Efficient Synthesis, Characterization, and Antibacterial Activity of Novel N-Acylsulfonamides and Sulfonylureas

Article abstract of DOI:10.1080/10426507.2013.865125

A series of novel sulfonylureas and N-acylsulfonamides derivatives were synthesized and characterized by ¹H NMR, ¹³C NMR, and HRMS. These compounds were synthesized efficiently in two steps (carbamoylation-sulfamoylation), using chlo

Full text of DOI:10.1080/10426507.2013.865125

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Phosphorus, Sulfur, and Silicon and the
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Efficient Synthesis, Characterization,
and Antibacterial Activity of Novel N-
Acylsulfonamides and Sulfonylureas
Cheloufi Hadjera, Berredjem Malikaa, Boufas Wahidaa, Bouchareb
Fouziaa, Djahoudi Abdelghanib & Aouf Nour-Eddinea
a Laboratory of Applied Organic Chemistry, Bioorganic Chemistry
Group, Sciences Faculty, Badji Mokhtar; Annaba University, BP 12,
Algeria
b Laboratory of Microbiology, Faculty of Medicine, University of Badji
Mokhtar, BP 205, Annaba, Algeria
Accepted author version posted online: 13 Mar 2014.Published
online: 21 Aug 2014.
To cite this article: Cheloufi Hadjer, Berredjem Malika, Boufas Wahida, Bouchareb Fouzia, Djahoudi
Abdelghani & Aouf Nour-Eddine (2014) Efficient Synthesis, Characterization, and Antibacterial Activity
of Novel N-Acylsulfonamides and Sulfonylureas, Phosphorus, Sulfur, and Silicon and the Related
Elements, 189:9, 1396-1404, DOI: 10.1080/10426507.2013.865125
To link to this article: http://dx.doi.org/10.1080/10426507.2013.865125
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Phosphorus, Sulfur, and Silicon, 189:1396–1404, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.865125
EFFICIENT SYNTHESIS, CHARACTERIZATION,
AND ANTIBACTERIAL ACTIVITY OF NOVEL
N-ACYLSULFONAMIDES AND SULFONYLUREAS
Cheloufi Hadjer,1 Berredjem Malika,1 Boufas Wahida,1
Bouchareb Fouzia,1 Djahoudi Abdelghani,2 and Aouf
Nour-Eddine1
1Laboratory of Applied Organic Chemistry, Bioorganic Chemistry Group, Sciences
Faculty, Badji Mokhtar; Annaba University, BP 12, Algeria
2Laboratory of Microbiology, Faculty of Medicine, University of Badji Mokhtar,
BP 205, Annaba, Algeria
GRAPHICAL ABSTRACT
Abstract A series of novel sulfonylureas and N-acylsulfonamides derivatives were synthesized
and characterized by 1H NMR, 13C NMR, and HRMS. These compounds were synthesized
efficiently in two steps (carbamoylation-sulfamoylation), using chlorosulfonyl isocyanate that
was a suitable reagent for allowing the introduction of a sulfonamide moiety. The antibacterial
activity (in vitro) of some newly formed compounds were investigated against some Gram-
positive and Gram-negative bacteria by applying the method of dilution and minimal inhibition
concentration methods. These compounds have significant bacteriostatic activity with totalities
of bacterial strains used.
Keywords Acylsulfonamides; sulfonylurea; antibacterial activity; chlorosulfonyl isocyanate,
MIC
INTRODUCTION
There are several different families of antibiotics that are commonly used to treat
infections.1 Each antibiotic family includes a highly variable number of molecules having
a similar basic chemical structure; some molecules can interfere with nucleic acid syn-
thesis at several different levels, such as trimethoprim,2 quinolones,3–5 rifamycins,6 and
nitroimidazoles.7,8 Sulfonamides also belong to this family as they inhibit the activity of
Received 24 August 2013; accepted 7 November 2013.
Address correspondence to Berredjem Malika, Laboratory of Applied Organic Chemistry, Bioorganic
Chemistry Group, Sciences Faculty, Badji Mokhtar; Annaba University, BP 12, Algeria. E-mail:
malika.berredjem@univ-annaba.org
1396

NOVEL SULFONYLUREAS AND N-ACYLSULFONAMIDES
1397
the enzyme dihydropteroate synthase,9 preventing the synthesis of folic acid (Vitamin B9),
intermediate necessary for life of certain bacteria.
The sulfonamide, acylsulfonamide, and sulfonylurea functionalities are found within
numerous marketed agents for a wide range of therapies.10–17 These molecules contain a
sulfonyl group attached to an amine. In some instances, the presence of the sulfonamide
fragment is merely a circumstantial occurrence, but in the vast majority of case, these drugs
can be categorized into distinct groups based on the role of the sulfonamide motif in the
drug’s primary pharmacology. Several drug classes are characterized by the presence of
the sulfonamide function: antibacterial, hypoglycemic, diuretic, antihypertensive, carbonic
anhydrase inhibitors, and antiviral drugs are among several examples.18–27 In less than ten
years, over 5000 sulfonamide derivatives were synthesized: sulfapyridine, sulfadiazine, and
sulfamethoxazole have been used therapeutically.28
The sulfonylurea receptor-1 (SUR1) is the molecular target for the sulfonylurea class
of antihyperglycemic drugs such as chlorpropamide,29 glipizide,30 and glimepiride,31 which
have been widely used in the treatment of type 2 diabetes mellitus and are maintained as
frontline therapeutic agents (Figure 1).
Asada et al. described novel N-acylsulfonamide analogs as potent and selective EP3
receptor antagonists.32 Anilkumar et al. discovered the indole C2 acyl sulfonamides as Novel
HCV NS5B polymerase inhibitors.33 Recently, novel derivatives of N-acylsulfonamides
have been useful as inhibitors of the hepatitis C virus (HCV) NS3 protease by Ba¨ck et al.34
(Figure 2).
In this study, various novel N-acylsulfonamide, and sulfonylurea derivatives were
efficiently synthesized and their antibacterial activity evaluated in vitro.
RESULTS AND DISCUSSION
In the literature, several works have been devoted to the acylation of various sul-
fonamides by direct condensation with anhydrides, esters, or acid chlorides or carboxylic
Figure 1 Some selective sulfonylureas for the treatment of type 2 diabetes.

1398
C. HADJER ET AL.
Figure 2 Some drugs containing N-Acylsulfonamides.
acids in the presence of coupling agents such as carbodimides (EDCI or DCC) or N, N’-
carbonyldiimidazole.35–37 In our case, the synthesis of N-modified acylsulfonamides and
sulfonylureas was easily accomplished in two steps (carbamoylation and sulfamoylation)
using chlorosulfonyl isocyanate (Scheme 1). We have established that chlorosulfonyl iso-
cyanate (CSI) is a suitable reagent allowing the introduction of sulfonamide, acylsulfamide,
or sulfonylureas moieties in diverse structures.38–42
Reaction of (L) ethyl lactate with (CSI) in the presence of an excess of triethyamine
resulted in the formation of the corresponding N-chlorosulfonyl-carbamate, which presents
an electrophilic reactivity. This precursor has already been described.43 In a second step,
the carbamate reacted with primary or secondary amines in presence of triethyalamine to
give mixtures of N-acylsulfonamides 1a-c and sulfonylureas 2a-c with yields respectively
70% and 20% (Scheme 1). The mixture of these two compounds is easily separable by
column chromatography eluted with dichloromethane.
We found that ethyl lactate behaves as an activated ester and is easily cleaved under
basic conditions in a second step. The structures of all compounds were unambiguously
confirmed by spectroscopic methods. For the resulting compounds 1a-1c, spectra showed
1
bands at 1785–1800 cm−1 (C=O) amide, and 1700–1705 cm−1 (C=O) ester. H-NMR

NOVEL SULFONYLUREAS AND N-ACYLSULFONAMIDES
1399
Scheme 1
spectra showed multiplet systems corresponding to the proton of an asymmetric carbon and
singlets corresponding to the proton of NH group. The disappearance of the (C=O) ester
band and the ethyl signal in NMR confirmed the removal of the lactate fragment.
Exceptional Cases
The addition of ( )-phenyl ethylamine onto carbamate leads to the formation of a
single compound (1d) as shown by TLC analysis and structural studies confirmed that this
product is N-acylsulfonamide (Scheme 2). This product is obtained as crystals in a high
yield.
for the same reaction, we used 2 equivalents of amine to obtain a mixture of N-
Acylsulfonamide 1d and sulfonylurea 2d (Scheme 3).
However, when adding one equivalent of the amine to carbamate, a single compound
is formed 2e. Structural studies confirmed that this product is sulfonylurea (Scheme 4).
Scheme 2

1400
C. HADJER ET AL.
Scheme 3
Experimental Section
The purification of the compounds was performed by column chromatography using
silica gel 60 (35–70 μm) or Merck h60 (Art. 9385). Mass spectra (MS) were scanned by
affecting FAB ionization JEOL-JMS-DX 300-SX 102 system and recorded in FAB positive
1
mode. The m/z values of the more intense peaks are mentioned. H NMR spectra were
recorded on Bruker AC 400-MHz Avance spectrophotometer in CDCl3 as the solvent and
tetramethyl silane as an internal standard at room temperature. Chemical shifts are given in
δ (ppm) scale and coupling constants (J values) are expressed in Hertz. Multiplicity is indi-
cated as s (singlet), d (doublet), t (triplet), and m (multiplet). All melting points were deter-
mined by open capillary tubes on an electro thermal apparatus (Barnstead/Electrothermal)
and are uncorrected. Selected MS and 1H NMR for 2b, 2c, and 2d are presented in the Sup-
plemental Materials (Figures S1–S6)
ꢀR
Clinical isolates from parietal distal takings of patients Escherichia coli , Escherichia
coli BLSE+, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter sp.
Proteus sp, Acinetobacter baumanii, Staphylococcus (Staphylococcus aureus et Staphylo-
coccus coagulas ne´gatif) et Enterococcus feacalis cultures were obtained from the laboratory
of microbiology – CHU Annaba. We used, as a control, 4 referenced strains: Escherichia
coli ATCC 25922, Staphylococcus aureus ATCC 25923, Pseudomonas aeruginosa ATCC
27853, Enterococcus feacalis ATCC 29212.
Minimal inhibitory concentrations (MIC) were determined by micro dilution broth
method following the National Committee for Clinical Laboratory Standard’s proce-
dures.44,45 MIC’s is defined as the lowest concentrations of the antimicrobial agents that
inhibited visible growth of the micro-organism. All tests were performed in Mueller Hinton
Broth. The compounds under the test were dissolved in analytically pure dimethylsulfoxide
(DMSO) and geometric dilutions of reason 2 ranging from 0.5 to 512 μg mL−1 of the
compounds.
Scheme 4

NOVEL SULFONYLUREAS AND N-ACYLSULFONAMIDES
1401
The culture suspensions were prepared and adjusted by comparing against 0.5 Mc
Farland turbidity tubes. Mueller- Hinton Agar (20 mL) was poured into each sterile Petri
dish after injecting cultures (100 μL) of microorganisms and distributing medium in Petri
dish homogeneously. Compounds were dissolved in DMSO of 10 mg mL−1 to prepare stock
solution. Empty sterilized discs of 6 mm were impregnated with 50 μL of compounds at
the required concentrations of 0.5–512 μg mL−1. Discs were placed on agar plates and
the cultures were incubated at 37◦C for 24 h. Reference disc used for control is SSS
commercial sulfonamide (Trisulfapyrimidine (triple sulfa), a combination of sulfadiazine,
sulfamerazine, and sulfamethazine). To insure that the solvent had no effect on the bacterial
growth, a control was performed at the test medium supplemented with DMSO at the same
dilutions as used in the experiments. Additional details are presented in the Supplemental
Materials (Table S 1, Figure S 1).
General Procedure for the Preparation of N-Acylsulfonamides and
Sulfonylureas
To a stirred solution of chlorosulfonyl isocyanate (1 mL) in anhydrous
dichloromethane (10 mL), ethyl lactate (11.4 mmol) was added drop wise at 0◦C.
After 30 min, the resulting solution was added slowly to primary or secondary amine
(11.4 mmol, 1 equiv.) in anhydrous CH2Cl2 (10 mL), in the presence of triethylamine (1.1
equiv.) under vigorous stirring at 0◦C. The mixture was stirred over a period of 2 h and the
progress of reaction was monitored by TLC until the conversion of amine was completed.
The mixture was diluted with CH2Cl2 and washed with 0.1 N HCl and water. The organic
phase was dried over MgSO4 or Na2SO4 and the solvent were evaporated under reduced
pressure. The products were purified by column chromatography over silica gel using
CH2Cl2 as eluent to obtain 70% of N-Acylsulfonamides and 20% of sulfonylureas.
Synthesis of N-Acylsulfonamides
Ethyl (S)- 2-(1-propylsulfamide carbamoyloxy)propanoate 1a. Yellow
1
solid, Yield 72%, Rf = 0.51 (CH2Cl2/MeOH, 9:1), mp: 96–99◦C, H NMR (400 MHz,
∗
CDCl3) δ: 7.40 (s,1H, NH), 5.25 (q, J = 7.20 Hz, 1H, CH-CH3), 5.20 (t, J = 6.23 Hz,
1H, NH-CH2,), 4.10 (q, J = 6.50 Hz, 2H, CH2-CH3), 3.20 (m, 2H, CH2-NH), 1.65 (m,
2H, CH3-CH2), 1.45 (t, J = 6.70 Hz, 3H, CH2-CH3), 1.36 (d, J = 6.30 Hz, 3H, ∗CH-CH3),
1.00 (t, J = 7.35 Hz, 3H, CH3-CH2). 13C NMR (CDCl3, δ ppm): 173.6; 153.2; 69.3; 64.2;
49.1; 23.9; 18.2; 15.1; 10.3. MS ESI+ 30eV m/z: 305 [M+ Na+], 283 [M+ H+]. HRMS
calcd. for C9H18O6N2S. M = 282. 3140.
Ethyl (S)-2-(1-cyclohexylsulfamide carbamoyloxy) propanoate 1b. White
solid, Yield 74%, Rf = 0.66 (CH2Cl2/MeOH, 9:1), mp = 119–121◦C, 1H NMR (400 MHz,
∗
CDCl3) δ: 7.60 (s,1H, NH), 5.15 (m,2H, CH-CH3 + NH), 4.20 (q, J = 7.16 Hz, 2H,
CH2-CH3), 3.30 (m, 1H, CH-NH), 1.90 (m, 2H, CH2 cyc), 1.60 (m,2H, CH2-cyc), 1.40
(m, 4H, 2CH2-cyc), 1.31 (m, 5H, CH2-CH3+ CH2-cyc). 13C NMR (CDCl3, δ ppm): 171.6;
151.2; 68.3; 63.2; 54.2; 34.1; 25.4; 25.3; 16.2; 15.1. MS ESI+ 30eV m/z: 323 [M+H]+,
345 [M+Na] +. HRMS calcd. for C12H22O6N2S. M = 322.3779.
Ethyl (S)-2- (4-phenylpiperazin-1-yl)sulfamide carbamoyloxy) propano
-ate 1c. White solid, Yield 77%. Rf = 0.61 (CH2Cl2/MeOH, 9:1), mp = 106–107◦C,
1H NMR (400 MHz, CDCl3) δ: 7.50 (s, 1H, NH), 7.30 (m, 3H, H-Ar), 6,90 (m, 2H, H-
∗
Ar), 5.10 (q, J = 7.52 Hz, 1H, CH-CH3), 4.20 (q, J = 7.20 Hz, 2H, CH2-CH3), 3.60

1402
C. HADJER ET AL.
(t, J = 6.80 Hz, 4H, N-CH2-CH2), 3.25 (t, J = 8.00 Hz, 4H, 2CH2), 1.51 (d, J = 5.76 Hz,
3H, CH-CH3), 1.25 (t, J = 6.56 Hz, 3H, CH2-CH3). 13C NMR (CDCl3, δ ppm): 170.6;
150.9; 146.3; 129.6; 125.2; 120.8; 68.3; 61.2; 56.3; 48.3; 18.2; 15.1. MS ESI+ 30eV m/z:
386 [M+H]+ 100%. HRMS calcd. for C16H23O6N3S. M = 385.4353.
Ethyl (S)-2- (phenylethyl)sulfamide carbamoyloxy) propanoate 1d. White
solid, Yield 89%, Rf = 0.45 (CH2Cl2/MeOH, 9:1), mp = 116–118◦C, 1H NMR (400 MHz,
CDCl3) δ: 7,32 (s, 1H, NH), 7.25 (s, 5H, Ar), 5.75 (d, J = 7.36 Hz, 1H, NH), 5.00
∗
∗
∗
(q, J = 7.00 Hz, 1H, CH), 4.95 (q, J = 7.12 Hz, 1H, CH), 4.55 (m, 2H, CH), 4.25
(q, J = 7.12 Hz, 2H, CH2-CH3), 1.60 (d, J = 6.88 Hz, 3H, ∗CH-CH3), 1.52 (d, J = 6.93 Hz,
3H, CH-CH3), 1.25 (t, J = 6.20 Hz, 3H, CH2-CH3). 13C NMR (CDCl3, δ ppm): 170.2;
∗
153.3; 145.0; 127.0; 126.5; 126.1; 69.7; 63.2; 47.0; 21.2; 18.3; 12.1. MS ESI+ 30eV m/z:
367 [M+ Na+], 345 [M+ H+]. HRMS calcd. for C14H20O6N2S. M = 344.3834.
Synthesis of Sulfonylureas
1,2,3,4-tetrahydroisoquinolin-2-ylsulfamide carbamoyloxy-1,2,3, 4- tetra
-hydroiso quinoline 2e. Yellow solid, Yield 86%, Rf = 0.54 (CH2Cl2/MeOH, 9:1),
1
mp = 150–151◦C, H NMR (400 MHz, CDCl3) δ: 7.25 (m, 8H, Ar), 5.30 (s, 1H, NH),
4.67(s, 4H, 2CH2), 3.75 (t, J = 5.88 Hz, 4H, 2CH2-N), 3.00 (t, J = 5.84 Hz, 4H, 2CH2-
CH2). MS ESI+ 30eV m/z: 371 [M]+ 100%, 372[M+H]+, 394 [M+Na]+. HRMS calcd.
for C19H21O3N3S. M = 371.4533.
Antibacterial Activity
In this work, the antibacterial activities of some derivatives N-Acylsulfonamides
(1c, 1d) and sufonylureas (2c, 2d, 2e) were screened against clinical strains isolated to
determine the MIC. A control antibiotic (sulfonamide SSS) was included in this study in
order to compare its activity to the new synthesized molecules. The results obtained were
collected in Table S 1 (Supplemental Materials).
CONCLUSION
In this study, we described here the synthesis of new series of N-acylsulfonamides
and sulfonylureas. We have developed a general and mild two steps approach (carbamoy-
lation and sulfamoylation) for the synthesis of alkyl or aryl sulfonamides using primary or
secondary amines with carbamate of chlorosulfonyl. The present study indicates that the
strains used for the antibacterial activity tests were sensitive to different concentrations of
molecules 1c, 1d, 2c, 2d, and 2e. We observed that five molecules gave a powerful result
with a very high sensitivity (32, 1, 4, 2, and 0.5μg mL−1) against Pseudomonas aeruginosa
and Acin etobacter baumanii.
FUNDING
This work was generously supported by the General Directorate for Scientific Re-
search and Technological Development (DG-RSDT), Algerian Ministry of Scientific Re-
search, National Fund of Research (FNR). We also thank Christian PERIGAUD and Suz-
zane PEYRROTES the university of Montpellier II for their help in the identification for
all products in NMR and MS.

NOVEL SULFONYLUREAS AND N-ACYLSULFONAMIDES
1403
SUPPLEMENTAL MATERIAL
Supplementary data for this article can be accessed on the publisher’s website,
www.tandfonline.com/gpss
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