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ANTIMICROBIAL ACTIVITY AND COMPUTATIONAL STUDY OF
NEW COBALT (II )COMPLEX OF BENZOTHIAZOLE DERIVATIVE
Wasfi A. Al-Masoudi*, Rasha M. Othman**, Rafid H. Al-Asadi***
Mohaned A. Ali*
*Department of Physiology, Pharmacology and Chemistry,College of Veterinary
Medicine,University of Basrah,Basrah,iraq
2Department of Microbiology, College of veterinary medicine,University of Basrah,Basrah,Iraq
***Department of Chemistry, College of Education for pure sciences ,University of Basrah, Iraq
(Received27 January 2015 ,Accepted 9 March 2015)
Keywords: Benzothiazol, , NMR Spectroscopy, Cobalt complex.
ABSTRACT
Condensation of 6-methoxy benzothiazol-2-amine with 2-hydroxy- naphthaldehyde gave new
Schiff-base derivative in good yield. The metal complex of Co(II) have been synthesized with
Schiff base of benzothiazol derivative. Spectroscopic study such as, two dimensional NMR of
new compound have been obtained by using nuclear magnatic resonance 600 MHz.
Computational study of all compounds was calculated using Gaussian 09 program package. The
synthesized compounds were screened for their antibacterial activity against Staphylococcus
aureus, Escherichia coli, Bacillus subtilis, Klebsiella pneumonia. Additionally, the compounds
were tested for antifungal activity against Candida albicans, Candida tropica, Aspergillus multi
and Aspergillus niger. Cobalt complex compound exhibited more activity as antifungal than
benzothiazole derivative.
INTRODUCTION
The condensation products of primary amines with carbonyl compounds were first reported
by Schiff in 1864 and the products are often referred to as Schiff bases(1-3). Schiff bases have
wide applications in food industry, dye industry, analytical chemistry, catalysis, fungicidal,
agrochemical and biological activities(4) With the increasing incidence of deep mycosis, there has
been increasing emphasis on the screening of new and more effective antimicrobial drugs with
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low toxicity(5). Benzothiazole is a privileged bicyclic ring system. Due to its potent and
significant biological activities it has great pharmaceutical importance; hence, synthesis of this
compound is of considerable interest. The small and simple benzothiazole nucleus if present in
compounds involved in research aimed at evaluating new products that possess interesting
biological activities. 2-substitued benzothiazole has emerged in its usage as a core structure in
the diversified therapeutically applications. The studies of structure–activity relationship
interestingly reveal that change of the structure of substituent group at C-2 position commonly
results the change of its bioactivity(6). In 1887, substituted benzothiazole was first synthesized
by A. W. Hofmann then because of diversified activity as well as simple cyclization mechanism
number of synthetic routes have been adopted and reported(6).
Benzothiazole derivatives were reported for their diversified activity viz., antitumor,
antitubercular, antimalarial, anticonvulsant, anthelmintic, analgesic, anti-inflammatory,
antifungal, a topical carbonic anhydrase inhibitor and an antihypoxic(7). The aim of the present
work was to synthesis some new complex of bezothiazole derivatives, in the hope to use them as
antimicrobial compounds.
MATERIALS AND METHODS
a) Physical measurmenets
One dimensional 1H , 13C NMR and two dimensional COSY, HSQC and HMBC NMR spectra
were measured on a Brucker at 600 MHz, with TMS as internal reference at Konstanz
university,Germany. Microanalysis for carbon, hydrogen and nitrogen were carried out by a
Perkin-Elmer 240B Elemental Analyzer. Melting points were measured by a Philip Harris
melting point apparatus and uncorrected.
b) Synthesis
Synthesis of Schiff- base
2.77 mmol (0.5g) of 6-methoxy-1, 3- benzothiazol-2-amine in 25 ml ethanol wasadded to 2.77
mmol (0.477g) of hot ethanolic solution of 2-hydroxy naphthaldehyde, two drops of glacial
acetic acid was added and resulting solution was refluxed for 3h and then lift over night in
refrigerator, the solid product obtained was filtered and washed with acetone and the final
product was recrystallized by using chloroform: ethanol 8:2 to yield orange crystals of 1-[(6-
methoxy-1,3- benzothiazol-2-yl) carbonoimidoyl]naphthalen-2-ol.
Yield;
80% , M.P.= 192-1940C. FT-IR(KBr, Cm-1), 3475(O-H), 2894(C-H), 2830(C-H),
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1622(C=N), 1602(C=C), 1190(C-O); 1H NMR(DMSO-d6); δ 3.66(s,3H-OCH3); 7.12-
8.77(m,9HAr-
H); 9.98(s,1H,CH=N ); 13.78(s,1H-OH). 13C NMR(DMSO-d6); 56.25(OCH3), 105.88-146.95
(C-Ar), 157.8( C-OH), 162.8(C-CH=N), 164.8 (C-C=N, 167.1(C-C-S); Anal. for C19H14N2O2S
(M.wt 334):Calc. C, 68.26; H, 4.19; N, 8.38; Found: C, 68.45; H, 4.62; N, 8.53.
N
O S
CH3
N CH
HO
N
O S
CH3
NH2 +
O
H
HO
Scheme 1; Synthesis of Schiff-base of benzothiazol derivative (Ligand)
Synthesis of Cobalt complex
For the synthesis of complexes (0.5g,1.5 mmol) Schiff-base of 6-methoxy benzothiazole (L)
solution was prepared in 60% ethanol–water solvent and refluxed for three hours with (0.179 g,
0.75 mmol) solution of cobalt chloride hexa hydrate. The refluxed solutions were kept for one
day. Solid crystalline compounds appeared in the solution, which were filtered, washed with
60% acetone–water mixture, dried and weighed. Melting point of the complexes was recorded.
Yield;
73% , M.P.= 202-2040C. IR(KBr, Cm-1),2950(C-H), 2890(C-H), 1608(C=N), 1598(C=C),
1196(C-O);1HNMR(DMSO-d6) δ 3.73(s,6H-OCH3);7.24-8.94(m,18H-Ar-H); 10.82(s,2H,CH=N
;12.02(s,2H-OH); 13CNMR(DMSO-d6); 56.25(OCH3), 100.01-145.95(C-Ar), 157.81(C-OH),
162.90(C-CH=N), 164.87(C-C=N), 167.22(C-C-S); Anal. for C38H26N4O4S2CoCl2 (M.wt 796):
(M.wt 796):Calc.C, 57.28; H, 3.26; N, 7.03; Found: C, 57.45; H, 3.67; N, 7.33.
Scheme 2; Synthesis of Cobalt complex of benzothiazol derivative (Complex)
Computational study
The quantum chemical calculations were performed by density functional theory (DFT) with
Gaussian 09 package. The geometry of the ligand and complex were optimized at the hyprid
functional Becke’s three parameter and the Lee, Yang, Parr (B3LYP) as a level of theory and
6-311G as a basis set.
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Antimicrobial activity
The synthesized compounds were screened in vitro for their antibacterial activity
against: Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Klebsiella pneumonia..
Additionally, the compounds were tested for antifungal activity against Candida albicans,
Candida tropica, Aspergillus multi and Aspergillus niger, using the paper disc-agar diffusion
technique on Muller Hinton agar as a culture media for antibacterial activity(8). The test
compounds were dissolved in DMSO solvent and recommended concentrations (50, 100 and
200μg/mL) were used in the disc-agar diffusion technique. Antibiotic drug Ampicillin and
Nystatin were used as control for bacteria and fungi, respectively. Petri plates containing 20
mL of Mueller Hinton Agar were used for all the bacteria tested. Aspergillus niger,
Aspergillus multi and Candida spp. strains were cultivated in Sabouraud dextrose agar. Sterile
Whatman no. 1 filter paper disks (6mm in diameter) impregnated with the solution in DMSO
of the test were placed on the Petri plates. A paper disk impregnated with
dimethylsulfoxide (DMSO) was used as negative control. The plates were incubated for 24 h
at 37°C in the case of bacteria and 72 h at 27°C for fungi. The inhibition zone diameters
were measured in millimeters.
RESULTS AND DISCUSSION
Schiff bases are versatile intermediates in organic synthesis and have been used to prepare
numerous pharmacologically important compounds(9) . In the present work a new ligand (L)
derived from benzothaizole and cobalt complex compounds were prepared by convenient
method. The preparation of azomethine compound based on condensation of 6-methoxy
benzothiazole with 2-hydroxy naphthaldehyde using glatial acetic acid. The new compound was
obtained as orange solid in 80% yield. Complexation of Schiff-base with cobalt chloride gave a
new cobalt complex compound as yellow crystal in good yield (Experimental section).
The new compounds are stable toward moisture and air. They were characterized by NMR (one
and two dimensional) and elemental analysis (CHN). IR spectra for synthesized compounds
displayed common features in certain regions and characteristic bands in the fingerprint and
other regions. The IR spectra of Schiff base(L) show broad strong bands in 3475 cm-1 due to
ν(O-H) which this band was disappeared in comolex compound. The IR spectra confirm the
presence of the imine groups (-CH=N-) stretching with a sharp region around 1622 -1608 cm-1.
The IR spectra of two compounds show a band at 1602-1598 cm-1 range can be attributed to
C=C aromatic. The azomethine vibration of the Schiff base ligand was appeared at 1622 cm-1.
Because of bond formation between the metal and the imine nitrogen, the C=N bond stretching
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was shifted to lower frequencies relative to the free Schiff base and appeared in 1608 cm-1 for the
metal complex(10).
1H NMR spectra of Schiff base (L) were recorded in DMSO-d6 solution and show all the
expected protons with proper intensity ratio, Fig.1. In two compounds the signal for protons of
methoxy groups appear as singlet in the region 3.66-3.73 ppm, The aryl protons show the
expected resonance for substituted benzene. The proton of azomethine resonate as a singlet
between 9.98-10.82 ppm for ligand and complex compounds respectively. The OH group in
both compounds appear as singlet in the region 12.02 and 13.78 ppm, Fig.1. The 13C NMR
spectra of ligand and complex compounds show the expected resonance signals and is consistent
with their structure. The large variation of carbon atoms bearing sulphar can be explained by the
polarity of the C-S bond in thiazole ring, Fig.1.
A B
Fig.1: A) 1H NMR, B) 13C NMR of benzothiazole derivative (L).
NMR Study
a- 2D COSY NMR Spectra
The 2D COSY NMR (600 MHz) of Schiff base of benzothiazole (L) shows the coupling of
each two protons. The cross-peak show protons signals a 7.87 and 7.47 ppm due to coupling of
(H-h- and H-g- ) and coupling at 7.88 and 7.25 ppm due to (H-c- and H-d- ), the two peaks at 8.13
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and 7.93 ppm due to (H-c and H-b), and the peaks at 7.47 and 7.14 ppm due to (H-f and H-g- ),
Table 1, Fig.2.
Table (1): COSY data for Schiff-base of 6-methoxy benzothiazole (L)
Compound 1H (ppm) 1H (ppm) Assignment
O
CH3
N
S
N CH
1 HO
2
3
4 5 a
b
c
d
e
a-
b- c-
d-
e-
f-
g-
h-
i-
j-
7.87
7.88
8.13
7.47
7.87
7.47
7.25
7.93
7.14
7.12
h- - gc-
- dc
– b
f - gh-
- i-
Fig. 2. COSY NMR spectra of Schiff-base of 6-methoxy benzothiazole (L).
b- HSQC NMR Spectra
The HSQC NMR spectrum of (L) shown that the 13C peak at 56.2 ppm is bonded to the
1H with peak at 3.8 ppm. Thus, the correlation of protons and carbon in aromatic rings such as
in positions (e and c), (c and d), ( i- and h), (g- and e- ) and in positions b and d are shown in
Table 2, Fig. 3.
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Table (2) HSQC data for Schiff-base of 6-methoxy benzothiazole (L)
Compound 1H (ppm) 13C(ppm) Assignment
O
CH3
N
S
N CH
1 HO
2
3
4 5 a
b
c
d
e
a-
b- c-
d-
e-
f-
g-
h-
i-
j-
3.86
7.85
8.13
7.93
7.12
7.25
7.47
56.25
129.9
138.21
132.7
116.24
120.0
124.0
C,H (OCH3)
C,H (e , c)
C,H (c , d)
C,H (b)
C,H ( i- , h)
C,H (d)
C,H (g- , e- )
Fig. 3. HSQC NMR spectra of Schiff-base of 6-methoxy benzothiazole (L).
c- HMBC NMR Spectra
The HMBC spectrum is used to correlate, or connect, 1H and 13C peaks for atoms separated
by multiple bonds (usually 2 or 3)(11).
The spectrum (600MHz) of (L) compound (Fig.4 ) shows that in aromatic rings, the most
common correlations is seen in region 7.47-8.13 ppm, the correlation of protons and multi
carbons are, H(e) and C(a,b,e), H(e) and C(f,e), H(g- ) and C(g-, f- ), H(b) and (c, b, d), H(h-)
and (f, e).The COSY and HSQC NMR of cobalt complex compound are shown in Figs, 5 and
6.
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Fig. 4. HMBC NMR spectra of Schiff-base of 6-methoxy benzothiazole (L).
Fig. 5. COSY NMR spectra of cobalt complex compound
Fig. 6. HSQC NMR spectra of cobalt complex compound.
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Computational study
The B3LYP has long been recognized as a good tool due to the fact that it is computationally
less demanding for inclusion of electron correlation and could provide accurate geometries(12)
meanwhile, a previous study (13).
The optimized structure of the ligand and Co(II) complex with labeling of the atoms are
presented in Figs. 7 and 8 respectively. The optimized structure parameters, bond lengths, bond
angles and dihedral angles are listed in Table 3 .
The ligand molecule deprotonates and then acts as a bidentate monoanionic Shiff-base ligand
framework, which has a N, O- binding mode. The calculated bond length C22-N21 in ligand is
1.323Å which is the approximate value for a C=N double bond length, this a bond is elongation in
the complex molecules to 1.352 Å because the coordination between lone pair on the nitrogen atom
and d-orbital of cobalt atom. This case observed in IR spectrum through the shifting of stretching
vibration position of C=N bond from 1622 cm-1 to 1608 cm-1. The C4-O23 in ligand has single bond
properties, the distance is 1.415 Å .While this bond in metal complex molecule has the single and
double bond properties, the distance of C12-O15 and C20-O39 are 1.322 Å and 1.326 Å, respectively.
These values suggest that electron density may be delocalized throughout the aromatic ring.
The calculated dihedral angles in ligand are N21-C17-S18-C11 (179°) and C5-C22=N21-C17
(175.5°), indicate the ligand molecule is slightly planner structure. Inversely the Co(II) complex
molecule has nonplaner structure, Table(3). On the other hand the theoretical angle values for the
Co(II) complex show some deviation from the octahedral geometry. For example, the calculated
angles obtained O15-Co-O39 , N37-Co-Cl50 and N37-Co-N42 are 176.34°, 174.86° and 95.86°,
respectively.
The atomic charges of the ligand and Co-complex calculated by the Mulliken method(14) are
given in Table(4). As can be seen, high charge electorphalic density was found at oxygen and
nitrogen atoms and charge of the N21 atom in the ligand (which is -0.364) is higher than charge of
N16 atom(-0.253). Hence, the N21 atom has a higher ability for coordination of the metal ion than
N16 because its has more basedity(15). On the other hand, the charges electorphalic density are
increasing for the Co-complex compare with ligand, this case in agreement with a high biological
activity of the complex, Table(6).
The Total energy, binding energy and HOMO-LUMO energy gap computed by using same
method and basis set and summarized in Table(5). The highest occupied molecular orbital
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(HOMO) and the lowest unoccupied molecular orbital (LUMO) and their energy gap reflect the
chemical activity of the molecule (16). From values of HOMO-LUMO energy gap observed the Cocomplex
molecule has higher reactivity than ligand molcule (ΔE LUMO-HOMO
complex =1.527eV,
ligand =1.908eV) which is good in agreement with the results that obtained from biological activity
tests. The HOMO and LUMO orbitals are depicted in Figure(9). The HOMO orbitals are localized
mainly on phenyl rings, Nitrogen atoms, Oxygen atoms and Cobalt atom moieties. Whereas the
LUMO of π nature are mostly located on the phenyl ring.
Table 3. Selected bond lengths , bond angles and dihedral angles of ligand and complex
calculated with B3LYP/6-311G method.
Bond length(Å) C17-N21 C22=N21 C17-S C5-C22 C4-O23 O23-H24 Co-O Co-N Co-Cl
Ligand 1.380 1.323 1.902 1.458 1.415 0.991 - - -
Complex 1.410
1.396
1.352
1.352
1.953
1.885
1.419
1.417
1.326
1.322
-
1.924
1.917
2.037
2. 030
2.362
2.348
Angles bond(0) N-C-S C=N-C N-Co-N Cl-Co-Cl O-Co-O N-Co-Cl
Ligand 116.58 120.36 - - - -
Complex 121.25
120.90
115.09
119.87
95.86 87.20 176.35 174.86
173.71
Dihedral angles(0) N-C-S-C C-C=N-C
N-Co-
N=C
O-Co-
N=C
Ligand 179.14 175.57 - -
Complex
175.30
-179.50
147.75
171.92
127.7
-66.47
29.64
34.27
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Table 4. The Mulliken atomic charges of ligand and complex calculated with B3LYP/6-311G
method.
Ligand O23 N16 N21 S O19 C4 C14 C17 C22 C5
-0.546 -0.253 -0.364 0.481 -0.475 -0.15 -0.15 -0.176 -0.046 0.029
Complex O15
O39
N4
N32
N37
N42
S0
S34
O35
O47
C12
C20
C30
C46
C2
C33
C38
C41
C11
C21
Cl39
Cl50
Co
-0.406
-0.405
-0.325
-0.407
-0.196
-0.195
-0.498
-0.402
-0.581
-0.583
-0.12
-0.11
-0.098
-0.099
-0.190
-0.191
-0.066
-0.068
0.022
0.023
-
0.460
-
0.463
0.687
Table 5. Values of total energy, binding energy and HOMO-LUMO energy gap of ligand and
complex calculated with B3LYP/6-311G method.
Total energy(eV) Binding energy(eV) HOMO energy
(eV)
LUMO
nergy(eV)
ΔE LUMO-HOMO
ligand -1390.2820 -6.8659 -4.801 -2.893 1.908
Complex -3845.88447 -13.9141 -4.801 -3.274 1.527
0
1
2
3
4
5
6
8 7
9
10
11
12
13
14
15
N
16
17
S
O 18
19
H3C
20
N 21
22
23 O
H
24
Figure (7): Optimized structure for Ligand together with its labeling
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Figure (8): Optimized structure for Co complex together with its labeling
Figure (9): Representation of the HOMO and LUMO orbitals of ligand and complex.
Antimicrobial activity
The studied compounds have been screened for their in vitro antibacterial and antifungal
activities, using the paper disc-agar diffusion technique(8) by measuring the inhibition zone in
mm. Antibiotic drug ampicillin and Nystatin were used as control for bacteria and fungi,
respectively. The antibacterial activity of the synthesized compounds were tested against two
HOMO
LUMO
HOMO
LUMO
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gram positive bacteria (Staphylococcus aureus, Bacillus subtilis, and two gram negative
bacteria (Klebsiella pneumonia, Escherichia coli ) at a concentration of 50, 100 and 200μg/mL
using DMSO as a solvent, which not effected the growth of microbes. Mueller Hinton agar was
used as culture media for antibacterial activity. The results of the antimicrobial activity are
shown in Table (6).
It is observed that the activity of compounds increases with an increase in the
concentration of the solutions. The synthesized compounds show activity against all the fungi
species. However, the compounds had the highest effect against Staphylococcus aureus, but were
inactive against Klebsiella pneumonia and active in high concentration against Bacillus subtilis
and Escherichia coli.
The antifungal activity show more activity of cobalt complex compound than
benzothiazole derivative.
Therefore, the possible explanations of our results attribute to the chemical structure of the
bacterial cells wall which provides important ligands for adherence and receptor sites for
antibiotics and drugs.
Table 6. Antibacterial activity of the studied compounds
Zone inhibition of antimicrobial sensitivity test of compounds
(mm)
Antibiotic disc (control)
(mm)
Bacteria and fungi types
Ligand (1) Complex(2)
200 100 50 200 100 50
Ampicillin Nystatine
1- Klebsiella pneumonia 40 - 0 0 0 0 0 0
2- Escherichia coli 20 - 15 0 0 0 0 0
3- Staphylococcus aureus 45 - 15 13 10 17 11 10
4- Bacillus subtillus 30 - 18 0 0 0 0 0
5- Aspergillus niger - 15 20 15 15 25 22 20
6- Aspergillus multi - 13 25 22 20 28 27 25
7- Candida albicans - 12 18 15 12 16 15 12
8- Candida tropica - 9 23 19 19 24 23 20
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ACKNOWLEDGEMENT
We are grateful to Miss Anka Friemel of chemistry department, University of Konstanz,
Germany are highly acknowledged for the NMR experiments. We are also grateful to
Departments of Physiology and Microbiology, College of Veterinary Medicine, Basrah
University, Iraq for providing the facilities.
الفعالیة المایکروبیة والدراسة الحاسوبیة لمعقد الکوبلت لمشتق البنزوثایازول الجدید
وصفی عبود المسعودی ، رشا منذر عثمان ، رافد حمیدان الاسدی ، مھند أدریس علی
الخلاصة
تکثیف المرکب 6-میثوکسی بنزوثایازول - 2- أمین مع 2-ھیدروکسی نافثالدیھاید أعطت مشتق قاعدة شیف الجدیدة بحصیلة
انتاجیة جیدة. حضر معقد الکوبلت بتفاعل الکوبلت الثنائی مع مشتق قاعدة شیف للثایازول. شخصت المرکبات المحضرة
ودرست طیفیا بأستخدام طیف الرنین النووی المغناطیس احادی وثناثی المحور 600 میکاھیرتز . درست المرکبات المحضرة
حاسوبیا باستخدام برنامج کاوسین 09
أختبرت المرکبات المحضرة کمضادات بکتیریة ضد :
Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Klebsiella pneumonia.
اضافة الى اختبارھا کمضادات فطریة ضد :
Candida albicans, Candida tropica, Aspergillus multi and Aspergillus niger.
أظھر معقد الکوبلت فعالیة اکبر ضد الفطریات من مشتق البنزاثایازول.
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