Synthesis of novel sulfonamide analogs containing sulfamerazine/sulfaguanidine and their biological activities

Article abstract of DOI:10.3109/14756366.2015.1079183

Sulfamerazine and sulfaguanidine are clenched with p-nitrobenzoyl chloride and the products obtained are reduced to Na_xS in ethanol–water. Novel sulfonamides (6a–g and 9a–g) were synthesized by the reaction of these reduced products (4 and 8) w

Full text of DOI:10.3109/14756366.2015.1079183

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Synthesis of novel sulfonamide analogs containing
sulfamerazine/sulfaguanidine and their biological
activities
Burak Aday, Pınar Sola, Ferdağ Çolak & Muharrem Kaya
To cite this article: Burak Aday, Pınar Sola, Ferdağ Çolak & Muharrem Kaya (2015): Synthesis
of novel sulfonamide analogs containing sulfamerazine/sulfaguanidine and their biological
activities, Journal of Enzyme Inhibition and Medicinal Chemistry
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Date: 10 September 2015, At: 00:08

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ISSN: 1475-6366 (print), 1475-6374 (electronic)
J Enzyme Inhib Med Chem, Early Online: 1–6
2015 Taylor & Francis. DOI: 10.3109/14756366.2015.1079183
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RESEARCH ARTICLE
Synthesis of novel sulfonamide analogs containing sulfamerazine/
sulfaguanidine and their biological activities
1
1
2
Burak Aday , Pınar Sola , Ferdag C¸olak , and Muharrem Kaya
3
˘
1Chemistry Department, 2Biology Department, and 3Biochemistry Department, Faculty of Arts and Science, Dumlupınar University, Ku¨tahya, Turkey
Abstract
Keywords
Sulfamerazine and sulfaguanidine are clenched with p-nitrobenzoyl chloride and the products
obtained are reduced to NaxS in ethanol–water. Novel sulfonamides (6a–g and 9a–g) were
synthesized by the reaction of these reduced products (4 and 8) with various sulfonyl chlorides
(5a–g). The structures of these compounds were characterized using spectroscopic analysis (IR,
1H-NMR, 13C-NMR and HRMS) technique. Antimicrobial activity of sulfonamides (3, 4, 7, 8, 6a–g
and 9a–g) was evaluated by the agar diffusion method. These compounds showed
antimicrobial activity against tested microorganism strains (Gram-positive bacteria, clinic
isolate and yeast and mold). Compounds 9d, 9e, 9a, 6d and 6e showed particularly
antimicrobial activity against tested Gram-positive (Bacillus cereus and B. subtilis) and Gram-
negative (Enterobacter aerogenes) bacteria.
Antimicrobial activity, clinic isolates,
Legionella pneumophila, sulfaguanidine,
sulfamerazine, sulfonamide
History
Received 25 June 2015
Revised 30 July 2015
Accepted 30 July 2015
Published online 31 August 2015
Introduction
epidermidis, Pseudomonas aeruginosa, Candida albicans and
Saccharomyces cerevisiae. These compounds were active on both
Gram-positive (Bacillus subtilis, B. cereus, Staphylococcus
aureus and Staphylococcus epidermidis) and Gram-negative
(Shigella flexneri, Salmonella spp., Escherichia coli and
Pseudomonas aeruginosa) bacteria.
Sulfonamide compounds, included in ‘‘privileged structures’’ in
medical chemistry, indicate many advantageous pharmacokinetic
properties including metabolic resistance mechanisms1.
Sulfonamides have many advantages like being cheap and durable
besides being broad-spectrum, bacteriostatic action and easily
implementable medicines2. Sulfonamide compounds, which are
used both for human health and in veterinary applications, have
Materials and methods
been clinically used as: antimicrobial3, diuretic4, antiobesity5,6
anticancer7 and antiglaucoma8–14
,
Materials
.
Sulfamerazine is a sulfonamide drug that inhibits bacterial
synthesis of dihydrofolic acid by competing with para-amino
benzoic acid for binding to dihydropteroate synthesizes. Thus, this
molecule can be used to treat anti-bacterial, anti-bronchitis, anti-
prostatitis and urinary tract infections.
The chemicals used in the synthesis of sulfonamide derivatives
were obtained from Merck and Aldrich Chemical Company. All
chemicals and solvents used for the synthesis were of spectro-
scopic reagent grade. Melting points were measured on a Bibby
Scientific Stuart Digital, Advanced and SMP30. Fourier
Transform Infrared (FTIR) spectra were recorded on Bruker
Sulfaguanidine is an antimicrobial substance used to treat
intestinal infections. Moreover, it is also reported that sulfagua-
nidine prevents infections that cannot be determined by natural
1
Optics, ALPHA FT-IR spectrometer. The H-NMR with Bruker
DPX-300 and 13C-NMR spectra was obtained in DMSO-d6 as
solvents with tetramethylsilane as the internal reference. HRMS
spectra were detected on an Agilent Technologies 6530 Accurate-
Mass Q-TOF LC/MS at the advanced technology research center
of Dumlupinar University (ILTEM).
and clinical studies15,16
.
Structures of sulfonamide compounds containing newly
synthesized sulfamerazine/sulfaguanidine were analyzed using
spectroscopic analysis methods (IR, 1H-NMR, 13C-NMR and
HRMS, respectively).
These newly synthesized sulfonamide compounds (6a–g and
9a–g) were evaluated for their antimicrobial activity against
Shigella sonnei, Salmonella 21.3, Bacillus subtilis, B. cereus,
Staphylococcus aureus, Escherichia coli, Staphylococcus
General procedure for preparation of N-(4-(N-(4-methylpyrimi-
din-2-yl) sulfamoyl) phenyl)-4-nitrobenzamide compound (3)
Sulfamerazine [4-amino-N-(4-methylpyrimidin-2-yl)benzene sul-
fonamide; 2.164 g, 10.1 mmol], p-nitrobenzoyl chloride (1.856 g,
10 mmol), in dry 5 mL pyridine were stirred for 5 h at room
temperature. The completion of the reaction is monitored by
TLC. Then the solvent was removed in vacuous and washed
with H2O. The raw product was purified by recrystallization
from ethanol (75%).
Address for correspondence: Muharrem Kaya, Biochemistry Department,
Faculty of Arts and Science, Dumlupınar University, Evliya C¸ elebi
Campus, 43100 Ku¨tahya, Turkey. Tel: +90 274 2652051. Fax: +90 274
2652056. E-mail: muharrem.kaya@dpu.edu.tr

2
B. Aday et al.
J Enzyme Inhib Med Chem, Early Online: 1–6
General procedure for preparation of 4-amino-N-(4-(N-(4-
methylpyrimidin-2-yl) sulfamoyl) phenyl) benzamide
compound (4)
4-(4-Methylphenylsulfonamido)-N-(4-(N-(4-methylpyrimidin-2-yl)
sulfamoyl)phenyl) benzamide (6c). As gray crystals (0.204 g,
76%), m.p. 287–293 ꢀC (ethanol). IR (cm–1): 3358 w (–NH), 3042
w (Ar–H), 2927 w (–CH3), 1641 s (C ¼ O), 1605 s (C ¼ C), 1157 s
(SO2); 1H NMR (300 MHz, DMSO-d6) ꢀ (ppm): 2.32 (s, 6H,
–CH3), 6.90 (d, 1H, J ¼ 5.02 Hz, Ar–H), 7.21 (d, 2H, J ¼ 8.74 Hz,
Ar–H), 7.37 (d, 2H, J ¼ 8.08 Hz, Ar–H), 7.70–7.96 (m, 9H, Ar-H),
8.32 (d, 1H, J ¼ 5.08 Hz, Ar–H), 10.38 (s, 1H, –NH), 10.70 (s, 1H,
–NH), 11.30–11.70 (br, 1H, –NH); 13C NMR (75 MHz, DMSO-
d6) ꢀ (ppm): 21.42, 23.72, 118.55, 119.71, 127.23, 129.32, 129.67,
129.71, 130.31, 134.94, 136.89, 141.71, 143.53, 144.10, 157.03,
165.72; HRMS (QTOF-ESI): m/z [M ꢁ H]ꢁ calcd. for
C25H22N5O5S2: 536.1062; found [M ꢁ H]ꢁ: 536.1059.
The compounds (3) were dissolved in 10 ml ethanol. Then, this
solution of sodium poly-sulfur was added drop wise to a stirred
and warm solution of compound 3 (1 mmol) in 50 ml ethanol–
water. The progress of the reaction was monitored by TLC. Once
the reaction is completed, the mixture was cooled to room
temperature and solid filtered off and washed with H2O. The
sulfonamide product was purified and recrystallized from the
ethanol (80%).
4-Amino-N-(4-(N-(4-methylpyrimidin-2-yl)sulfamoyl)phenyl)ben-
zamide (4). As yellow crystals (1, 906 g, 74%), m.p. 248–251 ꢀC
(ethanol). IR (cmꢁ1): 3449 w (–NH), 3394 w (–NH2), 3036 w
4-(4-Bromophenylsulfonamido)-N-(4-(N-(4-methylpyrimidin-2-yl)
sulfamoyl)phenyl) benzamide (6 d). As white crystals (0.229 g,
76%), m.p. 288–289 ꢀC (ethanol). IR (cm–1): 3392 w (–NH), 3045
w (Ar–H), 2871 w (–CH3), 1654 s (C ¼ O), 1572 s (C ¼ C), 1156 s
(SO2); 1H NMR (300 MHz, DMSO-d6) ꢀ (ppm): 2.30 (s, 3H,
–CH3), 6.90 (d, 1H, J ¼ 5.14 Hz, Ar–H), 7.22 (d, 2H, J ¼ 8.68 Hz,
Ar–H), 7.73–7.96 (m, 10H, Ar–H), 8.32 (d, 1H, J ¼ 5.10 Hz,
Ar–H), 10.40 (s, 1H, –NH), 10.85 (s, 1H, –NH), 11.40–11.70 (br,
1H, –NH); 13C NMR (75 MHz, DMSO-d6) ꢀ (ppm): 23.71,
115.30, 119.02, 119.75, 127.61, 129.18, 129.33, 129.76, 130.17,
133.02, 135.00, 138.97, 141.22, 143.49, 157.02, 158.00, 165.68,
168.71; HRMS (QTOF-ESI): m/z [M ꢁ H]ꢁ calcd. for
C24H19BrN5O5S2: 600.0011; found [M ꢁ H]ꢁ: 600.0002.
1
(Ar–H), 1664 s (C ¼ O), 1531 s (C ¼ C), 1181 s (SO2); H NMR
(300 MHz, DMSO-d6) ꢀ (ppm): 2.30 (s, 3H, –CH3), 5.60–6.10 (br,
2H, –NH2), 6.60 (d, 2H, J ¼ 13.40 Hz, Ar–H), 6.90 (d, 1H,
J ¼ 5.13 Hz, Ar–H), 7.72 (d, 2H, J ¼ 8.66 Hz, Ar–H), 7.95 (s, 4H,
Ar–H), 8.33 (d, 1H, J ¼ 5.11 Hz, Ar–H), 10.10 (s, 1H, –NH),
11.40–11.80 (br, 1H, –NH); 13C NMR (75 MHz, DMSO-d6) ꢀ
(ppm): 23.74, 112.44, 113.02, 115.37, 119.43, 120.82, 129.25,
130.09, 134.11, 144.24, 152.98, 153.40, 157.08, 166.07; HRMS
(QTOF-ESI): m/z [M + H]ꢁ calcd. for C18H16N5O3S: 382.0974;
found [M ꢁ H]ꢁ : 382.0978.
General procedure for preparation of sulfonamide derivatives
(6a–g, 9a–g)
4-(4-Methoxyphenylsulfonamido)-N-(4-(N-(4-methylpyrimidin-2-yl)
sulfamoyl)phenyl) benzamide (6e). As white crystals (0.192 g,
69%), m.p. 260–262 ꢀC (ethanol). IR (cmꢁ1): 3391 w (–NH),
3042 w (Ar–H), 1666 s (C ¼ O), 1591 s (C ¼ C), 1155 s (SO2); 1H
NMR (300 MHz, DMSO-d6) ꢀ (ppm): 2.30 (s, 3H, –CH3), 3.80 (s,
3H, –OCH3), 6.91 (d, 1H, J ¼ 5.02 Hz, Ar–H), 7.09 (d, 2H,
J ¼ 8.98 Hz, Ar–H), 7.20 (d, 2H, J ¼ 19.80 Hz, Ar–H), 7.75–7.96
(m, 8H, Ar–H), 8.32 (d, 1H, J ¼ 5.05 Hz, Ar–H), 10.40 (s, 1H,
–NH), 10.65 (s, 1H, –NH), 11.40–11.60 (br, 1H, –NH); 13C NMR
(75 MHz, DMSO-d6) ꢀ (ppm): 23.72, 56.13, 115.00, 115.32,
118.48, 119.72, 129.31, 129.44, 129.59, 129.66, 131.30, 134.94,
141.82, 143.53, 157.03, 163.10, 165.72, 168.75; HRMS (QTOF-
ESI): m/z [M ꢁ H]ꢁ calcd. for C25H22N5O6S2: 552.1011; found
[M ꢁ H]ꢁ: 552.1002.
A mixture of the 4-amino-N-(4-(N-(4-methyl pyrimidin-2-yl)
sulfamoyl) phenyl) benzamide (0.5 mmol) and the sulphonyl
chlorides 5a–g (0.5 mmol) in dry pyridine (5 mL) was stirred for
5 h at room temperature. After the solvent was removed in
vacuum, the crude product was purified by recrystallization from
ethanol (30–86%).
4-(Ethylsulfonamido)-N-(4-(N-(4-methylpyrimidin-2-yl)sulfamoyl)
phenyl)benzamide (6a). As white crystals (0.071 g, 30%), m.p.
268–270 ꢀC (ethanol). IR (cmꢁ1): 3381 w (–NH), 3035 w (Ar–H),
2942 w (–CH3), 1669 s (C ¼ O), 1536 s (C ¼ C), 1146 s (SO2); 1H
NMR (300 MHz, DMSO-d6) ꢀ (ppm): 1.20 (t, 3H, J ¼ 7.31 Hz,
–CH3), 2.40 (s, 3H, –CH3), 3.20 (q, 2H, J ¼ 7.32 Hz, –CH2), 6.91
(d, 1H, J ¼ 5.14 Hz, Ar–H), 7.32 (d, 2H, J ¼ 8.78 Hz, Ar–H),
7.92–7.99 (m, 5H, Ar–H), 8.33 (d, 1H, J ¼ 5.11 Hz, Ar–H), 10.25
(s, 1H, –NH), 10.45 (s, 1H, –NH), 11.30–11.70 (br, 1H, –NH);
13C NMR (75 MHz, DMSO-d6) ꢀ (ppm): 8.48, 23.72, 46.06,
113.41, 115.31, 118.13, 119.45, 119.79, 129.26, 129.84, 130.08,
134.95, 142.42, 143.57, 157.03, 158.04, 165.77; HRMS (QTOF-
ESI): m/z [M + Na]+ calcd. for C20H21N5NaO5S2: 498.0882;
found [M ꢁ H]+ : 498.0888.
N-(4 -(N-(4-Methylpyrimidin-2-yl)sulfamoyl)phenyl)-4-(2,4,6-tri-
methylphenylsulfonamido) benzamide (6f). As white crystals
(0.162 g, 57%), m.p. 237–238 ꢀC (ethanol). IR (cm ꢁ 1): 3375 w
(–NH), 3030 w (Ar–H), 2932 w (–CH), 1662 s (C ¼ O), 1502 s
1
(C ¼ C), 1147 s (SO2); H NMR (300 MHz, DMSO-d6) ꢀ (ppm):
2.20 (s, 3H, –CH3), 2.30 (s, 3H, –CH3), 2.60 (s, 6H, –CH3), 6.89–
7.08 (m, 5H, Ar–H), 7.79–7.95 (m, 6H, Ar–H), 8.30 (d, 1H,
J ¼ 5.06 Hz, Ar–H), 10.35 (s, 1H, –NH), 10.75 (s, 1H, –NH),
11.40–11.70 (br, 1H, –NH); 13C NMR (75 MHz, DMSO-d6) ꢀ
(ppm): 20.83, 23.71, 36.24, 115.00, 115.32, 118.48, 119.72,
129.31, 129.44, 129.59, 129.66, 131.30, 134.94, 141.82, 143.53,
157.03, 163.10, 165.72, 168.75; HRMS (QTOF-ESI): m/z [M –
H]ꢁ calcd. for C27H26N5O5S2: 564.1375; found [M ꢁ H]ꢁ:
564.1387.
N-(4-(N-(4-Methylpyrimidin-2-yl)sulfamoyl)phenyl)-4-(phenylsul-
fonamido)benzamide (6b). As white crystals (0.192 g, 73%),
m.p. 287–288 ꢀC (ethanol). IR (cmꢁ1): 3395 w (–NH), 3046 w
(Ar–H), 2980 w (–CH3), 1606 s (C ¼ O), 1504 s (C ¼ C), 1156 s
(SO2); 1H NMR (300 MHz, DMSO-d6) ꢀ (ppm): 2.25 (s, 3H,
–CH3), 6.90 (d, 1H, J ¼ 5.07 Hz, Ar–H), 7.23 (d, 2H, J ¼ 8.67 Hz,
Ar–H), 7.54–7.66 (m, 3H, Ar–H), 7.80–7.96 (m, 8H, Ar–H), 8.31
(d, 1H, J ¼ 5.09 Hz, Ar–H), 10.40 (s, 1H, –NH), 10.80 (s, 1H, N-(4-(N-(4-Methylpyrimidin-2-yl)sulfamoyl)phenyl)-4-(naphtha-
–NH), 11.40–11.70 (br, 1H, –NH); 13C NMR (75 MHz, DMSO- lene-2-sulfonamido) benzamide (6 g). As white crystals
d6) ꢀ (ppm): 23.71, 115.30, 118.70, 119.73, 126.42, 127.15, (0.246 g, 86%), m.p. 224–228 ꢀC (ethanol). IR (cmꢁ1): 3390 w
129.31, 129.69, 129.84, 129.90, 133.68, 134.96, 139.73, 141.57, (–NH), 3044 w (Ar–H), 1666 s (C ¼ O), 1591 s (C ¼ C), 1130 s
143.50, 157.01, 157.93, 165.72; HRMS (QTOF-ESI): m/z (SO2); 1H NMR (300 MHz, DMSO-d6) ꢀ (ppm): 2.30 (s, 3H,
[M ꢁ H]ꢁ calcd. for C24H20N5O5S2: 522.0906; found [M ꢁ H]ꢁ: –CH3), 6.89 (d, 1H, J ¼ 5.12 Hz, Ar–H), 7.26 (d, 2H, J ¼ 8.77 Hz,
522.0914.
Ar–H), 7.55–8.01 (m, 11H, Ar–H), 8.13–8.20 (m, 2H, Ar–H),

DOI: 10.3109/14756366.2015.1079183
Synthesis of sulfonamide analogs contain sulfamerazine/sulfaguanidine
3
8.30 (d, 1H, J ¼ 5.10 Hz, Ar–H), 8.55 (s, 1H, Ar–H), 10.35 (s, 1H, 81%), m.p. 262–265 ꢀC (ethanol). IR (cmꢁ1): 3411 w (–NH),
–NH), 10.90 (s, 1H, –NH), 11.30–11.70 (br, 1H, –NH); 13C NMR 3374 and 3325 w (–NH2), 1651 s (C ¼ O), 1590 s (C ¼ C), 1247
1
(75 MHz, DMSO-d6) ꢀ (ppm): 23.70, 115.29, 118.64, 119.70, and 1149 s (SO2); H NMR (300 MHz, DMSO-d6) ꢀ (ppm): 3.80
122.32, 128.27, 128.30, 128.74, 129.31, 129.63, 129.69, 129.76, (s, 3H, –CH3), 6.50–6.90 (br, 4H, 2 ꢂ –NH2), 7.08 (d, 2H,
119.82, 129.90, 130.17, 131.98, 134.80, 134.94, 136.66, 141.55, J ¼ 9.88 Hz, Ar–H), 7.21 (d, 2H, J ¼ 8.70 Hz, Ar–H), 7.69–7.84
143.50, 157.02, 165.69, 168.66; HRMS (QTOF-ESI): m/z (m, 8H, Ar–H), 10.30 (s, 1H, –NH), 10.70 (s, 1H, –NH); 13C
[M ꢁ H]ꢁ calcd. for C28H22N5O5S2: 572.1062; found [M ꢁ H]ꢁ: NMR (75 MHz, DMSO-d6) ꢀ (ppm): 56.13, 115.00, 118.53,
572.1073.
119.99, 126.85, 129.45, 129.60, 129.76, 131.30, 139.55, 141.72,
142.09, 158.52, 163.09, 165.58; HRMS (QTOF-ESI): m/z
[M ꢁ H]ꢁ calcd. for C21H20N5O6S2: 502.0855; found [M ꢁ H]ꢁ:
502.0855.
N-(4-(N-(Diamino methylene)sulfamoyl)phenyl)-4-(ethylsulfona-
mido)benzamide (9a). As black crystals (0.112 g, 72%), m.p.
233–235 ꢀC (ethanol). IR (cmꢁ1): 3427 w (–NH), 3352 w (–NH2),
3193 w (Ar–H), 1654 s (C ¼ O), 1606 s (C ¼ C), 1136 s (SO2); 1H
NMR (300 MHz, DMSO-d6) ꢀ (ppm): 1.20 (t, 3H, J ¼ 7.33 Hz,
–CH3), 3.19 (q, 2H, J ¼ 7.32 Hz, –CH2), 6.70–6.90 (br, 4H, 2 ꢂ –
NH2), 7.33 (d, 2H, J ¼ 8.74 Hz, Ar–H), 7.74 (d, 2H, J ¼ 8.78 Hz,
Ar–H), 7.91 (d, 2H, J ¼ 8.77 Hz, Ar–H), 7.99 (d, 2H, J ¼ 8.68 Hz,
Ar–H), 10.30 (s, 1H, –NH), 10.50 (s, 1H, –NH); 13C NMR
(75 MHz, DMSO-d6) ꢀ (ppm): 8.47, 46.06, 118.15, 120.13,
126.79, 129.33, 129.87, 139.47, 142.24, 142.39, 158.69, 165.59;
HRMS (QTOF-ESI): m/z [M ꢁ H]ꢁ calcd. for C16H18N5O5S2:
424.0749; found [M ꢁ H]ꢁ: 424.0751.
N-(4-(N-(Diaminomethylene)sulfamoyl)phenyl)-4-(2,4,6-trimethyl
phenylsulfonamido) benzamide (9f). As white crystals (0.251 g,
81%), m.p. 270–271 ꢀC (ethanol). IR (cmꢁ1): 3355 w (–NH2),
3185 w (Ar–H), 2964 w (C–H), 1679 s (C ¼ O), 1542 s (C ¼ C),
1267 and 1149 s (SO2); 1H NMR (300 MHz, DMSO-d6) ꢀ (ppm):
1.22 (s, 3H, –CH3), 2.65 (s, 6H, –CH3), 6.50–6.80 (br, 4H, 2 ꢂ –
NH2), 7.04–7.09 (m, 4H, Ar–H), 7.70 (d, 2H, J ¼ 8.83 Hz, Ar–H),
7.82 (dxd, 4H, J1 ¼ 2.86 Hz, J2 ¼ 11.59 Hz, Ar–H), 10.30 (s, 1H,
–NH), 10.70 (s, 1H, –NH); 13C NMR (75 MHz, DMSO-d6) ꢀ
(ppm): 20.83, 22.85, 117.33, 119.91, 126.85, 129.22, 129.65,
132.39, 133.93, 139.20, 139.50, 141.60, 142.12, 142.90, 158.51,
165.54; HRMS (QTOF-ESI): m/z [M ꢁ H]ꢁ calcd. for
C23H24N5O5S2: 514.1219; found [M ꢁ H]ꢁ: 514.1214.
N-(4-(N-(Diamino methylene)sulfamoyl)phenyl)-4-(phenyl sulfo-
namido)benzamide (9b). As white crystals (0.2318 g, 81%), m.p.
250–252 ꢀC (ethanol). IR (cmꢁ1): 3423 w (–NH), 3339 w (–NH2),
3110 w (Ar–H), 2905 w (C–H), 1650 s (C ¼ O), 1529 s (C ¼ C),
1152 s (SO2); 1H NMR (300 MHz, DMSO-d6) ꢀ (ppm): 6.50–6.80
(br, 4H, 2 ꢂ –NH2), 7.23 (d, 2H, J ¼ 8.73 Hz, Ar–H), 7.55–7.67
(m, 3H, Ar–H), 7.70 (d, 2H, J ¼ 8.80 Hz, Ar–H), 7.81–7.86 (m,
6H, Ar–H), 10.30 (s, 1H, –NH), 10.80 (s, 1H, –NH); 13C NMR
(75 MHz, DMSO-d6) ꢀ (ppm): 118.74, 119.97, 126.84, 127.16,
129.63, 129.90, 130.01, 133.67, 139.56, 139.74, 141.46, 142.06,
158.50, 165.55; HRMS (QTOF-ESI): m/z [M ꢁ H]ꢁ calcd. for
C20H18N5O5S2: 472.0749; found [M ꢁ H]ꢁ: 472.0753.
N-(4-(N-(Diaminomethylene)sulfamoyl)phenyl)-4-(naphthalene-
2-sulfonamido)benzamide (9 g). As brown crystals (0.260 g,
82%), m.p. 290–292 ꢀC (ethanol). IR (cm ꢁ 1): 3419 w (–NH),
3336 w (–NH2), 1653 s (C ¼ O), 1589 s (C ¼ C), 1259 and 1154 s
1
(SO2); H NMR (300 MHz, DMSO-d6) ꢀ (ppm): 6.50–6.90 (br,
4H, 2 ꢂ –NH2), 7.28 (d, 2H, J ¼ 8.74 Hz, Ar–H), 7.64–7.74 (m,
4H, Ar–H), 7.79–7.85 (m, 5H, Ar–H), 8.01 (d, 1H, J ¼ 7.51 Hz,
Ar–H), 8.10–8.24 (m, 2H, Ar–H), 8.57 (d, 1H, J ¼ 1.35 Hz, Ar–
H), 10.29 (s, 1H, –NH), 10.90 (s, 1H, –NH); 13C NMR (75 MHz,
DMSO-d6) ꢀ (ppm): 117.95, 118.96, 119.97, 120.31, 122.33,
123.20, 126.85, 127.21, 128.74, 129.76, 129.98, 130.16, 131.98,
134.80, 136.67, 139.93, 141.45, 142.08, 158.50, 165.55; HRMS
(QTOF-ESI): m/z [M ꢁ H]ꢁ calcd. for C24H20N5O5S2: 522.0906;
found [M ꢁ H]ꢁ: 522.0910.
N-(4-(N-(Diaminomethylene)sulfamoyl)phenyl)-4-(4-methylphe-
nylsulfonamido)benzamide (9c). As white crystals (0.235 g,
80%), m.p. 280–282 ꢀC (ethanol). IR (cm–1): 3511 w (–NH),
3436 and 3343 w (–NH2), 1653 s (C ¼ O), 1588 s (C ¼ C), 1293
1
and 1154 s (SO2); H NMR (300 MHz, DMSO-d6) ꢀ (ppm): 2.30
(s, 3H, –CH3), 6.40–6.70 (br, 4H, 2 ꢂ –NH2), 7.22 (d, 2H,
J ¼ 8.68 Hz, Ar–H), 7.37 (d, 2H, J ¼ 8.26 Hz, Ar–H), 7.69–7.74
(m, 4H, Ar–H), 7.83 (dxd, 4H, J1 ¼ 1.68 Hz, J2 ¼ 10.47 Hz, Ar–
H), 10.30 (s, 1H, –NH), 10.70 (s, 1H, –NH); 13C NMR (75 MHz,
DMSO-d6) ꢀ (ppm): 21.42, 118.60, 119.99, 126.85, 127.23,
129.61, 129.86, 130.30, 136.88, 139.54, 141.61, 142.08, 144.10,
158.51, 165.58; HRMS (QTOF-ESI): m/z [M ꢁ H]ꢁ calcd. for
C21H20N5O5S2: 486.0906; found [M ꢁ H]ꢁ: 486.0907.
Antimicrobial activity test
The synthesized sulfonamide compounds were tested for their
antimicrobial (antibacterial and antifungal) activities by disc-
diffusion method17,18. A total of 22 microbial species including
16 bacteria, 4 yeasts and 2 molds were used as test organisms in
this study. Seven of these microorganisms are clinical isolated
bacteria. Legionella pneumophila, being one of these bacteria,
was isolated from environmental (water).
To detect antimicrobial activity agar diffusion test with
standard test organisms were performed using Staphylococcus
aureus ATCC 25923, Bacillus cereus ATCC 7064, Bacillus
pumilus, Staphylococcus epidermidis ATCC 12228, Enterococcus
fecalis ATCC 29112, B. subtilis NRRL B-200, Methicillin-
resistant Staphylococcus aureus (MRSA) and Staphylococcus spp.
(clinic isolates) and Gram-negative (Escherichia coli ATCC
25922, Enterobacter aerogenes ATCC 13048, Aeromonas hydro-
philia NRRL 406); Vancomycin-resistant enterococci (VRE),
Moraxella catarrhalis, Salmonella spp. S. flexneri (clinic iso-
lates), Legionella pneumohila (isolated in our lab.) environmental
isolate, five yeasts Candida albicans (ATCC 10231), Rhodotorula
rubra DSM 70403, Saccharomyces cerevisa (wild), S. boulardii
(wild) and C. tropicalis (clinic isolate) and two mold species
4-(4-Bromophenylsulfonamido)-N-(4-(N-(diaminomethylene)sul-
famoyl)phenyl)benzamide (9 d). As white crystals (0.252 g,
83%), m.p. 268–270 ꢀC (ethanol). IR (cm ꢁ 1): 3462 w (–NH),
3361 and 3339 w (–NH2), 3102 w (Ar–H), 2906 w (C–H), 1645 s
(C ¼ O), 1590 s (C ¼ C), 1303 and 1151 s (SO2); 1H NMR
(300 MHz, DMSO-d6) ꢀ (ppm): 6.50–6.80 (br, 4H, 2 ꢂ –NH2),
7.23 (d, 2H, J ¼ 8.75 Hz, Ar–H), 7.70–7.87 (m, 10H, Ar–H),
10.35 (s, 1H, –NH), 10.85 (s, 1H, –NH); 13C NMR (75 MHz,
DMSO-d6) ꢀ (ppm): 118.57, 119.50, 126.35, 127.11, 128.68,
129.20, 129.83, 132.53, 138.47, 139.09, 140.62, 141.55, 158.01,
165.02; HRMS (QTOF-ESI): m/z [M ꢁ H]ꢁ calcd. for
C20H17BrN5O5S2: 549.9854; found [M ꢁ H]ꢁ: 549.9856.
N-(4-(N-(Diaminomethylene)sulfamoyl)phenyl)-4-(4-methoxyphe- (Aspergillus niger ATCC 10949 and A. fumigatus NRRL 163). In
nylsulfonamido)benzamide (9e). As white crystals (0.270 g, the disc-diffusion method, steril paper disc (Ø 6 mm) impregnated

4
B. Aday et al.
J Enzyme Inhib Med Chem, Early Online: 1–6
with 10 mL of the test compounds (dissolved DMSO compound at pneumophila strain was isolated from water. The strain was
concentrations of 100 mg) was used. Test bacteria were transferred stored at ꢁ70 ꢀC in sterile skimmed milk until use. Subculture of
to tubes containing 4–5 mL of Nutrient Broth. The test cultures frozen bacteria was grown on Buffered Charcoal Yeast Extract
were incubated at 37 ꢀC until they were visibly turbid. The density agar (BCYE). The density of this culture was adjusted to 0.5 Mc
of these cultures was adjusted to 0.5 Mc Farland (at 625 nm, 0.08– Farland (at 625 nm, 0.08–0.1 absorbance) with sterile saline. This
0.1 absorbance) with sterile saline. A suspension containing suspension contains approximately 108 CFU/ml for bacteria.
approximately 108 CFU/ml for bacteria, 107 CFU/mL for yeasts Then, the paper discs impregnated with the tested solutions of the
and 105 CFU/mL for mound was spread on the plates of NA. The sulfonamide compounds was placed on the surface of the media
entire surface of the NA plates was inoculated by streaking with a inoculated with the microorganisms. After pre-incubation for 1 h
sterile swab dipped into adjusted suspension. Legionella at 4 ꢀC, the plates were incubated at 37 ꢀC for 24 h for bacterial
O
N
O2
Cl
1
H2N
O
NH2
NH2
N
O
H2N
N
S
Pyridine
Pyridine
rt
S
O
N
N
rt
O
H
a
2
2b
H
O
O
N
NH2
N
N
S
S
O
O
O
O
H
N
N
2
N
N
H
H
N
O2
O2N
7
3
a
N
2S / S8
t
O
-
a
N
E
t
O
H
-
H
E
H
H
2O
2O
2S / S8
H
O
O
N
NH2
N
N
S
S
O
O
O
O
N
NH2
N
N
H
H
H2N
H2N
8
4
O
S
O
Pyridine
rt
Pyridine
rt
R
Cl
R
S
Cl
O
O
a-g
5
a-g
5
H
N
O
O
N
NH2
NH2
N
S
S
O
O
O
O
N
N
N
H
O
O
R
H
R
S
S
N
N
O
O
H
H
a-g
6
a-g
9
a
b
c
d
e
f
g
R
C2H5
C6H5 p-CH3C6H4 p-BrC6H4 p-CH3OC6H4 2,4,6-(CH3)3C6H2 C10H7
Scheme 1. The synthesis of novel sulfonamide derivatives containing sulfamerazine and sulfaguanidine.

DOI: 10.3109/14756366.2015.1079183
Synthesis of sulfonamide analogs contain sulfamerazine/sulfaguanidine
5
strains, 48 h for yeast and for 72 h for fungi at room temperature. 3193 and 3035 cmꢁ1 and the aliphatic C–H stretching bands were
L. pneumophila was incubated at 37 ꢀC in humidified air for 72 h. observed between 2980 and 2871 cmꢁ1. Stretching vibration of
Each assay in this experiment was repeated thrice. Erythromycin the carbonyl group contained in the structures of the synthesized
(15 mg/disc) for bacteria and Nystatin (100 U/disc) for yeast and molecule was observed at 1679–1641 cmꢁ1 and the stretching
fungi were used as positive controls.
vibrations of the C ¼ C bonds in the aromatic structure were
observed between 1606 and 1504 cmꢁ1. Symmetric and asym-
metric vibration bands of SO2, existing in the structure of the
novel sulfonamide compounds, were determined to give severe
Results and discussion
Chemistry
vibrations in the range of 1193–1136 cmꢁ1
.
General synthesis method of novel sulfonamide derivatives
The 1H-NMR spectra of compounds 4, 6a–g, 9c and 9f showed
containing sulfamerazine/sulfaguanidine (6a–g and 9a–g) is singlet peaks that belong to protons of the methyl groups between
shown in Scheme 1. 2.22 and 2.85 ppm. When the spectrums of compounds 6a and 9a
In the first step, N-(4-(N-(4-methyl pyrimidin-2-yl) sulfamoyl) are taken into consideration, the ethyl group –CH3 protons were
phenyl)-4-nitrobenzamide (3) and N-(4-(N-(diamino methylene) observed in the triplet peaks at 1.20 ppm, –CH2 protons were
sulfamoyl) phenyl)-4-nitrobenzamide (7) compounds are obtained observed in quartet peaks at 3.20 ppm. Protons of –OCH3 group
in high yields by interacting p-nitrobenzoyl chloride (1), 6e and 9e compounds were observed in singlet peak at 3.80 ppm.
sulfamerazine (2a) and sulfaguanidine (2b) in the presence of NH2 protons of compound 4 were observed as broad peak at
pyridine at room temperature, respectively.
5.90 ppm. Aromatic CH protons of all molecules were observed in
In the second step, synthesized starting compounds (3, 7) are the range of 6.60–8.54 ppm. –NH protons of carboxamide and
reduced in the presence of sodium poly-sulfur in ethanol–water sulfonamide groups were observed between 10 and 12 ppm for all
mixture (1:1). As a result of reduction, 4-amino-N-(4-(N-(4- compounds (4, 6a–g, 9a–g).
methyl pyrimidin-2-yl) sulfamoyl) phenyl) benzamide (4) and
4-amino-N-(4-(N-(diamino methylene) sulfamoyl) phenyl) benza- novel sulfonamide molecules are determined to be in line with the
mide (8) compounds are obtained. recommended molecule structures. Also, when their high reso-
The signals observed in 13C-NMR (APT) spectrums of all the
In the final step, new sulfonamide derivatives containing lution mass spectra (HRMS) are examined, the observed molecule
sulfamerazine/sulfaguanidine (6a–g and 9a–g) were obtained in ion peaks are in compliance with the recommended structures.
pyridine at room temperature by the reaction of various sulfonyl
chlorides (5a–g) with the compounds 4 and 8, which are obtained
Antimicrobial activity
as a result of reduction reaction (Scheme 1).
The results of the antimicrobial activity of the 4, 6a–g and 9a–g
by the agar diffusion method is presented in Table 1. The
comparison of the obtained result with the antibacterial and
antifungal agents used in the study is presented in Table 1 as well.
Stock solutions of the sulfonamide compounds were prepared
by dissolving with DMSO and loaded on disc (100 mg).
Infrared (IR) spectra of all sulfonamide compounds are taken
into consideration 4, 7, 8 and 9a–g of molecular vibration bands
specific to –NH2 were observed in the broad peaks between 3325
and 3436 cmꢁ1. Characteristic peaks of –NH stretching vibrations
of all molecules were observed at the intervals of 3355–
3511 cmꢁ1. Aromatic C–H stretching bands are observed between
Table 1. Antimicrobial activities of sulfonamide compounds (4, 6a–g and 9a–g) (discs Ø 6 mm).
Test microorganisms
Compounds (disc/100 mg)
6e 6f 6g 9a 9b 9c
Standard antibiotics
Gram (+)bacteria
S. aureus
Staphylococcus spp. (clinic)
B. cereus
B. pumilus
S. epidermidis
E.fecalis
B. subtilis
4
6a 6b 6c
6d
+
ꢁ
9d
+
9e
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
+
9f 9g
E
+++
+++
+++
+++
+
N
ꢁ
ꢁ
+
+
ꢁ
ꢁ
+
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
+
+
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
+
ꢁ
+
ꢁ
+
ꢁ
ꢁ
ꢁ
+
ꢁ
+
+
+
+
ꢁ
ꢁ
ꢁ
+
+
+
+
+
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
+
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
++ ++
+
ꢁ
ꢁ
ꢁ
+
ꢁ
+
ꢁ
ꢁ
+
ꢁ
+
ꢁ
+
ꢁ
++
+
++++
+++
MRSA (clinic)
+
Gram (ꢁ)bacteria
E. coli
E. aerogenes
L. pneumophila (water)
VRE (clinic)
M. catarrhalis(clinic)
Salmonella spp. (clinic)
S. flexneri (clinic)
A. hydrophilia
ꢁ
+
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
+
+
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
+
ꢁ
ꢁ
+
ꢁ
+
ꢁ
ꢁ
+
ꢁ
ꢁ
+
ꢁ
+
ꢁ
ꢁ
+
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
+
ꢁ
+
+
+
ꢁ
ꢁ
ꢁ
ꢁ
++
ꢁ
+
+
ꢁ
ꢁ
+
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
+++
+++
++
+++
+++
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
+
ꢁ
ꢁ
ꢁ
ꢁ
++++
Yeast and mold
C. albicans
C. tropicalis (clinic)
S. cerevisia
S. boulardii
+
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
+
+
ꢁ
+
ꢁ
ꢁ
+
ꢁ
ꢁ
+
+
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
++
++
++
++
+++
++
A. niger
A. fumigatus
ꢁ: no inhibition zone; E: (Erythromycin 15 mg/disc); N: Nystatin 100 U/disc); +, inhibition values 1–10 mm between control; ++, inhibition values
10–20 mm between control; +++, inhibition values 20–30 mm between control; ++++, inhibition values 30–40 mm between control.

6
B. Aday et al.
J Enzyme Inhib Med Chem, Early Online: 1–6
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7. Monti SM, Supuran CT, Simone GD. Anticancer carbonic anhydrase
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8. Zolnowska B, Slawinski J, Pogorzelska A, et al. Carbonic anhydrase
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XII. Eur J Med Chem 2014;71:135–47.
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their inhibitory effect on human carbonic anhydrase cytosolic
isozymes I and II and transmembrane tumor-associated isozymes IX
and XII. Eur J Med Chem 2014;84:59–67.
All sulfonamide compounds showed antimicrobial effective to
against at least one microorganism. Compound 9d showed highest
antimicrobial activity against tested Gram-positive bacteria B.
subtilis (14 mm) at 100 mg/disc test concentration. Compounds 9e
and 6d good showed antimicrobial activity against E. aerogenes
(13 mm) and B. cereus (12 mm), respectively. 6e and 9a showed
antibacterial activity against B. cereus and E. aerogenes with
diameters of zone 10 mm at 100 mg/disc concentration. The
B. cereus in Gram-positive spore-forming bacteria can cause
gastrointestinal diseases and severe eye infections in humans19.
Only 9d showed weak antibacterial activity against L. pneumo-
phila. Legionella are Gram-negative bacteria that are ubiquitous
in both natural aquatic and moist soil environment and in artificial
aquatic habitats. Human infection with Legionella has two distinct
forms: Legionnaires’ disease, which is a severe form of infection
which includes pneumonia; and Pontiac fever, a milder flu like
illness without pneumonia20.
9d and 9f showed antifungal activity against C. tropicalis
(8 mm) and S. boulardii (8 mm) at 100 mg/disc concentration.
Candida tropicalis is a diploid ascomycetes yeast commonly
found on the skin and in digestive tracts of healthy human hosts
worldwide. Infections caused by C. tropicalis are reported in
4–24% of patients with candidemia21,22. In general, sulfonamides
(4, 6a–g and 9a–g) show the low antifungal activity against the
yeast and mold. These compounds show no high activity against
the tested microorganisms. It was thought that the reason for this
event was the inability of sulfonamide molecules to pass through
the bacterial cell membrane due to their huge molecular
structures23. IR, 1H-NMR, 13C-NMR and HRMS spectrums of
all compounds are given in Supplementary information.
10. Slawinski J, Pogorzelska A, Zolnowska B, et al. Carbonic anhydrase
inhibitors. Synthesis of
a novel series of 5-substituted 2,4-
dichlorobenzenesulfonamides and their inhibition of human cyto-
solic isozymes I and II and the transmembrane tumor-associated
isozymes IX and XII. Eur J Med Chem 2014;82:47–55.
11. Ghorab MM, Ceruso M, Alsaid MS, et al. Novel sulfonamides
bearing pyrrole and pyrrolopyrimidine moieties as carbonic
anhydrase inhibitors: synthesis, cytotoxic activity and molecular
modeling. Eur J Med Chem 2014;87:186–96.
12. Kaya M, Basar E, C¸ akir E, et al. Synthesis and characterization of
novel dioxoacridine sulfonamide derivatives as new carbonic
anhydrase inhibitors. J Enzyme Inhib Med Chem 2012;27:509–14.
_
˘
13. Ulus R, Yes¸ildag I, Tanc¸ M, et al. Synthesis and characterization of
novel dioxoacridine sulfonamide derivatives as new carbonic
anhydrase inhibitors. Bioorg Med Chem 2013;21:5799–805.
_
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14. Yes¸ildag I, Ulus R, Basar E, et al. Facile, highly efficient, and clean
one-pot synthesis of acridine sulfonamide derivatives at room
temperature and their inhibition of human carbonic anhydrase
isoenzymes. Monatsh Chem 2014;145:1027–34.
Conclusion
15. Sayın F. Hayvanlarda coccidiosisin tedavisi ve bu hususta bilinmesi
¨
gereken bazı ozellikler. Bornova Vet Aras¸t Ens Derg 1968;9:
118–35.
Novel sulfonamide compounds containing sulfamerazine/sulfa-
guanidine were synthesized and their structures were character-
ized. In particular, 6d, 6e, 9a, 9d and 9e showed antimicrobial
activity against tested bacteria.
˘
¨
16. Mimioglu M, Goksu K, Sayın F. Veteriner ve Tıbbi Protozcoloji II.
¨
Ankara: A.U. Basımevi; 1969.
17. National Committee for Clinical Laboratory Standards. Performance
standards for antimicrobial disk susceptibility test. 4th ed. Vol. 10.
Approved Standard NCCLS Document, Villanova; 1990:9–15.
18. National Committee for Clinical Laboratory Standard. 2nd ed, vol.
10. Methods for dilution antimicrobial susceptibility tests for
bacteria that grow aerobically. Approved Standard NCCLS
Document, Villanova; 1999:12–15.
Declaration of interest
This research was financed by Dumlupınar University Research Fund
(Grant No. 2012-38).
19. Ramarao N, Sanchis V. The pore-forming haemolysins of Bacillus
cereus. Toxins 2013;5:1119–39.
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Supplementary material available online
Supplementary material