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Sulfonamide-derived compounds and their transition metal complexes synthesis biological evaluation and X-ray structure of 4-bromo-2-[(E)-{4-[(3 4-dimethylisoxazol-5 yl)sulfamoyl]phenyl} iminiomethyl] phenolate.

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Full Paper
Received: 22 December 2010
Revised: 27 March 2011
Accepted: 11 April 2011
Published online in Wiley Online Library: 18 May 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1807
Sulfonamide-derived compounds and their
transition metal complexes: synthesis,
biological evaluation and X-ray structure
of 4-bromo-2-[(E)-{4-[(3,4-dimethylisoxazol-5
yl)sulfamoyl]phenyl} iminiomethyl] phenolate
Zahid H. Chohan∗ and Hazoor A. Shad
Sulfonamide-derived new ligands, 4-({[(E)-(5-bromo-2-hydroxyphenyl)methylidene]-amino}methyl)benzenesulfonamide and
4-bromo-2-((E)-{4-[(3,4-dimethylisoxazol-5-yl)sulfamoyl]phenyl}iminiomethyl)phenolate and their transition metal [cobalt(II),
copper(II), nickel(II) and zinc(II)] complexes were synthesized and characterized. The nature of bonding and structure of
all the synthesized compounds were deduced from physical (magnetic susceptibility and conductivity measurements),
spectral (IR, 1 H and 13 C NMR, electronic, mass spectrometry) and analytical (CHN analysis) data. The structure of the
ligand, 4-bromo-2-((E)-{4-[(3,4-dimethylisoxazol-5-yl)sulfamoyl]phenyl} iminiomethyl)phenolate was also determined by X-ray
diffraction method. An octahedral geometry was suggested for all the complexes. In order to evaluate the biological
activity of the ligands and the effect of metals, the ligands and their metal complexes were screened for in vitro
antibacterial, antifungal and cytotoxic activity. The results of these studies revealed that all compounds showed moderate
to significant antibacterial activity against one or more bacterial strains and good antifungal activity against various fungal
c 2011 John Wiley & Sons, Ltd.
strains. Copyright Supporting information may be found in the online version of this article.
Keywords: sulfonamide; metal(II) complexes; antibacterial; antifungal; cytotoxic
Introduction
Appl. Organometal. Chem. 2011, 25, 591–600
Experimental Section
Material and Methods
All reagents and solvents used were of analytical grade. Elemental
analyses were carried out with a CHNSO Analyzer (Perkin Elmer
USA) model. 1 H and 13 C-NMR spectra of compounds were
recorded with a Bruker Spectrospin Avance DPX-400 using
TMS as internal standard and d6 DMSO as solvent. Infrared
spectra of the compounds were recorded on a Shimadzu FTIR
spectrophotometer. The melting points were determined with
a Gallenkamp melting point apparatus. In vitro antibacterial,
antifungal and cytotoxic properties were studied at HEJ Research
Institute of Chemistry, International Center for Chemical Sciences,
University of Karachi, Pakistan.
∗
Correspondence to: Zahid H. Chohan, Department of Chemistry, Bahauddin
Zakariya University, Multan, Pakistan. E-mail: dr.zahidchohan@gmail.com
Department of Chemistry, Bahauddin Zakariya University, Multan, Pakistan
c 2011 John Wiley & Sons, Ltd.
Copyright 591
Sulfonamides exhibit modified pharmacological and toxicological
potentials when administered in the form of their metal complexes. Prominent biological activity of various metal complexes
has been reported for antibacterial,[1 – 3] antitumor,[4] diuretic,[5]
anti-carbonic anhydrase,[6,7] hypoglycaemic,[8] anti-thyroid,[9]
protease inhibitor[10] and several other activities.[11 – 14] Various
biological aspects[15 – 17] of the metal complexes exclusively
depend on the ease of cleaving of the bond between the
metal ion and the ligand. It is therefore, essential to understand
coordination behavior and relationship of the metals and the
ligands in biological systems. In view of the versatile chemistry
of sulfonamides as ligand we have initiated a program[18 – 28] of
synthesizing and designing various metal-based sulfonamides
and investigating their structural and biological behavior. We
herein describe synthesis of two new sulfonamides, 4-({[(E)-(5bromo-2-hydroxyphenyl)methylidene]amino}methyl)benzenesulfonamide (L1 ) and 4-bromo-2-((E)-{4-[(3,4-dimethylisoxazol5-yl)sulfamoyl]-phenyl}iminiomethyl)phenolate (L2 ) derived
from the reaction of 4-methylbenzenesulfonamide and sulfisoxazole, respectively, with 5-bromosalicylaldehyde and
their cobalt, copper, nickel and zinc metal complexes. These
compounds were investigated for their in vitro antibacterial activity against four Gram-negative (Escherichia coli,
Staphylococcus flexenari, Pseudomonas aeruginosa, Salmonella
typhi) and two Gram-positive (Staphylococcus aureus, Bacillus
subtilis) bacterial strains and for antifungal activity against
Trichophyton longifusus, Candida albican, Aspergillus flavus,
Microsporum canis, Fusarium solani and Candida glabrata fungal
strains.
Z. H. Chohan and H. A. Shad
Synthesis of Sulfonamide-derived Ligand (L1 )
4-({[(E)-(5-Bromo-2-hydroxyphenyl)methylidene]amino}methyl)
benzenesulfonamide (L1 )
To an ethanol (30 ml) solution of 4-methylbenzenesulfonamide
(0.75 g, 0.004 mol), 5-bromosalisylaldehyde (0.81 g, 0.004 mol) in
ethanol (15 ml) was added with stirring. The solution was refluxed
for 3 h. It was cooled to room temperature and the solution
evaporated on rotary evaporator. The solid product thus obtained
was re-crystallized in hot ethanol (78% yield). The same method
was applied to prepare (L2 ).
Physical, Analytical and Spectral Data of the Ligands
4-({[(E)-(5-Bromo-2-hydroxyphenyl)methylidene]amino}methyl)
benzenesulfonamide (L1 )
◦
Yield: 78% (1.15 g). Off-white. M.p: 232–234 C. IR (KBr, cm−1 ):
3368 (OH), 3346 (NH2 ), 3055 (CH), 1595 (HC N), 1465 (CH2 ), 1342,
1112 (S O), 953 (S–N), 844 (C–S), 565 (C–Br). 1 H NMR (DMSO-d6 ,
δ, ppm): 3.88 (s, 2H, CH2 –N), 6.9–7.6 (m, 3H, Br–Ph), 7.7–8.2 (m,
4H, N–Ph), 8.91 (s, 1H, azomethine), 9.2 (s, 2H, – SO2 NH2 ), 12.42
(s, 1H, OH). 13 C NMR (δ, ppm): 64.4 (CH2 –N), 118.4 (C3 , Br–Ph),
120.5 (C1 , Br–Ph), 116.0 (C5 , Br–Ph), 127.2 (C3 , C5 , N–Ph), 129.4 (C2 ,
C6 , N–Ph), 134.0 (C6 , Br–Ph), 135.5 (C4 , Br–Ph), 136.7 (C4 , N–Ph),
142.1 (C1 , N–Ph), 160.0 (C2 , Br–Ph), 160.9 (C N, azomethine).
Anal. calcd for C14 H13 BrN2 O3 S (369.23): C: 45.54; H: 3.55; Br: 21.64;
N: 7.59; Found: C: 45.47; H: 3.62; Br: 21.57; N: 7.51. Mass spectrum
(ESI) [M]+ = 368.6.
Figure 1. ORTEP diagram of a single molecule found in the asymmetric
unit of L2 .
4-Bromo-2-((E)-{4-[(3,4-dimethylisoxazol-5-yl)sulfamoyl]phenyl}
iminiomethyl)phenolate (L2 )
Yield: 73% (1.37 g). Orange-red. M.p: 202–204 ◦ C. IR (KBr, cm−1 ):
3365 (OH), 3318 (NH), 3060 (CH), 1450 (CH3 ), 1597 (HC N), 1345,
1110 (S O), 1208 (CN), 953 (S–N), 842 (C–S), 561 (C–Br). 1 H NMR
(DMSO-d6 , δ, ppm): 2.35 (s, 6H, dimethylisoxazole), 6.9–7.6 (m,
3H, Br–Ph), 7.7–8.2 (m, 4H, N–Ph), 8.9 (s, 1H, azomethine), 8.97
(s, 1H, SO2 NH–), 12.42 (s, 1H, OH). 13 C NMR (δ, ppm): 9.9 (C3 ,
methylisoxazole), 11.1 (C4 , methylisoxazole), 158.9 (C2 , isoxazole),
159.9 (C4 , isoxazole), 100.5 (C3 , isoxazole), 118.4 (C3 , Br–Ph), 120.5
(C1 , Br–Ph), 122.6 (C2 , C6 , N–Ph), 116.0 (C5 , Br–Ph), 128.6 (C3 ,
C5 , N–Ph), 134.0 (C6 , Br–Ph), 135.5 (C4 , Br–Ph), 138.2 (C4 , N–Ph),
156.4 (C1 , N–Ph), 160.0 (C2 , Br–Ph), 160.9 (C N, azomethine).
Anal. calcd for C18 H16 BrN3 O4 S (450.33): C: 48.01; H: 3.58; Br: 17.74;
N: 9.33; Found: C: 48.12; H: 3.69; Br: 17.82; N: 9.23. Mass spectrum
(ESI) [M]+ = 449.5.
X-Ray Structure
filtered and reduced to half of its volume by evaporation of the
solvent in vacuo. The concentrated solution was left overnight
at room temperature, which led to the formation of a solid
product. It was filtered, washed with a small amount of dioxane
then with ether and dried. The solid product thus obtained was
recrystallized in DMF-ether (2 : 1, 78% yield). All other complexes
(2–8) were prepared following the same method using the
respective metal salts as chloride and the prepared sulfonamide
derived ligands. Physical measurements, analytical and spectral
data of the complexes are given in Tables 1 and 2.
NMR Data of Zn(II) Complexes 4 and 8
The X-ray structure of one of the ligands, 4-bromo-2-((E)-{4-[(3,
4-dimethylisoxazol-5-yl) sulfamoyl]phenyl}iminiomethyl)phenolate (L2 ) has already been published[29] and is also presented
here as Figs 1 and 2.
Synthesis of Metal(II) Complexes 1–8
[Co(L1 -H)2 (H2 O)2 ] (1)
592
To a hot magnetically stirred dioxane (10 ml) solution of
4-({[(E)-(5-bromo-2-hydroxyphenyl)methylidene]amino}methyl)
benzenesulfonamide (L1 ) (0.738 g, 0.002 mol), an aqueous
solution (15 ml) of Co(II) Cl2 .6H2 O (0.238 g, 0.001 mol) was added.
The mixture was refluxed for 2 h. The obtained solution was
wileyonlinelibrary.com/journal/aoc
Figure 2. The unit cell packing in L2 .
[Zn (L1 -H)2 (H2 O)2 ] (4)
1 H NMR (DMSO-d , δ, ppm): 4.2 (s, 4H, CH –N), 7.35–7.8 (m, 6H,
6
2
bromo-phenyl), 7.9–8.4 (m, 8H, N–Ph), 9.1 (s, 2H, azomethine),
9.2 (s, 4H, – SO2 NH2 ), 10.5 (s, 4H, H2 O); 13 C NMR (δ, ppm): 65.2
(CH2 –N), 118.4 (C3 , Br–phenyl), 120.5 (C1 , Br–phenyl), 116.0 (C5 ,
Br–phenyl), 127.2 (C3 , C5 , N–Ph), 129.4 (C2 , C6 , N–Ph), 134.0 (C6 ,
Br–phenyl), 135.5 (C4 , Br–phenyl), 136.7 (C4 , N–Ph), 142.1 (C1 ,
N–Ph), 160.8 (C2 , Br–phenyl), 161.5 (C N, azomethine).
[Zn (L2 -H)2 (H2 O)2 ] (8)
1H
NMR (DMSO-d6 , δ, ppm): 2.35 (s, 12H, dimethylisoxazole),
7.35–7.8 (m, 6H, bromo-phenyl), 8.1–8.5 (m, 8H, N–Ph), 9.1 (s, 2H,
c 2011 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 591–600
Sulfonamide-derived compounds and their transition metal complexes
Table 1. Physical measurements and analytical data of the metal(II) complexes
Found (calcd) (%)
No.
1.
2.
3.
4.
5.
6.
7.
8.
Molecular formula
◦
Molar mass
m.p. (dec.) ( C)
[831.39]
261–263
78
[831.15]
253–255
80
[836.02]
266–268
77
[837.85]
238–240
83
[993.56]
212–214
78
[993.35]
213–215
81
[998.2]
216–218
83
[1000.05]
224–226
79
1
[Co(L -H)2 (H2 O)2 ]
C28 H28 N4 O8 S2 Br2 Co
[Ni(L1 -H)2 (H2 O)2 ]
C28 H28 N4 O8 S2 Br2 Ni
[Cu(L1 -H)2 (H2 O)2 ]
C28 H28 N4 O8 S2 Br2 Cu
[Zn(L1 -H)2 (H2 O)2 ]
C28 H28 N4 O8 S2 Br2 Zn
[Co(L2 -H)2 (H2 O)2 ]
C36 H34 N6 O10 S2 Br2 Co
[Ni(L2 -H)2 (H2 O)2 ]
C36 H34 N6 O10 S2 Br2 Ni
[Cu(L2 -H)2 (H2 O)2 ]
C36 H34 N6 O10 S2 Br2 Cu
[Zn(L2 -H)2 (H2 O)2 ]
C36 H34 N6 O10 S2 Br2 Zn
Yield (%)
C
H
N
40.45
(40.51)
40.46
(40.52)
40.23
(40.3)
40.14
(40.2)
43.52
(43.46)
43.53
(43.59)
43.32
(43.25)
43.24
(43.3)
3.39
(3.46)
3.40
(3.47)
3.38
(3.29)
3.37
(3.31)
3.45
(3.5)
3.45
(3.39)
3.43
(3.5)
3.43
(3.37)
6.74
(6.82)
6.74
(6.8)
6.7
(6.78)
6.69
(6.74)
8.46
(8.4)
8.46
(8.4)
8.42
(8.54)
8.40
(8.46)
Table 2. Conductivity, magnetic and spectral data of metal(II) complexes
M
(−1 cm2 mol−1 )
B.M. (µeff )
1
14.7
2
λmax (cm−1 )
IR (cm−1 )
4.91
7409, 17 449, 20 585, 29 310
17.6
3.36
10 392, 15 708, 1568, 26 452, 29 875
3
12.8
1.89
14 996, 19 168, 30 375
4
16.4
Dia
28 935
5
17.4
4.95
7364, 17 516, 20 625, 29 355
6
13.8
3.38
10 434, 15 790, 26 495, 30 952
7
12.9
1.8
15 152, 19 213, 30 352
8
17.9
Dia
29 135
1566 (C N), 1391 (C–O),1345, 1110 (SO2 ), 955 (S–N), 842
(C–S), 438 (M–N), 530 (M–O)
(C N), 1392 (C–O), 1345, 1110 (SO2 ), 953 (S–N), 841
(C–S), 438 (M–N), 533 (M–O)
1392 (C–O), 1345, 1110 (SO2 ), 1567 (C N), 955 (S–N), 841
(C–S), 441 (M–N), 532 (M–O)
1567 (C N), 1391 (C–O),1345, 1110 (SO2 ), 955 (S–N), 841
(C–S), 440 (M–N), 530 (M–O)
1568 (C N), 1393 (C–O), 1345, 1110 (SO2 ), 955 (S–N), 841
(C–S), 441 (M–N), 534 (M–O)
1566 (C N), 1393 (C–O),1345, 1110 (SO2 ), 955 (S–N), 842
(C–S), 439 (M–N), 534 (M–O)
1566 (C N), 1394 (C–O),1345, 1110 (SO2 ), 954 (S–N), 841
(C–S), 441 (M–N), 529 (M–O)
1567 (C N), 1393 (C–O),1345, 1110 (SO2 ), 953 (S–N), 841
(C–S), 439 (M–N), 533 (M–O)
No.
azomethine), 8.97 (s, 2H, SO2 NH–), 10.5 (s, 4H, H2 O); 13 C NMR (δ,
ppm): 9.9 (C3 , methylisoxazole), 11.1 (C4 , methylisoxazole), 158.9
(C2 , isoxazole), 159.9 (C4 , isoxazole), 100.5 (C3 , isoxazole), 118.4
(C3 , Br–phenyl), 120.5 (C1 , Br–phenyl), 122.6 (C2 , C6 N–Ph), 116.0
(C5 , Br–phenyl), 128.6 (C3 , C5 N–Ph), 134.0 (C6 , Br–phenyl), 135.5
(C4 , Br–phenyl), 138.2 (C4 , N–Ph), 158.5 (C1 , N–Ph), 160.8 (C2 ,
Br–phenyl), 161.5 (C N, azomethine).
Biological Activity
In vitro antibacterial bioassay
Appl. Organometal. Chem. 2011, 25, 591–600
In vitro antifungal activity
The antifungal activity of all the compounds was studied against
six fungal strains using the disk diffusion method [31] . Sabouraud
dextrose agar (Oxoid, Hampshire, UK) was seeded with 105 cfu
c 2011 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
593
The synthesized sulfonamides (L1 and L2 ) and their metal(II)
complexes (1–8) were screened in vitro for their antibacterial
activity against four Gram-negative (E.coli, S.flexenari, P.aeruginosa
and S. typhi) and two Gram-positive (S. aureus and B. subtilis)
bacterial strains by the agar-well diffusion method.[30,31] The wells
(6 mm in diameter) were dug in the media with the help of a sterile
metallic borer with centers at least 24 mm apart. Bacterial inocula
(2–8 h old) containing approximately 104 –106 colony-forming
units (cfu) per milliliter were spread on the surface of the nutrient
agar with the help of a sterile cotton swab. The recommended
concentration of the test sample (50 µg µl−1 in DMSO) was
introduced in the respective wells. Other wells supplemented
with DMSO and a reference antibacterial drug, imipenum, served
as negative and positive controls, respectively. The plates were
incubated at 37 ◦ C for 24 h. Activity was determined by measuring
the diameter (mm) of zones showing complete inhibition. In order
to clarify any participating role of DMSO in the biological screening,
separate studies were carried out with the solutions alone of DMSO
and they showed no activity against any bacterial strains.
Z. H. Chohan and H. A. Shad
ml−1 fungal spore suspensions and transferred to Petri plates.
Disks soaked in 20 ml (200 µg ml−1 in DMSO) of all compounds
were placed at different positions on the agar surface. The plates
were incubated at 32 ◦ C for 7 days. The results were recorded
as percentage of inhibition and compared with standard drugs
miconazole and amphotericin B.
Minimum Inhibitory Concentration
Compounds containing high antibacterial activity (over 80%)
were selected for minimum inhibitory concentration (MIC) studies.
The MIC was determined using the disk diffusion technique by
preparing disks containing 10, 25, 50 and 100 µg ml−1 of the
compounds and applying the protocol.[32]
In Vitro Cytotoxicity
Brine shrimp (Artemia salina leach) eggs were hatched in a shallow
rectangular plastic dish (22 × 32 cm), filled with artificial seawater,
which was prepared with commercial salt mixture and doubledistilled water. An unequal partition was made in the plastic dish
with a perforated device. Approximately 50 mg of eggs were
sprinkled into the large compartment, which was darkened, while
the other compartment was opened to ordinary light. After 2 days
nauplii were collected by a pipette from the light side. A sample
of the test compound was prepared by dissolving 20 mg of each
compound in 2 ml of DMF. From this, stock solutions of 500, 50 and
5 µg ml−1 were transferred to nine vials (three for each dilutions
were used for each test sample and LD50 is the mean of the three
values) and one vial was kept as the control having 2 ml of DMF
only. The solvent was allowed to evaporate overnight. After 2 days,
when shrimp larvae were ready, 1 ml of seawater and 10 shrimps
were added to each vial (30 shrimps per dilution) and the volume
was adjusted with seawater to 5 ml per vial. After 24 h the number
of survivors was counted. Data were analyzed using the Finney
computer program to determine the LD50 values.[33,34]
Results and Discussion
Chemistry
Sulfonamides, L1 and L2 , were prepared by the reaction
of 5-bromosalicylaldehyde with the respective sulfonamides,
4-methylbenzenesulfonamide and sulfisoxazole, as shown in
Scheme 1. All sulfonamides were only soluble in dioxane, DMF and
DMSO. Their composition was consistent with their microanalytical
and mass spectral data. The metal(II) complexes 1–8 were
prepared in a stochiometric (metal : ligands, 1 : 2) molar ratio.
Cobalt, copper, nickel and zinc were used as chlorides (Scheme 2).
Physical measurements and analytical data for complexes 1–8 are
given in Tables 1 and 2.
Conductance and Magnetic Susceptibility Measurements
The complexes 1–8, showed (Table 2) molar conductance values
(in DMF) in the range 12.8–17.9 −1 cm2 mol−1 , indicating their
Scheme 1. Preparation of Schiff’s bases L1 and L2 .
594
Scheme 2. Proposed structure of the metal(II) complexes 1–8.
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c 2011 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 591–600
Sulfonamide-derived compounds and their transition metal complexes
nonelectrolytic nature[35] . The magnetic moment values of the
complexes at room temperature are given in Table 2. The observed
magnetic moment value for cobalt(II) complexes was found to be
as 4.91 and 4.95 B.M. for 1 and 5, respectively, consistent with
half-spin octahedral geometry. The magnetic moment values (1.8
and 1.89 B.M.) measured for the copper(II) complexes, 3 and
7 lay in the range expected for a d9 -system that contains one
unpaired electron corresponding to an octahedral geometry.[36]
The measured values, 3.36 and 3.38 B.M for the nickel(II) complexes
2 and 6, suggest[37] an octahedral geometry for these complexes.
The zinc(II) complexes 4 and 8 were found to be diamagnetic, as
expected.
IR Spectra
Some of the characteristic IR spectral bands of the synthesized
sulfonamides and its metal(II) complexes are given in the
Experimental Section and in Table 2. Both of the ligands L1
and L2 showed[38] potential donor sites such as, hydroxyl
(–OH), azomethine (–C N), sulfonamide (–S O) and (–SN),
which have the tendency to coordinate with the metal ions.
Generally, IR spectra of the ligands, exhibited a sharp new band at
1595–1597 cm−1 assigned to the azomethine ν(–C N) linkage
and also showed the absence of bands at 1775 and 3325 cm−1
assigned to aldehyde (CHO) and amino (NH2 ) groups of the
starting material. This showed that condensation and formation of
the desired products had successfully taken place. The IR spectra
of uncoordinated sulfonamides generally showed a broad band
at 3365–3368 cm−1 assigned[39] to the hydroxyl ν(OH) group.
Both the ligands showed sharp peaks at 1345 and 1110 cm−1
owing to symmetric and asymmetric stretching of νsymm (–S O)
and νasymm (–S O), assigned[40] to sulfonamide group. Similarly,
the Schiff base ligands showed bands at 956 and 841 cm−1
resulting from sulfonamide–SN and sulfonamide–CS stretchings,
respectively.
In all the metal complexes, 1–8, the band for azomethine
(C N) linkage was found to be on the lower frequency side
by 29 cm−1 (1566–1568 cm−1 ), indicating the formation of a new
bond between nitrogen and the metal ion. This is further supported
by the appearance of a new band at 438–441 cm−1 , assigned
to ν(M–N).[41] The coordination through the hydroxyl–O was
revealed by the disappearance of broad bands at 3365–3368 cm−1
and, in turn, the appearance of new band at 1391–1394 cm−1
owing to deprotonation and coordination of ν(OH) and an
establishment of the C–O mode. This is evident from the
appearance of a new band at 529–534 cm−1 owing to ν(M–O) in
the metal(II) complexes 1–8. The bands at 1345 and 1110 cm−1
present in the spectra of sulfonamide ligands owing to νasymm (SO2 )
and νsymm (SO2 ) were found to be unchanged[42] in the spectra
of their metal complexes, indicating that this group does not
take part in the coordination. This is further supported by the
unchanged modes of ν(S–N) and ν(C–S) appearing at 953–955
and 841–842 cm−1 , respectively, in the spectra of Schiff base
ligands as well as in their metal complexes. All other potential
donor sites similarly did not participate in coordination as their IR
frequencies remained unchanged after complexation.
1 H NMR Spectra
1H
Appl. Organometal. Chem. 2011, 25, 591–600
13 C NMR Spectra
The 13 C NMR spectra of the free sulfonamide and their diamagnetic
zinc(II) complexes were also recorded in DMSO-d6 . All assignments
of the carbons atoms in sulfonamides were found in their expected
region[43] and are well supported by their IR and 1 H NMR spectra.
Downfield shifting of the azomethine carbon from 160.9 ppm in
the sulfonamide ligands L1 and (L2 ) to 161.5 ppm in its Zn(II)
complexes 4 and 8 revealed coordination of the azomethine to
the metal atom. Similarly, the carbon of the phenyl ring (CH2 –Ph)
and Br–phenyl ring (C2 , Br–phenyl) in L), N-phenyl ring (C1 ,
N–Ph) and Br–phenyl rings (C2 , Br–phenyl) in L2 , being near
to the coordination sites, also showed downfield shifting by
0.8–2.1 ppm.[44] The spectra further indicated the presence of a
number of carbons in agreement with the expected number.
Mass Spectra
Mass spectral studies indicated[45,46] that both the ligands L1
and L2 were consistent with their formulations. The observed
molecular mass of ligand L1 , C14 H13 BrN2 O3 S, was 369.0 (calcd
369.23) and [C7 H8 N]+ m/z = 106 was considered as most stable
fragment of ligand L1 . Similarly, the observed molar mass of the
second ligand L2 , C18 H16 BrN3 O4 S, was 450 (calcd 450.31) and its
base peak for fragment [C13 H10 NOBr]+ was observed at m/z 276.
The fragmentation patterns of L1 and L2 are shown as Figures 3
and 4.
Electronic Spectra
The electronic spectral data of the metal(II) complexes 1–8 are
given in Table 2. The Co(II) complexes exhibited well-resolved,
low-energy bands at 7365–7409 and 17 449–17 516 and a strong
high-energy band at 20 585–20 625 cm−1 , which are assigned[45,47]
to the transitions 4 T1g (F) → 4 T2g (F), 4 T1g (F) → 4 A2g (F) and 4 T1g (F)
→ 4 T2g (P) in an octahedral geometry.[48] A high-intensity band at
29 310–29 355 cm−1 was assigned to the metal-to-ligand charge
transfer. The magnetic susceptibility measurements for the solid
Co(II) complexes are also indicative of three unpaired electrons
per Co(II) ion, suggesting[49] consistency with their octahedral
environment.
The electronic spectra of the Cu(II) complexes 3 and 7
showed two low-energy weak bands at 14 996–15 152 and
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NMR spectra of the free sulfonamides and their diamagnetic
zinc(II) complexes were recorded in DMSO-d6 . The 1 H NMR spectral data along with the possible assignments were recorded in
the Experimental Section. All the protons owing to heteroaromatic/aromatic groups were found to be in their expected
region.[43] The conclusions drawn from these studies provide
further support for the mode of bonding discussed with their IR
spectra. The coordination of the azomethine nitrogen was inferred
by the downfield shifting of the azomethine (CH N) proton signal from 8.9 ppm in the ligands L1 and L2 to 9.1 ppm in its Zn(II)
complexes, 4 and 8. It was further observed that the hydroxyl
proton present in the spectra of the ligands at 12.42 ppm disappeared in the spectra of its Zn(II) complexes, which was evidence
of deprotonation and coordination of the oxygen atom with the
zinc metal ion. Moreover, emergence of a new peak observed
at 10.5 ppm in the spectra of Zn(II) complexes showed the presence of water molecules that are coordinated with the metal ion.
All other protons underwent downfield shifting by 0.2–0.45 ppm
owing to the increased conjugation[44] and coordination with the
metal atoms. Furthermore, a number of protons calculated from
the integration curves, and those obtained from the values of the
expected CHN analyses, agreed well with each other.
Z. H. Chohan and H. A. Shad
Figure 3. The proposed fragmentation pattern of ligand L1 .
Figure 4. The proposed fragmentation pattern of ligand L2 .
596
19 168–19 213 cm−1 and a strong high-energy band at 30
352–30 375 cm−1 assigned to 2 B1g → 2 A1g and 2 B1g → 2 Eg
transitions, respectively.[50] The strong high-energy band, in turn,
was assigned to metal → ligand charge transfer. Also, the magnetic
moment values for the Cu(II) are indicative of anti-ferromagnetic
spin–spin interaction through molecular association indicative of
their octahedral geometry.[51]
wileyonlinelibrary.com/journal/aoc
The electronic spectra of the Ni(II) complexes showed dd bands
in the regions 10 392–10 434, 15 708–15 790 and 26 452–26
495 cm−1 . These were assigned[52] to the transitions 3 A2g (F)
→ 3 T2g (F), 3 A2g (F) → 3 T1g (F) and 3 A2g (F) → 3 T2g (P), respectively,
consistent with their well-defined octahedral configuration. The
band at 29 875–30 952 cm−1 was assigned to metal →
ligand charge transfer. The magnetic measurements showed two
c 2011 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 591–600
Sulfonamide-derived compounds and their transition metal complexes
unpaired electrons per Ni(II) ion, also suggesting[53] an octahedral
geometry for the Ni(II) complexes. The electronic spectra of the
Zn(II) complexes exhibited only a high-intensity band at 28 935–29
135 cm−1 assigned[54] to a ligand–metal charge transfer.
Biological Activity
average value of the respective ligands (18.74 mm). However, on
comparison of these average values, a conclusion[56] can be drawn
that the activity of synthesized sulfonamides increased upon
chelation/coordination[57] with the metal ions. The comparative
and average activity data is reproduced as Figs 5 and 6.
In Vitro Antifungal Bioassay
In vitro antibacterial bioassay
All the synthesized compounds were tested against four Gramnegative (E. coli, S. flexenari, P. aeruginosa and S. typhi) and two
Gram-positive (S. aureus and B. subtilis) bacterial strains (Table 3)
according to literature protocol.[30,31] The results were compared
with those of the standard drug imipenum (Fig. 6). The ligands,
L1 and L2 , and their metal(II) complexes, 1–8, exhibited varying
degree of inhibitory results on the growth of different tested
bacterial strains (Table 3 and Figs 5 and 6). From the obtained data,
it was observed that the ligands L1 and L2 showed[55] significant
activity (>17 mm) against bacterial strains a and c–f while
exhibiting moderate activity (11–17 mm) against b. The metal(II)
complexes 1–3 and 5–7 showed significant activity (>17 mm)
against all bacterial strains except b (<17 mm). However, the
zinc(II) complex, 4 and 8, showed well-pronounced activity against
all strains and also greater than the other metal(II) complexes. On
comparison of the average activity data, it was found that metal(II)
complexes showed an average value (19.6 mm) greater than the
The ligands, L1 and L2 and their metal(II) complexes 1–8 were
screened against T. longifusus, C. albican, A. flavus, M. canis, F. solani
and C. glaberate fungal strains (Table 4) according to the literature
protocol.[31] Miconazole and amphotericin B were used as standard
drugs. The data showed that majority of the compounds showed
good antifungal activity against different fungal strains. From
the data, it was observed that ligands L1 and L2 showed[55]
significant activity (>80%) against c, however, against a and d
they exhibited moderate activity (51–79%). The data showed
that both of the ligands were inactive or showed weak activity
(<50%) against b, e and f fungal strains. The metal(II) complexes
1 and 4 exhibited significant activity (>80%) against d while the
complexes 2,3 and 5–8 exhibited this activity (equal or >80%)
against c. The complexes 4,6 and 8 showed moderate activity
(51–79%) against a, and 3 and 8 showed activity against b. In
the same way, complexes 1 and 4 exhibited moderate activity
(51–79%) against c, 5 and 7 against d, 2–4 and 8 against e and
1,6 and 7 against f fungal strains. The studies of average values
Table 3. Antibacterial study (concentration used 50 µg µl−1 of DMSO) of ligands L1 and L2 and metal(II) complexes 1–8
Compound (zone of inhibition, mm)
Bacteria
Gram-negative
a
b
c
d
Gram-positive
e
f
Average
L
1
L
2
1
2
3
4
5
6
7
8
SD
20
16
17
19
21
15
18
18
20
16
17
21
22
16
19
20
20
15
18
18
23
21
20
23
23
16
21
17
21
16
20
19
22
15
19
18
23
19
21
22
21
17
19
20
22
18
18.66
21
20
18.83
21
17
18.67
23
18
19.67
22
19
18.67
21
23
21.83
19
17
18.8
20
18
19
18
20
18.67
23
20
21.3
22
19
19.67
Average of ligands L1 and L2 = 18.74 mm; average of complexes 1–8 = 19.6 mm,
a, E. coli; b, S. flexneri; c, P. aeruginosa; d, S. typhi; e, S. aureus; f , B. subtilis; <11, weak; >11, moderate; >17, significant. SD, standard drug imipenum.
597
Figure 5. Comparison of antibacterial activity.
Appl. Organometal. Chem. 2011, 25, 591–600
c 2011 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
Z. H. Chohan and H. A. Shad
Figure 6. Average antibacterial activity.
Table 4. Antifungal study (concentration used 200 µg ml−1 ) of ligands L1 and L2 and metal(II) complexes 1–8
Compounds (% inhibition)
Organism
a
b
c
d
e
f
Average
L1
L2
1
2
3
4
5
6
7
8
SD
57
21
82
51
35
00
41.0
62
32
82
65
00
00
40.16
32
45
56
86
00
52
45.16
38
51
83
00
60
35
44.5
34
56
80
41
55
00
44.33
52
43
66
86
51
00
49.66
37
30
86
54
47
00
42.33
58
48
84
00
00
69
43.16
40
36
81
58
00
65
46.67
65
58
84
45
57
00
51.5
A
B
C
D
E
F
Average of ligands L1 and L2 = 40.58%; average of complexes 1–8 = 45.91%.
a, T. longifusus; b, C. albicans; c, A. flavus; d, M. canis; e, F. solani; f , C. glabrata; SD, standard drugs. MIC (µg ml−1 ); A, miconazole (70 µg ml−1 ;
1.6822 × 10−7 M ml−1 ); B, miconazole (110.8 µg ml−1 ; 2.6626 × 10−7 M ml−1 ); C, amphotericin B (20 µg ml−1 ; 2.1642 × 10−8 M ml−1 ); D, miconazole
(98.4 µg ml−1 ; 2.3647 × 10−7 M ml−1 ); E, miconazole (73.25 µg ml−1 ; 1.7603 × 10−7 M ml−1 ); F, miconazole (110.8 µg ml−1 ; 2.66266 × 10−7 M ml−1 ).
revealed that the zinc(II) complexes 4 and 8 exhibited excellent
antifungal activity (49.67 and 51.5%, respectively) compared with
all other metal(II) complexes, against all tested fungal strains. On
comparison of the average activity data, it was found that metal(II)
complexes showed an average value (45.95%) greater than the
average value of the ligands (40.58%). However, on comparison
of these average values of the complexes with the ligands, a
fair conclusion[56,57] can be drawn that the antifungal activity is
increased upon chelation/coordination with the metal ions. The
comparative and average activity data are reproduced as Figs 7
and 8.
Minimum Inhibitory Concentration
598
In order to evaluate the MIC of the synthesized compounds, both
of the ligands L1 and L2 and their metal(II) complexes 1–8 were
investigated for antibacterial studies against four Gram-negative
(E. coli, S. flexneri, P. aeruginosa and S. typhi) and two Gram-positive
(S. aureus and B. subtilis) bacterial strains as described above. It was
shown from the data that the synthesized compounds exhibited
varying degrees of inhibitory effects on the growth of tested
bacterial strains. It was found from the preliminary antibacterial
screening that three complexes, 2,4 and 8, were found to be the
most active (above 80%) against both Gram-negative and Grampositive microorganisms. Based on their significant activity, these
compounds were therefore selected for MIC studies[32] (Table 5).
The MIC values of these compounds were found to be in the range
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6.578 × 10−8 to 2.795 × 10−7 M. Amongst these compounds,
complex 8 proved to be the most active by inhibiting the growth
of Staphylococcus aureus at 6.578 × 10−8 M.
In vitro Cytotoxic Bioassay
The ligands L1 and L2 and their metal(II) complexes 1–8 were
screened for their cytotoxicity (brine shrimp bioassay) using the
protocol of Meyer et al.[33] The data in Table 6 reveal that two
compounds, 3 and 7, showed effective cytotoxic activity against
Artemia salina, while all other compounds were almost inactive
(LD50 = 1.365 × 10−3 to 3.158 × 10−3 M ml−1 ) for this assay.
The compounds 3 and 7 showed activity (LD50 = 5.856 × 10−4
and 6.684 × 10−4 M ml−1 , respectively) in the present series
of compounds. It was interesting to note that only copper(II)
complexes showed potent cytotoxicity whereas the other metal
complexes did not. This activity relationship may serve as a
basis for the development of certain cytotoxic agents for clinical
applications.
Conclusion
In the present studies two ligands and their eight metal(II)
complexes were synthesized and characterized using different
physical, spectral and analytical techniques. In vitro antibacterial,
antifungal and cytotoxic activities of the compounds were
c 2011 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 591–600
Sulfonamide-derived compounds and their transition metal complexes
Figure 7. Comperison of antifungal activity.
Figure 8. Average antifungal activity.
Table 5. Minimum inhibitory concentration (M ml−1 ) of the selected
compounds 2, 4 and 8 against selected bacterial strains
Table 6. Brine shrimp study of the ligands L1 and L2 and their metal(II)
complexes 1–8
Bacterial strains
Compounds
Gram-negative
E. coli
P. aeruginosa
S. typhi
Gram-positive
S. aureus
B. subtilis
2
4
8
–
–
3.749 × 10−7
4.375 × 10−8
–
3.791 × 10−8
3.265 × 10−7
4.114 × 10−8
3.624 × 10−8
5.943 × 10−8
5.432 × 10−7
2.795 × 10−7
2.132 × 10−8
6.578 × 10−8
3.452 × 10−8
Appl. Organometal. Chem. 2011, 25, 591–600
>3.158 × 10−3
>2.967 × 10−3
>1.365 × 10−3
>1.968 × 10−3
5.856 × 10−4
>1.872 × 10−3
>1.581 × 10−3
>1.382 × 10−3
6.684 × 10−4
>2.551 × 10−3
been suggested that some functional groups such as azomethine
(–C N–) or hetero-aromatics present in these compounds play an
important role in antibacterial and antifungal activity,[62 – 65] which
may certainly be responsible for the enhancement of hydrophobic
character and liposolubility of the molecules.
c 2011 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
599
carried out on various bacterial/fungal strains by applying
different protocols. It has been suggested that the antibacterial
and antifungal activity of ligands L1 and L2 increased upon
coordination. The chelation process reduced the polarity of
the metal ion by coordinating with ligands, which increased
the lipophilic nature of the metal. This lipophilic nature of the
metal atoms enhanced[58 – 61] its penetration through the lipoid
layer of cell membrane of the microorganism. Further, it has
L1
L2
1
2
3
4
5
6
7
8
LD50 (M ml−1 )
Z. H. Chohan and H. A. Shad
Acknowledgment
One of us (H.A.Z.) is grateful to the Higher Education Commission,
Government of Pakistan for providing a scholarship under the
Indigenous Ph.D. Program (PIN 042-160410-PS2-117). We are also
thankful to HEJ Research Institute of Chemistry, University of
Karachi, Pakistan, for providing help in taking NMR and mass
spectra and also antibacterial and antifungal assays.
Supporting information
Supporting information may be found in the online version of this
article.
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compounds, sulfamoyl, evaluation, biological, iminiomethyl, phenyl, transitional, complexes, sulfonamide, brom, structure, synthesis, phenolate, metali, dimethylisoxazol, derived, ray
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