial and antifungal activities as compared to
the other compounds. In a word, the antimicrobial experiments
had indicated most of the synthesized compounds have shown
good antibacterial and antifungal activities as compared to their
Chim. Acta, 362, 1129 (2009).