Synthesis, characterization and biological studies of sulfonamide Schiff's bases and some of their metal derivatives

Article abstract of DOI:10.3109/14756366.2011.574623

A new series of Schiff base ligands derived from sulfonamide and their metal(II) complexes [cobalt(II), copper(II), nickel(II) and zinc(II)] have been synthesized and characterized. The nature of bonding and structure of all the synthesized compounds has been explored by physical, analytical and spectral data of the ligands and their metal(II) complexes. The authors suggest that all the prepared complexes possess an octahedral geometry. The ligands and metal(II) complexes have been screened for their in vitro antibacterial activity against bacterial strains, Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa, Salmonella typhi and for antifungal activity against fungal strains, Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glabrata. These assays enabled the identification of the metal complexes as an effective antimicrobial agent with low cytotoxicity.

Full text of DOI:10.3109/14756366.2011.574623

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(1): 58–68
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.574623
RESEARCH ARTICLE
Synthesis, characterization and biological studies of
sulfonamide Schiff’s bases and some of their metal derivatives
Zahid H. Chohan1, Hazoor A. Shad1, and Claudiu T. Supuran2
1Department of Chemistry, Bahauddin Zakariya University, Multan, Pakistan and 2University of Florence, Dipartimento
di Chimica, Laboratorio di Chimica Bioinorganica, Via della Lastruccia, Sesto Fiorentino, Firenze, Italy
Abstract
A new series of Schiff base ligands derived from sulfonamide and their metal(II) complexes [cobalt(II), copper(II),
nickel(II) and zinc(II)] have been synthesized and characterized. The nature of bonding and structure of all the
synthesized compounds has been explored by physical, analytical and spectral data of the ligands and their metal(II)
complexes. The authors suggest that all the prepared complexes possess an octahedral geometry. The ligands and
metal(II) complexes have been screened for their in vitro antibacterial activity against bacterial strains, Escherichia
coli, Shigella flexneri, Pseudomonas aeruginosa, Salmonella typhi and for antifungal activity against fungal strains,
Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida
glabrata. These assays enabled the identification of the metal complexes as an effective antimicrobial agent with low
cytotoxicity.
Keywords: Sulfonamides, metal(II) complexes, antibacterial, antifungal, cytotoxic
Introduction
in synthesizing and designing various metal-based
Sulfonamides and their Schiff base-derived compounds
are extensively used for antibacterial1, antitumour2,
diuretic3, anti-carbonic anhydrase (anti-CA)4, hypogly-
caemic5, anti-thyroid6 and protease inhibitor7 activities.
Many drugs possess modified pharmacological and
toxicological potentials when administered in the form
of their metal complexes. e most widely studied metal
ions in this respect are cobalt(II), copper(II), nickel(II)
and zinc(II)8,9. Sulfonamides possessing a free amino
group are easily derivatizable, leading to a wide range of
biomedical applications10. Sulfonamides incorporating
imino or hydrazino derivatized moieties also showed
effective inhibition of CA isozymes11.
Various biological aspects of the metal complexes
exclusively depend on the ease of cleaving the bond
between the metal ion and the ligand. It is therefore,
important to understand coordination behaviour and
relationship of the metals and the ligands in biologi-
cal systems. In view of the versatile chemistry of sul-
fonamides as ligand we have started a program12–14
sulfonamides and to investigate their structural and
biological behaviour. Continuing this work, we herein
describe the preparation of two new sulfonamides,
4-{[(Z)–(5-bromo-2-hydroxyphenyl)methylidene] amino}-
N-(5-methylisoxazol-3-yl)benzenesulfonamide (L1) and
4-(2-{[(E)–(5-bromo-2-hydroxyphenyl)methylidene]
amino}ethyl)benzenesulfonamide (L2) derived from the
reaction of sulfamethoxazole and 4-(2-aminoethyl)
benzenesulfonamide with 5-bromosalicyl aldehyde,
respectively. ese sulfonamides have been used for
complexation with the cobalt, copper, nickel and zinc
ions and then investigated for their in vitro antibacte-
rial activity against four Gram-negative (Escherichia coli,
Shigella flexneri, Pseudomonas aeruginosa, Salmonella
typhi) and two Gram-positive (Staphylococcus aureus
and Bacillus subtilis.) bacterial strains and for antifun-
gal activity against Trichophyton longifusus, Candida
albicans, Aspergillusflavus, Microsporumcanis, Fusarium
solani and Candida glabrata fungal species. e results
obtained from the biological studies revealed that all
Address for Correspondence: Dr. Zahid H. Chohan, Department of Chemistry, Bahauddin Zakariya University, Multan, 60800, Pakistan.
E-mail: dr.zahidchohan@gmail.com
(Received 23 January 2011; revised 21 March 2011; accepted 21 March 2011)
58

Sulfonamide-derived Schiff’s bases and their metal complexes 59
compounds showed moderate to significant activity
against various bacterial as well as fungal strains.
measured in millimeters (mm) as the zone of inhibition.
e data showed that all compounds exhibited varying
degree of inhibitory results on the growth of different
tested bacterial strains. It was observed from the data
that the ligands (L1) and (L2) showed moderate to sig-
nificant (>16 mm) activity against four Gram-negative
and two Gram-positive bacterial strains except strain (b)
where weak (<10 mm) activity was observed by both the
ligands. e complexes (1)–(8) exhibited overall a signifi-
cant activity against (a), (c), (d) and (f) bacterial strains
whereas, a moderate activity (>10 mm) was exhibited
against (b). Similarly, the complexes (2)–(4) and (6)–(8)
displayed significant activity (>16 mm) against bacterial
strain (e), while the complexes (1) and (5) showed mod-
erate activity (>10 mm) against the same strain. e data
showed that antibacterial activity is overall enhanced
upon complexation of the ligands (Figures 1 and 2) with
the metal ions. It was further observed from the data
that the zinc(II) complexes (4) and (8) interestingly were
proved to be the most active compounds against all bac-
terial species.
Chemistry
e Schiff base ligands (L1) and (L2) were prepared
by the reaction of 5-bromosalicylaldehyde with the
respective sulfonamide (Scheme 1). All newly synthe-
sized sulfonamides were only soluble in dioxane, N,N-
dimethylformamide (DMF) and dimethyl sulfoxide
(DMSO). Moreover, characterization has been assessed
by microanalytical and mass spectral data. e metal(II)
complexes (1)–(8) (Scheme 2) of these sulfonamides were
prepared in a stochiometric molar ratio as metal: ligand
(1: 2)]. Cobalt, copper, nickel and zinc were used as their
chloride salts. Physical measurements and analytical
data for complexes (1)–(8) are given in Tables 1 and 2.
Biological activity
In vitro antibacterial activity
All the synthesized compounds were tested against four
Gram-negative (E. coli, S. flexneri, P. aeruginosa, S. typhi)
and two Gram-positive (S. aureus, B. subtilis) bacterial
In vitro antifungal activity
e antifungal screening of the ligands (L1) and (L2) and
their metal(II) complexes (1)–(8) was carried out against
T. longifusus, C. albican, A. flavus, M. canis, F. solani and
C. glabrata fungal strains (Table 4) according to the
literature protocol16. e data showed that most of the
strains (Table 3) according to the literature protocol15,16
.
e antibacterial activity of the Schiff base ligands and
their metal complexes was studied in comparison to the
standard drug imipenum (Figure 1). e activity was
OH
OH
R
CHO
Ethanol
Reflux
N
H2N
R
Br
Br
O
O
S
(L2) R =
(L1) R =
NH
S
NH2
O
O
N
CH3
O
Scheme 1. Preparation of Schiff’s bases (L1) and (L2).
Br
OH
OH2
R
N
O
N
1,4 Dioxane
Reflux 2 h
2
MC12.XH2O
M
R
Br
N
R
O
OH2
X = 0, 2 or 6
Br
M = Co(II), Ni(II), Cu(II) and Zn(II),
O
S
NH
R =
O
R =
O
NH2
S
CH3
N
O
O
Scheme 2. Proposed structure of the metal(II) complexes (1)–(8).
© 2012 Informa UK, Ltd.

60 Z.H. Chohan et al.
Table 1. Physical measurements and analytical data of metal(II) complexes, (1)–(8).
Complexes
M.P. (dec.)
(°C)
Yield
(%)
79
Calculation (found) (%)
Molecular
mass
No.
Molecular formula
[Co(L1-H)2(H2O)2]
C34H30N6O10S2Br2Co
[Ni(L1-H)2(H2O)2]
C34H30N6O10S2Br2 Ni
[Cu(L1-H)2(H2O)2]
C34H30N6O10S2Br2Cu
[Zn(L1-H)2(H2O)2]
C34H30N6O10S2Br2 Zn
[Co(L2-H)2(H2O)2]
C30H32N4O8S2Br2 Co
[Ni(L2-H)2(H2O)2]
C30H32N4O8S2Br2 Ni
[Cu(L2-H)2(H2O)2]
C30H32N4O8S2Br2 Cu
[Zn(L2-H)2(H2O)2]
Colour
C
H
N
(1)
[965.53]
[965.26]
[970.14]
[971.98]
[859.47]
[859.23]
[864.08]
[865.93]
240–242
Red-brown
42.26 (42.38) 3.11 (3.10) 8.70 (8.62)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
234–236
223–225
235–237
208–210
202–204
220–222
212–214
Brown
Brick red
82
80
79
83
79
82
80
42.27 (42.38) 3.11 (3.1) 8.71 (8.63)
42.06 (42.15) 3.10 (3.04) 8.66 (8.72)
41.98 (42.11) 3.09 (3.06) 6.65 (6.74)
Brick red
Green-brown
Light green
Green-yellow
Brown
41.88 (42.01) 3.73 (3.66)
6.52 (6.6)
41.90 (41.89) 3.73 (3.72) 6.52 (6.75)
41.67 (41.78) 3.70 (3.78) 6.48 (6.42)
41.57 (41.64) 3.70 (3.76) 6.47 (6.44)
C30H32N4O8S2Br2 Zn
Table 2. Conductivity, magnetic and spectral data of metal(II) complexes, (1)–(8).
ωM
(ω−1 cm2 mol−1)
16.7
B.M.
(μeff)
4.91
λmax
(cm−1)
IR
(cm−1)
No.
(1)
7361, 17519,
20626, 29353
1569 (C=N), 1393 (C-O), 1345, 1110 (SO2), 954 (S-N), 841 (C-S), 441 (M-N), 534 (M-O)
(2)
(3)
15.6
13.9
3.36
1.85
10434, 15789,
26494, 30955
1566 (C=N), 1393 (C-O), 1345, 1110 (SO2), 954 (S-N), 842 (C-S), 439 (M-N), 534 (M-O)
1565 (C=N), 1394 (C-O), 1345, 1110 (SO2), 954 (S-N), 841 (C-S), 441 (M-N), 529 (M-O)
15156, 19210,
30356
(4)
(5)
15.9
17.6
Dia
29134
1567 (C=N), 1393 (C-O), 1345, 1110 (SO2), 953 (S-N), 841 (C-S), 439 (M-N), 533 (M-O)
1569 (C=N), 1395 (C-O), 1345, 1110 (SO2), 954 (S-N), 841 (C-S), 441 (M-N), 529 (M-O)
4.94
7297, 17492,
20485, 29362
(6)
(7)
(8)
18.1
15.2
15.7
3.32
1.88
Dia
10410, 15689,
26538, 29991
1565 (C=N), 1394 (C-O), 1345, 1110 (SO2), 954 (S-N), 841 (C-S), 440 (M-N), 531 (M-O)
1567 (C=N), 1395 (C-O), 1345, 1110 (SO2), 954 (S-N), 841 (C-S), 441 (M-N), 535 (M-O)
1569 (C=N), 1395 (C-O), 1345, 1110 (SO2), 954 (S-N), 841 (C-S), 439 (M-N), 529 (M-O)
14981, 19188,
30382
28984
IR, infrared.
Table 3. Antibacterial study (concentration used 1mg/mL of DMSO) of ligands (L1) and (L2) and metal(II) complexes (1)–(8).
Compound [zone of inhibition (mm)]
Bacteria
(L1)
(L2)
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
SD
Gram-negative
(a)
(b)
(c)
(d)
14
08
12
13
16
07
14
10
16
08
16
17
19
12
22
19
20
10
20
18
22
11
22
21
15
09
17
18
19
10
17
19
18
11
17
16
24
12
23
22
25
17
25
23
Gram-positive
(e)
(f)
Average
16
15
13
17
19
14
18
21
20
19
17
23
20
14
16
18
17
17
19
25
23
26
25
13.83
14.83
18.83
17.33
19.83
14.83
16.67
16.33
21.5
23.5
(a)=Escherichia coli, (b)=Shigella flexneri, (c)=Pseudomonas aeruginosa, (d)=Salmonella typhi, (e)=Staphylococcus aureus,
(f)=Bacillus subtilis; <10=weak, >10=moderate, >16=significant; SD=standard drug (imipenum).
DMSO, dimethyl sulfoxide.
compounds exhibited good antifungal activity against
different fungal strains. Ligands (L1) and (L2) exhibited17
excellent (above 80%) activity against fungal strain (c)
while moderate (50–80%) activity was observed against
(a) and (c). It was also, observed that both the ligands
were inactive and/or showed very weak activity (<50%)
against fungal strains (d), (e) and (f). e data further
exhibited that the complex (4) showed excellent activity
Journal of Enzyme Inhibition and Medicinal Chemistry

Sulfonamide-derived Schiff’s bases and their metal complexes 61
E. coli
S. flexneri
P. aeruginosa
S. typhi
S. aureus
B. subtilis
30
20
10
0
(L1)
(L2)
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
Imipenum
Compounds
Figure 1. Comparison of antibacterial activity of ligands (L1) and (L2) and metal(II) complexes (1)–(8).
25
Zn(L2)
Zn(L1)
20
15
10
(L1)
(L2)
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
Imipenum
Compounds
Figure 2. Average antibacterial activity of ligands (L1) and (L2) and metal(II) complexes (1)–(8).
Table 4. Antifungal study (concentration used 200 µg/mL) of ligands (L1) and (L2) and metal(II) complexes (1)–(8).
Compounds
Organism
(a)
(L1)
68
00
82
44
32
20
41
(L2)
00
(1)
75
(2)
68
(3)
38
(4)
69
(5)
53
(6)
51
(7)
46
(8)
72
SD
A
(b)
55
00
00
45
45
34
00
00
65
B
(c)
86
52
65
61
88
75
62
68
00
C
(d)
(e)
32
76
85
84
72
38
54
76
84
D
E
00
44
23
56
00
69
82
81
80
(f)
44
00
57
00
65
00
42
00
45
F
Average
36.16
41.16
49.67
47.33
56.5
44.83
48.5
45.16
57.67
(a) = Trichophyton longifusus; (b) = Candida albicans; (c) = Aspergillus flavus; (d) = Microsporum canis; (e) = Fusarium solani;
(f) = Candida glabrata; SD, standard drugs MIC µg/mL; A=miconazole (70 µg/mL:1.6822×10−7 M/mL), B=miconazole (110.8 µg/
mL:2.6626×10−7 M/mL), C=amphotericin B (20 µg/mL:2.1642×10−8 M/mL), D=miconazole (98.4 µg/mL:2.3647×10−7 M/mL),
E=miconazole (73.25 µg/mL: 1.7603×10−7 M/mL), F=miconazole (110.8 µg/mL: 2.66266×10−7 M/mL).
MIC, minimum inhibitory concentration.
(above 80%) against (c). Moreover, complexes (2), (3)
and (8) also showed excellent activity against (d) and
similarly (6)–(8) showed excellent activity (above 80%)
against fungal strain (e). e complexes (1), (2), (4)–(6)
and (8) exhibited moderate activity (50–80%) against (a),
A moderate activity of complex (8) was also observed
against (b). Similarly, complexes (1)–(3) and (5)–(7)
exhibited moderate activity against (c). Complexes
© 2012 Informa UK, Ltd.

62 Z.H. Chohan et al.
(1), (4), (6) and (7) likewise, showed moderate activity
against strain (d). A moderate activity was also, observed
by the complexes (3) and (5) against (e) and (2) and (4)
against (f) fungal strains. All other complexes showed
either a weak activity (below 50%) or were inactive. e
results of inhibition were compared with the standard
drugs, miconazole and amphotericin B. ese results
conclusively revealed that the zinc(II) complexes (4) and
(8), exhibited excellent average antifungal activity (56.5
and 57.67%) (Figure 3) as compared to all other metal(II)
complexes against all tested strains. On comparison of
the average activity data of the ligands with the metal
complexes (Figure 4), it was found that metal(II) com-
plexes showed greater average activity than the average
activity of the ligands. Based on these evidences, a con-
clusion can be drawn that the antifungal activity is also
increased upon coordination with the metal ions.
cytotoxic activity against Artemia salina, while all other
compounds were inactive for this assay. e copper com-
plexes (3) and (7) in the present series of compounds,
showed LD50 as 6.342 × 10−4 and 6.173 × 10−4 M/mL,
respectively. It is remarkable to mention that only copper
complexes showed potent cytotoxicity. is activity rela-
tionship may help to serve as a basis for future direction
towards the development of certain cytotoxic agents for
preclinical development.
Results and discussion
Infrared spectra
Characteristic infrared (IR) spectral bands of Schiff
base ligands (L1) and (L2) and their metal(II) complexes
(1)–(8) are given in Table 2 and in experimental. IR
spectra of uncoordinated Schiff base ligands, generally,
showed one broad and one sharp band at 3321–3325 and
1598–1605 cm−1, respectively assigned21 to the v(OH) and
azomethine (HC=N) linkage. Furthermore, two bands
appearing at 1345 and 1110 cm−1 were correspondingly
assigned to the vibrations vasymm(SO2) and vsymm(SO2). In
all the metal complexes (1)–(8), the band for azomethine
(C=N) linkage was found to be at lower frequency side
by 29–36 cm−1 (1565–1569 cm−1), indicating the formation
of a new bond between nitrogen and the metal ion. is
is further supported by the appearance of a new band at
439–441 cm−1 assigned to the v(M-N)22. e coordination
through the hydroxyl-O is revealed by the disappearance
of broad bands at 3325 and 3321 cm−1 and in turn, appear-
ance of new bands at 1393 and 1395 cm−1 due to deproto-
nation and coordination of v(OH) and an establishment
of the C-O mode. is is further supported by the appear-
ance of new bands at 529 and 535cm−1 due to v(M-O) in
the metal(II) complexes (1)–(8). e bands at 1345 and
1110 cm−1 present in the spectra of Schiff base ligands due
to vasymm(SO2) and vsymm(SO2) were found unchanged23
in the spectra of their metal complexes, indicating that
this group is not taking part in the coordination. is is
further supported by the unchanged modes of v(S-N)
Minimum inhibitory concentration
All compounds have shown variable average inhibi-
tion against different bacterial strains in the range
13.00 (55.31%) to 21.5 (91.48%) (Figure 2). e data
obtained after preliminary antibacterial screening
showed that compounds (2), (4) and (8) were the most
active (above 80%) and their average inhibition values
were 18.84 (80.17%), 19.84 (84.44%) and 21.5 (91.48%),
respectively. ese compounds were therefore, selected
for antibacterial minimum inhibitory concentration
(MIC) studies18 (Table 5). e MIC results of these most
active compounds were found in the range, 1.667 × 10−8
to 5.338 × 10−7 M. Among them, compound (4) was
proved to be the most active that inhibited the growth of
B. subtilis at 1.667 × 10−8 M.
In vitro cytotoxicity
e synthesized ligands (L1) and (L2) and their metal
complexes (1)–(8) were screened for their cytotoxic-
ity (brine shrimp bioassay) using the protocol of Meyer
et al19. It is revealed from the data reproduced in Table 6
that two compounds (3) and (7) exhibited20 effective
s
T. longifusus
C. albicans
A. flavus
M. canis
F. solani
C. glabrata
100
80
60
40
20
0
(L1)
(L2)
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
Compounds
Figure 3. Comparison of antifungal activity of ligands (L1) and (L2) and metal(II) complexes (1)–(8).
Journal of Enzyme Inhibition and Medicinal Chemistry

Sulfonamide-derived Schiff’s bases and their metal complexes 63
Zn(L2)
60
55
50
45
40
35
30
Zn(L1)
(L1)
(L2)
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
Compounds
Figure 4. Average antifungal activity of ligands (L1) and (L2) and metal(II) complexes (1)–(8).
Table 6. Brine shrimp study of the ligands (L1)–(L2) and their
metal(II) complexes (1)–(8).
Table 5. Minimum inhibitory concentration (M/mL) of the
selected compounds (2), (4) and (8) against selected bacterial
strains.
Compounds
LD50 (M/mL)
(L1)
(L2)
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
>3.284×10−3
>3.284×10−3
>3.284×10−3
>3.284×10−3
6.342×10v4
>3.284×10−3
>3.284×10−3
>3.284×10−3
6.173×10−4
>3.284×10−3
Bacterial strains
Gram-negative
Escherichia coli
(2)
(4)
(8)
–
–
4.168×10−8
–
2.215×10−7
3.294×10−8
Pseudomonas
aeruginosa
Salmonella typhi
1.341×10−7
3.394×10−8
3.714×10−8
Gram-positive
Staphylococcus
aureus
6.743×10−8
2.891×10−7
5.338×10−7
1.677×10−8
6.439×10−8
3.252×10−8
Bacillus subtilis
and v(C-S)24,25 appearing at 953–954 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
of the Schiff base ligands similarly, do not participate in
coordination as their IR frequencies remain unchanged
after complexation.
and coordination with the metal atoms. Furthermore,
number of protons calculated from the integration curves,
and those obtained from the values of the expected CHN
analyses agree well with each other.
Carbon nuclear magnetic resonance spectra
Carbon NMR (13C NMR) spectra of the Schiff base ligands
and their diamagnetic zinc(II) complexes were also
recorded in DMSO-d6. All assignments of the carbon
atoms in sulfonamides were found in their expected
Proton nuclear magnetic resonance spectra
Proton nuclear magnetic resonance (1H NMR) spectra of
the free sulfonamides and their diamagnetic zinc(II) com-
1
plexes were recorded in DMSO-d6. e H NMR spectral
1
region26 and are well-supported by their IR and H NMR
data along with the possible assignments is recorded in the
experimental part. All the protons due to heteroaromatic/
aromatic groups were found in their expected region26. e
conclusions drawn from these studies provide further sup-
port to the mode of bonding discussed in their IR spectra.
e coordination of the azomethine nitrogen is inferred
by the downfield shifting of the azomethine (CH=N)
proton signal from 8.9 and 8.91ppm in the ligands (L1)
and (L2) to 9.1ppm in its Zn(II) complexes. It was further
observed that the hydroxyl proton present in the spectra
of the ligands at 12.42ppm disappeared in the spectra of
its Zn(II) complexes which were an evidence of deproto-
nation and coordination of the oxygen atom with the zinc
metal ion. All other protons underwent downfield shift-
ing by 0.16–0.31ppm due to the increased conjugation27
spectra. Downfield shifting of the azomethine carbon
from 160.9 ppm in the spectra of ligands to 162.5 and
162.6 ppm in the spectra of its Zn(II) complexes revealed
coordination of the azomethine-N to the metal atom.
Similarly, carbons at N-phenyl ring (C1 N-Ph) and
Br-phenyl ring (C2 Br-phenyl), being nearer to the coordi-
nation sites also showed downfield shifting27. e spectra
further indicated the presence of number of carbons in
agreement with the expected number.
Mass spectra
e mass spectral data and main fragments of ligand (L2)
and its copper complex28,29 [Cu(L2-H)2(H2O)2] along with
their molecular complex ion peaks are given as Figures in
© 2012 Informa UK, Ltd.

64 Z.H. Chohan et al.
Supplementary material (Figures 5 and 6). Mass spectral
studies indicated that both the ligands were consistent
with their formulations. e observed molecular mass
of ligand (L1), C17H14BrN3O4S was 436.0 (calcd. 436.32)
and [C13H10NOBr]·+ m/z = 276 was considered as most
stable fragment of ligand (L1). Similarly, the observed
molar mass of second ligand (L2), C15H15BrN2O3S was
383.0 (calcd. 383.27) and its base peak for fragment
[C8H8ONBr]+ was observed at m/z 214. Moreover, it was
observed that the mass spectra of metal(II) complexes
(1)–(8) were also consistent with the calculated masses
of their proposed formulae. e molecular mass of com-
plex (1), C34H30N6O10S2Br2Co was observed at m/z 964.8
(calcd. 965.53). e complexes (2), (3), (4), (5), (6), (7)
and (8) have m/z 964.5 (calcd. 965.26), m/z 969.3 (calcd.
970.14), m/z 971 (calcd. 971.98), m/z 858.7 (calcd. 859.47),
m/z 858.4 (calcd. 859.23), m/z 863.2 (calcd. 864.08) and
m/z 865 (calcd. 865.93), respectively. It is interesting to
note that the base peak for all the metal(II) complexes
was observed at the same m/z as that of the respective
ligands.
magnetic moment value for cobalt(II) complexes (1)
and (5) was found to be as 4.94 and 4.91 B.M., respec-
tively, consistent with half-spin octahedral cobalt(II)
complexes. e magnetic moment values (1.85 and 1.88
B.M.) measured for the copper(II) complexes, (3) and
(7) lie in the range expected for a d9-system that con-
tains one unpaired electron consistent to an octahedral
geometry36. e measured values, 3.32 and 3.36 B.M. for
the nickel(II) complexes (2) and (6) also suggested37 an
octahedral geometry for these complexes. e zinc(II)
complexes (4) and (8) were found to be diamagnetic as
expected.
Supplementary material
X-ray structure of one of the ligand, 4-(2-{[(E)–
(5-bromo-2-hydroxyphenyl)methylidene]
amino}
ethyl)benzenesulfonamide (L2) has already been
published38 by us. e bond distances, bond angles,
calculated hydrogen atom positions, anisotropic dis-
placement parameters and calculated structure factors
can be obtained from the author. Fragmentation pattern
of ligand (L2) and its copper complex is also given in
Supplementary material.
Electronic spectra
e electronic spectral data of the metal(II) complexes
(1)–(8) are given in Table 2. e Co(II) complexes (1) and
(5) exhibited well-resolved, low-energy bands at 7297–
7361, 17492–17519 cm−1 and a strong high-energy band at
20485–20626 cm−1 which are assigned30 to the transitions
Conclusions
It has been suggested that the antibacterial and anti-
fungal activity of ligands (L1) and (L2) increased upon
coordination. e chelation/coordination process
reduces the polarity of metal ion by coordinating with
ligands which increase the lipophilic nature of the
metal. is lipophilic nature of metal enhanced39–42 its
penetration through the lipoid layer of the cell mem-
brane of the microorganism. Further, it has been sug-
gested that some functional groups such as azomethine
(–C=N-) or heteroatoms present in these compounds
play an important role in antibacterial and antifungal
activity that may also, be responsible for the enhance-
ment of hydrophobic character and liposolubility of the
molecules.
4
4
4T1g(F)→4T2g(F), T1g(F)→4A2g(F) and T1g(F)→4T2g(P) in
an octahedral environment31. A high-intensity band at
29353–29362 cm−1 was assigned to the metal→ligand
charge transfer.
e electronic spectra of the Ni(II) complexes showed
d-d bands in the region at 10410–10434, 15689–15789 and
26494–26538 cm−1. ese are assigned32 to the transitions
3
3
3A2g(F)→3T2g(F), A2g(F)→3T1g(F) and A2g(F)→3T2g(P),
respectively, consistent with their well-defined octahe-
dral configuration. e band at 29991–30955 cm−1 was
assigned to metal→ligand charge transfer.
eelectronicspectraoftheCu(II)complexes(Table2)
showed two low-energy weak bands at 14981–15156
and 19188–19210 cm−1 and a strong high-energy band
2
2
at 30356–30382 cm−1 assigned to B1g→2A1g and B1g→2Eg
transitions, respectively33. e strong high-energy band,
in turn, is assigned to metal→ligand charge transfer. e
electronic spectra of the Zn(II) complexes exhibited only
a high-intensity band at 28984–29134 cm−1 assigned34 to
ligand→metal charge transfer.
Experimental
Materials and methods
All reagents, chemicals and solvents used were of ana-
lytical grade and were obtained from the suppliers.
Elemental analyses were carried out with a Perkin Elmer
1
Analyzer (US model). H and 13C NMR spectra of the
Conductance and magnetic susceptibility
measurements
compounds were recorded with a Bruker Spectrospin
Avance DPX-400 using TMS as internal standard and d6
DMSO as a solvent. IR spectra of the compounds were
recorded on a SHIMADZU FTIR spectrophotometer.
Mass spectra of the compounds were recorded using
JEOL MS Route spectrometer in electron impact ioniza-
tion mode. e melting points were determined with a
Gallenkamp melting point apparatus. In vitro antibac-
terial, antifungal and cytotoxic properties were studied
e molar conductance values were obtained at room
temperature using DMF as a solvent and results are
recorded in Table 2. e complexes (1)–(8), showed
their molar conductance in the range 13.9–18.1 ω−1 cm2
mol−1 indicating their non-electrolytic nature35. e
magnetic moment values of the complexes (1)–(8) at
room temperature are given in Table 2. e observed
Journal of Enzyme Inhibition and Medicinal Chemistry

Sulfonamide-derived Schiff’s bases and their metal complexes 65
+
− +
Br
Br
N
N
CH3
O
OH
OH
S
NH
O
m/z 214 (94.3%)
m/z 382 (60.7%)
− +
− +
Br
Br
N
CH3
O
OH
OH
S
NH2
O
m/z 383 (M+)
H3C
m/z 187 (39.0%)
− +
− +
O
N
H2C
S
NH2
O
m/z 133 (27.3%)
m/z 185 (41.4%)
Figure 5. e proposed fragmentation pattern of ligand (L2).
at HEJ research Institute of Chemistry, International
Center for Chemical Sciences, University of Karachi,
Karachi, Pakistan.
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), 150.0 (C3 isoxazole), 156.4 (C1 N-Ph), 160.0
(C2 Br-phenyl), 160.9 (C=N, azomethine) 169.6 (C5 isox-
azole); Anal. Calcd. for C17H14BrN3O4S (436.32): C, 46.75;
H, 3.20; N, 9.63; found: C, 46.62; H, 3.49; N, 9.81. Mass
spectrum [(electrospray ionization (ESI)] [M]+ = 436.
Synthesis of ligand (L1)
To an ethanol (30 mL) solution of sulfamethoxazole
(1.02 g, 0.004 moles), 5-bromosalisylaldehyde (0.804 g,
0.004 moles) in ethanol (15 mL) was added with con-
stant stirring. e solution was refluxed for 3 h by
monitoring through thin-layer chromatography (TLC).
e solution was cooled to room temperature, filtered
and evaporated on rotary evaporator. e solid product
thus obtained was recrystallized in hot DMF/ether (75%
yield). Same method was adopted for the synthesis of
ligand (L2).
4-(2-{[(E)–(5-Bromo-2-hydroxyphenyl)methylidene]amino}
ethyl)- benzenesulfonamide (L2)
Yield 79% (1.26 g); yellow-green; m.p. 184–186°C; IR
(KBr, cm−1): 3321 (OH), 1598 (HC=N), 1344, 1110 (S=O),
1
955 (S-N), 842 (C-S), 565 (C-Br); H NMR (DMSO-d6, δ,
ppm): 3.13 (t, 2H, CH2-aromatic), 3.34 (t, 2H, CH2-N),
6.9–7.6 (m, 3H, bromo-phenyl), 7.7–8.2 (m, 4H, N-Ph),
8.91 (s, 1H, azomethine), 9.2 (s, 2H, -SO2NH2), 12.42 (s,
1H, OH); 13C NMR (δ, ppm): 37.5 (CH2-aromatic), 61.3
(CH2-N), 118.4 (C3 Br-phenyl), 120.5 (C1 Br-phenyl), 128.1
(C2, C6 N-Ph), 116.0 (C5 Br-phenyl), 127.2 (C3, C5 N-Ph),
134.0 (C6 Br-phenyl), 135.5 (C4 Br-phenyl), 136.8 (C4
N-Ph), 142.7 (C1 N-Ph), 160.0 (C2 Br-phenyl), 160.9 (C=N,
azomethine); Anal. Calcd. for C15H15BrN2O3S (383.27): C,
46.96; H, 3.94; N, 7.31; found: C, 47.0; H, 3.92; N, 7.3; mass
spectrum (ESI) [M]+ = 383.
4-{[(Z)–(5-Bromo-2-hydroxyphenyl)methylidene]amino}-N-(5-
methylisoxazol-3-yl) benzenesulfonamide (L1)
Yield 75% (1.36 g); yellow; m.p. 216–218°C; IR (KBr, cm−1):
3325 (OH), 1605 (HC=N), 1342, 1108 (S=O), 953 (S-N),
842 (C-S), 5654 (C-Br); 1H NMR (DMSO-d6, δ, ppm): 2.31
(s, 3H, methylisoxazole), 6.8 (s, 1H, isoxazole), 6.9–7.6
(m, 3H, bromo-phenyl), 7.7–8.2 (m, 4H, N-Ph), 8.9 (s,
1H, azomethine), 8.9 (s, 1H, SO2NH-), 12.42 (s, 1H, OH);
13C NMR (δ, ppm): 12.9 (C methylisoxazole), 95.1 (C4
© 2012 Informa UK, Ltd.

66 Z.H. Chohan et al.
following the same method using the respective metal
salts as chloride and ligand. Physical measurements,
analytical and spectral data of the complexes are given
in Tables 1 and 2.
Synthesis of metal (II) complex with 4-{[(Z)–(5-
bromo-2-hydroxyphenyl)-methylidene]amino}-N-(5-
methylisoxazol-3-yl)benzenesulfonamide (L1)
To a hot magnetically stirred dioxane (15 mL) solu-
tion of 4-{[(Z)–(5-bromo-2-hydroxyphenyl)methylidene]
amino}-N-(5-methylisoxazol-3-yl)benzenesulfonamide
(L1) (0.872 g, 0.002 moles), an aqueous solution (15 mL)
of Co(II) Cl2.6H2O (0.238 g, 0.001 moles) was added and
refluxed for 2 h. e completion of the reaction was mon-
itored through TLC. e obtained solution was filtered
and evaporated to half of its volume through rotary. e
concentrated solution was left overnight at room tem-
perature, which led to the formation of a solid product.
It was filtered, washed with small amount of dioxine
then with ether, dried and recrystallized in hot aqueous-
dioxane (2:5). All other complexes (2–8) were prepared
Zinc(II) complex of (L1) (4)
1H NMR of Zn(II) complex (DMSO-d6, δ, ppm): 2.31 (s,
6H, methylisoxazole), 6.8 (s, 2H, isoxazole), 7.4–7.8 (m,
6H, Br-Ph), 8.1–8.5 (m, 8H, N-Ph), 9.1 (s, 2H, azome-
thine), 9.1 (s, 2H, SO2NH-); 13C NMR of Zn(II) complex (δ,
ppm): 12.9 (C methylisoxazole), 95.1 (C4 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), 150.0 (C3 isoxazole), 158.5 (C1
N-Ph), 162.1 (C2 Br-Ph), 162.6 (HC=N, azomethine) 169.6
(C5 isoxazole).
− +
− +
Br
N
N
O
O
S
S
NH2
NH2
O
O
m/z 288 (48.6%)
m/z 367 (23.8%)
− +
Br
− +
CH
O
− +
Br
N
O
S
NH2
O
OH2
Cu
CH3
H2O
N
CH3
O
OH
O
S
OH
N
H2N
m/z 108 (22.4%)
CH
m/z 214 (100%)
O
Br
m/z 864 (M+)
+
− +
H2C
Br
O
S
NH2
O
CH
O
N
S
NH2
m/z 184 (53.1%)
− +
O
O
Cu
N
O
O
S
N
H2C
H2N
CH
O
Br
m/z 133 (14.6%)
m/z 828 (21.4%)
Figure 6. e proposed fragmentation pattern of complex [Cu(L2-H)2(H2O)2].
Journal of Enzyme Inhibition and Medicinal Chemistry

Sulfonamide-derived Schiff’s bases and their metal complexes 67
Zinc(II) complex of (L2) (8)
salt mixture and double distilled water. An unequal parti-
tion was made in the plastic dish with the help of a perfo-
rated device. Approximately 50 mg of eggs were sprinkled
into the large compartment, which was darkened while
the matter compartment was opened to ordinary light.
After two days nauplii were collected by a pipette from
the lighted side. A sample of the test compound was pre-
pared by dissolving 20 mg of each compound in 2 mL of
DMF. From this stock solutions 500, 50 and 5 µg/mL were
transferred to nine vials (three for each dilutions were
used for each test sample and LD50 is the mean of three
values) and one vial was kept as control having 2mL of
DMF only. e solvent was allowed to evaporate over-
night. After two days, when shrimp larvae were ready,
1 mL of seawater and 10 shrimps were added to each
vial (30 shrimps/dilution) and the volume was adjusted
with sea water to 5 mL per vial. After 24 h the number of
survivors was counted. Data were analyzed by Finney
computer program to determine the LD50 values19.
1H NMR of Zn(II) complex (DMSO-d6, δ, ppm): 3.13 (t,
4H, CH2-aromatic), 3.7 (t, 4H, CH2-N), 7.4–7.8 (m, 6H,
Br-Ph), 8.1–8.5 (m, 8H, N-Ph), 9.1 (s, 2H, azomethine),
9.3 (s, 4H, -SO2NH2); 13C NMR of Zn(II) complex (δ, ppm):
37.5 (CH2-aromatic), 61.3 (CH2-N), 118.4 (C3 Br-Ph), 120.5
(C1 Br-Ph), 128.1 (C2, C6 N-Ph), 116.0 (C5 Br-Ph), 127.2
(C3, C5 N-Ph), 134.0 (C6 Br-Ph), 135.5 (C4 Br-Ph), 136.8
(C4 N-Ph), 143.8 (C1 N-Ph), 162.1 (C2 Br-Ph), 162.5 (C=N,
azomethine).
Biological screening
In vitro antibacterial
e 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. flexneri, P. aeruginosa, S. typhi) and two
Gram-positive (S. aureus, B. subtilis) bacterial strains
by the agar-well diffusion method15,16. e 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/mL) were spread
on the surface of the nutrient agar with the help of a ster-
ile cotton swab. e recommended concentration of the
test sample (50 μg/μL in DMSO) was introduced in the
respective wells. Other wells supplemented with DMSO
and reference antibacterial drug, imipenum, served as
negative and positive controls, respectively. e plates
were incubated at 37°C for 24 h. Activity was determined
by measuring the diameter (mm) of zones showing com-
plete 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.
Acknowledgement
HAZ is grateful to Higher Education Commission (HEC),
Government of Pakistan for providing Scholarship under
Indigenous PhD Program (PIN 042–160410-PS2-117).
e authors are also thankful to HEJ research Institute of
Chemistry, University of Karachi, Pakistan, for providing
help in taking NMR and mass spectra and also antibacte-
rial and antifungal assays.
Declaration of interest
e authors report no conflict of interest. e authors
alone are responsible for the content and writing of the
article.
In vitro antifungal
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