Synthesis, structures and antibacterial activities of benzoylthiourea derivatives and their complexes with cobalt

Article abstract of DOI:10.1016/j.jinorgbio.2012.08.001

Four new thiocarbonyl fluorobenzamides and their complexes with cobalt have been synthesized and characterized by elemental analysis, FTIR, and ¹H NMR. Five crystal structures of the thioylbenzamides complexes of Co(PTCB)₃, Co(2FPTCB

Full text of DOI:10.1016/j.jinorgbio.2012.08.001

Journal of Inorganic Biochemistry 116 (2012) 97–105
Contents lists available at SciVerse ScienceDirect
Journal of Inorganic Biochemistry
journal homepage: www.elsevier.com/locate/jinorgbio
Synthesis, structures and antibacterial activities of benzoylthiourea derivatives and
their complexes with cobalt
a
Wen Yang a, Huanhuan Liu a, Mengying Li b, Fan Wang a, Weiqun Zhou a, , Jianfen Fan
⁎
a
College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren'ai Road, Suzhou, 215123, PR China
b
School of Biology and Basic Medical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, 215123, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2012
Received in revised form 1 August 2012
Accepted 1 August 2012
Available online 10 August 2012
Four new thiocarbonyl fluorobenzamides and their complexes with cobalt have been synthesized and char-
acterized by elemental analysis, FTIR, and 1H NMR. Five crystal structures of the thioylbenzamides complexes
of Co(PTCB)3, Co(2FPTCB)3, Co(4FPTCB)3, Co(2FMTCB)2 and Co(4FMTCB)3 have been determined by X-ray dif-
fraction. The antibacterial properties of these compounds against the bacteria, E. coli, Staphylococcus aureus,
B. subtilis, P. aeruginosa, and Shewanella sp. were investigated. The experiments showed that both compounds
and the complexes had the antibacterial activities against all of the studied bacteria. The thioylbenzamides had
stronger controls for the bacteria of E. coli, S. aureus, B. subtilis and P. aeruginosa than their corresponding cobalt
complexes. There was the contrary result against the bacteria of Shewanella sp. The para‐substitution of fluorine
atom increased antibacterial activities, while fluorine atom was substituted on ortho-benzoyl, the antibacterial
activity weakened. The thioylbenzamides linked to piperidine instead of a morpholine group may increase the
antibacterial activities.
Keywords:
Benzoylthiourea
Cobalt complexes
Crystal structures
Antibacterial activity
© 2012 Elsevier Inc. All rights reserved.
1. Introduction
antifungal [74,76] activities. In many cases upon coordination to metal
ions, the bioactivity of these compounds increases, suggesting that
Antibacterial agents have increased markedly in recent years [1–14]
due to the emergence and diversity of drug-resistant strains, the de-
mand for novel. So far, many researchers have studied a variety of com-
pounds to determine their biological activity including antibacterial
activity [15–24]. Thiourea, benzene sulfonyl urea, dihydropyrimidine
thiones, thiazines and their related analogues have become the focus
of interest recently on account of their pharmacological activities
[25–32]. Some compounds of urea and thiourea have shown bactericid-
al, fungicidal and herbicidal activities [33–40]. They can be used not only
in the control of animal pathogenic bacteria but also they have been
shown to possess antitubercular, antifungal, antithyroid, insecticidal, an-
thelmintic and rodenticidal properties [31–40]. In addition, with the
antibacterial activity, morpholine has been researched by some groups
recently [41–53] (refs. [44–46] and [48–53] are patent applications).
The effect of some transition metal complexes on the structure of
fungal and mammalian cell organelles has been studied [54–60]. And
the complexation capacity of thiourea derivatives is well known and
the biological activities of thiourea complexes have been studied for dif-
ferent biological systems [61–67]. For instance, thiosemicarbazones and
their metal complexes represent an interesting class of compounds
with a wide range of pharmacological applications [68]. Many examples
of this class of compounds have been evaluated as having antitumor
[69,70], antiviral [71], antiprotozoal [72,73], antibacterial [74,75] and
complexation can be an interesting strategy of dose reduction [77–81].
In recent years, our group has tested the antifungal activity
of substituted thioureas and their Co(III) complexes against the
major pathogens responsible for important plant diseases [82].
Selecting Co complexes as the main subjects for the study, we con-
ceive that the antibacterial effect of cobalt(III) ion had been known,
their complexes still being under study in order to find effective anti-
bacterial agents [83–89]. In the present work, we investigate the
antibacterial properties of six thiourea derivatives, named N-
(piperidylthiocarbonyl) benzamide (PTCB), N-(piperidyl‐thiocarbonyl)
2-fluorobenzamide (2FPTCB), N-(piperidylthiocarbonyl)-4-fluoro‐benz-
amide (4FPTCB), N-(morpholinothiocarbonyl) benzamide (MTCB), N-
(morpholinothiocarbonyl)-2-fluorobenzamide (2FMTCB) and N-
(morpholinothio- carbonyl)-4-fluorobenzamide (4FMTCB) (Scheme 1)
and their cobalt complexes, Co(PTCB)3, Co(2FPTCB)3, Co(4FPTCB)3,
Co(MTCB)3, Co(2FMTCB)2 and Co(4FMTCB)3 against the bacteria E. coli,
Staphylococcus aureus, B. subtilis, P. aeruginosa and Shewanella sp. The pur-
pose is to explore the potential antibacterial reagents of thiourea
derivatives.
2. Experimental
2.1. Materials and methods
Melting points were determined on a Kofler melting point appara-
tus and were uncorrected. IR spectra were obtained in KBr discs using
⁎ Corresponding author. Tel.: +86 512 65884827.
E-mail address: wqzhou@suda.edu.cn (W. Zhou).
0162-0134/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jinorgbio.2012.08.001

98
W. Yang et al. / Journal of Inorganic Biochemistry 116 (2012) 97–105
Scheme 1. The ligands in this study.
a Nicolet 170SX FT-IR spectrometer. 1H NMR (400.13 MHz) was
recorded in CDCl3 solution at room temperature on an INOVA 400 in-
strument. Elemental analyses were performed on a Yannaco CHNSO
Corder MT-3 analyzer. X-ray structure determination was carried
out with Rigaku Mercury CCD.
1149.6, 1087.8, 1018.4, 920.0, 852.5, 765.7, 648.1, 480.3, 432.1. 1H
NMR (CDCl3) (ppm) (Fig. S2b): 8.157–8.158 (d, 2H), 6.968–6.982
(d, 2H), 4.018–4.188 (m, 4H), 1.451–1.623 (m, 6 H).
2FMTCB: Colorless, m.p.: 147–149 °C. Anal. Calc. For
C
12H13FN2O2S: C, 53.73; H, 4.85; N, 10.45; S, 11.94; Found: C, 53.77;
H, 4.80; N, 10.49; S, 11.86. FTIR (cm−1) (Fig. S3a): 3498.4, 3272.8,
3024.0, 2939.1, 2875.5, 1683.6, 1610.3, 1525.5, 1461.9, 1427.1,
1355.8, 1270.9, 1249.7, 1201.5, 1147.5, 1099.3, 1066.5, 1029.9,
958.5, 916.1, 871.7, 835.1, 779.1, 752.1, 694.3, 657.6, 603.6, 540.0,
495.6, 470.6, 416.6. 1H NMR (CDCl3) (ppm) (Fig. S3b): 8.834–8.865
(d, 1H), 8.012–8.055 (m, 1H), 7.550–7.606 (m, 1H), 7.290–7.328 (t, 1H),
7.168–7.219 (q, 1H), 4.245 (s, 2H), 3.847 (s, 4H), 3.691 (s, 2H).
2.2. Synthesis and crystal growth of N-benzoyl-N′-dialkylthiourea
derivatives and their cobalt complexes
Thioylbenzamides and the complexes were synthesized following
the procedure given in the literature [82]. The complexes were also
obtained by the reaction of CoCl2·6H2O with the ligands (molar
ratio of CoCl2·6H2O: L=1:3) in ethanol in the presence of triethyl
amine. The oxidation of cobalt(II) by air (dissolved in solution)
occurred during the synthesis except for the coordination reaction
between the cobalt(II) and 2FMTCB. The complexes were isolated as
the solids and these were highly soluble in acetone, acetonitrile, DMSO,
DMF(N,N-dimethylformamide), partially soluble in ethanol, methanol,
chloroform and dichloromethane and insoluble in n-hexane. All the
complexes are air-stable and hence are suitable for antibacterial proper-
ties. The complexes were crystallized by evaporation of the solvent DMF
except Co(2FMTCB)2. The crystal of complex Co(2FMTCB)2 was prepared
by hydrothermal method. A mixture of CoCl2·2H2O (0.050 mmol),
o-fluorobenzoic acid (0.10 mmol) and DMF (20 ml) was placed in a
30 ml Teflon-lined stainless autoclave and heated at 150 °C for 4 d. It
was then slowly cooled to room temperature, and green-blue solution
as obtained. The resulting solution was allowed for slowly evaporation
about two weeks and dark-green crystals were grown.
Co(2FMTCB)2: Dark green, m.p.: 205.3–206.7 °C. Anal. Calc. For
C
24H24CoF2N4O4S2: C, 50.23; H, 4.19; N, 9.77; S, 11.16; Found: C,
50.26; H, 4.12; N, 9.74; S, 11.11. FTIR (cm−1) (Fig. S3a): 3467.6,
2927.6, 2854.3, 1583.3, 1517.8, 1488.9, 1417.5, 1351.9, 1307.6,
1269.0, 1226.6, 1114.7, 1027.9, 933.4, 860.1, 800.3, 756.0, 690.4, 659.6,
619.1, 584.4, 561.2, 455.1, 412.7. 1H NMR (CDCl3) (ppm) (Fig. S3b):
7.977 (s, 1H), 7.367 (s, 1H), 7.016–7.077 (t, 2H), 4.169–4.259 (t, 3H),
3.665–3.734 (d, 4H), 1.579 (s, 1H).
4FMTCB: Colorless, m.p.: 154–156 °C. Anal. Calc. For C12H13FN2O2S:
C, 53.73; H, 4.85; N, 10.45; S, 11.94; Found: C, 53.76; H, 4.91; N, 10.40; S,
11.99. FTIR (cm−1) (Fig. S4a): 3280.9, 3026.3, 2939.5, 2877.8, 1685.8,
1612.5, 1525.7, 1462.0, 1427.3, 1356.0, 1249.9, 1201.6, 1147.6, 1099.4,
1066.6, 1030.0, 958.6, 916.2, 873.8, 837.1, 779.2, 752.2, 692.4, 659.7,
605.6, 542.0, 495.7, 470.6, 422.4. 1H NMR (CDCl3) (ppm) (Fig. S4b):
8.509 (s, 1H), 7.848–7.883 (6 peaks, 2H), 7.151–7.193 (t, 2H), 4.238
(s, 2H), 3.859–3.861 (d, 2H), 3.817 (s, 2H), 3.648 (s, 2H).
Co(4FMTCB)3: Dark green, m.p.: 216.9–218.7 °C. Anal. Calc. For
2FPTCB: Light yellow, m.p.: 127–128 °C. Anal. Calc. For
C
36H36CoF3N6O6S3: C, 50.23; H, 4.19; N, 9.77; S, 11.16; Found: C,
C
13H15FN2OS: C, 58.65; H, 5.64; N, 10.53; S, 12.03; Found: C, 58.57; H,
50.16; H, 4.23; N, 9.80; S, 11.19. FTIR (cm−1) (Fig. S4a): 3456.0,
2921.7, 2852.3, 1600.7, 1515.9, 1479.2, 1415.6, 1348.1, 1292.1,
1261.3, 1224.6, 1147.5, 1114.7, 1027.9, 935.4, 854.4, 802.3, 765.6,
690.4, 653.8, 628.7, 567.0, 538.0, 453.2, 418.5. 1H NMR (CDCl3)
(ppm) (Fig. S4b): 8.144 (s, 2H), 6.971–7.008 (t, 2H), 4.201 (s, 3H),
3.617–3.726 (d, 4H), 1.582–1.591 (d, 1H).
5.69; N, 10.47; S, 12.08. FTIR (cm−1)(Fig. S1a): 3412.1, 3057.2, 2931.7,
2856.6, 1689.6, 1612.5, 1535.3, 1462.0, 1356.0, 1284.6, 1253.7, 1205.5,
1174.6, 1138.0, 1060.1, 1010.7, 949.0, 900.8, 871.8, 831.3, 787.0, 756.1,
711.7, 682.8, 636.5, 599.9, 543.9, 503.4, 453.3, 434.0, 410.8. 1H NMR
(CDCl3) (ppm) (Fig. S1b): 8.769 (s, 1H), 8.022–8.060 (t, 1H), 7.539–
7.588 (q, 1H), 7.299–7.318 (d, 1H), 7.157–7.208 (q, 1H), 4.178 (s, 2H),
3.634 (s, 2H), 1.807 (s, 2H), 1.729 (s, 4H).
2.3. X-ray determination
Co(2FPTCB)3: Dark green, m.p.: 188.8–190.1 °C. Anal. Calc. For
C39H45CoF3N6O3S3: C, 54.80; H, 4.92; N, 9.84; S, 11.24; Found: C,
54.73; H, 4.97; N, 9.89; S, 11.28. FTIR (cm−1) (Fig. S1a): 2937.6,
2856.6, 1585.5, 1525.7, 1489.0, 1413.8, 1357.9, 1244.1, 1205.5, 1132.2,
1020.3, 922.0, 898.8, 854.5, 758.0, 669.3, 474.5. 1H NMR (CDCl3)
(ppm) (Fig. S1b): 7.957–7.993 (m, 1H), 7.318–7.330 (m, 1H), 6.970–
7.065 (m, 2H), 4.235–4.264 (m, 2H), 3.978–4.089 (m, 2H), 1.560–
1.640 (t, 6 H).
4FPTCB: Colorless, m.p.: 126–127 °C. Anal. Calc. For C13H15FN2OS:
C, 58.65; H, 5.64; N, 10.53; S, 12.03; Found: C, 58.61; H, 5.68; N, 10.59;
S, 11.97. FTIR (cm−1)( Fig. S2a): 3178.7, 3037.9, 2989.7, 2929.9, 2866.2,
1651.1, 1602.8, 1531.5, 1473.6, 1350.2, 1280.7, 1253.7, 1180.4, 1153.4,
1093.6, 1064.7, 1018.4, 943.2, 877.6, 848.7, 810.1, 760.0, 698.2, 617.2,
567.1, 493.8, 432.1. 1H NMR (CDCl3) (ppm) (Fig. S2b): 8.769 (s, 1H),
8.022–8.060 (t, 1H), 7.539–7.588 (q, 1H), 7.299–7.318 (d, 1H), 7.157–
7.208 (q, 1H), 4.178 (s, 2H), 3.634 (s, 2H), 1.807 (s, 2H), 1.729 (s, 4H).
Co(4FPTCB)3: Dark green, m.p.: 195.2–196.8 °C. Anal. Calc. For
All measurements were made on a Rigaku Mercury CCD X-ray dif-
fractometer by using graphite monochromated MoKα radiation (λ=
0.71070 Å). Single crystals were mounted with grease at the top of a
glass fiber. Cell parameters were refined on all observed reflections by
using the program CrystalClear (Rigaku and MSC, Ver. 1.3, 2001). The
collected data were reduced by the program CrystalClear and an
absorption correction (multiscan) was applied.
2.4. Bacterial strains assay
The assayed bacteria were E. coli, S. aureus, B. subtilis, P. aeruginosa
and Shewanella sp. The bacterial cultures were grown in autoclaved LB
(Luria-Bertani) media at 30 °C for 48 h and stored in LB media at 4 °C.
2.5. Determination of inhibition zone
C
39H45CoF3N6O3S3: C, 54.80; H, 4.92; N, 9.84; S, 11.24; Found: C,
54.86; H, 4.85; N, 9.80; S, 11.29. FTIR (cm−1) (Fig. S2a): 2941.4,
2860.4, 1600.9, 1518.0, 1483.3, 1423.5, 1356.0, 1244.1, 1207.4,
The filter paper of thickness of 2.0 mm was made into wafer with di-
ameter of 6 mm by punch. After dry heat sterilization, it was soaked in

W. Yang et al. / Journal of Inorganic Biochemistry 116 (2012) 97–105
99
six kinds of test samples in the concentration 1000 mg/L for 5 min.
Then, it was taken out and attached to a tablet. Each medium
evenly puts eight wafers (including PTCB, 2FPTCB, 4FPTCB, MTCB,
2FMTCB, 4FMTCB, Co(PTCB)3, Co(2FPTCB)3, Co(4FPTCB)3, Co(MTCB)3,
Co(2FMTCB)2 and Co(4FMTCB)3 of the same concentration and DMSO
for reference, CoCl2 for comparison). Each test solution was used for
three tablets repeatedly. And then the media were inverted in the incu-
bator. After 24 h cultures with the optimum temperature of every
strain, measure the diameter of each inhibition zone.
methods using the SHELXTL software package [92]. The refined
using the SHELXL program [93]. All non-hydrogen atoms were refined
anisotropically. The hydrogen atoms were placed at calculated posi-
tions. A summary of the crystallographic information and the selected
bond lengths and bond angles are listed in Tables 1–2 respectively.
The final fractional coordinates, temperature parameters, bond dis-
tances and bond angles have been deposited in the Cambridge
Crystallographic Data Centre as CCDC 836546 (Co(PTCB)3), 855878
(Co(2FPTCB)3), 855877 (Co(4FPTCB)3), 876734 (Co(2FMTCB)2) and
876735 (Co(4FMTCB)3).
2.6. Theoretical calculations
The crystal structure of Co(MCTB)3 has been detected in the refer-
ence [82]. The other five crystal structures of the complexes were
established by X-ray crystallography and illustrated in Figs. 1–3.
Hardly any difference on the structures of Co(PCTB)3, Co(2FPCTB)3
and Co(4FPCTB)3 were observed. The oxidation of cobalt (II) by air
(dissolved in solution) occurred during the synthesis. The Co center
is chelated by three ligand anions, each of which coordinates in the
bidentate S, O mode. Within the octahedral geometry defined by
the O3 S3 donor set, the S atoms have a facial arrangement, and the
three O atoms define an octahedral face. The ranges of Co–S and
Co–O bond distances, Table 2, are each narrow. In terms of angles,
the deviations from the ideal octahedral geometry are small with
the cis angles ranging from 84.0° to 94.9°. Usually, the S–Co–O angles
are systematically wider than the O–Co–O angles and S–Co–S as
expected on size considerations, Table 2. The three phenyl rings lie
to the one side of the plane defined by the three O atoms whereas
the piperidyl groups lie to the other side defined by the three S
atoms. The C_S bond distances from 1.724 to 1.751 Å are signifi-
cantly longer than the CS distances, 1.6727 Å observed in the crystal
structure of the ligand of PTCB [94]. A similar observation pertains
to the C_O bond distances from 1.724 to 1.751 Å.
The GAUSSIAN-09 program package was used for all the calcula-
tions [90]. The geometry of ligands were fully optimized without
any symmetry restrictions in singlet ground-states with the DFT
(density functional theory) method using the B3LYP hybrid ex-
change–correlation functional. The calculations of complexes were
performed using LANL2DZ [91] basis set for the Cobalt and the stan-
dard 6–31 G(d) basis set for the other atoms. All the calculated vibra-
tional frequencies are real and positive, indicating that the optimized
structures represent real minima of the ground state potential energy
surface.
3. Results and discussion
3.1. Structural studies of ligands and complexes
In IR spectra of the complexes, the N\H and C_O stretching vi-
brations which exist in the ligands disappear, and appear the broad
peak of C_N bond 1580–1600 cm−1. The broad vibration at about
3400 cm−1 results from the formation of intramolecular hydrogen
bond, N\H···F in the ligands of 2FPTCB and 2FMTCB. In 1H NMR spec-
tra of the complexes, the δ>8 ppm of N\H is absent, manifesting that
all the complexes are coordinated as anions.
The reflection data for the five complexes were also corrected for
Lorentz and polarization effects. The crystal structures were solved
by direct methods and refined on F2 by full-matrix least-squares
Only a little difference on the intermolecular interactions is in
the three crystal structures of the complex 1–3. A number of
intermolecular C–H∙∙∙S interactions exist in the crystal of Co(PTCB)3.
For the crystal of Co(2FPTCB)3, more intermolecular C–H∙∙∙F interac-
tions are observed. And in the crystal of the Co(4FPTCB)3, both
intermolecular C–H∙∙∙S and C–H∙∙∙F interactions are found. The
Table 1
Summary of X-ray diffraction data.
Number
1
2
3
4
5
complexes
Co(PTCB)3
Co(2FPTCB)3
Co(4FPTCB)3
Co(2FMTCB)2
Co(4FMTCB)3∙2DMF
C42H50CoF3N8O8S3
Empirical formula
C39H45CoN6O3S3
C39H42CoF3N6O3S3
C39H42CoF3N6O3S3
C24H24CoF2N4O4S2
Formula weight
Crystal system
Space group
Dimensions
a (Å)
b (Å)
c (Å)
α (°)
β (°)
800.92
Triclinic
P-1
854.92
Triclinic
P-1
854.92
Triclinic
P-1
593.51
Monoclinic
C 2/c
0.50×0.20×0.18
22.122(8)
9.711(3)
12.789(5)
90
112.773
90
4
1.556
0.896
1006.98
Triclinic
P-1
0.38×0.10×0.10
10.551(2)
13.551(3)
13.996(4)
83.938(17)
88.270(17)
70.973(11)
2
0.50×0.40×0.20
10.6240(15)
13.4506(18)
14.1743(18)
95.262(3)
90.274(2)
107.552(4)
2
0.50×0.30×0.10
9.6549(16)
14.2309(5)
16.716(3)
65.16(2)
86.42(3)
70.33(3)
2
0.60×0.30×0.20
11.7627(12)
14.706(3)
15.515(2)
75.03(4)
69.18(3)
70.88(4)
4
γ (°)
Z
Dcalc (g/cm3)
μ (Mo Kα) (mm−1
F(0 0 0)
1.414
0.670
840
1.466
0.669
885
1.458
0.660
894
0.715
0.286
524
)
1220
θ range (°)
3.19 to 27.48
18,041
8485
0.0672
8485
3.16 to 27.49
18,605
8660
0.0340
8660
3.04 to 25.35
18,935
7111
0.0953
7111
3.12 to 25.35
11,682
2311
0.0416
2311
3.08 to 25.35
18,550
8106
0.0701
8106
Reflections collected
Independent reflections
R(int)
Data
Parameters
470
1.095
497
1.103
497
1.017
169
1.170
593
1.084
GOF on F2
R1 [I>2sigma(I)]
wR2 [I>2sigma(I)]
R1 (all data)
0.0816
0.1480
0.1346
0.1711
0.0725
0.2014
0.0965
0.2181
0.0835
0.1984
0.1358
0.2339
0.0785
0.1977
0.0969
0.2102
0.648 and −0.551
0.0842
0.2015
0.1251
0.2330
wR2 (all data)
Largest difference peak (e. A−3
)
0.540 and −0.352
2.626 and −0.649
1.108 and −0.641
0.908 and −0.683

100
W. Yang et al. / Journal of Inorganic Biochemistry 116 (2012) 97–105
Table 2
Some structure parameters for five complexes (the data in parentheses from the DFT calculation).
Co(PTCB)3
Distances
Co(2FPTCB)3
Distances
Co(4FPTCB)3
Distances
Co(2FMTCB)2
Distances
Co(4FMTCB)3∙2DMF
(Å)
(Å)
1.925
(Å)
(Å)
Distances
(Å)
1.920 (1.905)
Co(1)-O(1)
Co(1)-O(2)
Co(1)-O(3)
Co(1)-S(1)
Co(1)-S(2)
Co(2)-S(3)
S(1)-C(6)
S(2)-C(19)
S(3)-C(32)
O(1)-C(7)
O(2)-C(20)
O(3)-C(33)
1.908 (1.906) Co(1)-O(1)
1.927 (1.910) Co(1)-O(2)
1.934 (1.911) Co(1)-O(3)
2.217 (2.282) Co(1)-S(1)
2.204 (2.273) Co(1)-S(2)
2.222 (2.289) Co(2)-S(3)
1.729 (1.750) S(1)-C(8)
1.739 (1.752) S(2)-C(21)
1.751 (1.755) S(3)-C(34)
1.243 (1.269) O(1)-C(7)
1.272 (1.272) O(2)-C(20)
1.262 (1.270) O(3)-C(33)
Co(1)-O(1)
Co(1)-O(2)
Co(1)-O(3)
Co(1)-S(1)
Co(1)-S(2)
Co(2)-S(3)
S(1)-C(1)
S(2)-C(14)
S(3)-C(27)
O(1)-C(7)
1.941 Co-O(2)
1.930 Co-O(1)
1.908
1.914
2.228
2.199
2.213
1.751
1.728
1.739
1.257
1.919
1.926
Co-O(3)
Co-O(5)
2.262 Co-S(1)
Co-S(2)
Co-S(3)
1.721 S(1)-C(8)
S(2)-C(13)
S(3)-C(32)
1.274 O(1)-C(1)
O(3)-C(18)
1.923 (1.906)
1.928 (1.914)
2.210 (2.285)
2.205 (2.275)
2.202 (2.269)
1.720 (1.746)
1.736 (1.757)
1.735 (1.752)
1.258 (1.269)
1.266 (1.270)
1.249 (1.269)
2.193 Co-S
2.213
2.214
1.728 S(1)-C(8)
1.724
1.730
1.272 O(2)-C(1)
1.236
1.259(5) O(2)-C(20)
1.252
(°)
O(3)-C(33)
Angles
1.272
(°)
O(5)-C(25)
Angles
Angles
(°)
Angles
Angles
(°)
(°)
O(1)-Co(1)-O(2)
O(1)-Co(1)-O(3)
O(2)-Co(1)-O(3)
O(1)-Co(1)-S(2)
O(2)-Co(1)-S(2)
O(1)-Co(1)-S(1)
O(3)-Co(1)-S(1)
O(2)-Co(1)-S(3)
O(3)-Co(1)-S(3)
O(3)-Co(1)-S(2)
O(2)-Co(1)-S(1)
O(1)-Co(1)-S(3)
S(2)-Co(1)-S(1)
S(2)-Co(1)-S(3)
S(1)-Co(1)-S(3)
86.4 (87.5)
85.9 (86.2)
86.8 (88.2)
91.2 (90.8)
94.2 (92.8)
93.5 (92.2)
91.0 (89.9)
90.5 (89.5)
92.1 (91.3)
176.8 (176.9)
177.7 (177.0)
176.4 (176.7)
88.0 (88.9)
90.9 (91.7)
89.5 (90.9)
O(1)-Co(1)-O(2)
O(1)-Co(1)-O(3)
O(2)-Co(1)-O(3)
O(2)-Co(1)-S(2)
O(3)-Co(1)-S(2)
O(3)-Co(1)-S(3)
O(1)-Co(1)-S(3)
O(2)-Co(1)-S(1)
O(1)-Co(1)-S(1)
O(2)-Co(1)-S(1)
O(3)-Co(1)-S(2)
O(1)-Co(1)-S(3)
S(2)-Co(1)-S(3)
S(2)-Co(1)-S(1)
S(3)-Co(1)-S(1)
86.5
87.1
86.4
94.6
90.1
94.1
90.5
89.4
91.9
176.7
176.7
176.8
88.4
90.9
90.1
O(1)-Co(1)-O(2)
O(1)-Co(1)-O(3)
O(2)-Co(1)-O(3)
O(3)-Co(1)-S(1)
O(1)-Co(1)-S(1)
O(2)-Co(1)-S(2)
O(1)-Co(1)-S(2)
O(2)-Co(1)-S(3)
O(3)-Co(1)-S(3)
O(1)-Co(1)-S(2)
O(2)-Co(1)-S(3)
O(3)-Co(1)-S(1)
S(1)-Co(1)-S(2)
S(1)-Co(1)-S(3)
S(2)-Co(1)-S(3)
87.6
89.2
83.9
92.0
93.9
93.1
89.1
92.0
93.9
176.9
177.0
175.7
91.0
86.7
87.8
O(2)-Co-O(2)#1 111.9
O(1)-Co-O(3)
O(1)-Co-O(5)
O(3)-Co-O(5)
O(3)-Co-S(3)
O(5)-Co-S(3)
O(1)-Co-S(2)
O(3)-Co-S(2)
O(1)-Co-S(1)
O(5)-Co-S(1)
O(1)-Co-S(3)
O(5)-Co-S(2)
O(3)-Co-S(1)
S(2)-Co-S(1)
S(3)-Co-S(2)
S(3)-Co-S(1)
88.0 (87.9)
84.3 (85.7)
86.5 (86.2)
89.1 (89.2)
94.3 (92.8)
91.5 (91.2)
95.0 (92.9)
95.4 (92.9)
92.4 (91.3)
176.9 (177.3)
175 (176.1)
176.2 (177.0)
86.4 (89.9)
90.2 (91.4)
87.4 (89.9)
O(2)-Co-S(1)#1
O(2)-Co-S(1)
120.3
96.8
S(1)#1-Co-S(1)
intermolecular interactions preclude the S1 and S2, F2 and F3 atoms
forming significant intermolecular contacts. The most notable
intermolecular interactions operating in all three crystal structures
are of the type C–H∙∙∙π.
Complex 4 exhibits tetracoordinate structure and the space group
is C2/c. The oxidation of cobalt (II) by air (dissolved in solution) didn't
take place during the coordination reaction. The Co\S and Co\O bond
distance is 2.262 and 1.93 Å and longer than that of all octahedral com-
plexes (Table 2). The large O\Co\S angle is 120.3°. The small bond
angle of O\Cu\S in the equatorial plane is 96.8° resulting from the
strained 6-membered cycle constituted by Co\S1\C8\N1\C1\O1
atoms. This strained structure leads to the distorted quadrangle
geometry. In addition, the O\Co\O angle is 111.9°. Thus, the tetrahe-
dral structure of the complex 4 is distorted (Fig. 3). Interestingly, we
found that the molecules of Co(2FMCTB)2 have mirror-symmetric struc-
ture, which is similar to the cis-bis (N,N-diethyl-N′-pivaloylthioureato)
copper(II) [13]. The main intermolecular interactions are C\H∙∙∙O and
C\H∙∙∙F.
The existence of two solvent molecules of dimethyl formamide
(DMF) in the crystal cell didn't impact the crystal structure of Com-
plex 5. Similar to the structure of the complex Co(MTCB)3 [82], an ox-
idation reaction of the cation of cobalt must be taking place along
with the coordination process. An octahedral environment about
the Co center with the ligands coordinating was in a relatively distorted
Fig. 1. Crystal structures of Co(PTCB)3 and Co(2FPTCB)3 with thermal ellipsoids drawn at 40% probability.

W. Yang et al. / Journal of Inorganic Biochemistry 116 (2012) 97–105
101
as an excess radius (mm) from a 6 mm diameter filter paper disk
containing 2 μg of the sample, which was placed on a seeded agar
plate containing the organism tested. The photos of inhibition
zones of the ligands and their complexes against the studied bacterial
strains are shown in Fig. 4. The values of inhibition zones (ΔR/mm) of
the compounds are listed in Table 3. HL1–HL6 correspond to PTCB,
2FPTCB, 4FPTCB, MTCB, 2FMTCB and 4FMTCB, respectively. The infor-
mation in both Fig. 4 and Table 3 is recorded by one experiment.
For E. coli, the data in Table 3 exhibits that the sequence of
antibacterial activity is: 4FPTCB (2.75 mm)>PTCB (1.75 mm)>2FPTCB
(1.70 mm) and Co(4FPTCB)3 (1.85 mm)>Co(PTCB)3 (1.70 mm)>
Co(2FPTCB)3 (1.65 mm). The value of 2.75 mm makes us clear that
among not only the ligands with fluorine on para-benzoyl, with fluorine
on ortho-benzoyl, and without F atom, but also the cobalt complexes,
the antibacterial activity of 4FPTCB is the strongest. The best anti-
bacterial activity of the three complexes also belongs to Co(4FPTCB)3 in-
cluding F on para-benzoyl whose inhibition zone is 0.15 mm bigger
than Co(PTCB)3. Relative to controlled group DMSO and CoCl2, all
these compounds still have stronger antibacterial activities against E.
coli. The thickness of the restrain ring bacterial against S. aureus is
kept in this order: 4FPTCB (2.10 mm)>PTCB (1.75 mm)>2FPTCB
(1.50 mm) and Co(4FPTCB)3 (1.90 mm)>Co(PTCB)3 (1.65 mm)>
Co(2FPTCB)3 (1.40 mm). The sequence indicates that the antibacterial
activity of 4FPTCB including fluorine on para-benzoyl is the highest,
whose value of inhibition zone reaches 2.10 mm. The sequence of
antibacterial activity against B. subtilis is: 4FPTCB (1.80 mm)>PTCB
(1.70 mm)>2FPTCB (1.65 mm) and Co(4FPTCB)3 (1.60 mm)>
Co(PTCB)3 (1.45 mm)>Co(2FPTCB)3 (1.40 mm), which demonstrates
that the antibacterial activities of ligands containing 4-fluorine are
stronger than that with 2-fluorine against B. subtilis, too. Additionally,
the corresponding cobalt complexes consisting of 4-fluorine have
higher antibacterial activities than that without fluorine, while the
antibacterial activity of the one with 2-F is lower than Co(PTCB)3. The rea-
son for it may be the formation of intramolecular hydrogen bond N\H∙∙∙F
deactivates the ortho-fluorine, while the para-F of free-state can increase
the antibacterial effect. As shown in the result of P. aeruginosa, the thick-
ness of the inhibition zone is in the following order: 4FPTCB
(3.75 mm)>PTCB (2.00 mm)>2FPTCB (1.80 mm) and Co(4FPTCB)3
(2.00 mm)>Co(2FPTCB)3 (1.75 mm)=Co(PTCB)3 (1.75 mm). It reveals
that the ligand with F atom on para-benzoyl has the strongest
antibacterial activity due to its inhibition zone of ΔR of 3.75 mm, which
is much bigger than others. Moreover, the antibacterial activity of the cor-
responding Co (III) complex of 4FPTCB is the highest against P. aeruginosa,
too. Its inhibition zone reaches 2.00 mm in width. As for Shewanella sp.,
PTCB (1.85 mm)>4FPTCB (1.65 mm)>2FPTCB (1.55 mm), Co(PTCB)3
Fig. 2. Crystal structure of Co(4FPTCB)3 with thermal ellipsoids drawn at 40%
probability.
manner (O1\Co\S3=176.9°, O3\Co\S1=176.2°, O5\Co\S2=
175.3°), the three Co\O bonds (average 1.924 Å) were shorter than
the three Co\S bonds (average 2.206 Å) because of the divergent
geometry of the three arms, in order to allow the sulfur atom to ap-
proach the metal atom with reasonable bonding distance.
Because the solvent molecule DMF existed in the crystal cell of
Complex 5, the intermolecular interactions were different from the
complexes 1–3. Not only two oxygen atoms coordinated with the
metal cobalt, but also interacted to intermolecular interaction,
C\H∙∙∙O. In additionally, the observed intermolecular interactions
were C\H∙∙∙F, C\H∙∙∙O and C\H∙∙∙S. The intermolecular interaction
types of C\H∙∙∙π in all three crystal structures of the complexes 1–3
are not found in the crystal structure of the complex 5.
3.2. Antibacterial activities
The antibacterial activities of studied thiourea derivatives and
their metal complexes were carried out for three parallel experiments
using the culture of E. coli, B. subtilis, P. aeruginosa, Shewanella sp. and
S. aureus by the disk diffusion method, measuring the inhibition zone
Fig. 3. Crystal structure of Co(2FMTCB)2 and Co(4FMTCB)3 with thermal ellipsoids drawn at 40% probability.

102
W. Yang et al. / Journal of Inorganic Biochemistry 116 (2012) 97–105
Staphylococcus
Samples
DMSO
E. coli
B. subtilis
P. aeruginosa
Shewanella sp.
aureus
CoCl2
HL1
Co(L1)3
HL2
Co(L2)3
HL3
Co(L3)3
HL4
Co(L4)3
HL5
Co(L5)2
HL6
Co(L6)3
Fig. 4. The photos of inhibition zones of the ligands and their complexes against the studied bacterial strains.

W. Yang et al. / Journal of Inorganic Biochemistry 116 (2012) 97–105
103
Table 3
It can also be drawn from Table 3 that all the ligands and com-
plexes can resist the studied bacteria better than DMSO and CoCl2
which seem to have no antibacterial activities. On top of this, it
seems that the introduction of morpholine is not helpful to increase
the antibacterial activities of the synthesized compounds owing to
the almost every diameter of morpholine-containing substances
being smaller than the ones with a piperidine group.
The values of inhibition zones (ΔR/mm) of the ligands and their complexes against the
studied bacterial strains.
Samples E. coli Staphylococcus aureus B. subtilis P. aeruginosa Shewanella sp.
CoCl2
HL1
0.20
1.75
0.10
1.75
1.65
1.50
1.40
2.10
1.90
1.15
0.50
1.00
0.55
1.25
0.55
0.15
1.70
1.45
1.65
1.40
1.80
1.60
1.55
0.90
1.50
0.85
1.65
1.00
0.20
2.00
1.75
1.80
1.75
3.75
2.00
1.25
1.00
1.20
1.00
1.35
1.15
0.15
1.85
2.10
1.55
1.80
1.65
2.05
1.85
2.00
1.45
1.75
1.70
2.00
Co(L1)3 1.70
HL2 1.70
Co(L2)3 1.65
HL3 2.75
Co(L3)3 1.85
HL4 1.40
Co(L4)3 0.85
HL5 1.40
Co(L5)2 0.85
HL6 1.65
Co(L6)3 0.90
3.3. Structure–activity relationship
Full geometry optimization of ligands 1–6 (L1-L6) and two com-
plexes (Co(PTCB)3 and Co(4FMTCB)3)) were performed at the DFT
level of theory. Some selected geometric parameters of two com-
plexes are listed in Table 3. As shown in Table 3, most of the opti-
mized bond lengths and the bond angles of two complexes are
slightly longer than the experimental values. This happens because
the calculations were performed in the gaseous state, whereas pack-
ing molecules with intermolecular interactions are treated in the
experimental measurements. The ligands show accumulation of the
negative charge density on the oxygen and sulfur atoms, which is a
very important structural feature related directly to the ability to
bind the metal ions.
According to the molecular orbital theory, the frontier molecular or-
bital (HOMO and LUMO) and their nearby molecular orbitals play a pre-
dominant role in general chemical reactions and related properties of
complexes. The frontier occupied molecular orbitals (HOMO and
HOMO-x) are preferential to offering electrons, whereas the frontier un-
occupied molecular orbitals (LUMO and LUMO+x) are preferential to
accepting electrons. Some important electronic characteristics such as
the computed energies of HOMO and LUMO, dipole moments, and
charges of atoms of six ligands and two complexes are complied in
Table 4. The lower LUMO energy and the higher HOMO are advantageous
to the complex between the donor and acceptor of electron. For a simple
comparison, the energies of LUMO present the regulation as E-
LUMO(L3)bELUMO(L1)bELUMO(L2), ELUMO(L6)bELUMO(L4)bELUMO(L5), E-
LUMO(Co(L1)3)bELUMO(L1), and ELUMO(Co(L6)3)bELUMO(L6), which has
the inverse ratio to the antibacterial activities of these ligands and com-
plexes. That is to say, the lower is the LUMO energy, the higher is the
antibacterial activity. It can also be found that the rule of negative
charges on N3 atom on amido bond. The negative charges order is
Q(L3)>Q(L1)>Q(L2), Q(L6)>Q(L4)>Q(L5), Q(L1)>Q(Co(L1)3),
Q(L6)>Q(Co(L6)3), which has the same regulation to the antibacterial
activities of these ligands and complexes. We find that the negative
charges on N3 in L1, L2, L3 and Co(L1)3 are linear with the thickness of
inhibition zones for B. subtilis (Fig. 5). The linear equation is y=
−4.0621x−0.8305, r2 =0.86393. That is to say abundant negative
charges of atom N must be advantageous to the antibacterial activity.
Furthermore, the more is the positive charges on atom C1 and the neg-
ative charges on atom O2, the stronger is the antibacterial activity. It
seems that the polarity of carbonyl group is also in favor of the
antibacterial activity.
(2.10 mm)>Co(4FPTCB)3 (2.05 mm)>Co(2FPTCB)3 (1.80 mm). Con-
trary to the above, the antibacterial activities of cobalt complexes are
higher than those of corresponding ligands. Strangely, fluorine atom
linked to neither ortho- nor para-benzoyl increases antibacterial activity
in both the ligands and the complexes.
From Fig. 4 and Table 3, we can find the regulations that the studied
compounds containing para-fluorine atom on benzoyl have stronger
antibacterial activities than the ones without F atoms which are better
than those with ortho-F. Apart from this, the antibacterial activities
of ligands are higher than those of corresponding cobalt complexes.
For example, 4FPTCB (2.75 mm)>Co(4FPTCB)3 (1.85 mm) for E. coli,
2FPTCB (1.65 mm)>Co(2FPTCB)3 (1.40 mm) as for B. subtilis and
4FPTCB (3.75 mm)>Co(4FPTCB)3 (2.00 mm) in case of P. aeruginosa.
The reason should be that ligands are more reactive with the microele-
ments necessary for bacterial nutrition.
The ligands involving a morpholino group instead of a piperidine
group are also better to resist the studied bacteria except Shewanella
sp. than their corresponding complexes. The ligand 4FMTCB is the
most effective in the control of E. coli, S. aureus and P. aeruginosa,
while 2FMTCB has the best antibacterial effect against B. subtilis. For
Shewanella sp., the outcome is opposite to the above. The activity of
ligands increases on coordination with cobalt ion. The pronounced in-
crease in activity may be due to the formation of chelate, a less polar
form of the metalloelement, which thereby increases the lipophilic
character. The increased lipophilic character of chelate favors the in-
teraction of these complexes with cell constituents, resulting in inter-
ference with normal cell processes [95]. Besides, both the complex
and the ligand without fluorine atom are more effective in terms of
antibacterial activity than other compounds. As for E. coli, S. aureus,
B. subtilis and P. aeruginosa, the rule of introduction of F atom on
para-benzoyl increasing the antibacterial activity continues when a
piperidine group of samples is replaced by a morpholino group.
Table 4
Some theoretically computed HOMO, LUMO energies, dipole moments, and atom charges of six ligands and two complexes (the label of atoms see Scheme 1).
PTCB
2FPTCB
4FPTCB
MTCB
2FMTCB
4FMTCB
Co(PTCB)3
Co(4FMTCB)3
EHOMO (a.u.)
ELUMO (a.u.)
ΔEL-H (a.u.)
μ (debye)
−0.20649
−0.05351
0.1530
−0.20839
−0.05134
0.1571
−0.20889
−0.05519
0.1537
−0.20541
−0.05639
0.1490
−0.20785
−0.05502
0.1528
−0.20787
−0.05821
0.1497
−0.19867
−0.05448
0.1442
−0.21394
−0.06490
0.1490
3.40
2.64
3.14
6.30
6.60
3.14
3.50
3.16
Charge
C1
O2
N3
C4
0.5413
−0.4946
−0.6314
0.2951
0.5399
−0.4716
−0.6187
0.2955
0.5453
−0.4957
−0.6328
0.2941
0.5770
−0.4585
−0.6597
0.3243
0.5739
−0.4387
−0.6474
0.3191
0.5800
−0.4596
−0.6613
0.3233
0.5693
−0.5598
−0.5597
0.3325
0.5760
−0.5483
−0.5605
0.3263
S5
−0.2844
−0.2842
−0.2826
−0.2151
−0.2133
−0.2136
−0.0697
−0.068

104
W. Yang et al. / Journal of Inorganic Biochemistry 116 (2012) 97–105
Abbreviations
PTCB
N-(piperidylthiocarbonyl) benzamide
2FPTCB N-(piperidyl‐thiocarbonyl)2-fluorobenzamide
4FPTCB N-(piperidylthiocarbonyl)-4-fluoro‐benzamide
MTCB
N-(morpholinothiocarbonyl) benzamide
2FMTCB N-(morpholinothiocarbonyl)-2-fluorobenzamide
4FMTCB N-(morpholinothio‐carbonyl)-4-fluorobenzamide
DMF
m.p.
LB
N,N-Dimethylformamide
melting point
Luria-Bertani
DFT
Density functional theory
HOMO Highest Occupied Molecular Orbital
LUMO Lowest Unoccupied Molecular Orbital
Appendix A. Supplementary data
Fig. 5. The linear relation of charges and inhibition zones.
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.jinorgbio.2012.08.001.
Above all, the structure–activity relationships were existed among
the energies of LUMOs, the negative charge of atom N of amido bond,
the polarity of carbonyl group and the antibacterial activities. The
lower is the LUMO energy, the more is the negative charge of atom
N of the amido bond, and the more is the positive charges on atom
C1 and the negative charges on atom O2 of carbonyl group, the higher
is the antibacterial activity. Antibacterial experiments show the
thioylbenzamides linked to morpholine group instead of a piperidine
group may decrease the antibacterial activities. It indicated the exis-
tence of the oxygen atom in morpholine group is bad to increase
the antibacterial activities.
References
[1] A. Khalaj, M. Nakhjiri, A.S. Negahbani, M. Samadizadeh, L. Firoozpour, S.
Rajabalian, N. Samadi, M.A. Faramarzi, N. Adibpour, A. Shafiee, A. Foroumadi,
Eur. J. Med. Chem. 46 (2011) 65–70.
[2] František Bílek, Táňa Křížová, Marián Lehocký, Colloids Surf B Biointerfaces 88
(2011) 440–447.
[3] Najma Sultana, Asia Naz, M. Saeed Arayne, M. Ahmed Mesaik, J. Mol. Struct. 969
(2010) 17–24.
[4] G.B. Bagihalli, P.G. Avaji, S.A. Patil, P.S. Badami, Eur. J. Med. Chem. 43 (2008)
2639–2649.
[5] M.S. Karthikeyan, D.J. Prasad, B. Poojary, K.S. Bhat, B.S. Holla, N.S. Kumari, Bioorg.
Med. Chem. 14 (2006) 7482–7489.
[6] X.J. Chen, F. Niyonsaba, H. Ushio, D. Okuda, I. Nagaoka, S. Ikeda, K. Okumura, H.
Ogawa, J. Dermatol. Sci. 40 (2005) 123–132.
[7] H. Guo-Qiang, H. Li-Li, X. Song-Qiang, H. Wen-Long, Chin. J. Chem. 26 (2008)
1145–1149 (in Chinese).
4. Conclusion
[8] W. Monika, M. Swatko-Ossor, L. Mazur, Z. Rzaczynska, A. Siwek, J. Hetrocycl.
Chem. 45 (2008) 1893–1896.
[9] X.S. Cui, C. Jing, K.Y. Chai, J.S. Lee, Z.S. Quan, Med. Chem. Res. 18 (2009) 49–58.
[10] J. Chen, X.Y. Sun, K.Y. Chai, J.S. Lee, M.S. Song, Z.S. Quan, Bioorg. Med. Chem. 15
(2007) 6775–6781.
[11] K. Kannathasan, A. Senthilkumar, V. Venkatesalu, Asian Pac. J. Trop. Med. 4 (2011)
645–648.
[12] Abdul Viqar Khan, Qamar Uddin Ahmed, Indu Shukla, Athar Ali Khan, Asian Pac. J.
Trop. BioMed. 2 (2012) 189–194.
[13] T.N. Tun, T.A. Jenkins, Electrochem. Commun. 12 (2010) 1411–1415.
[14] W. Song, Y. Shi, M.Z. Xiao, H. Lu, T.J. Qu, P. Li, G. Wu, Y. Tian, Int. J. Antimicrob.
Agents 33 (2009) 237–243.
[15] P. Tulayakul, A. Boonsoongnern, S. Kasemsuwan, S. Wiriyarampa, J. Pankumnoed,
S. Tippayaluck, H. Hananantachai, R. Mingkhwan, R. Netvichian, S. Khaodhiar,
J. Environ. Sci. 23 (2011) 991–997.
[16] S.H. Wang, W.S. Hou, L.Q. Wei, H.S. Jia, X.G. Liu, B.S. Xu, Surf. Coat. Technol. 202
(2007) 460–465.
[17] S. Buffet-Bataillon, P. Tattevin, M. Bonnaure-Mallet, A. Jolivet-Gougeon, Int. J.
Antimicrob. Agents 39 (2012) 381–389.
[18] A. Oyane, Y. Yokoyama, M. Uchida, A. Ito, Biomaterials 27 (2006) 3295–3303.
[19] A. Salvador, J.-Y. Gautier, O. Pasquier, H. Merdjan, J. Chromatogr. B 855 (2007)
173–179.
[20] Aaron M. Socha, Nicholas Y. Tan, Kerry L. LaPlante, Jason K. Sello, Bioorg. Med.
Chem. 18 (2010) 7193–7202.
[21] Z.P. Xiao, T.W. Ma, M.L. Liao, Y.T. Feng, X.C. Peng, J.L. Li, Z.P. Li, Y. Wu, Q. Luo, Y.
Deng, X. Liang, H.L. Zhu, Eur. J. Med. Chem. 46 (2011) 4904–4914.
[22] Ji-Young Kim, Frederick E. Boyer, Allison L. Choy, Michael D. Huband, Paul J.
Pagano, J.V.N. Vara Prasad, Bioorg. Med. Chem. Lett. 19 (2009) 550–553.
[23] Eric S. Schweiger, Jeffrey M. Weinberg, J. Am. Acad. Dermatol. 50 (2004) 331–340.
[24] Peter A. Lio, Elaine T. Kaye, Med. Clin. North. Am. 95 (2011) 703–721.
[25] S. Braun, A. Botzki, S. Salmen, C. Textor, G. Bernhardt, S. Dove, A. Buschauer, Eur. J.
Med. Chem. 46 (2011) 4419–4429.
This research examined the five crystal structures of Co(PTCB)3,
Co(2FPTCB)3, Co(4FPTCB)3, Co(2FMTCB)2, Co(4FMTCB)3 and the
antibacterial activities of six thiourea derivatives and their complexes
with cobalt ions prepared by the reaction of 4-chlorobenzoyl chloride
with NH4SCN. The results of antibacterial tests show that all the syn-
thesized compounds are more efficient to inhibit growth of the bacte-
ria than DMSO and CoCl2 which hardly have antibacterial effects.
Except for Shewanella sp., stronger controls for the bacteria belong
to ligands since they are more reactive with the microelements nec-
essary for bacterial nutrition. In opposition to what was expected,
thiourea linked to morpholine instead of a piperidine group may de-
crease the antibacterial activity. Furthermore, substances involving
4-fluorine atom on benzoyl have higher antibacterial activities than
the ones of no F atoms. As for fluorine atom on ortho-benzoyl, the
antibacterial activity is not increased but be lower than others. We
consider that the 2-F atom is deactivated on account of the formation
of intramolecular hydrogen bond N\H∙∙∙F, while the 4-F of free-state
can enhance antibacterial activity. Therefore, we conclude that
4FPTCB has the best antibacterial effect in control of E. coli, S. aureus,
B. subtilis and P. aeruginosa. For Shewanella sp., it is increased on
antibacterial efficiency after forming complexes. And the difference
on antibacterial activity is not obvious whether pyridine or mor-
pholine is substituted on benzoyl. No matter the complexes or ligands,
the introduction of fluorine atom will reduce the antibacterial activity.
Theoretical calculation reveals that the antibacterial activities have
some connection with the LUMO energy, the negative charge of
atom N of the amido bond, and the positive charges on atom C1 and
the negative charges on atom O2 of carbonyl group.
[26] M. Kidwai, S. Saxena, M. Khalilur Rahman Khan, S.S. Thukral, Eur. J. Med. Chem. 40
(2005) 816–819.
[27] P. Sharma, A. Kumar, M. Sharma, Eur. J. Med. Chem. 41 (2006) 833–840.
[28] Mohamed I.M. Wazeer, Anvarhusein A. Isab, Spectrochim. Acta. Part
A Mol
Biomol. Spectrosc. 68 (2007) 1207–1212.
[29] S. Cesarini, A. Spallarossa, A. Ranise, S. Schenone, C. Rosano, P. La Colla, G. Sanna,
B. Busonera, R. Loddo, Eur. J. Med. Chem. 44 (2009) 1106–1118.
[30] V.K. Tandon, H.K. Maurya, D.B. Yadav, A. Tripathi, M. Kumar, P.K. Shukla, Bioorg.
Med. Chem. Lett. 16 (2006) 5883–5887.
It is anticipated that other thiourea derivatives may be applied to
afford analogous metal complexes to inhibit growths of other bacteria
or fungi with better antimicrobial activities. Studies on these respects
are under way in our laboratory.
[31] H.M. Faidallah, K.A. Khan, A.M. Asiri, J. Fluorine Chem. 132 (2011) 131–137.

W. Yang et al. / Journal of Inorganic Biochemistry 116 (2012) 97–105
105
[32] S.A. Khan, N. Singh, K. Saleem, Eur. J. Med. Chem. 43 (2008) 2272–2277.
[33] A. Saeed, U. Shaheen, A. Hameed, S.Z. Haider Naqvi, J. Fluorine Chem. 130 (2009)
1028–1034.
[68] H. Beraldo, D. Gambino, Mini-Rev. Med. Chem. 4 (2004) 31–39.
[69] J.E. Karp, F.J. Giles, I. Gojo, L. Morris, J. Greer, B. Jojnson, M. Thein, M. Sznol, J. Low,
Leuk. Res. 32 (2008) 71–77.
[34] M.B. Krajačić, P. Novak, M. Dumić, M. Cindrić, H.Č. Paljetak, N. Kujundžić, Eur. J.
[70] D. Kovala-Demertzi, A. Alexandratos, A. Papageorgiou, P.N. Yadav, P. Dalezis, M.A.
Demertzis, Polyhedron 27 (2008) 2731–2738.
Med. Chem. 44 (2009) 3459–3470.
[35] E. Rodríguez-Fernández, J.L. Manzano, J.J. Benito, R. Hermosa, E. Monte, J.J. Criado,
J. Inorg. Biochem. 99 (2005) 1558–1572.
[36] M.K. Rauf, I.A. Badshah, M. Gielen, M. Ebihara, D. de Vos, S. Ahmed, J. Inorg.
Biochem. 103 (2009) 1135–1144.
[37] H.M. Faidallah, K.A. Khan, A.M. Asiri, J. Fluorine Chem. 132 (2011) 870–877.
[38] V.R. Avupati, R.P. Yejella, G. Guntuku, P. Gunta, Bioorg. Med. Chem. Lett. 22 (2012)
1031–1035.
[39] H.J. Zhang, X. Qin, K. Liu, D.D. Zhu, X.M. Wang, H.L. Zhu, Bioorg. Med. Chem. 19
(2011) 5708–5715.
[71] L.M. Finkielsztein, E.F. Castro, L.E. Fabián, G.Y. Moltrasio, R.H. Campos, L.V.
Cavallaro, A.G. Moglioni, Eur. J. Med. Chem. 43 (2008) 1767–1773.
[72] A. Pérez-Rebolledo, L.R. Teixeira, A.A. Batista, A.S. Mangrich, G. Aguirre, H.
Cerecetto, M. González, P. Hernández, A.M. Ferreira, N.L. Speziali, H. Beraldo,
Eur. J. Med. Chem. 43 (2008) 939–948.
[73] C. Rodrigues, A.A. Batista, J. Ellena, E.E. Castellano, D. Benítez, H. Cerecetto, M.
González, L.R. Teixeira, H. Beraldo, Eur. J. Med. Chem. 45 (2010) 2847–2853.
[74] R. Ramachandran, M. Rani, S. Kabilan, Bioorg. Med. Chem. Lett. 19 (2009)
2819–2823.
[40] Z.M. Zhong, R.E. Xing, S. Liu, L. Wang, S.B. Cai, P.C. Li, Carbohydr. Res. 343 (2008)
566–570.
[75] C. Costello, T. Karpanen, P.A. Lambert, P. Mistry, K.J. Parker, D.L. Rathbone, J. Ren,
L. Wheeldon, T. Worthington, Bioorg. Med. Chem. Lett. 18 (2008) 1708–1711.
[76] T.O. Bastos, B.M. Soares, P.S. Cisalpino, I.C. Mendes, R.G. dos Santos, H. Beraldo,
Microbiol. Res. 165 (2010) 573–577.
[77] I.C. Mendes, J.P. Moreira, N.L. Speziali, A.S. Mangrich, J.A. Takahashi, H. Beraldo, J.
Braz. Chem. Soc. 17 (2006) 1571–1577.
[78] I.C. Mendes, M.A. Soares, R.G. dos Santos, C. Pinheiro, H. Beraldo, Eur. J. Med.
Chem. 44 (2009) 1870–1877.
[79] J.G. da Silva, L.S. Azzolini, S.M.S.V. Wardell, J.L. Wardell, H. Beraldo, Polyhedron 28
(2009) 2301–2305.
[80] I.C. Mendes, J.P. Moreira, J.D. Ardisson, R.G. dos Santos, P.R.O. da Silva, I. Garcia, A.
Castiñeiras, H. Beraldo, Eur. J. Med. Chem. 43 (2008) 1454–1461.
[81] D.C. Reis, M.C.X. Pinto, E.M. Souza-Fagundes, S.M.S.V. Wardell, J.L. Wardell, H.
Beraldo, Eur. J. Med. Chem. 45 (2010) 3904–3910.
[82] W.Q. Zhou, W. Yang, L.Q. Xie, X.C. Cheng, J. Inorg. Biochem. 99 (2005) 1314–1319.
[83] X.Q. Feng, X.F. Li, S. Yang, Yingyong Huaxue 28 (9) (2011) 1012–1016
(in Chinese).
[41] P.G. Sudhakar, B.R. Rahul, S.S. Mangesh, K. Nandini, D.K. Maharashtra, U.
Mahavidyalay, Chin. Chem. Lett. 22 (8) (2011) 883–886.
[42] L.O. Jun, O.O. Arike, B. Shridhar, PCT Int. Appl. (2011) 119 pp.
[43] P.J. Mahesh, K. Preeti, L.N. Shachindra, L.V.G. Nargund, J. Ultra Chem. 6 (2) (2010)
239–246.
[44] B.G. Steven, H. Pamela, S. Brian, F. Zhou, PCT Int. Appl. (2010) 220 pp.
[45] T. Ling, L.J. Brian, S.B. Bandarpalle, K. Seong-Heon, W.S. Yu, K.A. Joseph, W.K.C.
Michael, L. Chen, G.W. Zhou, R.K. Razia, F. Robert, K.A. Maria, D.Y. Yang, C.Y.
Dai, F. Luke, G.M. Vinay, D.S. Li, P.-M. Janeta, R.E. Judson, R.E. Kristin, S.M. Arshad,
L.P. Yang, PCT Int. Appl. (2010) 591 pp.
[46] H.D. John, C.L. George, PCT Int. Appl. (2009) 107 pp.
[47] U.R. Shankar, K.M. Girish, V.N. Rao, V.J. Kishore, D.S. Shailesh, S. Vivek, C. Jyoti,
Bioorg. Med. Chem. 17 (13) (2009) 4681–4692.
[48] G. Joseph, J.T. Cross, S. Sarah, X.C. Sun, J. Qiu, R.C. John, PCT Int. Appl. (2009) 252
pp.
[49] L. Chen, D.M. Patrick, L.C. Feng, H.R. Charles, M.M. Yang, PCT Int. Appl. (2008) 85
pp.
[84] R. Wajid, S. Irum, M. Bakhtiar, H. Zonera, S.W.H. Shah, K. Salimullah, Rev. Inorg.
Chem. 30 (3) (2010) 175–183.
[50] G. Joseph, J. Thale, S. Sara, X.C. Sun, PCT Int. Appl. (2008) 100 pp.
[51] H.D. Ryall, C.L. George, P.N. John, M.D. Robert, A.J. Frederick, S.C. Richard, L.
Tamara, PCT Int. Appl. (2007) 110 pp.
[52] V.N. Huu, S.J. Chen, Q.L. Che, Y. Xie, PCT Int. Appl. (2007) 210 pp.
[53] Q. Anna, D. Jerome, C. David, D. Gwenaelle, R. Thomas, PCT Int. Appl. (2006) 149
pp.
[85] Z.J. Wu, X.B. Liu, L.J. Chen, Faming Zhuanli Shenqing Gongkai Shuomingshu
(2010) (7 pp. (in Chinese)).
[86] M. Salih, B. Mustafa, S. Satyanarayana, Afr. J. Pure Appl. Chem. 3 (9) (2009)
170–176.
[87] S.H. Baiu, M.M. El-Ajaily, N.M. El-Barasi, Asian J. Chem. 21 (1) (2009) 5–10.
[88] X.G. Mei, X.P. Wang, Faming Zhuanli Shenqing (2008) (17 pp. (in Chinese)).
[89] A.S. Orabi, H.K. Ibrahim, E.H. El-Tamany, A. Radwan, Asian J. Chem. 20 (3) (2008)
2022–2036.
[90] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G.
Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, T. Vreven, J.A. Montgomery, J.E. Peralta, F. Ogliaro, M. Bearpark,
J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega,
J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W.
Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J.
Dannenberg, S. Dapprich, A.D. Daniels, O. Farkas, J.B. Foresman, J.V. Ortiz, J.
Cioslowski, D.J. Fox, Gaussian 09, Revision A.1, Gaussian, Inc., Wallingford CT,
2009.
[54] U. El-Ayaan, J. Mol. Struct. 998 (2011) 11–19.
[55] S. Nadeem, M. Bolte, S. Ahmad, T. Fazeelat, S.A. Tirmizi, M.K. Rauf, S.A. Sattar, S.
Siddiq, A. Hameed, S.Z. Haider, Inorg. Chim. Acta 363 (2010) 3261–3269.
[56] M. Devereux, M. McCann, D.O. Shea, R. Kelly, D. Egan, C. Deegan, K. Kavanagh, V.
McKee, G. Finn, J. Inorg. Biochem. 98 (2004) 1023.
[57] B. Coyle, P. Kinsella, M. McCann, M. Devereux, R.O. Connor, M. Clynes, K.
Kavanagh, Toxicol. In Vitro 18 (2004) 63.
[58] A. Eshwika, B. Coyle, M. Devereux, M. McCann, K. Kavanagh, Biometals 17 (2004)
415.
[59] B.S. Creaven, D.A. Egan, D. Karcz, K. Kavanagh, M. McCann, M. Mahon, A. Noble, B.
Thati, M. Walsh, J. Inorg. Biochem. 101 (2007) 1108.
[60] M. McCann, B. Coyle, S. McKay, P. McCormack, K. Kavanagh, M. Devereux, V.
McKee, P. Kinsella, R. O'Connor, M. Clynes, Biometals 17 (2004) 635.
[61] H. Arslan, U. Florke, N. Kulcu, Turk. J. Chem. 28 (2004) 673–678.
[62] K. Muekerrem, P. Fatih, T. Sevil, Transit. Met. Chem. 33 (6) (2008) 705–710.
[63] C. Sulekh, G. Archana, T. Monika, Transit. Met. Chem. 32 (8) (2007) 1079–1084.
[64] Bayazeed H. Abdullah, Asian J. Chem. 19 (5) (2007) 3903–3910.
[65] N. Penumaka, L.J.N. Lavanya, P. Pallavi, S. Harish, S. Satyanarayana, Can. J.
Microbiol. 52 (12) (2006) 1247–1254.
[91] P.J. Hay, W.R. Wadt, J. Chem. Phys. 82 (1985) 270–283.
[92] C.M. Sheldrick, T.R. Schneider, Methods Enzymol. 277 (1997) 319.
[93] L.J.J. Farrugia, Appl. Crystallogr. (1997) 565.
[94] A.A. Al-abbasi, M.A. Yarmo, M.B. Kassim, Acta Crystallogra. E66 (2010) o2896.
[95] B. Murukan, K. Mohanan, Synthesis, J. Enzyme Inhib. Med. Chem. 22 (2007) 65.
[66] G.L. Kumar, C. Sulekh, Transition Met. Chem. 31 (3) (2006) 368–373.
[67] M.F. Emen, H. Arslan, N. Kulcu, U. Florke, N. Duran, Pol. J. Chem. 79 (10) (2005)
1615–1626.