Synthesis, characterization, electrochemical behavior, and antimicrobial activities of aromatic/heteroaromatic sulfonylhydrazone derivatives

Article abstract of DOI:10.1007/s00044-013-0907-7

The aromatic/heteroaromatic sulfonylhydrazone derivatives as indole-3-carboxaldehyde methanesulfonylhydrazone (1), indole-3- carboxaldehydeethanesulfonyl hydrazone (2), thiophene-2- carboxaldehydeethanesulfonylhydrazone (3), 2-hydroxybenzaldehydeethanesul

Full text of DOI:10.1007/s00044-013-0907-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0907-7
ORIGINAL RESEARCH
Synthesis, characterization, electrochemical behavior,
and antimicrobial activities of aromatic/heteroaromatic
sulfonylhydrazone derivatives
¨
¨
¨
•
•
Ayla Balaban Gu¨ndu¨zalp Ummu¨han Ozdemir Ozmen
•
•
Bekir Sıtkı C¸ evrimli Serhat Mamas¸ Servet C¸ ete
Received: 2 November 2013 / Accepted: 30 December 2013
Ó Springer Science+Business Media New York 2014
Abstract The aromatic/heteroaromatic sulfonylhydra-
zone derivatives as indole-3-carboxaldehyde methanesul-
fonylhydrazone (1), indole-3-carboxaldehydeethanesulfonyl
hydrazone (2), thiophene-2-carboxaldehydeethanesulfonyl-
hydrazone (3), 2-hydroxybenzaldehydeethanesulfonyl hydra-
zone (4), 2-hydroxyacetophenoneethanesulfonylhydrazone
(5) and 2-hydroxy-1-naphth aldehydeethane sulfonylhydra-
zone (6) were synthesized by the reaction of sulfonic acids
with aromatic/heteroaromatic aldehydes and characterized
Keywords Sulfonylhydrazones ꢀ
Electrochemical behavior ꢀ Antimicrobial activity ꢀ
Well diffusion method
Introduction
The sulfonamides (–SO2NH–) are used widely as antibac-
terial agents because of their lower cost, lower toxicity and
1
by using elemental analysis, H–13C NMR, LC–MS and IR
most activity against bacterial diseases (Ozc¸elik et al.,
¨
spectra. The electrochemical behavior of the sulfonylhyd-
razones in DMSO at glassy carbon electrode was investi-
gated using cyclic voltammetry, controlled potential
electrolysis and chronoamperometry techniques. The num-
ber of electrons transferred, diffusion coefficient and stan-
dard heterogeneous rate constants were determined using
electrochemical methods. Antimicrobial activities of the
compounds 1–6 were tested against some microorganisms.
The biological activity screening showed that compound 6
exhibited better activity than the others. Structure–activity
relationship analysis of the sulfonylhydrazone derivatives
was performed to explain the trend of activity with molec-
ular descriptors. The indicator descriptors for compound 6
having naphtyl ring are the most important descriptos that
are sensitive both to the size and electrophility of the
molecules.
2004). Sulfo drugs are used as chemotherapeutic agents
with large spectrum of activity and they are widely used
today for various bacterial, protozoal and fungal infections
(Alyar et al., 2012a, b). Methane sulfonamide derivatives
possess DNA-binding ability and show cytostatic effects
which have usage in cancer chemotherapy. Having
hydrophilic characters like sulfonyl group are considered
as a suitable pharmacophoric equivalent for replacing
active sites in drug design (Jensen et al., 1990; Finlay et al.,
1990; Alyar et al., 2011a, b). Sulfonylhydrazones derived
from sulfonamides have pharmacological properties as
antibacterial, antitumor, diuretic, antiviral, antinociceptive
activity and enzyme inhibition especially to carbonic
¨
anhydrase species (Dodoff et al. 1999; Ozdemir et al.
2010). Many of the physiologically active hydrazones have
applications in the treatment of illness like tuberculosis,
leprosy, and mental damage. For this reason, the electro-
chemical behavior of the hydrazones may be very helpful
for their efficient uses. The enlightening of the electrore-
duction mechanism can serve as models for the biological
pathway of the hydrazones, because their activity depends
on reductive processes in the body. The chemical and
biological activities of the hydrazones vary in different
media. Accordingly, the knowledge of the electrochemical
reduction of these compounds is useful to understand their
¨
¨ ¨
A. B. Gu¨ndu¨zalp (&) ꢀ U. O. Ozmen ꢀ S. Mamas¸ ꢀ S. C¸ ete
Department of Chemistry, Faculty of Arts and Science,
Gazi University, Teknikokullar, Ankara, Turkey
e-mail: balaban@gazi.edu.tr
B. S. C¸ evrimli
Department of Chemistry, Atatu¨rk Vocational School,
Gazi University, Akyurt, Ankara, Turkey
123

Med Chem Res
mechanism in chemical and biological processes (Demirel
¨
Ozel et al., 2009). Due to the widespread usage of the
Candida albicans ATCC 10239. The activities were
determined by well-diffusion method and results were
exhibited as inhibition zone diameter (mm) (Alyar et al.,
2011a, b). The geometry optimization was performed on
B3LYP/6-311G(d,p) methods with GAUSSIAN 03 soft-
ware. The molecular descriptors such as logP, dipole
moment (DM), surface area (SA), volume(V), refractivity
(R), mass (M), hydration enthalpy(DHhyd), binding energy
(DEb), heat of formation (DHf), and HOMO and LUMO
energies were determined with Hyperchem 8 PM3-based
QSAR models, respectively. Reduction potentials of C=N,
OH and SO2 groups were evaluated with molecular
descriptors. Structure–activity relationship (SAR) analysis
of the sulfonylhydrazone derivatives was performed to
explain the effect of the molecular descriptors on biological
hydrazones in drug industry, the redox properties of these
compounds are thought to be useful to understand the met-
abolic fate of the drug-containing hydrazones or pharmaco-
logical activities (Baymak et al., 2003; Aleksic et al., 2004).
Electrochemical reduction mechanism of sulfonylhyd-
razones was also proposed that hydrazones have electro-
chemical reduction (EC) mechanism corresponding to
semireversible two electron transfer steps and that a radical
anion formed in the first step followed rapid proton
abstraction and a second electron transfer. Electrochemical
reduction (EC) mechanism contributes to the suggestion of
¨
the biochemical behavior of the hydrozones (Demirel Ozel
et al., 2009).
¨
activity (Ozbek et al., 2009).
In previous studies, we reported the antibacterial and
cytotoxic effect of methanesulfonic acid hydrazide (msh:
CH3SO2NHNH2) and its hydrazone derivatives (Dodoff
et al., 1999) as well as their transition metal carbonyl
Experimental section
¨
complexes (Ozdemir et al., 2003; Sert et al., 2004; Ozd-
¨
¨
emir et al., 2004; Ozdemir et al., 2006). In this article, six
Physical measurements
aromatic/heteroaromatic sulfonylhydrazone derivatives;
indole-3-carboxaldehydemethanesulfonylhydrazone
indole-3-carboxaldehydeethanesulfonylhydrazone
(1),
(2),
Elemental analysis was performed according to standard
microanalytical procedures using LECO CHNS-932
model (TUBITAK Laboratories, Ankara). 1H–13C NMR
spectra of dimethylsulfoxide-d6 (DMSO-d6) solutions of
the compounds were registered on a Bruker WM-400
spectrometer (400 MHz) using tetramethylsilane as
internal standard. D2O-exchange was applied to confirm
the assignment of the NH- and OH-signals (compounds
4–6). The infrared spectra of the compounds as KBr-
disks were recorded in the range of 4000–400 cm-1 with
a Mattson 1000 FT-IR spectrometer. Melting points of
sulfonamide derivatives were determined with a Gal-
lenkamp melting point apparatus. The solvents used were
purified and distilled according to routine procedures.
2-Hydroxy-1-naphthaldehyde and indole-3-carboxalde-
hyde were recrystallized from aqueous ethanol. Meth-
anesulfonyl chloride, ethanesulfonyl chloride, hydrazine
hydrate, thiophene-2-carboxaldehyde, indole-3-carboxal-
dehyde, 2-hydroxybenz aldehyde, 2-hydroxyacetophe-
none, and 2-hydroxy-1-naphthaldehyde were commercial
products (purum).
´
¨
thiophene-2-carboxaldehydeethanesulfonylhydrazone (3),
2-hydroxy benzaldehydeethanesulfonyl hydrazone(4),
2-hydroxyacetophenoneethanesulfonylhydrazone (5), and
2-hydroxy-1-naphthaldehydeethane sulfonylhydrazone (6)
have been synthesized by the reaction of methane sulfonic
acid hydrazide (msh: CH3SO2NHNH2) and ethane sulfonic
acid hydrazide (esh: CH3CH2SO2NHNH2) with aromatic/
heteroaromatic aldehydes and characterized using ele-
1
mental analysis, H–13C NMR, LC–MS, and IR spectra.
The electrochemical behaviors of aromatic/heteroaro-
matic sulfonylhydrazones were evaluated by cyclic vol-
tammetry (CV), controlled potential electrolysis, and
chronoamperometry (CA) techniques in the presence of
0.10 M tetrabutylammonium tetrafluoroborate (TBATFB)
in dimethylsulfoxide (DMSO) at glassy carbon electrode.
The number of electrons transferred (n), and diffusion
coefficients (D) were determined using an ultramicro
electrode (UME). The standard heterogeneous rate con-
stants (ks) were calculated using Klingler–Kochi technique.
Electrochemical reduction mechanism of these aromatic/
heteroaromatic sulfonylhydrazones was also proposed that
sulfonylhydrazones follow electrochemical reduction (EC)
mechanism which follows semireversible electron transfer
steps.
Synthesis of the aromatic/heteroaromatic
sulfonylhydrazone derivatives
The procedure of preparation of sulfonylhydrazone deriv-
Antimicrobial activities of the compounds 1–6 have
been tested against Pseudomonas aeroginosa ATCC
29212, Bacillus cereus RSKK 863, Micrococcus luteus
NRLL B-4375, Staphylococcus aureus ATCC 259231,
Yersinia enterocolitica ATCC 1501 and Yeast Cell:
atives 1–6 is similar to that applied by us (Dodoff et al.,
¨
¨
1999; Ozdemir Ozmen and Olgun, 2008). Thus, solution of
1.10 g (10 mmol) methanesulfonic acid hydrazide or eth-
anesulfonic acid hydrazide in 5 ml of water was mixed
with hot solution of 12 mmol of the corresponding
123

Med Chem Res
Thiophene-2-carboxaldehydeethanesulfonylhydrazone (3)
carbonyl compound (thiophene-2-carboxyaldehyde, indole-
3-carboxaldehyde, 2-hydroxybenzaldehyde, 2-hydroxy-
acetophenone, and 2-hydroxy-1-naphthaldehyde, respec-
tively) in 10 ml of ethanol and stirred for 1 h. Upon
cooling, the obtained crystalline precipitates were filtered,
washed with ethanol-ether, recrystallized from water and
dried in vacuo over P2O5. They are colorless and light
yellow crystalline solids, stable at normal conditions and
soluble in methanol, ethanol, acetonitrile, dimethylform-
amide, DMSO and poorly soluble in benzene, water.
The general synthetic method described above afforded a
light yellow crystalline solid from mmol ethanesulfonic
acid hydrazide (10 mmol) and thiophene-2-carboxaldehyde
(12 mmol). The results were as follows: yield: 70 %; m.p.
110–112 °C; IR (KBr) = 3198 (s, mNH), 1611 (m, mC=N),
1329 (s, mas(SO2), 1157 (s, msymSO2), 709 (w, dNH), 515
(m, dSO2); 1H NMR (400 MHz, DMSO-d6); d = 11.15 (s,
1H, NH), 8.02 (s, 1H, N=CH-6), 7.47 (d, 1H, H-5), 7.29 (d,
1H, H-3), 6.97 (t, 1H, H-4), 3.00 (s, 2H, SO2CH2-7), 1.07
(s, 3H, CH3-8); 13C NMR (100.62 MHz, DMSO-d6);
d = 142.8 (N=CH, C-6), 139.0 (C, C-2), 131.5 (CH, C-3),
129.5 (CH, C-5), 128.5 (CH, C-4), 39.2 (SO2CH2, C-7), 8.6
(CH3, C-8); EIMS m/z 217.1 (45) [M]?; 121.8 (34)
[C2H5N2SO2]?; Anal. Calcd. for: C7H10N2S2O2
(218.2457 g/mol): calcd. C, 38.524; H, 4.623; N, 12.833;
S, 31.394; found: C, 38.075; H, 4.479; N, 12.875; S,
31.162.
Indole-3-carboxaldehydemethanesulfonylhydrazone (1)
The general synthetic method described above afforded a
yellowish needles solid from methanesulfonic acid hydra-
zide (10 mmol) and indole-3-carboxaldehyde (12 mmol).
The results were as follows: yield 60 %; m.p. 144–145 °C;
IR (KBr) = 3190 (s, mNH), 1628 (m, mC=N), 1317 (s,
mas(SO2), 1157 (s, msymSO2), 650 (w, dNH), 520 (m, dSO2);
1H NMR (400 MHz, DMSO-d6); d = 12.99 (s, 1H,
NH(ring)), 10.01 (s, 1H, NH), 8.36 (s, 1H, N=CH–10), 7.94
(s, 1H, H-2), 7.79 (d, 1H, H-5), 7.24 (d, 1H, H-8), 7.08 (t,
1H, H-7), 7.06 (t, 1H, H-6), 3.08 (s, 3H, CH3-11); 13C
NMR (100.62 MHz, DMSO-d6): d = 159.6 (HC=N,
C-10), 138.7 (CH, C-2), 133.4 (C, C-9), 132.6 (C, C-4),
120.5 (CH, C-7), 119.2 (CH, C-6), 119.1 (CH, C-5), 117.7
(C, C-3), 110.9 (CH, C-8), 46.7 (CH3, C-11); EIMS m/z 238.1
(36) [M]?, 107.1 (87) [CH3N2SO2]?; Anal. Calcd. for:
C10H11N3SO2 (237.1433 g/mol): calcd. C, 50.634; H,
4.644; N, 17.723; S, 13.498; found: C, 51.019; H, 4.864; N,
17.937; S, 13.822.
2-Hydroxybenzaldehydeethanesulfonylhydrazone (4)
The general synthetic method described above afforded a
colorless solid from ethanesulfonic acid hydrazide
(10 mmol) and 2-hydroxybenzaldehyde (12 mmol). The
results were as follows: yield: 60 %; m.p. 133–134 °C; IR
(KBr) = 3188 (s, mNH), 1625 (m, mC=N), 1320 (s,
mas(SO2), 1268 (s, mCO), 1142 (s, msymSO2) 643 (s, dNH),
528 (m, dSO2); 1H NMR (400 MHz, DMSO-d6);
d = 11.35 (s, 1H, OH), 10.23 (s, 1H, NH), 8.27 (s, 1H,
N=CH-7), 7.56 (d, 1H, H-6), 7.49 (t, 1H, H-4), 6.92 (t, 1H,
H-5), 6.88 (d, 1H, H-3), 3.22 (s, 2H, SO2 CH2–8), 1.22 (s,
3H, CH3-9); 13C-NMR (100.62 MHz, DMSO-d6):
d = 154.9 (CO, C-2), 149.7 (N=CH, C-7), 131.9 (C, C-1),
128.9 (CH, C-6), 120.2 (CH, C-5), 119.1 (CH, C-4), 117.3
(CH, C-3), 45.1 (SO2CH2, C-8), 8.0 (CH3, C-9); EIMS m/
z 229.0 (76) [M]?; 121.8 (34) [C2H5N2SO2]?; Anal. Calcd.
for: C9H12N2SO3 (228.1396 g/mol): calcd. C, 47.362; H,
5.263; N, 12.278; S, 14.030; found: C, 47.411; H, 5.453; N,
12.152; S, 13.943.
Indole-3-carboxaldehydeethanesulfonylhydrazone (2)
The general synthetic method described above afforded a
yellowish solid from ethanesulfonic acid hydrazide
(10 mmol) and indole-3-carboxaldehyde (12 mmol). The
results were as follows: yield: 55–65 %; m.p.
158–160 °C; IR (KBr) = 3191 (s, mNH), 1627 (m,
mC=N), 1320 (s, mas(SO2), 1157 (s, msymSO2), 707(w,
1
dNH), 527 (m, dSO2); H NMR (400 MHz, DMSO-d6);
2-Hydroxyacetophenoneethanesulfonyl-hydrazone (5)
d = 12.97 (s, 1H, NH(ring)), 11.22 (s, 1H, NH), 8.08 (s,
1H, N=CH-10), 7.62 (s, 1H, H-2), 7.49 (d, 1H, H-5), 7.23
(d, 1H, H-8), 6.96 (t, 1H, H-7), 6.94 (t, 1H, H-6), 3.13 (s,
2H, SO2CH2-11), 1.13 (s, 3H, CH3-12); 13C NMR (100.62
Mz, DMSO-d6): d = 159.8 (HC=N, C-10), 139.6 (CH,
C-2), 133.6 (C, C-9), 132.9 (C, C-4), 120.2 (CH, C-7),
119.8 (CH, C-6), 119.6 (CH, C-5), 118.1 (C, C-3), 111.3
(CH, C-8), 46.9 (SO2CH2, C-11), 9.1 (CH3, C-12); EIMS
m/z 252.0 (33) [M]?; 93.0 (100) [C2H5SO2]?; Anal.
Calcd. for: C11H13N3SO2 (251.1243 g/mol): calcd. C,
52.566; H, 5.215; N, 16.723; S 12.763 found: C, 52.314;
H, 5.390; N, 16.926; S, 12.473.
The general synthetic method described above afforded a
light yellow solid from ethanesulfonic acid hydrazide
(10 mmol) and 2-hydroxyacetophenone (12 mmol). The
results were as follows: yield: 55 %, m.p. 142–143 °C; IR
(KBr) = 3206 (s, mNH), 1642 (m, mC=N), 1339 (s,
mas(SO2), 1260 (s, mCO), 1160 (s, msymSO2), 650 (w, dNH),
525 (m, dSO2); 1H NMR (400 MHz, DMSO-d6);
d = 11.71 (s, 1H, OH), 10.60 (s, 1H, NH), 7.54 (d, 1H,
H-6), 7.47 (t, 1H, H-4), 6.92 (t, 1H, H-5), 6.89 (d, 1H, H-3),
3.24 (s, 2H, SO2 CH2-8), 2.32 (s, 3H, N=CCH3-7a), 1.27
123

Med Chem Res
(s, 3H, CH3-9); 13C NMR (100.62 MHz, DMSO-d6):
d = 158.7 (CO, C-2), 157.9 (N=CH, C-7), 131.9 (C, C-1),
129.7 (CH, C-6), 121.0 (CH, C-5), 119.7 (CH, C-4), 118.1
(CH, C-3), 45.6 (SO2CH2, C-8), 15.0 (N=CCH3-7a), 8.2
(CH3, C-9); EIMS m/z 243.0 (100) [M]?; Anal. Calcd. for:
C10H14N2SO3 (242.1267 g/mol): calcd. C, 49.583; H,
5.777; N, 11.571; S, 13.221; found: C, 49.413; H, 5.558; N,
11.907; S, 12.964.
Preparation of microbial cultures
Microorganisms were provided from the culture collection
of the Biotechnology Laboratory of the Science and Art
Faculty of Gazi University, Turkey. Pseudomonas aero-
ginosa ATCC 29212, Bacillus cereus RSKK 863, Micro-
coccus luteus NRLL B-4375, Staphylococcus aureus
ATCC 259231, Yersinia enterocolitica ATCC 1501, and
Yeast Cell: Candida albicans ATCC 10239 were used as
the test organisms in this study. Candida albicans was
inoculated into YPD Broth (Difco) and incubated at 30 °C
for 48 h. Bacterial strains were inoculated into Nutrient
Broth (Difco) and incubated at 30 0.1 °C for 24 h. In
order to test the antimicrobial effects of sulfonyl hydrazone
derivatives, 15 mL of Mueller–Hinton agar (Merck) for
bacteria, and YPD Agar (Merck) were placed in petri
dishes which were then inoculated with strains of bacteria
by taking 100 lL from cell culture media. In order to test
the antimicrobial effects, sulfonyl hydrazone derivatives
and 15 mL of YPD Agar (Merck) were placed in petri
dishes which were then inoculate temperature for a while,
and then holes were made on top with a sterile stick. It was
left to solidify at room entities stated above were then
added to these holes. Petri dishes were left at 4 °C for 2 h.
Then, bacterial cultures were incubated at 34 0.1 °C for
24 h, and yeast cultures were incubated at 30 0.1 °C for
72 h. And the end of incubation time, the inhibition zones
on the bacterial and yeast nutrient media were measured as
2-Hydroxy-1-naphthaldehydeethanesulfonylhydrazone (6)
The general synthetic method described above afforded a
colorless solid from ethanesulfonic acid hydrazide
(10 mmol) and 2-hydroxy-1-naphthaldehyde (12 mmol).
The results were as follows: yield: 55 %, m.p. 185–186 °C;
IR (KBr) = 3182 (s, mNH), 1625 (m, mC=N), 1329 (s,
mas(SO2), 1241 (s, mCO), 1151 (s, msymSO2), 673 (w, dNH),
537 (m, dSO2); 1H NMR (400 MHz, DMSO-d6);
d = 11.18 (s, 1H, OH), 11.15 (s, 1H, NH), 8.81 (s, 1H,
N=CH-11), 8.39 (s, 1H, H-10), 7.49 (d, 1H, H-5), 7.43 (t,
1H, H-6), 7.37 (d, 1H, H-8), 7.29 (t, 1H, H-7), 7.26 (s, 1H,
H-3), 3.15 (s, 2H, SO2CH2-12), 1.15 (s, 3H, CH3-13); 13C
NMR (100.62 Mz, DMSO): d = 159.4 (CO, C-2), 138.6
(N=CH, C-11), 134.3 (C, C-4), 130.0 (CH, C-10), 128.7
(CH, C-8), 128.2 (CH, C-6), 127.1 (CH, C-5), 123.8 (CH,
C-7), 118.4 (C, C-9), 118.0 (CH, C-3), 110.8 (C, C-1), 46.5
(SO2CH2, C-12), 8.6 (CH3, C-13); EIMS m/z 276.9 (17)
[M]?; 93.1 (100) [C2H5SO2]?; Anal. Calcd. for:
C13H14N2SO3 (278.3257 g/mol): calcd. C, 56.103; H,
5.033; N, 10.074; S, 11.507; found: C, 55.855; H, 4.950; N,
10.023; S, 11.388. The structure of the compounds is
exhibited in Fig. 1.
¨
¨
diameter zone, mm (Ozdemir et al., 2009; Ozdemir et al.,
2013). The control samples were only absorbed in DMSO.
The antimicrobial activity results are the average data of
three experiments.
Fig. 1 The structure of the
aromatic/heteroaromatic
sulfonylhydrazones (1–6)
O
5
8
10
3
H
3
4
C
H
N
N
S
O
6
4
9
6
O
S
2
H
C
H
N
N
O
2
R
5
7
1
S
8
1
N
H
7 CH2 CH3
11
(3)
(1) R = CH3
(2) R =11CH212CH3
6
O
S
R
10
8
5
O
1
H
9
H
H
1
5
C
7
N
N
O
7
6
N
N
S
O
C
11
2
13
12
2
CH2CH3
CH2 CH3
4
8
9
OH
4
OH
3
3
(4) R = H
(5) R =7aCH3
(6)
123

Med Chem Res
Fig. 2 Optimized geometries
(DFT/B3LYP/6-311G(d,p)) of
conformations
Electrochemical studies
The number of electrons transferred and diffusion
coefficients were determined using ultramicro electrode
CV technique of Baranski (Nora and de Souza 2005). And
also, the heterogeneous rate constants were calculated
according to Klingler–Kochi method (Alyar and Karacan
2009).
Voltametric measurements were carried out with IVIUM
Stat Electrochemical Analyzer. Glassy carbon electrode
(BAS MF-2012) and 11 lm-ultramicro carbon electrode
(BAS MF-2007) were used as a working electrode. The
electrodes were polished with 1, 0.3 and 0.05 lm alu¨mina
slurries made from dry Buehler alumina and ultra pure
water (18 MX cm) on polishing microcloth before each
use. A platinum wire was used as the auxiliary electrode
(BAS MW-1032). The reference electrode was a silver
wire in contact with 0.01 M AgNO3 in dimethylsulfoxide
(BAS MF-2052). All solutions were deaerated for 10 min.
with pure nitrogen. All the measurements were taken at
room temperature, 21 1 °C. For each measurements, the
background currents were automatically subtracted from
obtained currents.
Computational section
The DFT calculations were carried out using Becke’s
three-parameter hybrid functional (B3LYP) method (Kar-
¨
acan et al., 2012; Ozbek et al., 2012; Alyar et al., 2012a,
b). The geometry optimizations were performed for the
ground states of these compounds, and these ground states
were assumed to be a singlet state (Bajaj et al., 2005). All
the above-mentioned calculations for geometry optimiza-
tion (Fig. 2) and HOMO and LUMO shapes (Fig. 3) were
123

Med Chem Res
Fig. 3 HOMO and LUMO
shapes along with the
electrostatic potential maps of
the sulfonylhydrazones
carried out by GAUSSIAN 03 quantum chemistry pro-
gram-package (Rohrbaugh and Jurs 1987). The molecular
descriptors such as logP, dipole moment (DM), surface
area (SA), volume(V), refractivity (R), mass (M), hydration
enthalpy (DHhyd), binding energy (DEb), heat of formation
(DHf), and HOMO and LUMO energies were determined
by means of Hyperchem 8, PM3-based QSAR models to
determine the structure–activity relation.
123

Med Chem Res
The octanol–water partition coefficient (logP) has been
considered as descriptors of the hydrophobic effect. The
dipole moment can be used to qualitatively analyze the
trend in the hydrophobic values (logP). Surface area, vol-
ume, refractivity, and mass parameters depend on the size
of molecules and also, binding energy, heat of formation,
and hydration enthalpy are the thermodynamic parameters.
The frontier molecular orbitals, in particular, the highest
occupied molecular orbital (HOMO) and the lowest
unoccupied molecular orbital (LUMO) are very important
because they are related not only to the spectral properties,
but also to the activity of the compounds.
respectively. Shifting was explained by the existence of
intramolecular hydrogen bond between the hydroxyl group
and the imine nitrogen atom by the authors (Dodoff et al.,
1999).
In compound 1 and 2, NH(ring) protons are observed at
12.99 and 12.97 ppm; NH protons belong to sulfonic acid
hydrazide at 10.01 and 11.22 ppm; azomethine (HC=N)
protons at 8.36 and 8.08 ppm (H-10); indole ring protons at
7.94 and 7.62 ppm (H-2), 7.79 and 7.49 ppm (H-5), 7.24
and 7.23 ppm (H-8), 7.08 and 6.96 ppm (H-7), 7.06 and
6.94 ppm (H-6); CH3 and CH2 protons bonded to SO2 at
3.08 and 3.13 ppm (H-11); CH3 protons bonded to SO2CH2
¨
for compound 2 at 1.13 ppm (H-12) (Asiri, 2000; Ozbek
1
et al., 2007). H NMR spectra of compound 3 exhibit azo-
Results and discussion
methine (HC=N) protons at 8.02 ppm (H-6); thiophene ring
protons at 7.47 ppm (H-5), 7.29 ppm (H-3), and 6.97 ppm
(H-4) (Balaban et al., 2008); SO2CH2 protons at 3.00 ppm
(H-7) and CH3 protons bonded to CH2 at 1.07 ppm (H-8). In
this study, OH and NH signals of compounds 4–6 are
observed over 10.00 ppm as singlet at low-field area, and the
chemical shift values of OH protons are higher than NH
protons. For compound 4 and 5, OH protons of salicyl ring
are observed at 11.35 and 11.71 ppm; NH protons at 10.23
and 10.60 ppm. For compound 6, OH and NH signals
observed at 11.18 and 11.15 ppm are very close to each
other. Similar feature has been also observed for hydrazone
compounds of 2-hydroxy-1-naphthaldehyde (Dodoff et al.,
1999). Azomethine (HC=N) protons for compound 4 and 6
are observed at 8.27 ppm (H-7) and 8.81 (H-11) ppm as
singlet. In compound 4 and 5, aromatic protons are observed
at 7.56 and 7.54 ppm (H-6), 7.49 and 7.47 ppm (H-4), 6.92
and 6.92 ppm (H-5), 6.88 and 6.89 ppm (H-3); SO2CH2
protons at 3.22 and 3.24 ppm (H-8) and CH3 protons bonded
to CH2 at 1.22 and 1.27 ppm (H-9); acetyl (N=CCH3) pro-
tons for compound 5 at 2.32 ppm (H-7a). In compound 6,
naphtyl ring protons are observed at 8.39 ppm (H-10),
7.49 ppm (H-5), 7.43 ppm (H-6), 7.37 ppm (H-8), 7.29 ppm
(H-7), and 7.26 ppm (H-3); SO2CH2 protons at 3.15 ppm
(H-12) and CH3 protons at 1.15 ppm (H-13).
In 13C NMR spectra, azomethine (CH=N) carbon atoms
for compound 1–4, 6 are observed at 159.6 ppm (C-10),
159.8 ppm (C-10), 142.8 ppm (C-6), 149.7 ppm (C-7) and
138.6 ppm (C-11). Compound 4–6 have the highest
chemical shifts at 154.9 ppm, 158.7 ppm and 159.4 ppm
(C-2) belong to phenolic carbons. Compound 1 and 2 have
the indole carbons which have the highest chemical shifts
at 138.7 ppm and 139.6 ppm (C-2) and the lowest chemi-
cal shifts at 110.9 ppm and 111.3 ppm (C-8). And also, the
other carbons belong to indole ring are observed in these
ranges. In compound 3, the chemical shifts of the thiophene
ring are observed at 139.0 ppm (C-2), 131.5 ppm (C-3),
129.5 ppm (C-5) and 128.5 ppm (C-4). CH3 carbon bonded
to SO2 at 46.7 ppm (C-11) for compound 1; SO2CH2CH3
The structure of the aromatic/heteroaromatic sulfonylhydra-
zone derivatives (Fig. 1) named as indole-3-carbox-
aldehydemethane
sulfonylhydrazone
(1),
indole-3-
carboxaldehydeethanesulfonyl hydrazone (2), thiophene-2-
carboxaldehydeethanesulfonylhydrazone (3), 2-hydroxy-
benzaldehyde ethanesulfonylhydrazone (4), 2-hydro-
xyacetophenoneethanesulfonylhydrazone (5) and 2-hydroxy-
1-naphthaldehydeethanesulfonylhydrazone (6) have been
characterized using elemental analysis, H–13C NMR, LC–
1
MS and IR spectra. The electrochemical behavior and anti-
microbial activities of the sulfonylhydrazones were investi-
gated as mentioned below and correlated with functional
groups in the structure (SAR’s).
NMR spectra
The comparison of the spectra of the aldehyde (in com-
pound 1–4, 6) and ketone (in compound 5) derivatives
facilitate the distinguishing of the signals of the methyl
¨
protons from the CH3C=N (Ozdemir et al., 2006), CH3SO2
fragments and the HC=N protons (Dodoff et al., 1999). For
salicylaldimines and related compounds which regarded as
potentially tautomeric systems, phenol–imine and quinoid
form being possible much number of sulfonylhydrazones,
it has been shown that only phenol–imine structure is
registered at normal conditions. (Dodoff et al., 1999; Percy
and Thornton, 1972; Teyssie and Charette, 1963). In our
1
study, H-NMR spectra suggests that this is also the case
with sulfonylhydrazone derivatives (compounds 4–6).
Because, the signals of the HC=N protons show no split-
ting, and the position of the signals of the ring protons is
typical for aromatic, rather then for quinoid proton. The
assignment of the NH signals of compounds 1–6 and OH
signals of compounds 4–6 was confirmed by deutero-
exchange. It was reported that NH and OH signals of
several methane sulfonamide derivatives were observed in
the range of 9.40–11.10 and 11.00–11.68 ppm,
123

Med Chem Res
carbons at 46.9 ppm (C-11) and 9.1 ppm (C-12) for com-
pound 2; 39.2 ppm (C-7) and 8.6 ppm (C-8) for compound
3; 45.1 ppm (C-8) and 8.0 ppm (C-9) ppm for compound
4; 45.6 ppm (C-8) and 8.2 ppm (C-9) for compound 5;
46.5 ppm (C-12) and 8.6 ppm (C-13) ppm for compound
6. Acetyl carbon (N=CCH3) of compound 5 is observed at
15.0 ppm (C-7a) ppm.
potential electrolysis, and chronoamperometry (CA) tech-
niques. The cyclic voltametry (CV) of compound 1–6 in
DMSO containing 0.1 M TBATFB on glassy carbon elec-
trode at a scan rate of 0.01 V s-1(vs. Ag/Ag?) are exhibited
in Figs. 4 and 5. The reduction potentials (Epc) of the C=N,
OH, and SO2 groups are presented in Table 2. Epc values of the
sulfonylhydrazones are evaluated with molecular descriptors
for the structure–activity relationship (SAR) analysis.
The number of electrons transferred (n) during the
reduction of sulfonylhydrazones and their diffusion coef-
ficients (D) was determined using ultramicro electrode and
chronoamperometry. n and D values were calculated as
follows:
IR spectra
The assignment of the bands was made taking into consider-
ation the literature data for compounds containing appropriate
structural fragments; sulfonamides, sufonylhydrazines, and
sulfonylhydrazones, methanesulfonyl derivatives (Dodoff
et al., 1999; Percy and Thornton, 1972; Katritzky and Jones,
1960; Bacon et al., 1965). It should be noted the position and
shape of the OH-stretching bands in compounds 4–6. They
appear at quite low-wave numbers (2832–2633 cm-1) and are
split into several components. Similar feature has been
described for a number of Schiff bases derived from salicyl-
aldehyde and has been explained by the participation of the
hydroxyl group into hydrogen bond with the imine nitrogen
atom (Faniran et al., 1974; Lenco et al., 1999). In the infrared
spectra of synthesized compounds, the most characteristic
absorptions at 1611–1642 cm-1 are assigned to the stretching
vibration of the azomethine (–CH=N–) group, the absorptions
at 3182–3206 cm-1 are assigned to NH groups (Balaban
et al., 2003; Hamurcu et al., 2008). Compounds 4–6 also
display bands at 1241–1268 cm-1 which are assigned to m(C–
O) stretching vibrations of the phenolic-OH, respectively
(Vance et al., 1998). SO2 group has three vibration types as
nsS2isCs
S2s iC
DsS2s i2
D ¼
S2i2s
n ¼
where i is limiting steady-state current, S is the slope of the
of the chronoamperometric i vs. t-1/2 plot for hydrazone
compounds.
The limiting steady-state currents for sulfonylhydraz-
ones were determined using linear sweep voltammetry
method. The diffusion coefficient (D) is related with the
diffused amount of compounds to the electrode surface
(Table 3). The heterogeneous standard rate constants (ks)
are found from cyclic voltammogram at different scan
rates. In general, as the scan rate is increased, reduction
peak potential (Epc) and the peak width values (Ep/2) show a
change which affects the value of ks which is calculated
from the formulas below. ks values at 21 °C, which are
independent of v (Table 3) and they are the indicator of
¨
semireversible behavior (Demirel Ozel et al., 2009; Klin-
mas(SO2) observed at 1339–1317 cm-1
,
msym(SO2) at
.
gler and Kochi 1981).
1160–1142 cm-1 and d(SO2) at 537–515 cm-1
ꢀ
ꢁ
1=2
DbnFv
RT
RT
nFðEpc ꢁ Ec
Þ
ks ¼ 2:18
b ¼ 1:857
LC–MS spectra
p=2
The current function (ipc/v1/2C) values were plotted
against the scan rate (v) to apply the Nicholson–Shain
criteria. The current function decreases exponentially
toward the higher scan rates shows that the mechanism of
electron transfer is followed by EC type (Nicholson and
Shain 1964), and 2e- transferred reduction occurs in
–CH=N– group as shown in Fig. 6. Their action mecha-
nism can be useful for pharmacokinetic and pharmacody-
namic purposes in biological systems as drugs.
Fragmentation steps of all aromatic/heteroaromatic sul-
fonylhydrazones in LC–MS spectra are presented in
Table 1. Compounds 1–6 give the molecular ions, [M]? at
the desired positions: m/z (abudance %) = 238.1 (36),
252.0 (33), 217.1 (45), 229.0 (76), 243.0 (100), and 276.9
(17). The fragmentation steps of aromatic/heteroaromatic
sulfonylhydrazones are assigned as fragm. I belong to
removal of –SO2R group, fragm. II belong to removal of
=N–NH–SO2R, and fragm. III belong to removal of aro-
matic/heteroaromatic groups (R00–CR0=) as seen in Table 1
¨
(Ozdemir Ozmen et al., 2007).
¨
Antimicrobial activity
The antibacterial screening of the compound was evaluated
at the concentration of 400 lg/0.05 mL, and the inhibition
zones were measured in mm. The activity results of the
sulfonylhydrazones and positive controls (antibiotics and
antifungals) are exhibited in Table 4.
Electrochemical behavior
The electrochemical behavior of aromatic/heteroaromatic
sulfonylhydrazones in DMSO at glassy carbon electrode was
investigated using cyclic voltammetry (CV), controlled
123

Med Chem Res
Table 1 The fragments of compounds, m/z (abudance %)
Fragm. III
R'
C
H
R
N
N
SO2
R''
Fragm.I
Fragm.II
[M]+
Fragm. I
Fragm. II
Fragm. III
Compound
m/z (%)
m/z (%)
m/z (%)
m/z (%)
O
S
H
CH
O
O
H
C
N
N
O
H
-S
O
N
N
S O
CH3
N
H
1
N
H
CH3
CH3
CH3N2SO2
107.1 (87)
CH3SO2
79.2 (23)
C9H7N
128.1(7)
C10H11N3SO2
238.1(36)
O
H
CH
C
N
N
S
O
O
O
H
H
C2H5
-S
O
N
N
S O
N
H
N
H
2
C2H5
C2H5
C9H7N
C2H5N2SO2
121.1 (48)
C2H5SO2
93.0 (100)
C11H13N3SO2
252.0(33)
128.0(25)
O
O
O
H
H
H
-S
O
C
N
N
S O
N
N
S O
CH
S
C2H5
S
C2H5
C2H5
3
4
C5HS
97.0(14)
C2H5N2SO2
122.1 (25)
C7H10N2S2O2
217.1(45)
C2H5SO2
91.1 (15)
O
S
H
C
O
H
H
C
O
H
N
N
O
-S
O
N
N
S O
C2H5
OH
C2H5
C2H5
OH
C7H6O
106.1(11)
C2H5N2SO2
121.8 (34)
C2H5SO2
93.1 (30)
C9H12N2SO3
229.0 (76)
O
CH3
O
H
O
S
CH3
C
-S
O
N
N
S O
H
C
N
N
O
C2H5
C2H5
OH
C2H5
5
OH
C2H5N2SO2
121.1 (28)
C8H8O
121.0(29)
C10H14N2SO3
243.0 (100)
C2H5SO2
93.8 (12)
O
O
H
H
O
S
C=
H
H
-S
O
N
N
S O
C
N
N
O
C2H5
OH
C2H5
C2H5
6
OH
C13H14N2SO3
276.9 (17)
C11H8O
156.0(45)
C2H5N2SO2
121.9 (40)
C2H5SO2
93.1 (100)
123

Med Chem Res
screening including compound 6 shows that ligands have
less activity against fungi; Candida albicans. Besides, the
inhibition zones formed by standard antibiotics (Erythro-
mycin, Vancomycin and Tetracycline) against all bacteria
and antifungals (Oxiconazole and Isoconazole) against
˘
Candida albicans (Keskioglu et al., 2008; C¸ ete et al., 2006;
Katircioglu et al. 2006) are reported in Table 4.
Theoretical calculations
The geometry optimization was performed on B3LYP/6-
311G(d,p) methods with GAUSSIAN 03 software. And
also, the relations between some molecular descriptors and
antimicrobial activity, the selected parameters such as
logP, dipole moment (DM), surface area (SA), volume (V),
refractivity (R), mass (M), hydration enthalpy (DHhyd),
binding energy (DEb), heat of formation (DHf), and HOMO
and LUMO were calculated by Hyperchem 8, PM3-based
QSAR models to determine the structure–activity relation
Fig. 4 Cyclic voltammogram (CV) of compound 1–3 in DMSO
containing 0.1 M TBATFB on glassy carbon electrode at a scan rate
of 0.01 V s-1(vs. Ag/Ag?)
¨
(Alyar et al., 2011a, b; Ozbek et al., 2009) and tabulated in
Table 5.
2-Hydroxy-1-naphth aldehydeethanesulfonylhydrazone
(6) containing naphtyl group shows higher activity because
of the cation–pi interaction and aromatic pi-stacking
through the whole ring. The naphthalene having higher
electron density may encounter a cation or a positively
charged group on protein, receptor site bonds the aromatic
ring to make charge-transfer complex. The correlations
between molecular descriptors and antimicrobial activities
(SAR) show that compound 6 has the highest activity
against microorganisms, and its activity is effected with
some of the selected desctriptors. These descriptors indi-
cate that the presence of naphtyl ring having big size and
especially cation–pi interaction and aromatic pi-stacking
through the naphtyl ring may have importance on antimi-
crobial activity as mentioned by Aslan et al., 2012. And
also, electrostatic interactions, electrophilic reactivity
control the activity of the compounds. The molecular
descriptors suggest that the presence of naphtyl ring plays a
dominant role in the microbial activity on as compound 6.
The octanol–water partition coefficient (logP) has been
considered as descriptors of the hydrophobic effect. As
shown in Table 5, logP and size parameters related to
surface area, volume, refractivity, and molecular mass
increase with a decrease in activity of the compound 6. The
components of the frontier molecular orbitals as well as
dipole moment play an important role. The decrease in
dipole moment can be used to reasonably explain the rise
of the antimicrobial activity in compound 6. Binding
energy is a thermodynamic parameter and refers to the
chemical stability of the molecule. In our series, activity
increases especially in compound 6 with decreasing bind-
ing energy.
Fig. 5 Cyclic voltammogram (CV) of compound 4–6 in DMSO
containing 0.1 M TBATFB on glassy carbon electrode at a scan rate
of 0.01 V s-1(vs. Ag/Ag?)
The activity results showed that the sulfonylhydrazones
have poor activity against microorganism at studied con-
centration. However, compound 6 has enhanced activity
against all microorganism. Staphylococcus aureus is the
most influenced bacteria against compound 6 having the
diameter zones of 27 mm (Fig. 7). Reason of this phenom-
ena can be explained due to presence delocalization of p
electrons over the whole aromatic naphtyl ring and also its
activity may be arise from the hydroxyl group which may
play an important role in the antimicrobial activity. The
electronic delocalization supposed within the aromatic ring
system may increase the lipophilic character of the com-
pound 6, and the lipophilicity leads to breakdown of the
permeability barrier of the cell and this regards the normal
cell processes (Raman et al., 2001). By the way, the entrance
of the compounds into the cells increases, and thus, the
microorganisms are effected mostly. But, the fungicidal
123

Med Chem Res
Table 2 Reduction peak potentials (Epc) of sulfonylhydrazones at different scanning rates
Compound
Epc, V (0.01 V s-1
)
Epc, V (0.05 V s-1
)
Epc, V (0.1 V s-1
)
Epc, V (0.5 V s-1
)
Epc, V (1 V s-1
)
Epc, V (5 V s-1
)
1
2
3
-0.69
-0.70
-0.61
-2.54
-0.67
-1.47
-1.80
-2.49
-0.57
-2.42
-0.64
-1.28
-1.56
-2.18
-0.74
-0.72
-0.74
-2.55
-0.73
-1.51
-1.83
-2.57
-0.65
-2.45
-0.69
-1.29
-1.59
-2.24
-0.77
-0.75
-0.75
-2.57
-0.75
-1.52
-1.86
-2.61
-0.68
-2.46
-0.70
-1.30
-1.64
-2.27
-0.83
-0.80
-0.80
-2.64
-0.78
-1.59
-1.95
-2.72
-0.75
-2.48
-0.77
-1.38
-1.75
-2.39
-0.82
-0.81
-0.81
–
-0.85
-0.93
-0.85
–
4
-0.83
-1.62
-1.99
-2.84
-0.79
-2.51
-0.81
-1.42
-1.82
-2.47
-0.90
-1.69
–
-2.60
-0.87
–
5
6
-0.86
-1.49
-1.91
-2.54
Table 3 Electrochemical properties of sulfonylhydrazones
Compound
UME limiting steady-state
current (iss, A)
Cottrell slope (S)
of –CH=N– peak
Diffusion coefficients
(D, cm2 s-1)
Standard heterogeneous
rate constant ks (cm s-1
)
1
2
3
4
5
6
4.523 9 10-10
2.873 9 10-10
2.331 9 10-10
6.300 9 10-10
5.175 9 10-10
3.634 9 10-10
3.124 9 10-5
2.407 9 10-5
2.17 9 10-5
3.86 9 10-5
3.23 9 10-5
2.84 9 10-5
2.41 9 10-6
1.64 9 10-6
1.33 9 10-6
3.06 9 10-7
2.95 9 10-7
1.88 9 10-7
9.97 9 10-4
9.39 9 10-4
9.12 9 10-4
1.04 9 10-6
1.03 9 10-6
9.59 9 10-7
O
S
H
C
O
H
C
H
2e-
H
N
N
O
N
N
S O
C2H5
C2H5
OH
OH
Fig. 6 The reduction mechanism of –CH=N– group in compound 6
One of the most important descriptors is LUMO energy
which describes electrophilicity of the compound, and its
level has the importance because of the donor–acceptor
interactions. In general, molecules with low-LUMO energy
values accept the electrons more easily than the highers.
The lower LUMO energy in other words lower LUMO–
HOMO energy gap (DeLUMO–HOMO) affects the noncova-
lent binding affinities of the compounds to DNA as
receptor. The antimicrobial activity of the compound 6
increases with the lowest energy of LUMO and also,
DeLUMO–HOMO energy gap (Aslan et al., 2012).
that of other compounds and has no trendy with
activity, but the increasing potentials of OH and SO2
groups may be explained by the increasing activity of
¨
compound 6 (Ozbek et al., 2012). In particular, it can
be very interesting behavior to explain the SAR’s of
such similar series, because they have partial differ-
ences in their chemical structures, they contrarily have
a sharp difference in their activity as seen in compound
¨
6 (Karacan et al., 2012; Ozbek et al., 2012). The
structure–activity relationships (SAR’s) were applied to
offer a theoretical reference on the molecular designs of
¨
antimicrobial agent (Alyar et al., 2011a, b; Ozbek
Electrochemical study shows that reducing potentials
of imine (C=N) group of compound 6 is very close to
et al., 2012).
123

Med Chem Res
Table 4 Antimicrobial activities of compound 1–6 and positive controls as zone diameter (mm)
Compound
B. cereus
RSKK 863
S. aureus
ATCC 259231
M. luteus
NRLL, B-4375
P. aeroginosa
ATCC 29212
Y. enterecolitice
ATCC 1501
C. albicans
ATCC 10239
1
3
[2
[2
[2
[2
[2
27
17
8
[2
[2
[2
[2
[2
13
31
16
23
–
4
4
[2
[2
[2
[2
[2
10
5
2
3
5
3
[2
[2
[2
14
23
12
17
–
3
6
4
2
4
5
2
3
6
14
[2
[2
4
3
Erythromycina
Vancomycina
Tetracyclinea
Oxiconazoleb
Isoconazoleb
a
[2
[2
16
–
–
15
–
–
–
–
17
17
–
–
–
–
–
b
Standard antibiotic and standard antifungal ref. (Rohrbaugh and Jurs, 1987; Percy and Thornton, 1972; Teyssie and Charette, 1963)
Fig. 7 Antimicrobial activities of compound 6 against bacteria
Table 5 Calculated molecular descriptors for compound 1–6
3
V (A ) R
˚
Compound logP DM SA
(D)
M
DHhyd
B.E.
(kcal mol-1 (kcal mol-1) (eV)
DHf
HOMO LUMO DeLUMO–HOMO
2
(A )
3
(A ) (amu) (kcal mol-1
)
)
(eV)
(eV)
˚
˚
1
2
3
4
5
6
-1.22 4.87 394.37 675.71 66.22 237.28 -13.12
-0.88 5.28 422.72 733.19 70.97 251.30 -11.79
-0.44 4.26 393.59 617.27 56.97 218.29 -9.34
-0.07 5.28 403.12 661.25 61.28 228.27 -12.68
-0.07 5.05 403.12 661.25 61.28 228.27 -12.68
0.00 3.68 427.17 780.92 79.48 278.33 -13.03
-2,799.31
-2,689.88
-2,197.86
-2,689.88
-2,970.22
-3,463.81
7.23
-55.57
-2.69
-8.44
-0.61
-0.71
-0.95
-0.71
-0.55
-0.97
7.83
8.43
8.28
8.43
8.78
7.68
-9.14
-9.23
-9.14
-9.33
-8.64
-55.57
-60.82
-41.73
Conclusions
method. The electrochemical behaviors of aromatic/het-
eroaromatic sulfonylhydrazones were evaluated by means
of cyclic voltammetry (CV), controlled potential electrol-
ysis, and chronoamperometry (CA) techniques. Electro-
chemical reduction mechanism of compound 1–6 was also
proposed that sulfonylhydrazones follow EC mechanism
which follows semireversible electron transfer steps.
The molecular structure of the aromatic/heteroaromatic
sulfonylhydrazones was discussed in this article on the
basis of spectroscopic methods (1H and 13C NMR, FT-IR,
LC–MS) and optimized by DFT calculations carried out
using Becke’s three-parameter hybrid functional (B3LYP)
123

Med Chem Res
Baymak MS, Celik H, Lund H, Zuman P (2003) Contribution to
electroreduction of hydrazones. Electrochem Soc 12:94–96
C¸ ete S, Dis¸li A, Yıldırır Y, Yas¸ar A (2006) Synthesis and
antimicrobial effects of some phenylazopropanedinitriles and
Antibacterial activity and the structural relationships
(SAR’s) of the compounds showed that activity of the
compound 6 increases weakly to the increasing logP val-
ues, surface area (SA), volume (V), refractivity (R), and
molecular mass and reduction potential of OH, SO2 groups.
The reduction potential of C=N group, hydration enthalpy
(DHhyd), heat of formation (DHf), HOMO energy values
can not be correlated with the activity while dipole moment
(DM), binding energy (DEb), LUMO–HOMO energy gap
decrease with the increasing activity.
their derivatives. Asian J Chem 18:2061–2066
de Souza MVN (2005) Synthesis and biological activity of natural
thiazoles: an important class of heterocyclic compounds. J Sulfur
Chem 26:429–449
¨
˙
Demirel Ozel A, Durmus¸ Z, C¸ ukurovalı A, Yılmaz I, Kılıc¸ E (2009)
Electroreduction of some substituted hydrazones on platinum
electrode in dimethylformamide. Acta Chim Slovencia 56:797–806
¨
¨
Dodoff NI, Ozdemir U, Karacan N, Gorgieva M, Konstantinov SM,
Stefanova ME (1999) Schiff bases of methanesulfonylhydrazine.
Synthesis, spectroscopic characterization, conformational ana-
lysis and biological activity. Z Naturforsch 54:1553–1562
Faniran JA, Patel KS, Bailar JC (1974) Infrared spectra of N,N0-
bis(salicylidene)-1,1-(dimethyl)ethylenediamine and its metal
complexes. J Inorg Nucl Chem 36:1547–1551
Acknowledgments This research was supported by Gazi University
Research Found under Project No. 05/03-15. The authors thank
TUBITAK for allocation of time at the 1H–13C-NMR, LCMS, and
˙
elemental analyses.
Finlay GJ, Baguley BC, Snow K, Judd W (1990) Multiple patterns of
resistance of human leukemia cell sublines to amsacrine
analogues. Natl Cancer Inst 82:662–667
Hamurcu F, Balaban Gu¨ndu¨zalp A, C¸ ete S, Erk B (2008) The
synthesis, characterization and antimicrobial activity of N,N0-
bis(2-thiophenecarboxamido)-1,3-diaminopropane and N,N0-
bis(2-furancarboxamido)-1,3-diaminopropane and their Cu(II),
Zn(II), Co(III) complexes. Trans Met Chem 33:137–141
Jensen PB, Sorensen BS, Demant EJ, Sehested M, Jensen PS,
Vindelov L, Hansen HH (1990) Antagonistic effect of aclaru-
bicin on the cytotoxicity of etoposide and 40-(9-acridinylami-
no)methanesulfon-m-anisidide in human small cell lung cancer
cell lines and on topoisomerase II-mediated DNA cleavage.
Cancer Res 50:3311–3316
Karacan MS, Yakan C¸ , Yakan M, Karacan N, Zharmukhamedov SK,
Shitov A, Los DA, Klimov VV, Allakhverdiev SI (2012) Quanti-
tative structure–activity relationship analysis of perfluoroiso-
propyldinitrobenzene derivatives known as photosystem II electron
transfer inhibitors. Biochim Biophys Acta 1817:1229–1237
References
Aleksic M, Kapetanovic V, Zuman P (2004) Polarographic and Voltam-
metric Behavior of the Antibiotic Cefetamet; reduction of the
Methoxyimino group. Collect Czech Chem Commun 69:1429–1442
Alyar S, Karacan N (2009) Synthesis, characterization, antimicrobial
activity and structure–activity relationships of new aryldisulf-
onamides. J Enzyme Inhib Med Chem 24:986–992
¨
Alyar S, Karacan N, Ozbek N, Kuzukıran K (2011a) Quantitative
structure–activity relationships studies for prediction of antimi-
crobial activity of synthesized disulfonamide derivatives. Med
Chem Res 20:175–183
¨
Alyar S, Zengin H, Ozbek N, Karacan N (2011b) Synthesis,
characterization, spectroscopic properties, theoretical calculation
and antimicrobial activity of new aryldisulfonamides. J Mol
Struct 992:27–32
˘
Katircioglu H, Beyatlı Y, Aslim B, Yuksekdag Z, Atici Z (2006)
Screening for antimicrobial agent production of some microal-
gae in freshwater. Internet J Microbiol 2(2):1–9
Katritzky AR, Jones RA (1960) Infrared absorption of substituents in
aromatic systems. Part VI. Methanesulphonamides. J Chem Soc
4497–4499
¨
¨
Alyar H, Alyar S, Unal A, Ozbek N, S¸ahin E, Karacan N (2012a)
Synthesis, characterization and antimicrobial activity of m-tolu-
enesulfonamide, N,N0-1,2-ethanediylbis (mtsen) and [Cu(II)(phe-
nanthroline)2]mtsen complex. J Mol Struct 1028:116–125
¨
Alyar H, Unal A, Ozbek N, Aylar S, Karacan N (2012b) Conformational
˘
Keskioglu E, Balaban Gu¨ndu¨zalp A, C¸ ete S, Hamurcu F, Erk B
analysis, vibrational and NMR spectroscopic study of the methane-
sulfonamide-N,N’-1,2-ethanediylbis. Spectrochim Acta A 91:39–47
Asiri AM (2000) (Indol-3-yl)barbituric acid. Molecules 5:M183
(2008) Cr(III), Fe(III) and Co(III) complexes of tetradentate
(ONNO) Schiff base ligands: synthesis, characterization, prop-
erties and biological activity. Spectrochim Acta A 70:8634–8640
Klingler RJ, Kochi JK (1981) Electron-transfer kinetics from cyclic
voltammetry. Quantitative description of electrochemical revers-
ibility. J Phys Chem 85:1731–1741
¨
Aslan HG, Ozcan S, Karacan N (2012) The antibacterial activity of
some sulfonamides and sulfonyl hydrazones, and 2D-QSAR
study of a series of sulfonylhydrazones. Spectrochim Acta A
98:329–336
Lenco A, Mealli C, Paoli P, Dodoff N, Kantarcı Z, Karacan N (1999)
Structure and vibrational spectroscopy of methanesulfonic acid
hydrazide: an experimental and theoretical study. New J Chem
23:1253–1256
Bacon N, Boulton AJ, Brownlee RTC, Katritzky AR, Topsom RD
(1965) Infrared absorption of substituents in heterocyclic
systems. Amine–imine tautomerism by infrared spectroscopy.
J Chem Soc Part IX:5230–5233
Nicholson RS, Shain I (1964) Theory of stationary electrode polarog-
raphy: single scan and cyclic methods applied to reversible,
irreversible and kinetic systems. Anal Chem 36:706–723
Bajaj S, Sambi SS, Madan AK (2005) Prediction of anti-inflammatory
activity of N-arylanthranilic acids: computational approach using
refined Zagreb indices. Croat Chem Acta 78:165–174
Balaban A, Sekerci M, Erk B (2003) Synthesis, physico-chemical
characterization, and stability constants of metal complexes of
pyridine-2-carbaldehyde thiosemicarbazone. Synth React Inorg
Met-Org Chem 33:1775–1786
¨
˘
Ozbek N, Katırcıoglu H, Karacan N, Baykal T (2007) Synthesis,
characterization and antimicrobial activity of new aliphatic
sulfonamide. Bioorg Med Chem 15:5105–5109
¨
Ozbek N, Aylar S, Karacan N (2009) Experimental and theoretical studies
on methanesulfonic acid 1-methylhydrazide: antimicrobial activities
of its sulfonyl hydrazone derivatives. J Mol Struct 938:48–53
Ozbek N, Aylar S, Mamas¸ S, S¸ahin E, Karacan N (2012) Synthesis,
¨
Balaban A, C¸ olak N, Unver H, Erk B, Durlu TN, Zengin DM (2008)
Synthesis, spectroscopic studies and crystal structure of N,N0-
bis((thiophene-2-carboxamido)propyl)piperazine. J Chem Cryst
38:369–372
¨
crystal structure, antibacterial activities, and electrochemical
123

Med Chem Res
studies of new N,N0-polymethylene bis-sulfonamides. J Mol
Struct 1010:1–7
effects of new arylsulfonylhydrazone and their Ni(II), Co(II)
complexes. Spectrochim Acta A 75:121–126
¨
¨
¨
¨
¨ ¨
¨
Ozc¸elik S, Dinc¸er M, S¸ekerci M, Balaban A, Ozdemir U (2004) N-
Phenyl-N-(2-thienylmethylene)hydrazine. Acta Crystallogr Sect
E 60:1552–1553
Ozdemir OU, Akkaya N, Ozbek N (2013) New Ni(II), Pd(II), Pt(II)
complexes with aromatic methanesulfonylhydrazone based
ligands. Synthesis, spectroscopic characterization and in vitro
antibacterial evaluation. Inorg Chim Acta 400:13–19
¨
¨
¨
Ozdemir Ozmen U, Olgun G (2008) Synthesis, characterization and
antibacterial activity of new sulfonyl hydrazone derivatives and
their nickel(II) complexes. Spectrochim Acta A 70:641–645
Percy GC, Thornton DA (1972) N-aryl salicylaldimine complexes:
ınfrared and PMR spectra of the ligands and vibrational frequencies
of their metal(II) chelates. Inorg Nucl Chem 34:3357–3367
Raman N, Kulandaisamy A, Shunmugasundaram A, Jeyasubramanian
K (2001) Synthesis, spectral, redox and antimicrobial activities
of Schiff base complexes derived from 1-phenyl-2,3-dimethyl-4-
aminopyrazol-5-one and acetoacetanilide. Trans Met Chem
26:131–135
Rohrbaugh RH, Jurs PC (1987) Description of molecular shape
applied in studies of structure/activity and structure/property
relationships. Anal Chim Acta 199:99–109
Sert S, Senturk OS, Ozdemir U, Karacan N, Ugur F (2004) Synthesis
and characterization of the products reaction of metal carbon-
yls[M(CO)6 (M Cr, Mo, W), Re (CO)5Br, Mn(CO)3Cp] with
¨
¨
Ozdemir U, Sentu¨rk OS, Sert S, Karacan N, Ugur F (2003)
Photochemical reactions of metal carbonyls [M(CO)6 (M Cr,
Mo, W), Re(CO)5Br, Mn(CO)3Cp] with 2-hydroxyacetophe-
none methanesulfonylhydrazone (apmsh). Trans Met Chem
28:443–446
¨
¨
˘
Ozdemir U, Karacan N, S¸entu¨rk OS, Sert S, Ugur F (2004) Synthesis
and characterization of metal carbonyl complexes of
M(CO)(6)(M Cr, Mo, and W), Re(CO)(5)Br, and Mn(CO)(3)CP
with-acetone methanesulfonylhydrazone (amsh) and metha-
nesulfonylhydrazone (msh). Synth React Inorg Met-Org Chem
34:1057–1067
¨
¨
˘
Ozdemir U, S¸entu¨rk OS, Sert S, Karacan N, Ugur F (2006) Reaction
of metal carbonyls with 2-hydroxy-1-napthaldehyde metha-
nesulfonylhydrazone and characterization of the substitution
products. J Coord Chem 59:1905–1911
salicylaldehyde methanesulfonyl-hydrazone.
57:183–188
J Coord Chem
Teyssie P, Charette JJ (1963) Physico-chemical properties of co-
ordinatingcompounds-III: infra-redspectraof N-salicyclidenealkyl-
amines and their chelates. Spectrochim Acta A 19:1407–1423
Vance AL, Alcock NW, Heppert JA, Busch DH (1998) An octahedral
template based on a new molecular turn: synthesis and structure
of a model complex and a reactive, diphenolic ligand and its
metal complexes. Inorg Chem 37:6912–6920
¨
¨
Ozdemir U, Gu¨venc¸ P, S¸ahin E, Hamurcu F (2009) Synthesis,
characterization and antibacterial activity of new sulfonamide
derivatives and their nickel(II), cobalt(II) complexes. Inorg Chim
Acta 362:2613–2618
¨
¨
Ozdemir U, Arslan F, Hamurcu F (2010) Synthesis, characterization,
antibacterial activities and carbonic anhydrase enzyme inhibitor
123