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Synthesis characterization and biological properties of sulfonamide-derived compounds and their transition metal complexes.

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Full Paper
Received: 15 January 2009
Revised: 17 April 2009
Accepted: 17 April 2009
Published online in Wiley Interscience: 28 May 2009
(www.interscience.com) DOI 10.1002/aoc.1513
Synthesis, characterization and biological
properties of sulfonamide-derived compounds
and their transition metal complexes
Zahid H. Chohana∗ , Hazoor A. Shada and Faiz-ul-Hassan Nasimb
Sulfonamide-derived compounds and their first row d-transition metal chelates [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 have been proposed
from magnetic susceptibility and conductivity measurements, IR, 1 H and 13 C NMR, electron spectra, mass spectrometry and CHN
analysis data. The structure of ligand, 4-{[(E)-(5-chloro-2-hydroxyphenyl) methylidene] amino}-N-(4,6-dimethyl pyrimidin-2-yl)
benzene sulfonamide has also been determined by X-ray diffraction method. An octahedral geometry has been suggested for
all the complexes. The ligands and metal complexes have been screened for their in vitro antibacterial, antifungal and cytotoxic
activity. The results of these studies revealed that all compounds showed moderate to significant antibacterial activity against
c 2009 John Wiley & Sons,
one or more bacterial strains and good antifungal activity against various fungal strains. Copyright Ltd.
Keywords: sulfonamide; metal (ii) complexes; antibacterial; antifungal; cytotoxic
Introduction
Appl. Organometal. Chem. 2009 , 23, 319–328
Materials and Methods
All reagents and solvents used were of analytical grades. Elemental
analyses were carried out with a CHNS/O Analyser (Perkin Elmer
USA) model. 1 H and 13 C NMR spectra 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. 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.
Synthesis of Ligands
4-{[(E)-(5-chloro-2-hydroxyphenyl)methylidene]amino}-N-(4,6dimethylpyrimidin-2-yl)benzenesulfonamide (L1 )
To an ethanol (30 ml) solution of sulfamethazine (1.11 g,
0.004 mol), 5-chlorosalisylaldehyde (0.63 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 evaporated the solvent on rotary evaporator. The solid product thus obtained was
re-crystallized in hot ethanol. The same method was applied to
prepare other ligands (L2 –L3 ).
∗
Correspondence to: Zahid H. Chohan, BZ University, Chemistry, Department of
Chemistry, BZ University, Multan, Punjab 87000, Pakistan.
E-mail: dr.zahidchohan@gmail.com
a Department of Chemistry, Bahauddin Zakariya University, Multan, Pakistan
b Department of Chemistry, The Islamia University of Bahawalpur, Pakistan
c 2009 John Wiley & Sons, Ltd.
Copyright 319
Sulfonamides are extensively used for their antibacterial,[1 – 3]
antitumor,[4]
diuretic,[5]
anti-carbonic
anhydrase,[6,7]
[8]
[9]
hypoglycaemic,
anti-thyroid
and protease inhibitor[10]
activities. Many drugs possess modified pharmacological and
toxicological potentials when administered in the form of their
metal compounds. The most widely studied metal ions in this
respect are cobalt (II), copper (II), nickel (II) and zinc (II) because
they form low molecular weight complexes and thus prove to be
beneficial against several diseases.[11 – 14] All sulfonamides have
one free amino group, which offers an extendable chemistry
and makes them interesting potential ligands.[15 – 17] 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 vital to understand coordination
behaviour and relationship between the metals and the ligands
in various biological systems. In view of the versatile chemistry
of sulfonamides we have commenced a programme[18 – 28] of
synthesizing and designing various metal-based sulfonamides
and investigating their structural and biological behaviour.
We herein describe preparation of three new sulfonamides,
4-{[(E)-(5-chloro-2-hydroxy
phenyl)
methylidene]amino}-N(4,6-dimethylpyrimidin-2-yl) benzenesulfonamide, 4-{[(E)-(5chloro-2-hydroxy-phenyl)methylidene]amino}-N-(pyrimidin-2yl)benzene sulfonamide and 4-{[(E)-(5-chloro-2-hydroxyphenyl)
methylidene]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide
obtained from the reaction of sulfamethazine, sulfadiazine
and sulfathiazole with 5-chlorosalicylaldehyde respectively
and their cobalt (II), copper (II), nickel (II) and zinc (II) metal
complexes. These compounds have been investigated for their
in vitro antibacterial activity against four Gram-negative (E. coli,
S. flexenari, P. aeruginosa, S. typhi) and two Gram-positive (S. aureus,
B. subtilis) bacterial strains and for antifungal activity against
T. longifusus, C. albican, A. flavus, M. canis, F. solani and C. glaberate
fungal strains. These studies indicate that all compounds show
moderate to significant activity that increases upon coordination.
Z. H. Chohan, H. A. Shad and F.-ul-H. Nasim
Table 1. Physical measurements and analytical data of the metal (II) complexes
M.p. (dec.) Yield
◦
No.
1
Found (calcd) (%)
( C)
(%)
C
H
N
1
[Co(L -H)2 (H2 O)2 ] [926.71] C38 H36 N8 O8 S2 Cl2 Co
264–266
82
49.11 (49.25)
3.81 (3.92)
11.98 (12.09)
2
[Ni(L1 -H)2 (H2 O)2 ] [926.47] C38 H36 N8 O8 S2 Cl2 Ni
252–254
84
49.78 (49.26)
4.06 (3.92)
12.52 (12.09)
3
[Cu(L1 -H)
Cl2 Cu
246–248
73
50.54 (49.01)
4.03 (3.90)
12.47 (12.03)
4
[Zn(L1 -H)2 (H2 O)2 ] [933.18] C38 H36 N8 O8 S2 Cl2 Zn
260–262
80
48.29 (48.9)
4.02 (3.89)
12.45 (12.01)
5
[Co(L2 -H)2 (H2 O)2 ] [870.60] C34 H28 N8 O8 S2 Cl2 Co
253–255
78
46.78 (46.91)
3.43 (3.24)
12.24 (12.87)
6
[Ni(L2 -H)2 (H2 O)2 ] [870.36] C34 H28 N8 O8 S2 Cl2 Ni
275–278
77
46.42 (46.89)
3.43 (3.21)
12.24 (12.87)
7
[Cu(L2 -H)
Cu
255–258
75
46.35 (46.60)
3.40 (3.22)
12.20 (12.80)
8
[Zn(L2 -H)2 (H2 O)2 ] [877.09] C34 H28 N8 O8 S2 Cl2 Zn
266–268
78
46.42 (46.56)
3.39 (3.22)
12.18 (12.78)
2 (H2 O)2 ] [931.32] C38 H36 N8 O8 S2
2 (H2 O)2 ] [875.21] C34 H28 N8 O8 S2 Cl2
3
9
[Co(L -H)2 (H2 O)2 ] [880.68] C32 H26 N6 O8 S4 Cl2 Co
252–254
83
43.92 (43.63)
3.18 (2.98)
9.89 (9.54)
10
[Ni(L3 -H)2 (H2 O)2 ] [880.44] C32 H26 N6 O8 S4 Cl2 Ni
262–264
78
43.94 (43.65)
3.14 (2.98)
9.88 (9.55)
11
[Cu(L3 -H)
Cu
248–250
81
43.60 (43.41)
3.15 (2.96)
9.95 (9.49)
12
[Zn(L3 -H)2 (H2 O)2 ] [887.15] C32 H26 N6 O8 S4 Cl2 Zn
258–260
80
43.47 (43.32)
3.11 (2.95)
9.93 (9.47)
2 (H2 O)2 ] [885.29] C32 H26 N6 O8 S4 Cl2
Table 2. Conductivity, magnetic and spectral data of metal (II) complexes
No.
M
(−1 cm2 mol−1 )
BM
(µeff )
λmax (cm−1 )
1.
74.2
4.88
7402, 17445, 20585, 29308
1572 (C N), 1395 (C–O),1345, 1110 (SO2 ), 956 (S–N), 841 (C–S),
441(M–N), 529 (M–O)
2.
69.6
3.32
10392, 15705, 26451, 29872
1566 (C N), 1395 (C–O), 1345, 1110 (SO2 ), 956 (S–N), 841 (C–S),
438(M–N), 537 (M–O)
3.
72.5
1.89
14995, 19160, 30375
1567 (C N), 1395 (C–O), 1345, 1110 (SO2 ), 956(S–N), 841 (C–S),
442(M–N), 532 (M–O)
4.
68.0
Dia
28938
1570 (C N), 1395 (C–O),1345, 1110 (SO2 ), 956(S–N), 841 (C–S),
440(M–N), 530 (M–O)
5.
66.7
4.89
7365, 17510, 20625, 29355
1569 (C N), 1395 (C–O), 1345, 1110 (SO2 ), 956(S–N), 841 (C–S),
442(M–N), 534 (M–O)
6.
70.2
3.36
10436, 15788, 26495, 30955
1571 (C N), 1395 (C–O),1345, 1110 (SO2 ), 956(S–N), 841 (C–S),
438(M–N), 534 (M–O)
7.
63.2
1.85
15155, 19205, 30355
1570 (C N), 1395 (C–O),1345, 1110 (SO2 ), 956(S–N), 841 (C–S),
442(M–N), 527 (M–O)
8.
67.9
Dia
29128
1567 (C N), 1395 (C–O),1345, 1110 (SO2 ), 956 (S–N), 841 (C–S),
439(M–N), 537 (M–O)
9.
66.9
4.95
7288, 17495, 20485, 29362
1569 (C N), 1395 (C–O),1345, 1110 (SO2 ), 956(S–N), 841 (C–S),
441(M–N), 529 (M–O)
10.
69.1
3.34
10405, 15692, 26530, 29991
1571 (C N), 1395 (C–O), 1345, 1110 (SO2 ), 956(S–N), 841 (C–S),
438(M–N), 536 (M–O)
11.
74.2
1.82
14985, 19180, 30385
1567 (C N), 1395 (C–O), 1345, 1110 (SO2 ), 956(S–N), 841 (C–S),
441(M–N), 535 (M–O)
12.
69.7
Dia
28980
1569 (C N), 1395 (C–O), 1345, 1110 (SO2 ), 956(S–N), 841 (C–S),
439(M–N), 529 (M–O)
Physical, Analytical and Spectral Data of the Ligands (L1 - L3 )
4-{[(E)-(5-chloro-2-hydroxyphenyl)methylidene]amino}-N-(4,6dimethylpyrimidin-2-yl)benzenesulfonamide (L1 )
320
Yield 82%; m.p. 224–226 ◦ C; IR (KBr, cm−1 ): 3365 (NH), 3315
(OH), 1597 (HC N), 1345, 1110 (S O), 956 (S–N), 841 (C–S),
610 (C–Cl); 1 H NMR (DMSO-d6 , δ, ppm): 2.35 (s, 6H, CH3 ), 6.9 (m,
1H pyrimidine), 7.2–7.5 (m, 3H, Cl–Ph), 7.7–8.2 (m, 4H, N–Ph),
8.91 (s, 1H, azomethine), 8.9 (s, 1H, SO2 NH-), 12.42 (s, 1H, OH);
www.interscience.wiley.com/journal/aoc
IR (cm−1 )
13 C
NMR (δ, ppm): 25.1 (C1 , C2 -methyl), 103.1 (C4 -pyrimidine),
117.4 (C3 Cl–Ph), 119.9 (C1 Cl–Ph), 122.6 (C2 , C6 N–Ph), 127.0 (C5
Cl–Ph), 128.6 (C3 , C5 N–Ph), 130.7 (C6 Cl–Ph), 132.6 (C4 Cl–Ph),
138.2 (C4 N–Ph), 156.4 (C1 N–Ph), 159.2 (C2 Cl–Ph), 160.1 (C N,
azomethine) 165.3 (C3 , C5 -pyrimidine), 168.5 (C1 -pyrimidine). Anal.
calcd. for C19 H17 ClN4 O3 S (416.88): C, 54.74; H, 4.11; N, 13.44;
found: C, 54.89; H, 4.19; N, 13.38%. Mass spectrum (ESI) [M]+ =
416.10.
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2009, 23, 319–328
Properties of sulfonamide-derived compounds and their transition metal complexes
4-{[(E)-(5-chloro-2-hydroxyphenyl)methylidene]amino}-N(pyrimidin-2-yl)benzenesulfonamide (L2 )
Yield 85%; m.p. 242244 ◦ C; IR (KBr, cm−1 ): 3365 (NH), 3315 (OH),
1597 (HC N), 1345, 1110 (S O), 956 (S–N), 841 (C–S), 615 (C–Cl);
1 H NMR (DMSO-d , δ, ppm): 6.9 (t, 1H pyrimidine), 7.2–7.5 (m, 3H,
6
Cl–Ph), 7.7–8.2 (m, 4H, N–Ph), 8.9 (s, 1H, azomethine), 8.38 (d, 2H,
pyrimidine), 8.9 (s, 1H, SO2 NH-), 12.42 (s, 1H, OH); 13 C NMR (δ, ppm):
110.3 (C4 -pyrimidine), 117.4 (C3 Cl–Ph), 119.9 (C1 Cl–Ph), 122.6
(C2 , C6 N–Ph), 127.0 (C5 Cl–Ph), 128.6 (C3 , C5 N–Ph), 130.7 (C6
Cl–Ph), 132.6 (C4 Cl–Ph), 138.2 (C4 N–Ph), 156.4 (C1 N–Ph), 157.9
(C3 , C5 -pyrimidine), 159.2 (C2 Cl–Ph), 160.9 (C N, azomethine),
169.3 (C1 -pyrimidine). Anal. calcd for C17 H13 ClN4 O3 S (388.83): C,
52.51; H, 3.37; N, 14.41; found: C, 52.79; H, 3.19; N, 14.38%. Mass
spectrum (ESI) [M]+ = 388.16.
4-{[(E)-(5-chloro-2-hydroxyphenyl)methylidene]amino}-N-(1,3thiazol-2-yl)benzenesulfonamide (L3 )
N–Ph), 9.3 (s, 2H, azomethine), 9.2 (s, 2H, SO2 NH-), 10.5 (s, 4H
H2 O); 13 C NMR of Zn (II) complex (δ, ppm): 25.1 (C1 , C2 -methyl),
103.1 (C4 -pyrimidine), 117.4 (C3 Cl–Ph), 119.9 (C1 Cl–Ph), 122.6
(C2 , C6 N–Ph), 127.0 (C5 Cl–Ph), 128.6 (C3 , C5 N–Ph), 130.7 (C6
Cl–Ph), 132.6 (C4 Cl–Ph), 138.2 (C4 N–Ph), 157.5 (C1 N–Ph), 160.3
(C2 Cl–Ph), 161.45 (C N, azomethine) 165.3 (C3 , C5 -pyrimidine),
168.5 (C1 -pyrimidine).
[Zn (L2 -H)2 (H2 O)2 ] (8)
1H
NMR of zinc (II) complex (DMSO-d6 , δ, ppm): 7.15 (t, 2H
pyrimidine), 7.6–7.9 (m, 6H, Cl–Ph), 8.1–8.5 (m, 8H, N–Ph), 9.28 (s,
2H, azomethine), 8.7 (d, 4H, pyrimidine), 9.2 (s, 2H, SO2 NH-), 10.5 (s,
4H H2 O); 13 C NMR of Zn (II) complex (δ, ppm): 110.3 (C4 -pyrimidine),
117.4 (C3 Cl–Ph), 119.9 (C1 Cl–Ph), 122.6 (C2 , C6 N–Ph), 128.6 (C3 ,
C5 N–Ph), 127.0 (C5 Cl–Ph), 132.6 (C4 Cl–Ph), 130.7 (C6 Cl–Ph),
138.2 (C4 N–Ph), 157.5 (C1 N–Ph), 157.9 (C3 , C5 -pyrimidine), 161.74
(C N, azomethine), 169.3 (C1 -pyrimidine), 160.3 (C2 Cl– Ph).
Yield 80%; m.p. 237–238 ◦ C; IR (KBr, cm−1 ): 3365 (NH), 3315 (OH),
1604 (HC N), 1345, 1110 (S O), 956 (S–N), 841 (C–S), 615 (C–Cl);
1 H NMR (DMSO-d , δ, ppm): 6.56 (d, 1H, thiazole), 7.2–7.5 (m,
6
3H, Cl–Ph), 7.6 (d, 1H, thiazole), 7.7–8.2 (m, 4H, N–Ph), 8.9 (s,
1H, azomethine), 8.9 (s, 1H, SO2 NH-), 12.42 (s, 1H, OH). 13 C NMR
(δ, ppm): 108.0 (C2 thiazole), 117.4 (C3 Cl–Ph), 119.9 (C1 Cl–Ph),
122.6 (C2 , C6 N–Ph), 127.0 (C5 Cl–Ph), 128.6 (C3 , C5 N–Ph), 130.7
(C6 Cl–Ph), 132.6 (C4 Cl–Ph), 138.2 (C4 N–Ph), 139.2 (C3 thiazole),
156.5 (C1 N–Ph), 159.2 (C2 Cl–Ph), 160.5 (C N, azomethine), 171.7
(C1 thiazole); Anal. calcd for C16 H12 ClN3 O3 S2 (393.87): C, 48.79; H,
3.07; N, 10.67; found: C, 48.91; H, 3.18; N, 10.38%. Mass spectrum
(ESI) [M]+ = 393.19.
NMR of zinc (II) complex (DMSO-d6 , δ, ppm): 6.74 (d, 2H,
thiazole), 7.6–7.9 (m, 6H, Cl–Ph), 7.8 (d, 2H, thiazole), 8.1–8.5
(m, 8H, N–Ph), 9.3 (s, 2H, azomethine), 9.2 (s, 2H, SO2 NH-),
10.5 (s, 4H H2 O); 13 C NMR of Zn (II) complex (δ, ppm): 108.0
(C2 thiazole), 117.4 (C3 Cl–Ph), 119.9 (C1 Cl–Ph), 122.6 (C2 , C6
N–Ph), 127.0 (C5 Cl–Ph), 128.6 (C3 , C5 N–Ph), 130.7 (C6 Cl–Ph),
132.6 (C4 Cl–Ph), 138.2 (C4 N–Ph), 139.2 (C3 thiazole), 157.3 (C1
N–Ph), 160.1 (C2 Cl–Ph), 160.45 (C N, azomethine), 171.7 (C1
thiazole).
X-ray Structure
In vitro antibacterial bioassay
The X-ray structure of one of the ligands, 4-{[(E)-(5-chloro-2hydroxyphenyl) methylidene] amino}-N-(4,6-dimethyl pyrimidin2-yl) benzenesulfonamide (L1 ), has already been published[29]
by us.
Synthesis of Metal (II) Complexes
[Co(L1 -H)2 (H2 O)2 ] (1)
To a hot magnetically stirred dioxane (10 ml) solution of
4-{[(E)-(5-chloro-2-hydroxyphenyl) methylidene] amino}-N-(4,6dimethylpyrimidin-2-yl) benzene sulfonamide (L1 ) (0.832 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 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 small amount of
dioxane then with ether and dried. All other complexes (2–12)
were prepared following the same method using the respective
metal salts as chloride and the respective sulfonamides. Physical
measurements, analytical and spectral data of the complexes are
given in Tables 1 and 2.
NMR Data of Zinc (II) Complexes
[Zn (L1 -H)2 (H2 O)2 ] (4)
NMR of zinc (II) complex (DMSO-d6 , δ, ppm): 2.45 (s, 12H, CH3 ),
7.1 (m, 2H pyrimidine), 7.6–7.9 (m, 6H, Cl–Ph), 8.1–8.5 (m, 8H,
Appl. Organometal. Chem. 2009, 23, 319–328
1H
Biological Activity
The synthesized sulfonamides (L1 –L3 ) and their metal (II)
complexes (1–12) were screened in vitro for their antibacterial
activity against four Gram-negative (E. coli, S. flexenari, P.
aeruginosa, S. typhi) and two Gram-positive (S. aureus, 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 colonyforming units (CFU/ml) were spread on the surface of the nutrient
agar with a sterile cotton swab. The 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. 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.
In vitro antifungal activity
Antifungal activity of all the compounds was studied against
six fungal cultures. Sabouraud dextrose agar (Oxoid, Hampshire, UK) was seeded with 105 (cfu) ml−1 fungal spore
suspensions and transferred to Petri plates. Discs soaked
in 20 ml (200 µg/ml 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
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
321
1H
[Zn (L3 -H)2 (H2 O)2 ] (12)
322
www.interscience.wiley.com/journal/aoc
L1
c 2009 John Wiley & Sons, Ltd.
Copyright 4.3359
L3
4.8442
20
16
2.8578
18
17
07
15
11
17
15
09
13
13
L2
4.6224
23
22
20
12
23
25
1
2.9439
17
18
15
11
18
19
2
1.8619
18
17
17
13
17
18
3
3.6878
19
19
16
10
18
20
5
3.8987
20
21
16
11
19
21
6
4.2622
18
19
22
10
21
19
7
Compound [zone of inhibition (mm)]
4.7223
25
25
23
13
24
25
4
4.7223
24
24
24
12
22
23
8
3.8297
20
19
19
10
18
20
9
3.6009
19
20
21
11
19
17
10
4.1952
20
10
20
18
11
22
18
26
13
24
25
12
5.0365
25
26
29
22
24
25
SD
a = E. coli; b = S. flexenari; c = P. aeruginosa; d = S. typhi; e = S. aureus; f = B. subtilis. 10 <, weak; >10, moderate; >16, significant. SD = standard drug (imipenum); SA = statistical analysis.
SA
Gram-positive
e
18
30
f
17
26
Gram-negative
a
19
b
07
c
15
d
14
Bacteria
Table 3. Antibacterial bioassay (concentration used 1 mg/ml of DMSO) of ligands and metal (II) complexes
3.0332
Z. H. Chohan, H. A. Shad and F.-ul-H. Nasim
Appl. Organometal. Chem. 2009, 23, 319–328
Properties of sulfonamide-derived compounds and their transition metal complexes
recorded as percentage inhibition and compared with standard
drugs miconazole and amphotericin B.
Minimum Inhibitory Concentration
Compounds containing significant antibacterial activity (over
80%) were selected for minimum inhibitory concentration (MIC)
studies. The minimum inhibitory concentration was determined
using the disc diffusion technique by preparing discs containing
10, 25, 50 and 100 µg/ml 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 the help of 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
lighted side. A sample of the test compound was prepared by
dissolving 20 mg of each compound in 2 ml of DMF. From the
stock solutions 500, 50 and 5 µg/ml were transferred to nine
vials (three for each dilution were used for each test sample
and LD50 was the mean of three values) and one vial was kept
as control having 2 ml of DMF only. The solvent was allowed
to evaporate overnight. After w days, when shrimp larvae were
ready, 1 ml of sea water 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 analysed by Finney computer program to determine
the LD50 values.[33,34]
Scheme 1. Preparation of ligands.
Scheme 2. Proposed structure of metal (II) complexes.
Result and Discussion
Chemistry
The sulfonamides L1 –L3 were prepared by the reaction of
5-chlorosalicylaldehyde with the respective sulfonamides to obtain the desired new sulfonamides as shown in Scheme 1.
All sulfonamides were only soluble in Dioxane, DMF and
DMSO. The composition is consistent with their microanalytical and mass spectral data. The metal (II) complexes 1–12
were prepared in a stochiometric (metal : ligands 1 : 2) molar ratio. Cobalt (II), copper (II), nickel (II) and zinc (II) were
used as chlorides (Scheme 2). Physical measurements and analytical data of the complexes (1–12) are given in Tables 1
and 2.
Conductance and Magnetic Susceptibility Measurements
Appl. Organometal. Chem. 2009, 23, 319–328
IR Spectra
Some of the characteristic IR spectral bands of sulfonamides and
its metal complexes are given in Table 2 and in the Experimental.
The sulfonamides contain potential donor sites such as hydroxyl
oxygen (-OH), azomethine nitrogen (-C N), sulfonamide oxygen
(-S O), sulfonamide nitrogen (-S–N) and pyrimidine/thiazole
nitrogen (-C–N), which can coordinate with the metal ions. The
absence of bands at 3345, 3190 and 1705 cm−1 due to ν(NH2 )
amine and ν(CHO) aldehyde and the appearance of a sharp band
at 1604–1597 cm−1 were assigned to the stretching of ν(C N)
azomethine, suggesting the formation of the condensation
product. The IR spectra of uncoordinated sulfonamides generally
showed a broad band at 3315 assigned[38] to the ν(OH). Two bands
νasymm (SO2 ) and νsymm (SO2 ) appeared at 1345 and 1110 cm−1
respectively. The band for azomethine (C N) linkage was found
at a lower frequency by 28–40 cm−1 (1564–1569 cm−1 ) in all of its
metal complexes, indicating the formation bond between nitrogen
and metal ions. This is further supported by the appearance of a
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
323
The complexes 1–12 showed their molar conductance values (DMF) in the ranges 63.2–74.2/ cm2 /mol indicating their
non-electrolytic nature.[35] The magnetic moment values of
the complexes at room temperature are given in Table 2.
The observed magnetic moment value for cobalt complexes
was found to be 4.88–4.95 BM, consistent with half-spin
octahedral cobalt (II) complexes. The magnetic moment values (1.82–1.89 BM) measured for the copper (II) complexes
lie in the range expected for the d9 -system containing one
unpaired electron consistent with an octahedral geometry.[36]
The measured values, 3.32–3.36 BM for the nickel (II) complexes, also suggest[37] an octahedral geometry for these complexes. The zinc (II) complexes were found to be diamagnetic as
expected.
Z. H. Chohan, H. A. Shad and F.-ul-H. Nasim
Figure 1. Comparison of antibacterial activity.
Figure 2. Average antibacterial activity.
new band at 438–444 cm−1 due to the ν(M–N) stretching.[39] The
coordination through the hydroxyl oxygen was revealed by the
disappearance of the mode at 3315 cm−1 and the appearance of
a new band at 1395 cm−1 due to deprotonation and coordination
of the C–O mode. This was further confirmed by the appearance
of the new band at 525–540 cm−1 due to ν(M–O) in the metal
complexes. The bands in the sulfonamides due to νasymm (SO2 )
and νsymm (SO2 ) appeared unchanged at 1345 and 1110 cm−1 ,
respectively,[40] in the complexes, indicating that this group was
not participating in coordination. This was supported by the
unchanged ν(S–N) and ν(C–S) modes[41,42] appearing at 956 and
841 cm−1 in the sulfonamides after complexation. All the other
Figure 3. Comparison of antifungal activity.
324
Figure 4. Average antifungal activity.
www.interscience.wiley.com/journal/aoc
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2009, 23, 319–328
c 2009 John Wiley & Sons, Ltd.
Copyright 36.6192
SA
34.1916
78
00
72
64
82
20
L2
33.0131
00
45
81
00
00
32
L3
30.3672
36
45
00
62
91 66
35
1
28.1401
41
35
58
00
72
00
2
31.1111
26
60
55
00
00
84
3
29.4528
49
40
45
90
54
62
4
27.3234
65
00
42
36
33
00
5
6
32.3584
68
00
40
86
46
77
Compound
36.7405
00
75
41
88
00
00
7
24.4104
38
60
45
00
84
00
9
16.8691
47
65
62
38
85
45
10
µg/ml: 1.6822 × 10−7
29.2945
79
65
48
72
29
71
8
18.0074
32
60
50
56
81
43
11
E
31.5574
45
72
55
00
85
12
F
A
B
C
D
SD
a = T. longifucus; b = C. albicans; c = A. flavus; d = M. canis; e = F. solani; f = C. glaberata. SD = standard drugs MIC, µg/ml; A = miconazole (70
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). SA = statistical analysis.
82
00
32
81
38
00
L1
a
b
c
d
e
f
325
Appl. Organometal. Chem. 2009, 23, 319–328
Organism
Table 4. Antifungal bioassay (concentration used 200 µg/ml) of ligands and metal (II) complexes
Properties of sulfonamide-derived compounds and their transition metal complexes
www.interscience.wiley.com/journal/aoc
Z. H. Chohan, H. A. Shad and F.-ul-H. Nasim
donor sites of the sulfonamides did not participate in coordination,
as their IR frequencies remained unchanged after complexation.
1
H NMR Spectra
1H
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. All the protons due to heteroaromatic/aromatic
groups were found to be in their expected region.[43] The
conclusions drawn from these studies provide further support to
the mode of bonding discussed in their IR spectra. The coordination
of the azomethine nitrogen was inferred by the downfield shifting
of the -CH N- proton signal from 8.9–8.91 ppm in the ligand to
9.28–9.3 ppm in the complexes. Hydroxyl proton at 12.42 ppm
in the spectra of zinc (II) complexes disappeared, indicating
deprotonation and coordination of the oxygen with the metal ion.
All other protons underwent downfield shift by 0.22–0.36 ppm
due to the increased conjugation[44] and coordination with the
metal atoms. Furthermore, the number of protons calculated from
the integration curves and those obtained from the values of the
expected CHN analyses agree well with each other.
13 C NMR Spectra
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 were well supported by their IR and
1 H NMR spectra. Downfield shifting of the azomethine carbon
from 160.1–160.8 ppm in the sulfonamide to 160.45–161.74 ppm
in its metal (II) complexes revealed coordination of the azomethine
to the metal atom (Figure 4). Similarly, carbons of N-phenyl and
Cl-phenyl rings being near to the coordination sites also showed
downfield shifting by 0.9–1.1 ppm.[44] The results also indicate
that the present number of carbons agrees well with the expected
number of carbons.
Mass Spectra
The mass spectral data is consistent with the formulations:
C19 H17 ClN4 O3 S, 415.9 (calcd 416.88), C17 H13 ClN4 O3 S, 388 (calcd
388.83), C16 H12 ClN3 O3 S2 , 392.8 (calcd 393.5) of the sulfonamides.
The base peak for L1 was observed at 139.0 for fragment
[C7 H4 ClO]+ , for L2 at 171.0 for fragment [C6 H7 N2 SO2 ]+ and for L3
at 230.0 for fragment [C13 H9 ClNO]+ . These are expected to be the
most stable fragments of L1 –L3 .
Electronic Spectra
326
The cobalt (II) complexes exhibited well-resolved, low-energy
bands at 7288–7402 and 17 445–17 510 and a strong highenergy band at 20 485–20 625 cm−1 (Table 2), assigned[45] 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.[46] A high intensity band at
29 308–29 362 cm−1 was assigned to the M–L (metal → ligand)
charge transfer. The magnetic susceptibility measurements for the
solid cobalt (II) complexes are also indicative of three unpaired
electrons per cobalt (II) ion, suggesting[47] consistency with their
octahedral environment.
The electronic spectra of the copper (II) complexes (Table 2) showed two low-energy weak bands at 14 982–15 151
www.interscience.wiley.com/journal/aoc
and 19 156–19 201 cm−1 and a strong high-energy band at
30 359–30 387 cm−1 assigned to 2 B1g → 2 A1g and 2 B1g → 2 Eg
transitions, respectively.[48] The strong high-energy band, in turn, is
assigned to metal → ligand charge transfer. Also, the magnetic moment values for the copper (II) are indicative of anti-ferromagnetic
spin–spin interaction through molecular association indicative of
their octahedral geometry.[49]
The electronic spectra of the nickel (II) complexes showed
d-d bands in the region 10 392–10 436, 15 692–15 788 and
26 451–26 530 cm−1 . These are assigned[50] to the transitions
3 A (F) → 3 T (F), 3 A (F) → 3 T (F) and 3 A (F) → 3 T (P),
2g
2g
2g
1g
2g
2g
respectively, consistent with their well-defined octahedral configuration. The band at 29 872–29 991 cm−1 was assigned to metal
→ ligand charge transfer. The magnetic measurements showed
two unpaired electrons per Ni (II) ion, suggesting[51] also an octahedral geometry for the nickel (II) complexes. The electronic spectra
of the zinc (II) complexes exhibited only a high-intensity band
at 28 938–29 128 cm−1 assigned[52] to a ligand–metal charge
transfer.
Biological Activity
In vitro antibacterial bioassay
All the synthesized compounds were tested against four Gramnegative (E. coli, S. flexenari, P. aeruginosa, S. typhi) and two
Gram-positive (S. aureus, B. subtilis) bacterial strains (Table 3)
according to literature protocol.[30,31] The bioactivity of these
compounds was compared with those of the standard drug
imipenum (Fig. 1). The synthesized compounds exhibited varying
degree of inhibitory result on the growth of different tested strains
except the activity of all compounds against strain b where no
moderate to significant activity was observed. Compounds 1–12
showed overall a significant activity against E. coli, P. aeruginosa,
S. typhi, S. aureus and B. subtilis. However, a moderate activity was
observed by compounds L3 , 5,6 and 9 against a, L1 , L3 , 3 and 10
against c and d, L1 , 2,3 and 10 against f . From Table 3, it is clear that
the metal complexes have shown more inhibition than the ligands
on Gram-positive and Gram-negative bacterial species. However,
the zinc(II) complexes of all the ligands have the most inhibitory
effect on Gram-negative and Gram-positive bacteria as compared
with the other metal complexes (Figure 2). The increased activity
of the metal complexes can be explained on the basis of chelation
theory.[53]
On chelation, the polarity of the metal ion will be reduced
significantly due to the overlap with the ligand orbital. Further, it
increases the delocalization of π -electrons over the whole chelate
ring and enhances the lipophilicity of the complexes.[54] It was
interesting to note that molecular mass of the metal chelates
had an impact on the bactericidal activity. As the molecular mass
decreases from compounds 1–12 the bactericidal activity was
increased.
In vitro antifungal bioassay
The antifungal screening of all compounds was carried out against
T. longifusus, C. albican, A. flavus, M. canis, F. solani and C. glaberate
fungal strains (Table 4) according to the literature protocol.[31]
Most of the synthesized compounds showed 50–60% antifungal
activity against one or more fungal strains (Figure 3). Compounds
10 and 11 overall showed activities of 60–80%, while all other
compounds showed 50–90% (moderate to excellent) activity. The
compounds L1 , L2 , 8 and 12 showed good antifungal activities
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2009, 23, 319–328
Properties of sulfonamide-derived compounds and their transition metal complexes
Table 5. Minimum inhibitory concentration (M/ml) of the selected compounds (1, 4, 8 and 12) against selected bacteria
No.
1
4
8
12
Gram-negative
E. coli
P. aeruginosa
S. typhi
–
–
1.341 × 10−7
–
6.146 × 10−8
3.324 × 10−8
1.282 × 10−7
3.204 × 10−8
3.834 × 10−8
6.275 × 10−8
3.093 × 10−8
1.237 × 10−8
Gram-positive
S. aureus
B. subtilis
–
–
1.330 × 10−7
6.186 × 10−8
6.408 × 10−8
3.204 × 10−8
1.237 × 10−7
6.647 × 10−8
Table 6. Brine shrimp bioassay data of the ligands L1 –L3 and their
metal (II) complexes 1–12
Compound
L1
L2
L3
1
2
3
4
5
6
7
8
9
10
11
12
LD50 (M/ml)
>3.164 × 10−3
>2.839 × 10−3
>2.924 × 10−3
>1.461 × 10−3
5.256 × 10−4
>1.548 × 10−3
>1.392 × 10−3
>1.471 × 10−3
6.694 × 10−4
>1.342 × 10−3
>1.481 × 10−3
>1.251 × 10−3
4.945 × 10−4
>1.326 × 10−3
>1.247 × 10−3
(72–82%) against T. longifusus. Similarly, compounds 7 and 8
against C. albican, compounds L2 , L3 against A. flavus, compounds
L1 , L2 , 1,4,6,7,8 and 12 against M. canis, compounds L2 , 1,3,6 and
8 against F. Solani and compounds 3,6 and 8 against C. glaberata
also showed 70–90% activity against the observed fungal strains
while all other compounds showed either a moderate activity
or were inactive against various fungal strains, as shown in the
Table 4. Generally, zinc II complexes 4,8 and 12 had the best
inhibitory effect (49–90%) on T. longifucus and F. solani. These
results were compared with the standard drugs miconazole and
amphotericin B.
Minimum Inhibitory Concentration
The data obtained after preliminary antibacterial screening
showed that compounds 1,4,8 and 12 were the most active (above
80%) and their average inhibition values were 20.84 (80.15%), 22.5
(86.54%), 21.5 (82.69%) and 23.17 (89.12%), respectively. These
compounds were therefore, selected for MIC studies (Table 5).
The MIC of these compounds was in the range 6.647 × 10−8 to
1.237 × 10−7 M. The compound 12 proved to be the most active.
It inhibited the growth of B. subtilis at 6.647 × 10−8 M.
In vitro cytotoxic bioassay
Appl. Organometal. Chem. 2009, 23, 319–328
Conclusion
It has been suggested that the antibacterial and antifungal activity
of ligands L1 –L3 increased upon coordination. The chelation
process reduces the polarity of metal ion by coordinating
with ligands, which increase the lipophilic nature of the metal.
This lipophilic nature of metal enhanced[55 – 59] its penetration
through the lipoid layer of cell membrane of the microorganism.
Further, it has been suggested that some functional groups
such as azomethine (-C N-) or hetero-aromatics present in
these compounds played an important role in antibacterial
and antifungal activity[60 – 64] that may be responsible for the
enhancement of hydrophobic character and liposolubility of the
molecules.
Acknowledgment
One of us (H.A.Z.) is grateful to Higher Education Commission (HEC),
Government of Pakistan for the award to carry out this research. 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.
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