Journal of Biomaterials and Nanobiotechnology, 2011, 2, 144-149
doi:10.4236/jbnb.2011.22018 Published Online April 2011 (http://www.scirp.org/journal/jbnb)
Synthesis, Structure Analysis and Antibacterial
Activity of New Potent Sulfonamide Derivatives
Abdulhakeem Alsughayer1, Abdel-Zaher A. Elassar2, Seham Mustafa1 , Fakhreia Al Sagheer2
1Pharmaceutical Science Department, College of Health Science, The Public Authority for Applied Education and Training, Adaili-
yah, Kuwait; 2Chemistry Department, Faculty of Science, Kuwait University, Kuwait City, Kuwait.
Received October 6th, 2010; revised January 9th, 2011; accepted January 10th, 2011.
ABSTRACT
Modification of sulfonamide drug using different principles of chemical reactions was investigated. These reactions
involve the condensa tion of an amino group with triethyl ortho formate and dimethylformamide d imethyl acetal. Ability
of sulfa to condense with active keto compounds, like ethyl pyruvate and piprazine carboxyaldehye was studied. Alkyla-
tion of sulfa with different chloro deriva tives was also reported. The structur e of the isolated compound was elucidated
and confirmed using elemen tal analysis and spectral data. The bioactivity of the obtain ed compounds was investigated
against different gram positive and g ram negative bacteria. The study reveals that most of the modified drugs show high
to moderate antiba c terial activity.
Keywords: Sulfonamide, Sulfa Drug, Gram Positive, Gram Negative Bacteria
1. Introduction
The demand for novel chemotherapeutic antibacterial
remains attractive in the field of medicinal chemistry.
The discovery of sulfonamides as antibacterial in the
early 30s was the beginning of the most fascinating era
of chemotherapeutic agents [1-4]. Since the introduction
of prontosil over 70 years ago, sulfa drugs have been
widely used to treat a broad spectrum of microbial dis-
eases [5]. However, due to the rapid emergence of sul-
fonamide resistance organisms and the development of
more potent drugs have limited their clinical use. The
sulfonamide group is considered as a pharmacophore
which is present in a number of biologically active
molecules, particularly in antimicrobial agents [6-10]. In
addition, numerous sulfonamide derivatives have been
reported as carbonic anhydrase inhibitors [11-15], anti-
cancer [16], and anti-inflammatory agents [17]. Some
organisms are resistant to all approved antibiotics and
can only be treated with experimental and potentially
toxic drugs. Therefore, there is an overwhelming need to
develop more effective antibacterial agents to treat infec-
tions caused by antibiotic resistant bacterial pathogens.
Sulfonamides exert their effect by targeting on dihy-
dropteroate synthase (DHPS) enzyme, which catalyzes
folic acid pathway in bacteria and some eukaryotic cells
[18] but is not present in human cells [19]. This is the
basis for the selective effect of sulfonamides on bacteria
and for their broad spectrum of antibacterial activity.
Since sulfanilamide first came into use, different deriva-
tives have appeared on the market. Chemically modified
sulfanilamide is prepared to achieve more effective anti-
bacterial activity, wider spectrum of microorganisms
affected, or more prolonged action. Because of their low
cost they are still used in many parts of the world. The
substances are still used to treat some urinary tract infec-
tions, leprosy, and in combination with other drugs, fun-
gal diseases such as toxoplasmosis. The pharmaceutical
industry has responded with new classes of drugs, thus a
great insight to search for potential pharmacologically
active sulfanilamide and its derivatives is still of inter-
esting.
This study deals with the synthesis of N-substituted
sulfonamide derivatives. The structure was established
and confirmed using elemental analysis and spectral data
e.g. IR, 1H NMR, 13C NMR and MS spectra. Biological
activity of the synthesized compounds against gram posi-
tive and gram negative bacteria has been investigated.
2. Materials and Methods
Sulfanilamide, triethyl orthoformate, ethyl pyruvate, 3-
chloro-2,4-pentanedione, dimethylformamide dimethy-
lacetal (DMFDMA), piprazinecarboxyaldehyde, chloro-

Synthesis, Structure Analysis and Antibacterial Activity of New Potent Sulfonamide Derivatives 145
acetonitrile and chloroacetone (aldrich, milwaukee, wi)
were used as received. All other chemicals were reagent
grade and were used without further purification.
2.1. Elemental Analysis and Physical
Measurements
All melting points are uncorrected. IR spectra were re-
corded in KBr with a IR spectrophotometer Shimadzu
408. 1H NMR and 13C NMR spectra were recorded on
Varian EM-390 MHz spectrometer using TMS as an in-
ternal reference with the chemical shifts expressed as δ ppm.
Mass spectra were measured on a Shimadzu GCMS-QP
1000 Ex mass spectrometer. Microanalytical data were
obtained from the ANALAB Unit at chemistry depart-
ment, Kuwait University.
2.2. Synthesis of N, N`-(4-sulfonamido) forma-
midine (2b); of N, N`-Bis (4-sulfonamido) for-
mamidine (3); Ethyl N-(4-benzenesulfonaMido)
-2-Iminopropanoate (4); 4-(Pipra- Zin-1-ylme-
thyleneamino) benzenesulfonamide (7); 4-(Cya-
nomethylamino) benzenesulfonamide (8); 4- (2-
Oxopropylamino) benzene-Sulfonamide (9);4-
(2,4-Dioxopentan-3-ylamino)benzenesulfonamide
(10)
To a solution of 1 (0.01 mol) in toluene (20 ml) and
DMF (10 ml) mixture, dimethyl formaminde dimethyl
acetal or triethyl orthoformate or ethyl pyruvate or pip-
razine carboxyaldehyde or chloroacetonitrile or 1-chloro-
2-propanone or 3-chloro-2,4-pentanedione (0.01 mol)
was added. The reaction mixture was heated under reflux
for 3 h. The solvent was evaporated under vacuum and
the solid product formed after cooling was collected by
filtration, washed by ether and crystallized from proper
solvent (cf. Table 1).
2.3. 4-(3,5-Dimethyl-1H-pyrazol-4-ylamino)
benzenesulfonamide (11)
To a solution of 10 (0.01 mol) in DMF (20 ml), hydrazine
hydrate (0.01 mol) was added. The reaction mixture was
heated under reflux for 3h. The solvent was evaporated
under vacuum and the yellow solid product so formed
after cooling was collected by filtration, washed by ether
and crystallized from ethanol. Compound 11 was col-
lected as pale brown crystal 66% yield (cf. Table 1).
2.4. Drug Susceptibility Test
The drugs were tested by disc-diffusion method. Diluted
bacterial cultures (100 mL) were spread on sterile Muel-
ler-Hinton agar plates, after which 8 mm diameter discs
(sterile blank) impregnated with drug for testing (10-100
mg) were placed on the plates. The plates were incubated
for 24 h at 37℃ under aerobic conditions and the diame-
ter of the inhibition zone around each disc was then
measured and recorded. If the drugs were found to be
active in the disc diffusion test (inhibition zone > 10 mm),
they were further evaluated for determining minimum
inhibitory concentration (MIC) values.
2.5. Minimum Inhibitory Concentration (MIC)
The drugs were screened for their antibacterial activity
against E. coli, P. aeruginosa, B. subtilis and S. aureus.
MIC was evaluated by turbidity method. A loop full of
bacteria was inoculated in 100 mL of nutrient broth at
37℃ for 20 h in a test-tube shaker at 150 rev min-1. The
test compounds were prepared by dissolving in a mini-
mal volume of DMSO and were serially diluted in Muel-
ler-Hinton broth at concentrations in the range of 1 - 100
mg/mL. The 24-h bacterial cultures were then transferred
into 10 mL of Muller-Hinton broth (control and test
compounds) and incubated at 37℃ for 24 h. The growth
of the bacteria was determined by measuring the turbid-
ity after 24 h. Thus, the MIC was generally read as the
smallest concentration of drug in the series that prevents
the development of visible growth of test organism. All
the experiments were done in triplicate.
2.6. Statistical Analysis
The MIC value and modified drug susceptibility test
were measured in triplicate. Statistical analysis of the
MIC value was performed using the unpaired Student’s
t-test. Differences were considered significant when P <
0.01.
3. Results and Discussion
3.1. Chemistry
Sulfanilamide 1 reacted with triethyl orthoformate to
give 4-(ethoxymethyleneamino) benzenesulfonamide 2a
or N,N`-bis (4-sulfonamido)formamidine 3 (cf. scheme
1). Compound 2a was ruled out based on accurate mass
m/z 354.04 which referred that the reaction took place
with 1:2 molar ratios and was in agreement with the mo-
lecular formula C13H14N4O4S2 (cf. Table 1). While in the
case of dimethyl formamide dimethyl acetal (DMFDMA)
N,N`-(4-sulfonamido)formamidine 2b was isolated. Fur-
ther reaction of 2b with 1 gives 3. The structure of com-
NH
2
SO
2
NH
2
N
SO
2
NH
2
XN
SO
2
NH
2
HN SO
2
NH
2
H
2
NSO
2
NH
2
(EtO)2CH
12a: X=OEt
b: X=NMe
2
3
OR DMFDMA
Scheme 1
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Synthesis, Structure Analysis and Antibacterial Activity of New Potent Sulfonamide Derivatives 146
pound 3 was established based on elemental analysis and
spectral data. The IR reveals the presence of amino
groups and NH at 3461, 3293 (assigned for -NH2), and
3203 cm–1 (assigned for NH). The stretching vibrations
assigned to the C-S linkage occur in 801 and 704 cm–1.
Two characteristic bands for sulfonamide absorb strongly
at 1295 and 1145 cm–1. In addition, 1H NMR reveals the
presence of imine proton at  6.74 ppm (cf. Table 2, 3).
Activity of amino group in sulfanilamide 1 towards ac-
tive ketone compound was investigated. Thus, com-
pound 1 reacted with ethyl pyruvate to give the conden-
sation product, ethyl N-(4-benzesulfonamido)-2-
iminopropanoate 4 or 5 (cf. scheme 2). The latter com-
pound 5 was ruled out based on the spectral data. Thus,
accurate mass assigned to compound 4 was found to be
m/z 270.07 in agreement with the molecular formula
C11H14N2O4S. 1H NMR reveals the presence of the ethyl
group as a triplet and a quartet at 1.71 and 4.21 ppm with
J value 6.8 Hz, respectively (cf. Table 3). Moreover, a
characteristic band for ester carbonyl in IR was observed
at 1738 cm–1. Sulfanilamide 1 reacted with piprazine
carboxyaldehyde 6 to give the condensation product,
4-(piprazin-1-ylmethyleneamino) benzenesulfonamide, 7
(cf. scheme 3). The structure of the reaction product was
believed to be formed through the addition of nucleo-
philic amino group to the electrophilic carbonyl carbon
followed by loss of water molecule to give the isolated
product 7. 1H NMR reveals the presence of aromatic
protons as dd at
 7.46, 7.43 ppm with J value 8.0 Hz and
imine protons at
 6.62 ppm. In addition, the methylene
protons of piprazine ring appeared at
 2.62 and 2.57
ppm. 13C NMR with 1H NMR are confirmed the presence
of -CH=N- carbon and proton at
 160.30 ppm and 6.62
ppm, respectively. Alkylation of sulfanilamide 1 with
chloroacetonitrile, chloroacetone and 2-chloro-2,4-pen-
tadione was created to yield N-alkyated derivatives 8-10,
respectively (cf. scheme 4). The ac-curate mass of the
alkylated products 8-10 was m/z 211.04, 228.05 and
270.07, respectively. Compound 10 reacted with hydra-
zine hydrate to afford the N-pyrazolylsulfanilamide de-
rivative 11. 1H NMR showed bands at  7.46, 7.40, 6.61
and 6.59 ppm for aromatic protons with J value 8.0 Hz.
The pyrazole-H appeared at
 7.30 ppm with J value 7.6
Hz other protons are shown in Table 2. Furthermore, 13C
NMR showed bands at
 151.94, 149.08, 135.35, 129.86,
127.90, 127.36 and 126.66 assigned for aromatic carbons
and pyrazole carbons. Two sp3 carbons were appeared at
 26.68 and 25.16 ppm.
Table 1. Data , accurate mass and elemen tal analysis of the prepared compounds.
Elemental analysis Calcd/found (%)
Compound No. Mp (˚C) Solvent (yield %)Accurate mass
C H N S
2b 159-160 DMF/EtOH 89%C9H13N3O2S 227.0747.56
47.76
5.77
5.88
18.49
18.29
14.11
14.27
3 273-274 DMF/EtOH 60%C9H14N4O4S2 354.0444.06
44.07
3.98
4.20
15.81
15.88
18.10
17.96
4 142-144 EtOH 73% C11H14N2O4S 270.0748.88
48.80
5.22
5.22
10.36
10.54
11.86
11.81
7 153-155 EtOH 60% C11H16N4O2S 268.1049.24
49.22
6.01
5.99
20.88
21.01
11.95
12.11
8 134-135 EtOH 78% C8H9N3O2S 211.04 45.49
45.51
4.29
4.31
19.89
19.88
15.18
15.21
9 182-185 EtOH 76% C9H12N2O3S 228.0547.35
47.34
5.30
5.30
12.27
12.31
14.05
13.97
10 >250 DMF/EtOH 71%C11H14N2O4S 270.0748.88
49.01
5.22
5.12
10.36
10.33
11.86
12.01
11 179-180 EtOH 75% C11H14N4O2S 266.0849.61
49.60
5.30
5.22
21.04
21.22
12.04
11.89
Table 2. IR of the prepared compounds.
Cpd No. IR (cm–1)
2b 3451, 3351(NH2); 1275, 1135 (-SO2NH2); 844, 689 (S-O)
3 3461,3293 (NH2); 3203 (NH); 1295, 1145 (-SO2NH2); 801, 704 (S-O)
4 3463, 3374 (NH2); 1738 (ester CO); 1629 (C=N); 1311, 1151 (-SO2NH2); 829, 722 (S-O)
7 3471, 3372 (NH2); 3252 (NH); 1632 (C=N);1312, 1145 (-SO2NH2); 827, 692 (S-O)
8 3477, 3382(NH2); 2200 (CN); 1310, 1150 (-SO2NH2); 825, 694 (S-O)
9 3477, 3382 (NH2); 3318 (NH); 1723 (CO); 1310, 1150 (-SO2NH2); 825, 741 (S-O)
10 3476, 3373, 3272 (NH2 & NH); 1698 (CO); 1295, 1145 (-SO2NH2); 801, 704 (S-O)
11 3473, 3374, 3265 (NH2, NH); 1318, 1148 (-SO2NH2); 840, 686 (S-O)

Synthesis, Structure Analysis and Antibacterial Activity of New Potent Sulfonamide Derivatives 147
Table 3. 1H NMR and 13C NMR of the prepared compounds.
Cpd No. 1H NMR  (ppm) 13C NMR  (ppm)
2b 11.40, 11.37 (br 2H, NH2, D2O-exchange)); 8.54-6.76 (dd,
4H,C6H4, J=8.8); 6.74 (s, 1H, CH=) 2.75, 2.74(s, 6H, 2Me).
162.35(imine carbon); 157.96, 141.71, 128.07, 127.27,
121.26, 121.13 (aromatic carbons)
3
11.38 (d, 1H, NH, D2O-exchange); 7.88, 7.77 (br, 4H, 2NH2,
D2O-exchange); 8.52-7.30(m, 8H, 2 C6H4); 6.74 (d, 1H,
-CH=N, J=7.6 Hz)
162.38 (imine carbon); 158.03, 155.75, 140.91, 140.85
(C and C4 in two benzene rings); 121.27, 121.34,
128.88, 128.78 (other aromatic-C).
4
9.00 (br, 2H, NH2, D2O-exchange ); 7.95-6.57(dd, 4H,C6H4,
J=8.8); 4.21(q, 2H, CH2, J=6.8Hz); 1.71 (t, 3H, Me, J=6.8
Hz)
163.45 (CO); 161.12 (imine carbon); 152.36, 138.42,
128.01, 123.29 (aromatic carbons); 61.24 (CH2); 15.62,
14.35 (2 Me).
7
8.00 (d, 2H, NH2); 7.46, 7.43 (dd, 4H, C6H4, J=8.4Hz); 6.62
(s, 1H, CH=); 5.72 (s, 1H, NH); 2.62, 2.57 (tt, 8H, 4CH2,
J=5.6Hz)
160.3 (imine carbon); 152.11, 131.01, 128.21, 112.64
(aromatic carbons); 5.32, 47.01 (piprazine carbons).
8
7.51, 7.49 (d, 2H, C6H4, J=8.0 Hz); 6.95 ( br, 1H, NH,
D2O-exchange); 6.65, 6.63 (d, 2H, Ar-H, J=8.0 Hz); 5.80 (br,
2H, NH2, D2O-exchange); 2.86 (s, 2H, CH2)
151.88, 132.70, 127.44, 112.53 (aromatic carbons);
129.90 (CN); 30.80 (CH2).
9
7.56 (d, 2H, C6H4 , J=8.4 Hz); 6.75 (d, 2H, C6H4 , J=8.8 Hz),
6.91 (br, 2H, NH2, D2O-exchange); 8.02 (br, 1H, NH,
D2O-exchange); 4.45 (s, 2H, CH2); 2.91(s, 3H, Me)
162.45 (CO); 152.67, 130.84, 127.86, 112.90 (aromatic
carbons); 35.49 (CH2); 30.35 (Me).
10
7.46 (d, 2H, C6H4 , J=8.4 Hz); 6.93 (br, 2H, NH2,
D2O-exchange); 6.60 (d, 2H, C6H4 , J=8.0 Hz); 5.83 (s, 1H,
NH, D2O-exchange); 3.42 (s, 1H, CH); 2.50 (s, 6H, 2Me)
169.00 (CO); 151.99, 130.00, 127.47, 112.46 (aromatic
carbons); 85.00 (CH); 25.50 (Me)
11
7.46, 7.40 (d, 2H, C6H4 , J=8 Hz); 7.30 (d, 1H, pyrazole-H,
J=7.6 Hz); 6.97 (br, 1H, NH, D2O-exchange); 6.61, 6.59 (d,
2H, C6H4 , J=8 Hz); 5.51 (br, 2H, NH2, D2O-exchange); 1.67
(s, 6H, 2Me)
151.94, 149.08, 135.35, 129.86, 127.90, 127.36, 126.66
(aromatic & pyrazole carbons); 26.68, 25.16 (2Me)
3.2. Antimicrobial Activity
Substitution on the sulfanilamide nitrogen is referred to
as N1-substitution and N4-substitution on the 4-amino
group as N-substitution. The therapeutically active de-
rivatives are usually N1-substitutes. The MIC values
(average of triplicates) of the sulfanilamide and sulfa-
nilamide derivatives are shown in Table 4 and Figures
1-5. It can be observed from Figures 1 and 2 that the
antimicrobial results of compound 2b has high effect on
S. Aureus and E. coli, while compound 9 and 4 have a
low effect. In the case of E. coli compound 8 showed
high effects as compared to compound 4 at low concen-
tration (10-40 mg mL-1). In contrast at high concentration
(70-100 mg) compound 4 showed greater effects than
compound 8. Similar behavior was observed in the case
of E. coli with compound (3 and 8) and (7 and 9). Severe
effect was observed by compound 9 toward P. Aerugi-
nosa and B. subtilis (cf. Figure 3 and 4). In general most
compounds showed better effect with increase its con-
centration. In contrast to this, for compounds 2b and 7 at
high concentration (more than 80 mg mL–1), the effect of
compound 2b was more than compound 7, while at low
concentration (less than 80 mg mL-1) compound 7
showed greater effect than compound 2b. Figure 5
represents the average zone of inhibition against sample
number.
It shows that the effect of compound 2a on microor-
ganism can be arranged as follows: E. coli > S. Aureus >
P. Aeruginosa > B. subtilis (from highest to lowest); in
the case of compound 3 the only observed effect is on E.
coli followed by S. Aureus. Compound 4 showed severe
NH
2
SO
2
NH
2
1
N
CH
3
CO
2
CH
2
CH
3
CH
3
COCO
2
Et
H
2
NO
2
S
H
N
O
H
2
NO
2
S
O
CH
3
5
4
Scheme 2
N
SO
2
NH
2
7
N
NH
NH
2
SO
2
NH
2
1
HNN CHO
6
Scheme 3
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148 Synthesis, Structure Analysis and Antibacterial Activity of New Potent Sulfonamide Derivatives
NHH
2
NO
2
S
NH
2
SO
2
NH
2
1
10
8
CH
2
CN
NHH
2
NO
2
S
9
CH
2
COCH
3
NHH
2
NO
2
S
COCH
3
COCH
3
ClCH
2
CN
ClCH
2
COCH
3
ClC(COCH
3
)
2
NHH
2
NO
2
S
N
NH
H
3
C
H
3
C
11
Scheme 4
E. Coli
Concentration (mg/ml)
020 40 60 80100120
Zone of inhibition ( mm)
5
10
15
20
25
30
35
40
1
2b
3
4
7
8
9
Cpd No.
Figure 1. Effect of concentration of sulfa derivatives on E.
Coli.
S.Aureus
Concentr at ion (mg/ml)
0 20406080100120
Zone of inhibition ( mm)
5
10
15
20
25
30
35
40
45
1
2b
3
4
7
8
9
Cpd No.
Figure 2. Effect of concentration of sulfa derivatives on S.
Aureus.
effect with S. Aureus followed by P. Aeruginosa,
B.subtilis and E. coli. Compound 7 showed a severe ef-
fect in the case of S. Aureus followed by E. Coli. Both P.
Aeruginosa and B. subtilis showed approximately the
same zone of inhibition. Compound 8 showed effect only
P. Aeruginosa
Concentration (mg/ml)
0 20406080100120
Zone of inhibition ( mm)
10
15
20
25
30
35
40
1
2b
4
7
9
Cpd No.
Figure 3. Effect of concentration of sulfa derivatives on P.
Aeruginosa.
Figure 4. Effect of concentration of sulfa derivatives on B.
Subtilis.
Figure 5. Zone of inhibition (mm) at different concentration
against sample number.
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Synthesis, Structure Analysis and Antibacterial Activity of New Potent Sulfonamide Derivatives 149
on E. coli and S. Aureus. Compound 9 showed a severe
effect on P. Aeruginosa and B. subtilis. A moderate ef-
fect on E. coli and low effect was observed on S. Aureus.
4. Acknowledgements
The authors would like to acknowledge the Public Au-
thority for Applied Education and Training for the provi-
sion of grant No. HS-07-01 and the authors would like
also to acknowledge Kuwait University for the general
facility projects grant Nos. GS 01/01 and GS 03/01.
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