Synthesis and evaluation of α-glucosidase inhibitory activity of sulfonylurea derivatives

Article abstract of DOI:10.1515/znb-2020-0134

Two series of sulfonylureas derivatives including 24 compounds (4, 7, 5a-5o, 8a-8h), among them 17 new derivatives, have been synthesized and evaluated for their α-glucosidase inhibitory activity. Compounds 5c, 5h and 8e showed significant in vitro α-glucosidase inhibition with IC50 values of 5.58, 79.85 and 213.36 μm, respectively, comparing with the standard compounds acarbose (IC50 = 268.29 μm) and glipizide (IC50 = 300.47 μm). The preliminary structure-activity relationships (SARs) of the synthesized compounds were also investigated.

Full text of DOI:10.1515/znb-2020-0134

Z. Naturforsch. 2021; 76(3–4)b: 163–171
Thi Thoi Bui, Van Loc Tran, Dai Quang Ngo, Van Chien Tran, Van Sung Tran and
Thi Phuong Thao Tran*
Synthesis and evaluation of α-glucosidase
inhibitory activity of sulfonylurea derivatives
https://doi.org/10.1515/znb-2020-0134
Received July 26, 2020; accepted October 12, 2020;
published online March 4, 2021
their responsiveness to insulin action, by increasing the
number of insulin receptors [1]. The side effect of these
reagents is, however, associated with hypoglycemia, weight
gain and cardiovascular risks. The combination of sulfo-
nylureas with α-glucosidase inhibitors, an add-on therapy,
have been reported to improve lipid profiles, decrease body
weight, prevent macroangiopathy, reduce the hemoglobin
A1c and control the glycemic level in type 2 diabetic patients
[9, 10].
The present study is aimed to develop novel sulfonylurea
derivatives with increased α-glucosidase inhibitory activity as
well as decreasing the diabetic complications during treat-
ment by sulfonylureas. Two series of sulfonylurea derivatives
based on the structure of glipizide (Figure 1), an antidiabetic
medicament, have been synthesized. Various phenyl and
heterocyclic rings were incorporated into the sulfonylurea
scaffold. As a result, 24 derivatives (4, 7, 5a–5o, 8a–8h) were
obtained, 17 of which (5a, 5c, 5e, 5g–5k, 5n, 5o, 8a–8h) are
new. All of the synthesized compounds were evaluated for
α-glucosidase inhibition.
Abstract: Two series of sulfonylureas derivatives including
24 compounds (4, 7, 5a–5o, 8a–8h), among them 17 new
derivatives, have been synthesized and evaluated for their
α-glucosidase inhibitory activity. Compounds 5c, 5h and 8e
showed significantinvitro α-glucosidase inhibition with IC50
values of 5.58, 79.85 and 213.36 µM, respectively, comparing
with the standard compounds acarbose (IC50 = 268.29 µM)
and glipizide (IC50 = 300.47 µM). The preliminary structure-
activity relationships (SARs) of the synthesized compounds
were also investigated.
Keywords: α-glucosidase inhibitory activity; sulfonylureas
derivatives; synthesis.
1 Introduction
Sulfonylurea derivatives are compounds containing a
central S-aryl sulfonylurea unit with p-substituents on the
phenyl ring (R1) and substituents at the urea’s N′-terminus
(R2) [1] (Figure 1). They exhibit a wide range of biological
activity such as antidiabetic [2], diuretic [3], antitubercular
[4], antimalerial [5], anticancer [6], anti-inflammatory [7],
thromboxane A2 receptor antagonism activity [8]. Especially
sulfonylureas are widely used in medicine as potent blood
glucose-reducing agents for the treatment of diabetes. Sul-
fonylureas alter the plasma membrane of cells to increase
2 Results and discussion
2.1 Chemistry
The synthetic routes of compounds 5a–5o and 8a–8h are
shown in Schemes 1 and 2, respectively. The structure of
glipizide was modified at N-phenylethylsulfamoyl moiety
(R1 substitution), while the cyclohexyl ring at the N-terminus
was maintained (Scheme 1). The desired products were
synthesized by a general method for the synthesis of sulfo-
nylurea derivatives by treatment of sulfonamides with
appropriate isocyanides in the presence of base (Scheme 1)
[1]. Compound 1 (4-(2-aminoethyl)benzenesulfoamide) was
used as the starting material. N-Boc protection of 1 gave
compound 2 which was then reacted with cyclohexyl
isocyanate in the presence of K2CO3 to afford 3. Deprotection
of 3 with trifluoroacetic acid (TFA) in DCM provided the key
intermediate 4. Finally, coupling of 4 with various of car-
boxylic acids in the presence of ethyl chloroformate and
triethylamine (TEA) gave the target compounds 5a–5l.
Instead of SOCl2 or (COCl)2 as reagent to activate carboxylic
*Corresponding author: Thi Phuong Thao Tran, Institute of Chemistry,
Vietnam Academy of Science and Technology (VAST), and Graduate
University of Science and Technology (VAST), Nr. 18 Hoang Quoc Viet
Road, Cau Giay district, Hanoi, Viet Nam,
E-mail: ntuelam2010@gmail.com
Thi Thoi Bui, Vietnam Institute of Industrial Chemistry, Nr. 2 Pham Ngu
Lao street, Hoan Kiem distric, Ha Noi, Viet Nam
Van Loc Tran, Van Chien Tran and Van Sung Tran, Institute of
Chemistry, Vietnam Academy of Science and Technology (VAST), and
Graduate University of Science and Technology (VAST), Nr. 18 Hoang
Quoc Viet Road, Cau Giay district, Hanoi, Viet Nam
Dai Quang Ngo, Vietnam National Chemical Group, Nr. 1A Trang Tien
street, Hoan Kiem district, Ha Noi, Viet Nam

164
T.T. Bui et al.: Inhibitory activity of sulfonylurea derivatives
acid, ethyl chloroformate was used to avoid the formation of formation of amide bond in 5h. The appearance of four
additional aromatic protons signals at δH = 7.85–
7.81 ppm, and the carbon signals at δC = 167.60 (COOH),
134.40 and 131.43 ppm (C–Ar) confirmed the structure of
compound 5m. The aromatic pyridine protons at
δH = 8.96–7.77 ppm, together with the carbon signals at
δC = 166.03, 165.93 (CONH imide) indicated the formation
of the imide ring in 5n. The correlation of δH = 8.05 ppm
(4‴-H)/δC = 167.9 ppm (COOH) and δH = 8.66 ppm (6‴-H)/
δC = 165.06 ppm (CONH) was observed in HMBC spectrum
of 5o, suggesting the location of carboxylic acid and
amide moiety at C-3‴ and C-2‴ of pyridine ring, respec-
tively. Furthermore, the formation of the amide bond in
compound 5o was confirmed by the correlation of CONH
by-products (Scheme 1). The sulfonylurea derivatives (5a–5l)
were obtained in moderate to good yields (66–82%).
Compounds 5m, 5n and 5o were prepared by treatment of
2,3-pyridine dicarboxylic anhydride or phthalic anhydride
with amine 4. According to the literature, the reactivity of
2,3-pyridine dicarboxylic anhydride toward nitrogen nucle-
ophiles under different conditions affords different products
[11]. In our study, treatment of 4 with 2,3-pyridine dicarbox-
ylic anhydride in glacial acetic acid at room temperature gave
nicotinic acid derivative 5o. This was compatible with the
studies of Ammar YA et al. for the similar reaction [11]. It was
reported that refluxing 2,3-pyridine dicarboxylic anhydride
with amine in glacial acetic acid for 3 h led to the dicarbox-
ylation of the carboxylic acid group, providing nicotiamide as
main product and nicotiimide as as a minor product [11].
However, in our case, nicotiimide 5n was obtained as the
main product, even heating the reaction for 7 h.
(δH
=
8.76) ppm/C=O (δC 165.06 ppm), C-2’’
(δC = 39.83 ppm).
In Scheme 2, various substitutions at N-terminus of the
urea moiety (R1) were introduced to provide sulfonylureas
mimic glipizide. Compound 5-methylpyrazin-2-carboxylic
acid was treated with ethyl chloroformate in the presence of
TEA, following by the addition of 1 to yield sulfonamide (6).
This compound was subsequently refluxed with ethyl
chloroformate in the presence of anhydrous potassium
carbonate (K2CO3) to obtain the key intermediate carbamate
7. Finally, sulfonylurea derivatives 8a–8h were synthesized
by condensation of 7 with various of amines in toluene. The
use of toluene as solvents gave the products in the best
yields, comparing with other solvents such as dioxane or
DMF. The structures of the products were elucidated by
means of 1H and 13C NMR spectroscopy. The 1H NMR spec-
trum of compound 6 indicated the presence of two singlet
signals of pyrazine protons at δH = 9.02 ppm (s, 1H, 3‴-H)
and δH = 8.59 ppm (s, 1H, 6‴-H). The appearance of the NH
protons at δH = 8.91 ppm (t, J = 6.0 Hz, 1H, CONH),
The structures of the synthesized compounds were
confirmed by means of MS, 1D (1H, 13C) and 2D (HSQC,
1
HMBC) spectra. The H NMR spectra of 2 indicated the
additional signal of tert-butyl group at δH = 1.36 ppm (9H,
3 × CH3), together with the corresponding signals of 1. The
formation of urea cyclohexyl moiety in compound 3 was
confirmed by the appearance of the signals at δH = 1.65–
1.18 ppm (C6H11), 10.25 ppm (br s, 1H, SO2NH), and at
δC = 150.35 ppm (NHCONH), 48.01–24.10 ppm (C6H11). The
lack of the tert-butyl signal in the 1H NMR of compound 4
indicated the removing of the protecting group in the
structure of 4. The formation of the amide urea moiety in 4
was further confirmed by the correlation between CONH-
C6H11 (δH = 6.62 ppm)/C-8′ (δC = 150.49 ppm), C-1
(δC = 48.06 ppm) and C-2, C-6 (δC = 32.24 ppm) in HMBC
spectrum. The presence of additionally aromatic proton
signals as well as the signals of amide groups at δH = 8.07–
9.83 ppm (CONH) and δC = 165.0–168.2 ppm (CONH)
proved the formation of the sulfoamide derivative (5a–5l).
Compound 5c showed the signals of an AB substituted
aromatic ring at δH = 7.38 ppm (d, J = 8.5 Hz, 2H, 2‴-H,
6‴-H) and δH = 6.79 ppm (d, J = 8.5 Hz, 2H, 3‴-H, 5‴-H).
The correlation of H-6‴ (δH = 8.17 ppm)/CONHCH2
(δC = 168.04 ppm) in HMBC spectrum confirmed the
1
δH = 7.27 ppm (s, 2H, SO2NH2) in the H NMR spectrum
confirmed the structure the amide product 6. The NMR
spectra of 7 exhibited additionally signals at δH = 3.99 ppm
(q, J = 7.0 Hz, 2H) and δH = 1.07 ppm (t, J = 7.0 Hz, 3H), and at
δC = 151.01, 61.83 and 13.88 ppm, corresponding to the
carbamate moiety (NHCOOCH2CH3). The disappearance of
the ethyl ester protons and the presence of aromatic protons
at δH = 7.01–7.89 ppm in 1H NMR spectra of 8a–8h clearly
confirmed the formation of urea derivatives. The carbonyl
carbons of the urea groups (NHCONH) were resonated at
δC = 156–158 ppm in the 13C NMR spectra of 8a–8h.
2.2 Biological activity
Twenty-two compounds (5a–5o, 8a–8h) were evaluated
for their ability to inhibit α-glucosidase. Acarbose and
Figure 1: Structures of sulfonylureas and glipizide.

T.T. Bui et al.: Inhibitory activity of sulfonylurea derivatives
165
Scheme 1: Synthesis of sulfonylurea derivatives (5a–5o). Reagents and conditions: a) DMF, Boc2O, r.t., 4 h, 95%; b) Cyclohexyl isocyanate,
K2CO3, acetone, r.t., 6 h, 96.6%; c) TFA, DCM, r.t., 4 h, 92%; d) ClCO2C2H5, TEA, acetone, 0–5 °C, 1 h; e) 4, TEA, acetone, r.t., 4 h, 69.3–81.1%; f)
4, acetic acid, reflux, 7 h, (5m: 81.5%, 5n: 66.1%); g) 4, acetic acid, r.t., 1 h, 72.5%.
glipizide wereusedasstandardcompoundsto comparewith respectively). The p-substituted hydroxyl group at trans-
the synthesized derivatives. Compound 5c (R = 4–OH–C6H4) cinnamoyl moiety plays an important role of the activity.
was the most active compound with an IC50 value of 5.58 µM, This is confirmed due to the observation that compound 5d
48 and 60 times much better than the standard drug acar- without the OH group (R = –C6H5) did not show α-glucosi-
bose and glipizide (IC50 of 268.29 and 300.47 µM, dase inhibition. Preliminary structure-activity relationships

166
T.T. Bui et al.: Inhibitory activity of sulfonylurea derivatives
Scheme 2: Synthesis of sulfonylurea derivatives 8a–8h. Reagents and conditions: a) i. ClCO2Et, TEA, acetone, 0 °C, 1 h; ii. 1, TEA, acetone, r.t.,
3 h, 93.4%; b) K2CO3, acetone, ClCO2C2H5, reflux, 4 h, 89.2%; c) toluene, R2NH2, reflux, 4 h, 68.4–84.2%.
Table : α-Glucosidase inhibitory activity of sulfonylurea
derivatives.
showed moderate activity with IC50 values of 226.03, 322.49
and 312.12 µM, respectively (Table 1, Scheme 1). Compound 8e
(R1 = 3–CF3–4–NO2–C6H3) and 8g (R1 = 2–OH–4–NO2–C6H3)
Nr
Compound
IC (µM)
Nr
Compound
IC (µM)
exhibited good activity with an IC50 of 213.36 and 269.44 µM,
respectively (Table 1, Scheme 2), comparing with acarbose
and glipizide (IC50 = 268.29 and 300.47 µM), respectively. The
introduction of the nitro group into the aromatic rings of the

a
b
c
d
e
f
g
h
i
> 
> 
.












n
o
a
b
c
d
e
f
g
h
Acarbosea
Glipizideb
> 
.
> 



> 
> 
> 
.
.
.
> 
.
> 
> 

>  series products in Scheme 2 seems to enhance the α-gluco-

> 
.
> 
.
> 
sidase inhibitory activity. Other compounds were found to be
inactive.






k
l
m
.
.
3 Conclusions
a, bStandard compounds.
In conclusion, 24 sulfonylurea derivatives have been
synthesized and evaluated for their α-glucosidase inhibitory
activity. Amongthem, compound 5c, 5h, 5land 8e exhibited
significant α-glucosidase inhibition, comparing with the
commercially available acarbose and glipizide. The intro-
duction of 4-hydroxyl-trans-cinnamoyl moiety at N-phe-
nylethylsulfamoyl unit (compound 5c) considerably
increased α-glucosidase inhibitory activity. Our newly syn-
thesized sulfonylurea derivatives exhibited promising
α-glucosidase inhibition, which would be supported for the
“add on therapy” to prevent the complications during the
treatment of diabetics by sulfonylurea agents. Comprehen-
sive pharmacological investigation of these compounds
should be taken under consideration for further research.
(SARs) presumed that trans-cinnamoyl derivatives are weak
intestinal α-glucosidase inhibitors [12]. However, the pres-
ence of a hydroxyl group at para position enhanced signifi-
cantly the inhibition, probably because they may form
hydrogen bonds with the polar groups (amide, guanidine,
peptide, amino, and carboxyl groups) of amino acid residues
in the active site of intestinal α-glucosidase enzyme [12].
Compound 5h (R = 2–OH–3,5–di–I–C6H2) exhibited good
activity with an IC50 value of 79.85 µM. Comparing the activity
of 5h with 5g (R = 2–I–C6H4, IC50 of 278.88 µM), the installation
of OH and disubstituted iodine seems to enhance the activity.
Compound 5l, 5i and 5o with heterocyclic substitutions
(quinoxaline, isoquinoline and picolinic, respectively)

T.T. Bui et al.: Inhibitory activity of sulfonylurea derivatives
167
continuously refluxed for 6 h. The solvent was removed under reduced
pressure and the residue was added water (100 mL), neutralized with 1%
HCl to pH = 5–6. The product was collected by filtration and washed with
water. Pure compound 3 was obtained by recrystallization from ethanol/
water (6.99 g). Yield: 96.6 %, white powder; m.p. 213–215 °C. – IR (film,
KBr): ν = 3336 (NH), 2932 (–CH, alkane), 1691 (C=C, aromatic), 1536 (C=O,
amide), 1351 and 1168 (O=S=O), 1296.52 (C–O) cm−1. – 1H NMR (500 MHz,
DMSO-d6) δ = 10.25 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H),
6.88 (t, J = 5.5 Hz, 1H), 6.30 (d, J = 7.5Hz, 1H), 3.19 (q, J = 7.5 Hz, 2H), 2.78 (t,
J = 7.5 Hz, 2H), 1.65–1.63 (m, 2H), 1.59–1.56 (m, 2H), 1.49–1.47 (m, 1H), 1.34
(s, 9H), 1.25–1.18 (m, 2H), 1.15–1.04 (m, 4H). – 13C NMR (125 MHz, DMSO-
d6): δ = 155.46, 150.35, 145.20, 138.00, 129.14, 127.13, 77.52, 48.01, 40.00,
35.15, 32.21, 28.16, 24.92, 24.10. – MS ((−)-ESI): m/z (%) = 424.0 (100)
[M−H]−. – MS ((+)-ESI): m/z (%) = 448.0 (100) [M+Na]+.
4 Experimental section
4.1 Materials and methods
Reagents were purchased from Aldrich and Merck with analytical
grade and used without further purification. Solvents for column
chromatography were distilled before using. Melting points (in °C)
were determined on a Thermo Mel-temp 3.0 (U.S.A). IR spectra were
recorded on an IMPACT 410 Nicolet spectrometer. ESI-MS spectra were
measured on 1100Agilent LC/MS ion Trap. NMR spectra (1H, 13C, DEPT,
HSQC, and HMBC) were recorded on a Bruker Avance 500 MHz. Thin
layer chromatography was performed on a pre-coated silica gel 60
F254 (Merck) and were visualized under UV light (λmax = 254 nm) and
stained with a solution of 1% (w/w) vanillin in H2SO4. Column chro-
matography was performed on silica gel 300–400 mesh (Merck).
4.5 Synthesis of 4-(2-aminoethyl)-N-
(cyclohexylcarbamoyl)benzenesulfonamide (4) [14]
4.2 α-Glucosidase inhibition assay
In a 100 mL three-necked flask compound 3 (7.3 g, 0.017 mol) was
The assay was performed on 96 well-plates (200 µL per well). The test dissolved in 75 mL DCM. The solution was cooled in an ice bath and
trifluoroacetic acid (TFA) (20 mL) was added dropwise. The reaction
sample was dissolved in 10% DMSO and diluted further to the
concentrations of 1024, 256, 64, 16, 4, 1 μg mL−1. Each concentration of mixture was stirred at room temperature for 4 h, and the solvent was
the test sample (10 μL) was incubated at T = 37 °C with phosphate buffer removed under reduced pressure. Cool water (100 mL) was added to the
100 mM (pH = 6.8, 40 µL), α-glucosidase 0.4 U mL−1 (25 µL), p-nitro-
residue and the solid appeared was filtered, washed with distilled
phenyl α-D-glucopyranoside 2.5 mM (25 µL). After 30 min, the reaction water, recrystallized by ethanol/water (20/2) to give the product 4
was stopped by adding 100 µL of 0.1 M Na2CO3. The enzyme activities (5.1 g). Yield: 92.0 %, white solid; m.p. 199–201 °C. – 1H NMR (500 MHz,
DMSO-d6): δ = 10.48 (br s, 1H, 7′-H), 7.93 (br s, 2H, NH2), 7.85 (d,
were determined by measuring the absorbance at λmax = 405 nm. The
control was prepared using the same procedure replacing the tested J = 8.5 Hz, 2H, 2′-H, 6′-H), 7.48 (d, J = 8.5 Hz, 2H, 3′-H, 5′-H), 6.62 (d,
sample by distilled water, while activity of the reference was tested by J = 8.0 Hz, 1H, NH), 3.26–3.28 (1H, m, 1-H), 3.11 (m, 2H, 2″-H), 2.96(m, 2H,
1’’-H), 1.65–1.63 (m, 2H), 1.60–1.57 (m, 2H), 1.49–1.47(m, 1H), 1.24–1.17
(m, 2H,), 1.14–1.01 (m, 2H), 1.09–1.05 (m, 1H). – 13C NMR (125 MHz,
DMSO-d6): δ = 150.49 (C-8′), 142.78 (C-4′), 138.88 (C-1′), 129.20 (C-3′,
C-5′), 127.47 (C-2′, C-6′), 48.06 (C-1), 40.00 (C-2″), 32.74 (C-1’’), 32.24 (C-2,
C-6), 24.94 (C-4), 24.15 (C-3, C-5). – MS ((+)-ESI): m/z (%) = 325.9 (100)
[M+H]+. – MS ((−)-ESI): m/z (%) = 323.9 (100) [M−H]−.
replacing the sample with acarbose. Percentage of inhibition was
calculated as followed:
α − glucosidaseꢀinhibition
%
=
Abs( n egativecontrol) − Abs
Abs
( control)
(
)
[
( sample)]/
× 100%
4.3 Synthesis of tert-butyl(4-sulfamoylphenethyl)
4.6 General procedure for the preparation of
carbamate (2) [13]
sulfonylureas 5a–5l
4-(2-Aminoethyl)benzenesulfonamide (1) (4.0 g, 0.020 mol) was
dissolved in dimethylformamide (DMF) (75 mL). The solution was
cooled to 0–5 °C in an ice bath and solution of di-tert-butyl dicarbonate
(Boc2O) (4.8 g, 0.022 mol) was added. The ice bath was then removed to
allow the reaction to room temperature and kept for 4 h. The reaction
solution was then poured into 300 mL water. The white powder was
precipitated, filtered and dried to give 2 (5.7 g). Yield: 95.0%, white
powder; m.p. 180–182 °C. – 1H NMR (500 MHz, DMSO-d6): δ = 7.73 (d,
J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.26 (s, 2H), 6.89 (br s, 1H), 3.17 (q,
J = 7.0 Hz, 2H), 2.76 (t, J = 7.0 Hz, 2H), 1.36 (s, 9H). – 13C NMR (125 MHz,
DMSO-d6): δ = 155.45, 143.59, 141.94, 128.98, 125.56, 77.51, 40.00, 35.05,
28.16.
Appropriate carboxylic acid, (0.01 mol) was dissolved in anhydrous
acetone (50 mL) and triethylamine (1.42 mL, 0.01 mol). After 15 min at
0 °C, ethyl chloroformate (0.97 mL, 0.01 mol) was added dropwise and
the reaction was kept for 60 min, followed by addition of 4-
(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (4) (3.25 g,
0.01 mol) and triethylamine (1.42 mL, 0.01 mol) in anhydrous acetone
(20 mL). The resulting mixture was stirred for 4 h at room temperature.
Acetone was removed under reduced pressure, and the residue was
acidified with 5% HCl to pH ≈ 5. White solid product was collected and
washed with water and dried at 65 °C.
4.6.1 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}-
2-hydroxynicotinamide (5a): Yield: 72.0%, white powder; m.p. 170–
172 °C. – IR (film, KBr): ν = 3267 (NH), 3114 (OH), 2931.86, (–CH, alkane),
1669 (C=C, aromatic), 1543 (C=O, amide), 1424 (C=N), 1308 and 1147
(O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 12.43 (br s, 1H), 10.27
4.4 Synthesis of tert-butyl-{4-[N-(cyclohexylcarbamoyl)
sulfamoyl]phenethyl}carbamate (3) [14]
Compound 2 (5.1 g, 0.017 mol) and potassium carbonate (4.7 g, (br s, 1H), 9.83 (t, J = 5.5 Hz, 1H), 8.32 (dd, J = 2.5, 7.5 Hz, 1H), 7.81 (d,
0.034 mol) in acetone (200 mL) was refluxed for 1 h, followed by addition J = 8.5 Hz, 2H), 7.68 (br s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 6.46 (t, J = 6.5 Hz,
of cyclohexyl isocyanate (2.70 g, 0.022 mol). The reaction mixture was 1H), 6.30 (d, J = 8.0 Hz, 1H), 3.58 (q, J = 7.0 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H),

168
T.T. Bui et al.: Inhibitory activity of sulfonylurea derivatives
1.65–1.06 (10H, m). – 13C NMR (125 MHz, DMSO-d6): δ = 163.25, 162.20, 4.6.6 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}-
150.53, 145.08, 143.83, 139.31, 138.25, 129.14, 127.24, 120.23, 106.17, 4-methoxybenzamide (5f) [16]: Yield: 69.9%, white powder; m.p. 209–
48.02, 40.00, 35.05, 32.22, 24.94, 24.12. – MS ((+)-ESI): m/z (%) = 446.9 211 °C. – IR (film, KBr): ν = 3301(NH), 3454 (CH3), 2940 (–CH, alkane), 1684
(60) [M+H]+. – MS ((−)-ESI): m/z (%) = 444.9 (40) [M−H]−.
(C=C, aromatic), 1529 (C=O, amide), 1256 (C–O), 1340.43 and 1167.70
(O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 8.42 (t, J = 5.5 Hz, 1H),
7.81 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 6.98
(d, J = 8.5 Hz, 2H), 6.31 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 3.51 (q, J = 7.0 Hz,
2H), 2.94 (t, J = 7.0 Hz, 2H), 1.66–1.07 (m, 10H). – 13C NMR (125 MHz,
DMSO-d6): δ= 165.78, 161.48, 150.42, 145.42, 138.07, 129.20, 128.89, 127.24,
126.71, 113.44, 55.30, 48.07, 40.20, 34.92, 32.24, 24.95, 24.14. – MS
((−)-ESI): m/z (%) = 458.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 459.9
(50) [M+H]+.
4.6.2 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}benza-
mide (5b) [15]: Yield: 81.1%, white powder; m.p. 189–191 °C. – IR (film,
KBr): ν = 3344 (NH), 2934 (–CH, alkane), 1654 (C=C, aromatic, 1536 (C=O,
amide), 1343.91 and 1164.09 (O=S=O) cm−1. – 1H NMR (500 MHz,
DMSO-d6): δ = 10.27 (br s, 1H), 8.56 (t, J = 5.5 Hz, 1H), 7.82–7.78 (m, 4H),
7.53–7.42 (m, 5H), 6.30 (d, J = 7.5 Hz, 1H), 3.53 (q, J = 6.5 Hz, 2H), 2.95 (t,
J = 7 Hz, 2H), 1.65–1.06 (m, 10H). – 13C NMR (125 MHz, DMSO-d6):
δ = 166.25, 150.43, 145.31, 138.11, 134.5, 131.07, 129.20, 128.23, 127.26,
127.07, 48.03, 40.24, 34.81, 32.24, 24.95, 24.15. – MS ((−)-ESI): m/z (%) =
427.7 (100) [M−H]−. − MS ((+)-ESI): m/z (%) = 428.7 (70) [M+H]+.
4.6.7 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}-
2-iodobenzamide (5g): Yield: 78.1%, white powder; m.p. 160–162 °C. –
IR (film, KBr): ν = 3306 (NH), 2934 (–CH, alkane), 1681 (C=C, aromatic),
1534 (C=O, amide), 1335 and 1164 (O=S=O), 1244 (C–I) cm−1. – 1H NMR
(500 MHz, DMSO-d6): δ = 10.26 (s, 1H), 8.44 (t, J = 5.5 Hz, 1H), 7.85–7.79
(m, 3H), 7.50 (m, 1H), 7.42–7.39 (m, 2H), 7.21 (dd, J = 1.5 Hz, 8.0 Hz, 1H),
7.15–7.13 (m, 1H), 6.30 (br s, 1H), 3.50 (q, J = 7.0 Hz, 2H), 2.95 (t,
J = 7.0 Hz, 2H), 1.66–1.07 (m, 10H). – 13C NMR (125 MHz, DMSO-d6):
δ = 168.79, 150.53, 144.97, 143.03, 138.95, 130.54, 129.23, 129.08, 127.83,
127.79, 127.15, 93.24, 47.99, 41.08, 34.48, 32.23, 24.90, 24.09. – MS
((−)-ESI): m/z (%) = 553.9 (30) [M−H]−. – MS ((+)-ESI): m/z (%) = 555.9
(70) [M+H]+.
4.6.3 (E)-N-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl}-3-
(4-hydroxyphenyl)acrylamide (5c): Yield: 76.3%, white powder; m.p.
144–145 °C. – IR (film, KBr): ν = 3313 (OH), 2931.14 (NH), 2854 (–CH,
alkane), 1653, (C=C, aromatic, 1535 (C=O, amide), 1341 and 1159 (O=S=O)
cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 10.28 (br s, 1H, SO2NH), 9.80 (s,
1H, OH), 8.07(t, J= 6 Hz, 1H, CONH), 7.82 (d, J= 8.5 Hz, 2H, 2′-H, 6′-H), 7.46
(d, J = 8.5 Hz, 2H, 3′-H, 5′-H), 7.38 (d, J = 8.5 Hz, 2H, 2‴-H, 6‴-H), 7.32 (d,
J = 15.5 Hz, 1H, 7‴-H), 6.79 (d, J = 8.5 Hz, 2H, 3‴-H, 5‴-H), 6.37 (d,
J =15.5Hz, 1H, 8‴-H), 6.32 (d, J = 8.0 Hz, 1H, CONH), 3.45 (q, J = 7.0 Hz, 2H,
2″-H), 2.88 (t, J = 7.0 Hz, 2H, 1″-H), 1.66–1.64 (m, 2H), 1.60–1.57 (m, 2H),
1.50–1.47 (m, 1H), 1.25–1.17 (m, 2H), 1.15–1.06 (m, 4H). – 13C NMR
(125 MHz, DMSO-d6): 165.43 (CONH), 158.78 (C-4‴), 150.45 (C-8′), 145.27
(C-4′), 138.73 (C-7‴), 138.13 (C-1′), 129.16 (2C, C-2‴, C-6‴), 129.14 (2C, C-3’’,
C-5’’), 127.22 (2C, C-2′, C-6′), 125.84, 118.49, 115.68 (2C, C-3‴, C-5‴), 48.03
(C-1), 40.00 (C-2″), 34.92 (C-1″), 32.23 (C-2, C-6), 24.93, 24.11 (C-3, C-5). –MS
((+)-ESI): m/z (%) = 472.3 [M+H]+.
4.6.8 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}-
2-hydroxy-3,5-diiodobenzamide (5h): Yield: 69.3%, white powder; m.p.
178–180 °C. – IR (film, KBr): ν = 3745 (OH phenol), 3297 (NH), 2929 (–CH,
alkane), 1682 (C=C, aromatic), 1537 (C=O, amide), 1329 and 1161 (O=S=O),
1274, 1252 (C–I) cm−1. –1H NMR (500 MHz, DMSO-d6): δ=13.95(s, 1H), 10.27
(s, 1H, SO2NH), 9.27 (s, 1H, CONH), 8.17 (d, J = 2.0 Hz, 1H, 6‴-H), 8.15 (s, 1H,
4‴-H), 7.82 (d, J = 8.5 Hz, 2H, 2′-H, 6′-H), 7.47 (d, J = 8.5 Hz, 2H, 3′-H, 5′-H),
6.31 (d, J= 7.5 Hz, 1H, CONH), 3.56 (q, J= 7.0 Hz, 2H, 2″-H), 2.96 (q, J=7.0Hz,
2H, 1’’-H), 1.64–1.62 (m, 2H), 1.58–1.56 (m, 2H),1.49–1.46 (m, 1H), 1.24–1.17
(m, 2H), 1.14–1.06 (m, 3H). – 13C NMR (125 MHz, DMSO-d6): δ = 168.04
(CONH), 159.87 (C-2‴), 150.33 (CONH), 149.31 (C-6‴), 144.77 (C-4′), 138.22
(C-1′), 135.11 (C-4‴), 129.16 (C-3′, C-5′), 127.27 (C-2′, C-6′), 88.82 (C-3‴), 81.12
(C-5‴), 48.00 (C-1), 40.28 (C-2″), 34.21 (C-1″), 32.18 (C-2, C-6), 24.92 (C-4),
24.08 (C-3, C-5). – MS ((−)-ESI): m/z (%) = 695.8 (15) [M−H]−. – MS ((+)-ESI):
m/z (%) = 697.7 (15) [M+H]+.
4.6.4 N-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl}cinnama-
mide (5d) [16]: Yield: 74.1%, white powder; m.p. 163–164 °C. – IR (film,
KBr): ν = 3345 (NH), 2935 (–CH, alkane), 1654 (C=C, aromatic), 1540 (C=O,
1
amide), 1341 and 1162 (O=S=O) cm−1. – H NMR (500 MHz, DMSO-d6):
δ = 7.91 (d, J = 8.5 Hz, 2H), 7.56–7.55 (m, 3H), 7.49 (d, J = 8.5 Hz, 2H), 7.41
(d, J = 16.5 Hz, 1H), 7.42–7.37(m, 3H), 6.57 (d, J = 16.00 Hz, 1H), 3.61 (t,
J = 7.0 Hz, 2H), 3.46–3.41(m, 1H), 3.00 (t, J = 7.0 Hz, 2H), 1.79–1.15 (m,
10H). – 13C NMR (125 MHz, DMSO-d6): δ = 164.94, 150.44, 145.18, 138.59,
138.16, 134.84, 129.36, 129.13, 128.85, 127.44, 127.22, 122.06, 48.01, 40.00,
34.83, 32.21, 24.92, 24.10. – MS ((−)-ESI): m/z (%) = 454.0 (100) [M−H]−. –
MS ((+)-ESI): m/z (%) = 455.9 (40) [M+H]+, 478.1 (100) [M+Na]+.
4.6.9 N-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl}isoquino-
line-1-carboxamide (5i): Yield: 72.0%, white powder; m.p. 123–
124 °C. – IR (film, KBr): ν = 3351 (NH), 2931 (–CH, alkane), 1662 (C=C,
aromatic), 1531 (C=O, amide), 1341 and 1161(O=S=O) cm−1. – 1H NMR
(500 MHz, DMSO-d6): δ = 8.93 (t, J = 5.5 Hz, 1H), 8.72 (d, J = 8.5 Hz, 1H),
8.51 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 5.5 Hz, 1H),
7.81 (d, J = 8.0 Hz, 2H), 7.79 (t, J = 8.5 Hz, 1H), 7.68 (t, J = 8.5 Hz, 1H),
7.49 (d, J = 8.0 Hz, 1H), 6.30 (d, J = 6.5 Hz, 1H), 3.65 (q, J = 7.0 Hz, 3H),
3.00 (t, J = 7 Hz, 2H), 1.64–1.05 (m, 10H). – 13C NMR (125 MHz, DMSO-
d6): δ = 166.15, 151.38, 140.81, 136.49, 130.62, 129.17, 128.28, 127.18,
127.03, 126.54, 125.40, 123.18, 48.06, 40.00, 34.82, 32.33, 25.00,
24.19. – MS ((−)-ESI): m/z (%) = 479.0 (100) [M−H]−. – MS ((+)-ESI): m/
z (%) = 481.0 (40) [M+H]+.
4.6.5 4 Amino-N-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl}
benzamide (5e): Yield: 76.3%, white powder; m.p. 165–166 °C. – IR
(film, KBr): ν = 3440 (NH2), 3336 (NH), 2931 (–CH, alkane), 1688 (C=C,
aromatic), 1533 (C=O, amide), 1335 and 1158 (O=S=O) cm−1. – 1H NMR
(500 MHz, DMSO-d6): δ = 10.27 (s, 1H), 8.09 (t, J = 5.5 Hz, 1H), 7.80 (d,
J = 8.5 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 6.52 (d,
J = 8.5 Hz, 2H), 6.31 (d, J = 7.5 Hz, 1H), 5.56 (br s, 2H), 3.46 (q, J = 7.0 Hz,
2H), 2.90 (t, J = 7.0 Hz, 2H), 1.65–1.06 (m, 10H). – 13C NMR (125 MHz,
DMSO-d6): δ = 166.25, 151.50, 150.37, 145.55, 137.98, 129.12, 128.57,
127.20, 121.19, 112.48, 48.02, 40.00, 35.12, 32.22, 24.93, 24.11. – MS
((−)-ESI): m/z (%) = 443.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 445.0
(60) [M+H]+, 467.0 (100) [M+Na]+.

T.T. Bui et al.: Inhibitory activity of sulfonylurea derivatives
169
4.6.10 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}-
(t, J = 3.5 Hz, 1H, SO2NH), 8.96 (d, J = 5.0 Hz, 1H,), 8.27 (d, J = 7.5 Hz, 1H),
3-methylpicolinamide (5k): Yield: 74.0%, white powder; m.p. 120– 7.78 (d, J = 8.0 Hz, 2H), 7.77 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 6.28
121 °C. – IR (film, KBr): ν = 3345 (NH), 2938 (–CH, alkane), 1673 (C=C, (d, J = 7.5 Hz, 1H, CONH), 3.88 (t, J = 7.5 Hz, 2H), 3.03 (t, J = 7.5 Hz, 3H),
aromatic), 1534 (C=O, amide), 1354 and 1163 (O=S=O) cm−1. – 1H NMR 1.65–1.62(m, 2H), 1.8–1.56 (m, 1H), 1.49–1.46 (m, 1H), 1.23–1.18 (m, 2H),
(500 MHz, DMSO-d6): δ = 8.68 (t, J = 6.0 Hz, 1H), 8.41 (d, J = 4.5 Hz, 1H), 1.10–1.06 (m, 3H). – 13C NMR (125 MHz, DMSO-d6, 25 °C, TMS):
7.81 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), δ = 166.03, 165.93, 154.08, 151.31, 150.47, 143.90, 138.50, 131.22, 129.21,
7.42 (dd, J = 4.5, 8.0 Hz, 1H), 6.32 (d, J = 7.5 Hz, 1H), 3.55 (q, J = 7.0 Hz, 127.83, 127.32, 127.08, 48.03, 40.00, 38.37, 32.21, 24.94, 24.12. – MS
2H), 2.94 (t, J = 7.0 Hz, 2H), 2.46 (s, 3H), 1.65–1.16 (m, 10H). – 13C NMR ((−)-ESI): m/z (%) = 455.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 456.9
(125 MHz, DMSO-d6): δ = 166.00 (CONH), 150.36, 149.24, 145.69, 145.20, (40) [M+H]+.
140.03, 138.07, 133.05, 129.13, 127.16, 125.28, 48.00, 40.00, 34.81, 32.19,
24.90, 24.07, 19.09. – MS ((−)-ESI): m/z (%) = 443.0 (100) [M−H]−. – MS
4.7.3 3-({4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}carba-
moyl)picolinic acid (5o): Yield: 72.5%, white powder; m.p. 174–
((+)-ESI): m/z (%) = 444.9 (60) [M+H]+.
176 °C. – IR (film, KBr): ν = 3742 (OH), 3324 (NH), 2936 (–CH, alkane),
1721 (C=O, acid), 1653 (C=C, aromatic), 1540 (C=O, amide), 1338 and
1163 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 8.76 (t,
J = 5.5 Hz, 1H, CONH), 8.66 (dd, J = 1.5, 5.0 Hz, 1H, 6‴-H), 8.05 (dd,
J = 1.5, 8.0 Hz, 1H, 4‴-H), 7.82 (d, J = 8.5 Hz, 2H, 2′-H, 6′-H), 7.60 (dd,
J = 4.5, 7.5 Hz, 1H, 5‴-H), 7.49 (d, J = 8.5 Hz, 2H, 3′-H, 5′-H), 6.36 (d,
J = 7.5 Hz, 1H, CONH), 3.54–3.50 (m, 3H, 1-H, 2″-H), 2.95 (t, J = 7.5 Hz,
2H, 1″-H), 1.65–1.62 (m, 2H), 1.58–1.56 (m, 2H), 1.13–1.16 (m, 2H), 1.23–
1.17 (m, 2H), 1.09–1.07 (m, 2H). – 13C NMR (125 MHz, DMSO-d6):
δ = 167.90 (COOH), 165.06 (C-7‴), 150.42 (C-2‴), 150.17 (C-3‴), 149.57
(C-6‴), 145.14 (C-4′), 138.13 (C-1′), 136.77 (C-4‴), 129.11 (C-2′, C-6′),
127.22 (C-3′,C-5′), 125.14 (C-5‴), 48.02 (C-1), 39.83 (C-2″, 34.55 (C-1″),
32.20 (C-2, C-6), 24.92 (C-4), 24.08 (C-3, C-5). – MS ((−)-ESI): m/z
(%) = 473.0 (20) [M−H]−. – MS ((+)-ESI): m/z (%) = 474.8 (70) [M+H]+.
4.6.11 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}quinoxa-
line-2-carboxamide (5l) [17]: Yield: 76.1%, white powder; m.p. 197–
199 °C. – IR (film, KBr): ν = 3324 (NH), 2942 (–CH, alkane), 1687 (C=C,
aromatic), 1530 (C=O, amide), 1338 and 1163 (O=S=O) cm−1. – 1H NMR
(500 MHz, DMSO-d6): δ = 9.44 (s, 1H), 9.16 (t, J = 5.5 Hz, 1H), 8.18 (dd,
J = 3.5, 6.0 Hz, 2H), 7.98 (m, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.48 (d,
J = 8.0 Hz, 2H), 6.26 (d, J = 5.5 Hz, 1H), 3.65 (q, J = 7.5 Hz, 2H), 3.02 (t,
J = 7.5 Hz, 2H), 1.63–1.15 (m, 10H). – 13C NMR (125 MHz, DMSO-d6):
δ = 163.14, 144.30, 143.63, 142.94, 139.77, 131.85, 131.26, 129.38,
129.07, 127.20, 48.02, 40.00, 34.77, 32.31, 24.98, 24.16. – MS ((−)-ESI):
m/z (%) = 480.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 481.9 (70)
[M+H]+.
4.7 General procedure for the preparation of
sulfonylureas 5m, 5n, 5o
4.8 Synthesis of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-
5-methylpyrazin carboxamide (6) [19]
Phthalic anhydride or 2,3-pyridinedicarboxylic anhydride (0.01 mol)
in glacial acetic acid (30 mL) was added 4-(2-aminoethyl)-N-(cyclo-
hexylcarbamoyl)benzenesulfonamide (4) (0.01 mol). The reaction
mixture was refluxed for 7 h and the reaction was cooled to room
temperature. The white solid was filtered and washed with water,
recrystallized in ethanol/water to obtain pure product 5m or 5n.
2,3-pyridinedicarboxylic anhydride (0.01 mol) in glacial acetic
acid (30 mL) was added 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)
benzenesulfonamide (4) (0.01 mol). The reaction mixture was stirred
at room temperature for 1 h. The white solid was filtered and washed
with water, recrystallized in ethanol/water to obtain 5o.
To a stirred solution of 5-methyl-pyrazin-2-carboxylic acid (0.01 mol) in
anhydrous acetone (50 mL) and triethylamine (1.42 mL, 0.01 mol) at
0 °C, ethyl chloroformate (0.97 mL, 0.01 mol) was added dropwise and
the reaction was further stirred for 60 min. A solution of 4-
(2-aminoethyl)-benzenesulfonamide (2.0 g, 0.01 mol) and triethylamine
(1.42 mL, 0.01 mol) in anhydrous acetone was then added. The resulting
mixture was stirred for 3 h at room temperature. Acetone was then
removed, and the residuewas acidifiedwith5%HCltopH ≈ 5. The white
solid was collected and washed with distilled water. Pure product (6)
was obtained by recrystallization from ethanol (2.99 g).
Yield: 93.4%, brown powder; m.p. 237–239 °C. – IR (film, KBr):
ν = 3309 (NH), 1695 (C=C, aromatic), 1528 (C=O, amide), 1340 and 1158
1
(O=S=O) cm−1. – H NMR (500 MHz, DMSO-d6): δ = 9.02 (s, 1H), 8.91 (t,
4.7.1 2-((4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl)carba-
moyl)benzoic acid (5m) [18]: Yield: 81.5%, white powder; m.p. 161–
163 °C. – IR (film, KBr): ν = 3071 (OH), 3349 (NH), 2935 (-CH, alkane), 1718
(C=O, acid), 1655 (C=C, aromatic), 1536 (C=O, amide), 1342 and 1122
(O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 10.24 (s, 1H), 7.85–7.81
(m, 4H), 7.78 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.31 (d, J = 8.0 Hz,
1H), 3.85 (t, J = 7.0 Hz, 2H), 3.46 (q, J = 7.0 Hz, 1H), 3.03 (t, J = 7.0 Hz, 2H),
1.64–1.05 (m, 10H). – 13C NMR (125 MHz, DMSO-d6): δ = 168.55, 167.60,
150.35, 144.02, 138.36, 134.40, 131.43, 131.11, 129.22, 127.49, 123.01, 48.03,
40.00, 38.25, 33.25, 34.51, 24.94, 24.13. – MS ((−)-ESI): m/z (%) = 471.9
(100) [M−H]−. – MS ((+)-ESI): m/z (%) = 474.0 (100) [M+H]+.
J=6.0Hz, 1H, CONH),8.59(s, 1H), 7.73(d,J= 8.0 Hz, 2H), 7.42 (d, J=8.0Hz,
2H), 7.27 (s, 2H, SO2NH2), 3.57 (q, J = 7.0 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H), 2.58
(s, 3H, CH3). – 13C NMR (125 MHz, DMSO-d6): δ = 162.99 (CONH); 156.85
(CONH), 143.54, 142.83, 142.36, 142.04, 129.08, 126.55, 125.68, 40.0, 34.65,
21.31(CH3). – MS ((−)-ESI): m/z (%) = 319 (100) [M−H]−. – MS ((+)-ESI): m/z
(%) = 321 (100) [M+H]+.
4.9 Synthesis of ethyl-({4-[2-(5-methylpyrazine-
2-carboxamido)ethyl]phenyl}sulfonyl)-carbamate
(7)
4.7.2 N-(Cyclohexylcarbamoyl)-4-{2-(5,7-dioxo-5,7-dihydro-6H-
pyrrolo[3,4-b]pyridin-6yl)-ethyl}benzenesulfonamide (5n): Yield: N-(4-sulfamoylphenethyl) carboxamide derivatives (6) (0.01 mol) were
66.1%, white powder; m.p. 224–226 °C. – IR (film, KBr): ν = 3309 (NH), mixed with a solution of ethyl chloroformate (1.23 mL, 0.013 mol),
2918 (–CH, alkane), 1709 (C=C, aromatic), 1531 (C=O, amide), 1341and anhydrous potassium carbonate (2.0 g, 014 mmol) in dry acetone
1163 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6, 25 °C, TMS): δ = 10.27 (300mL). Thereactionwasrefluxedfor 4 h andthesolventwas removed

170
T.T. Bui et al.: Inhibitory activity of sulfonylurea derivatives
under reduced pressure. The residue was suspended in water (100 mL), 7.33 (d, J = 7.5 Hz, 1H), 3.66 (t, J = 7.5 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.61
neutralized with 1% HCl. The white solid was filtered and washed with (s, 3H). – 13C NMR (125 MHz, DMSO-d6): δ = 165.57, 158.6, 144.54, 144.37,
distilled water to obtain 3.5 g of the desired product 7. Yield: 89.2%, 143.44, 136.76, 130.21, 129.98, 128.79, 128.76, 128.67, 128.49, 127.7, 121.94,
brown powder; m.p. 159–161 °C. – IR (film, KBr): ν = 3349 (NH), 1743 117.15, 41.55, 36.28, 21.55. – MS ((+)-ESI): m/z (%) = 533.0 (100) [M+H]+. –
(C=O, carbamate), 1660 (C=C, aromatic), 1518 (C=O, amide), 1340 and MS ((−)-ESI): m/z (%) = 531.0 (100) [M−H]−.
1160 (O=S=O), 1229 (C–O, carbamate) cm−1. – 1H NMR (500 MHz, DMSO-
d6): δ = 9.01 (d, J = 1.5 Hz, 1H, 3‴-H), 8.92 (t, J = 6.0 Hz, 1H, CONH), 8.58
(s, 1H, 6‴-H), 7.80 (d, J = 8.5 Hz, 2H, 2′-H, 6′-H), 7.48 (d, J = 8.5 Hz, 2H,
3′-H, 5′-H), 3.99 (q, J = 7.0 Hz, 2H, COOCH2CH3), 3.59 (q, J = 7.0 Hz, 2H,
2″-H), 2.98 (t, J = 7.0 Hz, 2H, 1″-H), 2.57 (s, 3H, CH3), 1.07 (t, J = 7.0 Hz, 3H,
COOCH2CH3). – 13C NMR (125 MHz, DMSO-d6): δ = 162.96 (CONH), 156.77
(C-5‴), 151.01 (NHCOOCH2CH3), 145.65 (C-4′), 142.75 (C-3’’’), 142.33
(C-6‴), 142.01 (C-2‴), 137.09 (C-1′), 129.32 (2C, C-3′, C-5′), 127.43 (2C, C-6′,
C-2′), 61.83 (COOCH2CH3), 40.0 (C-2″), 34.65 (C-1″), 21.25 (CH3-5‴), 13.88
(COOCH2CH3).
4.10.4 N-(4-{N-[(3-Fluoro-4-methoxyphenyl)carbamoyl]sulfamoyl}
phenethyl)-5-methylpyrazine-2-carboxamide (8d): Yield: 81.9%,
white powder; m.p. 181–182 °C. – IR (film, KBr): ν = 3298 (NH), 1650,
(C=C, aromatic), 1521 (C=O, amide), 1223 (C–O), 1341 and 1161 (O=S=O)
cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.01 (d, J = 1.5, Hz, 1H), 8.93 (t,
J = 6.0 Hz, 1H), 8.80 (s, 1H), 8.57 (d, J = 1.0 Hz, 1H), 7.86 (d, J = 8.5 Hz,
1H), 7.47 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 2.5, 13.5 Hz, 1H), 7.05 (d,
J = 13.0 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H) 3.77 (s, 3H), 3.59 (q, J = 7.0 Hz,
2H), 2.97 (t, J = 7.0 Hz, 2H), 2.57 (s, 3H). – 13C NMR (125 MHz, DMSO-d6):
δ = 162.99, 158.08, 156.85, 143.53, 142.83, 142.36, 142.04, 129.21, 129.08,
127.47, 125.68, 116.11, 114.15, 111.85, 109.34, 57.01, 34.76, 34.64, 21.30. –
MS ((+)-ESI): m/z (%) = 487.9 (60) [M+H]+. – MS ((−)-ESI): m/z
(%) = 485.9 (100) [M−H]−.
4.10 General procedure for the preparation of
sulfonylurea derivatives (8a–h)
Carbamate derivatives (7) (0.01 mol) and amines (0.011 mol) in toluene
was refluxed for 4 h. The reaction was then allowed to cool to room
temperature. The solid was filtered, washed with water and recrys-
tallized in ethanol.
4.10.5 5-Methyl-N-[4-(N-{[4-nitro-3(trifluoromethyl)phenyl]
carbamoyl}sulfamoyl)phenethyl]pyrazine-2-carboxamide (8e): Yield:
68.4%, white powder; m.p. 182–183 °C. –IR (film, KBr): ν = 3371 (NH), 1662
(C=C, aromatic), 1547 (C=O, amide), 1494 (NO2), 1346 and 1149 (O=S=O),
1182 (CF3) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.73 (s, SO2NH, 1H),
9.00 (s, H-3‴, 1H), 8.93 (t, J = 6.0 Hz, CONH), 8.57 (s, H-6’’’, 1H), 8.12 (d,
J= 9.0 Hz, 1H, H-5), 8.02 (d, J= 2.0 Hz, 1H, H-2), 7.88 (d, J= 8.0 Hz, 2H, H-2′,
H-6′), 7.80 (dd, J = 2.5, 8.0 Hz, 1H, H-6), 7.50 (d, J = 8.0 Hz, 2H, H-3′, H-5′),
3.59 (q, J = 7.0 Hz, 2H, H-2″), 2.97 (t, J = 7.0 Hz, 2H, H-1″), 2.56 (s, 3H,
CH3). –13C NMR (125 MHz, DMSO-d6): δ=163.01(C-7′), 156.86 (C-8′), 154.33
(C-5‴), 143.54 (C-2‴), 142.84 (C-4′), 142.80 (C- 6‴), 142.36 (C-3‴), 133.77
(C-1), 129.64 (C-3), 129.09 (2C, C-3′, C-5′), 127.55 (C-2), 125.69 (2C, C-2′, C-6′),
125.17 (C-5), 124.92 (C-4), 123.58 (CF3), 121.41 (C-1′), 114.48 (C-6), 40.00
(C-2″), 34.78 (C-1″), 21.3 (CH3). – MS ((+)-ESI): m/z (%) = 552.9 (100)
[M+H]+. – MS ((−)-ESI): m/z (%) = 550.9 (100) [M−H]−.
4.10.1 5-Methyl-N-{4-[N-(phenethylcarbamoyl)sulfamoyl]phenethyl}
pyrazine-2-carboxamide (8a): Yield: 74.9%, white powder; m.p. 191–
193 °C. – IR (film, KBr): ν = 3347 (NH), 1674 (C = C, aromatic), 1536
1
(C=O, amide), 1341 and 1167 (O=S=O) cm−1. – H NMR (500 MHz,
DMSO-d6): δ = 9.01 (d, J = 1.0 Hz, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.57 (d,
J = 1.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.26–
7.10 (m, 5H), 3.58 (q, J = 7.0 Hz, 2H), 3.16 (q, J = 7.0 Hz, 2H), 2.95 (t,
J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.56 (s, 3H). – 13C NMR
(125 MHz, DMSO-d6): δ = 162.98, 156.78, 142.78, 142.34, 142.03,
139.21, 137.27, 128.60, 128.58, 128.25, 126.98, 126.0, 40.81, 35.33,
34.70, 33.12, 21.27. – MS ((+)-ESI): m/z (%) = 467.9 (100) [M+H]+. –
MS ((−)-ESI): m/z (%) = 465.9 (100) [M−H]−.
4.10.6 N-(4-[N-(Cyclopentylcarbamoyl)sulfamoyl]phenethyl)-
5-methylpyrazine-2-carboxamide (8f): Yield: 76.4%, white powder;
m.p. 202–203 °C. – IR (film, KBr): ν = 3325 (NH), 2957 (CH, alkane), 1683
(C=C, aromatic) 1530 (C=O, amide), 1333 and 1160 (S=O=S) cm−1. – 1H
NMR (500 MHz, DMSO-d6): δ = 9.02 (d, J = 1.5 Hz, 1H), 8.93 (t, J = 6.0 Hz,
1H), 8.59 (d, J = 1.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz,
1H), 6.38 (d, J = 7.0 Hz, 1H), 3.77–3.70 (m, 1H), 3.58 (q, J = 7.5 Hz, 2H),
2.97 (t, J = 7.5 Hz, 2H), 2.57 (s, 3H), 1.75–1.68 (m, 2H), 1.58–1.52 (m, 2H),
1.49–1.42 (m, 2H), 1.29–1.23 (m, 2H). – 13C NMR (125 MHz, DMSO-d6):
δ = 162.99, 156.79, 150.82, 145.03, 142.79, 142.35, 142.03, 138.2, 129.13,
127.23, 51.00, 40.00, 34.7, 32.29, 23.05, 21.28. – MS ((+)-ESI): m/z
(%) = 431.9 (60) [M+H]+. – MS ((−)-ESI): m/z (%) = 430.0 (100) [M−H]−.
4.10.2 5-Methyl-N-(4-{N-[(2,3,4-trifluorophenyl)carbamoyl]
sulfamoyl}phenethyl)pyrazine-2-carboxamide (8b): Yield: 84.2%,
white powder; m.p. 179–180 °C. – IR (film, KBr): ν = 3327 (NH), 1651
(C=C, aromatic), 1529 (C=O, amide), 1348 and 1160 (O=S=O) cm−1. – 1H
NMR (500 MHz, DMSO-d6): δ = 10.98 (s, 1H), 9.02 (dd, J = 1.5, 9.5 Hz,
1H), 8.93 (t, J = 6.0 Hz, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 7.87 (d, J = 8.0 Hz,
2H), 7.48 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz,
1H), 3.58 (q, J = 6.5 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H), 2.58 (s, 3H). – 13C NMR
(125 MHz, DMSO-d6): δ = 162.99, 156.84, 143.54, 142.82, 142.36, 142.04,
140.5, 140.25, 140.04, 139.89, 138.59, 134.62, 129.07, 125.68, 111.6,
111.47, 40.0, 34.65, 21.31. – MS ((+)-ESI): m/z (%) = 494.0 (100)
[M+H]+. – MS ((−)-ESI): m/z (%) = 491.9 (100) [M−H]−.
4.10.7 N-(4-{N-[(2-Hydroxy-4-nitrophenyl)carbamoyl]sulfamoyl}
phenethyl)-5-methylpyrazine-2-carboxamide (8g): Yield: 76.9%,
white powder; m.p. 196–198 °C. – IR (film, KBr): ν = 3399 (OH), 3234
4.10.3 N-[4-(N-{[4-Cyano-3-(trifluoromethyl)phenyl]carbamoyl}
sulfamoyl)phenethyl]-5-methylpyrazine-2-carboxamide (8c): Yield: (NH), 1655 (C=C, aromatic, 1538 (C=O, amide), 1425 (NO2), 1327 and
71.9%, white powder; m.p. 165–166 °C. – IR (film, KBr): ν = 3356 (NH), 1185 (O=S=O), 1153 (C–N) cm−1. – 1H NMR (500 MHz, DMSO-d6):
2227 (C=N), 1658 (C=C, aromatic), 1529 (C=O, amide), 1333 and 1149 δ = 11.24 (s, 2H), 9.0 (d, J = 1.5 Hz, 1H), 8.93 (t, J = 6.0 Hz), 8.77 (s, 1H),
(O=S=O), 1183 (CF3) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.03 (s, 8.57 (d, J = 0.5 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H),
1H), 8.50 (s, 1H), 7.96 (br s, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.84 (d, J = 8.5 Hz, 7.70 (dd, J = 2.5, 9.0 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 8.5 Hz,
1H), 7.64 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 2H), 2H), 3.57 (q, J = 7.0 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.56 (s, 3H). – 13C NMR

T.T. Bui et al.: Inhibitory activity of sulfonylurea derivatives
171
(125 MHz, DMSO-d6): δ = 162.99, 156.82, 145.81, 145.51, 143.51, 142.80,
142.77, 142.40, 142.34, 142.03, 135.51, 129.05, 125.66, 118.26, 111.14,
108.62, 40.00, 34.75, 21.26. – MS ((+)-ESI): m/z (%) = 501.0 (100)
[M+H]+. – MS ((−)-ESI): m/z (%) = 498.8 (20) [M−H]−.
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5-methylpyrazine-2-carboxamide (8h): Yield: 84.2%, white powder;
m.p. 199–200 °C. – IR (film, KBr): ν = 3339 (NH), 1650 (C=C, aromatic), 1533
(C=O, amide), 1336 and 1163 (O=S=O) cm−1. –1H NMR (500 MHz, DMSO-d6):
δ = 9.02 (d, J = 1.0 Hz, 1H), 8.94 (t, J = 6.0 Hz, 1H), 8.59 (s, 1H), 7.81 (d,
J = 8.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 7.0 Hz, 2H), 7.19 (t,
J = 7.0 Hz, 1H), 7.13 (d, J = 7.0 Hz, 2H), 6.97 (t, J = 6.0 Hz, 1H), 4.15 (d,
J = 6.0 Hz, 2H), 3.59 (q, J = 6.5 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.57 (s, 3H). –
13C NMR (125 MHz, DMSO-d6): δ = 163.10, 156.88, 151.63, 145.14, 142.86,
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40.00, 34.77, 21.33. – MS ((−)-ESI)): m/z (%) = 451.9 (100) [M−H]−. – MS
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Suppoting information
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Author contribution: All the authors have accepted
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Research funding: None declared.
Conflict of interest statement: The authors declare no
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