Synthesis and antimicrobial activity of some new amido/sulfonamido-linked 3,4-disubstituted pyrroles

Article abstract of DOI:10.1007/s00044-014-0908-1

A new series of pyrrolyl carboxamides, pyrrolyl sulfonamides, and pyrrolyl pyrimidine derivatives were prepared from simple starting compounds-ethyl 3-phenylacrylate and ethyl 3-furanylacrylate under ultrasonication and screened for their antimicrobial ac

Full text of DOI:10.1007/s00044-014-0908-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-0908-1
ORIGINAL RESEARCH
Synthesis and antimicrobial activity of some new amido/
sulfonamido-linked 3,4-disubstituted pyrroles
•
Kaveri Syamaiah Guda Mallikarjuna Reddy
•
•
Venkatapuram Padmavathi Adivireddy Padmaja
Received: 23 September 2013 / Accepted: 4 January 2014
Ó Springer Science+Business Media New York 2014
Abstract A new series of pyrrolyl carboxamides, pyrrolyl
sulfonamides, and pyrrolyl pyrimidine derivatives were pre-
pared from simple starting compounds—ethyl 3-phenylacry-
late and ethyl 3-furanylacrylate under ultrasonication and
screened for their antimicrobial activity. Among the tested
compounds pyrrolyl pyrimidine derivatives and chloro-
substituted pyrroles displayed excellent activity when com-
pared to the other compounds. The chloro-substituted pyrrolyl
sulfonamides are the potent antimicrobial agents particularly
against P. aeruginosa and P. chrysogenum.
antibiotics (Neidle, 2001; Wemmer, 2001) which have
carboxamide group. The sulfonamide –SO2NH– group
occurs in numerous biologically active compounds, which
include antimicrobial drugs, saluretics, carbonic anhydrase
(CA) inhibitors, insulin-releasing sulfonamides, antithyroid
agents, and antitumor drugs (Anand, 1996; Supuran and
Scozzafava, 2002; Scozzafava et al., 2003). The sulfona-
mides constitute an important class of inhibitors of the zinc
enzyme CA (Chegwidden et al., 2000) due to their use in
antiglaucoma therapy (Sugrue, 1989, 1997; Maren et al.,
2000; Supuran and Scozzafava, 2001). The classical
methods, such as the Knorr, Hantzsch, and Parr–Knorr
syntheses, are widely used for the preparation of pyrroles.
Pyrroles have also been prepared from Michael acceptors
and tosylmethyl isocyanide (TosMIC) (Leusen et al., 1972;
Padmavathi et al., 2004). Thus, the literature reflects that
there is a constant strive for the development of a variety of
heterocycles of pharmacological potency. Based on these
observations and our continued interest in the synthesis and
study of pharmacologically active heterocycles (Mural-
ikrishna et al., 2012; Padmavathi et al., 2011; Padmaja
et al., 2009), we designed the present work to prepare a
new class of amide/sulfonamide-linked pyrroles and to
study their antimicrobial properties (Figs. 1, 2).
Keywords Aryl acrylate ꢀ Pyrrole derivatives ꢀ
Antimicrobial activity ꢀ Amide ꢀ Sulfonamide
Introduction
Among nitrogen-containing heterocyclic compounds pyr-
role is one of the most popular core units in many natural
products, synthetic pharmaceuticals, and useful building
blocks for various biologically active molecules and
functional materials (Abele et al., 2004; Leeper and Kelly,
2013; Cadierno and Crochet, 2008). Pyrroles and their
derivatives have extensive biological activities such as
antibacterial (Daidone et al., 1990), anti-inflammatory
(Kaiser and Glenn, 1972), antioxidant (Demir et al., 2002),
antitumor, antifungal (Meshram et al., 2010), and immune
suppressant activities (Davis et al., 2008). Netropsin,
Distamycin-A, and NetAmsa are naturally occurring
Results and discussion
Chemistry
A new series of pyrrole-linked amido/sulfonamido units
were synthesized utilizing the Michael acceptors ethyl
3-phenylacrylate (1) and ethyl 3-furanylacrylate (2). The
treatment of 1 and 2 with TosMIC in a solvent mixture of
DMSO and dry ether resulted 4-phenyl-1H-pyrrole-3-
K. Syamaiah ꢀ G. Mallikarjuna Reddy ꢀ V. Padmavathi ꢀ
A. Padmaja (&)
Department of Chemistry, Sri Venkateswara University,
Tirupati 517 502, Andhra Pradesh, India
e-mail: adivireddyp@yahoo.co.in
123

Med Chem Res
Staphylococcus aureus 12.5 µg/well
Staphylococcus aureus 25 µg/well
Staphylococcus aureus 50 µg/well
Staphylococcus aureus 100 µg/well
Bacillus subtilis 12.5 µg/well
Fig. 1 The in vitro antibacterial
activity of compounds 7–20
45
40
35
30
25
20
15
10
5
Bacillus subtilis 25 µg/well
Bacillus subtilis 50 µg/well
Bacillus subtilis 100 µg/well
Pseudomonas aeruginosa 12.5 µg/well
Pseudomonas aeruginosa 25 µg/well
Pseudomonas aeruginosa 50 µg/well
Pseudomonas aeruginosa 100 µg/well
Klebsiella pneumoniae 12.5 µg/well
0
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Klebsiella pneumoniae 25 µg/well
Klebsiella pneumoniae 50 µg/well
Klebsiella pneumoniae 50 µg/well
Control (DMSO
Chloamphenicolr
Tested Compounds
Klebsiella pneumoniae 100 µg/well
40
35
30
25
20
15
10
5
Fig. 2 The in vitro antifungal
activity of compounds 7–20
Aspergillus niger 12.5 µg/well
Aspergillus niger 25 µg/well
Aspergillus niger 50 µg/well
Aspergillus niger 100 µg/well
Pencillium chrysogenum 12.5 µg/well
Pencillium chrysogenum 25 µg/well
Pencillium chrysogenum 50 µg/well
Pencillium chrysogenum 100 µg/well
0
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Ketoconazole
Control (DMSO)
Tested Compounds
carboxylic acid ethyl ester (3) and 4-furanyl-1H-pyrrole-3-
carboxylic acid ethyl ester (4). Hydrolysis of 3 and 4 with
dil. NaOH in tetrahydrofuran (THF) gave the respective
pyrrolyl acids, 4-phenyl-1H-pyrrole-3-carboxylic acid (5)
and 4-(furan-2-yl)-1H-pyrrole-3-carboxylic acid (6)
3-carboxamide (9), and N-(3,4,5-trimethoxyphenyl)-4-
phenyl-1H-pyrrole-3-carboxamide (11), respectively.
Adopting a similar methodology, 4-(furan-2-yl)-N-(4-
chlorophenyl)-1H-pyrrole-3-carboxmide (8), 4-(furan-2-
yl)-N-(4-methoxyphenyl)-1H-pyrrole-3-carboxamide (10),
and 4-(furan-2-yl)-N-(3,4,5-trimethoxyphenyl)-1H-pyrrole-
3-carboxamide (12) were prepared from 4-(furan-2-yl)-1H-
1
(Scheme 1). The H NMR spectra of 5 and 6 displayed a
singlet at d 6.90 and 7.41 ppm due to C5–H of pyrrole ring,
respectively, and another singlet due to C2–H at slightly
downfield region and merged with aromatic protons. Two
broad singlets were observed at 11.42, 11.58 and 11.60,
11.79 ppm in these compounds due to NH and OH; which
disappeared when D2O was added. The condensation of
4-phenyl-1H-pyrrole-3-carboxylic acid (5) with 4-chloro-
aniline, 4-methoxyaniline, and 3,4,5-trimethoxyaniline in
the presence of O-(7-azabenzotriazole-1-yl)-N,N,N0,N0-tet-
ramethyluroniumhexafluorophosphate (HATU) and N,N-
diisopropylethylamine (DIPEA) in N,N-dimethylformam-
ide (DMF) under ultrasonication at room temperature
produced N-(4-chlorophenyl)-4-phenyl-1H-pyrrole-3-car-
boxamide (7), N-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-
1
pyrrole-3-carboxylic acid (6). The H NMR spectra of 7–
12 exhibited two broad singlets in the regions d
11.29–11.47 and 9.14–9.55 ppm due to pyrrolyl NH and
amide NH which disappeared on deuteration. Further, a
singlet was observed at 6.96 in 7, at 6.42 in 8, at 6.52 in 9,
at 6.50 in 10, at 6.91 in 11, and at 6.43 ppm in 12 which
were attributed to C5–H. However, the singlet due to C2–H
in these compounds appeared along with aromatic protons.
In addition to these, a singlet was observed at 3.68 and
3.71 ppm in 9 and 10 due to methoxy protons and two
singlets at 3.61, 3.71 and 3.62, 3.75 ppm in 11 and 12 due
to three methoxy protons. The slightly downfield signals
were assigned to methoxy protons at p-position. On the
123

Med Chem Res
Scheme 1 Synthesis of amido/
sulfonamide-linked 3,4-
disubstituted pyrroles
O
O
O
O
NaOH, THF
H2O
TosMIC
O
O
OH
OH
4
3
DMSO, Et2O
5
2
1
N
N
H
H
1
5
3
O
4'
3'
O
5'
2'
NaOH, THF
H2O
1'
TosMIC
O
O
O
O
4
5
1
3
DMSO, Et2O
O
2
N
N
H
H
6
4
2
Cl
O
R
OMe
N
3
4
1
O
H
5
2
O
O
O
R
N
R
S
N
H
N
H
H
7/8
N
Cl
N
H
H
9/10
i
19/20
ii
OMe
OMe
OMe
vii
O
O
R
iii
O
O
S
N
H
5/6
R
N
H
N
vi
11/12
H
iv
OMe
N
H
v
F
17/18
Cl
O
O
N
O
O
R
S
R
N
H
N
N
3
2
4
1
H
5
N
N
H
H
13/14
15/16
i.
ii. 4-Methoxyaniline, HATU, DIPEA, THF / US
iii. 3,4,5-Trimethoxyaniline, HATU, DIPEA, THF / US
4-Chloroaniline, HATU, DIPEA, THF / US
iv. 5-Chloro-4-fluoropyrimidine-2-amine, HATU, DIPEA, THF / US
v. Phenylsulfonamide, HATU, DIPEA, THF / US
vi. 4-Methoxyphenylsulfonamide, HATU, DIPEA, THF / US
vii. 4-Chlorophenylsulfonamide, HATU, DIPEA, THF / US
other hand, pyrrolyl pyrimido derivatives—N-(5-chloro-4-
fluoropyrimidin-2-yl)-4-phenyl-1H-pyrrole-3-carboxamide
(13) and N-(5-chloro-4-fluoropyrimidin-2-yl)-4-(furan-2-
yl)-1H-pyrrole-3-carboxamide (14) were prepared by the
reaction of 5 and 6 with 5-chloro-4-fluoropyrimidine-2-
amine in the presence of HATU, DIPEA in DMF under
ultrasonication. The 1H NMR spectra of 13 and 14
showed one singlet at d 6.70 and 6.75 ppm due to C5–H.
The other proton (C2–H) of pyrrole ring displayed a
singlet at slightly downfield region and merged with
aromatic protons. In our interest to develop the molecule
having more electron-withdrawing substituents, the com-
pounds N-(4-phenyl-1H-pyrrole-3-carbonyl)benzenesul-
fonamide (15), N-(4-phenyl-1H-pyrrole-3-carbonyl)-4-
methoxybenzenesulfonamide (17), and N-(4-phenyl-1H-
phenylsulfonamide, 4-methoxyphenylsulfonamide, and
4-chlorophenylsulfonamide, respectively, in the presence
of HATU, Et3N in THF under ultrasonication. Likewise,
the compounds N-(4-furan-2-yl-1H-pyrrole-3-carbonyl)ben-
zenesulfonamide (16), N-(4-furan-2-yl-1H-pyrrole-3-car-
bonyl)-4-methoxybenzenesulfonamide (18), and N-(4-furan-
2-yl-1H-pyrrole-3-carbonyl)-4-chlorobenzenesulfonamide
(20) were prepared by the reaction of 4 with the
1
respective sulfonamides. The H NMR spectra of 15–20
showed two broad singlets in the regions d 12.27–12.49
and 9.38–9.53 ppm due to NH of pyrrole ring and NH of
sulfonamide, which disappeared when D2O was added.
In addition, one singlet was observed at 6.56 in 15, at
6.61 in 16, at 6.60 in 17, at 6.72 in 18, at 6.74 in 19, and
at 6.81 ppm in 20 due to C5–H of pyrrole ring. How-
ever, another singlet due to C2–H appeared at much
downfield region and merged with aromatic protons. The
pyrrole-3-carbonyl)-4-chlorobenzenesulfonamide
were prepared by the reaction of
(19)
with
5
123

Med Chem Res
123

Med Chem Res
Table 2 The in vitro antifungal activity of compounds 7–20
Compound
Diameter of zone of inhibition (mm)
A. niger
P. chrysogenum
12.5 lg/well
25 lg/well
50 lg/well
100 lg/well
12.5 lg/well
25 lg/well
50 lg/well
100 lg/well
7
14
16
12
12
07
09
23
24
21
23
17
19
26
28
29
–
2
1
2
2
2
1
2
1
2
1
1
2
3
2
1
17
19
15
15
09
11
25
27
24
24
20
22
28
30
31
–
3
1
1
3
1
2
2
1
1
1
3
1
2
3
2
19
21
17
18
12
13
28
30
26
27
23
25
31
32
33
–
2
3
2
1
3
1
3
1
1
2
1
2
2
3
3
22
23
20
21
15
16
32
32
29
30
26
27
32
35
36
–
2
3
1
2
2
2
1
2
2
1
2
3
1
1
2
18
19
14
16
10
12
26
27
24
26
20
21
29
31
33
–
2
2
1
2
1
2
1
2
1
1
2
2
1
3
2
20
22
16
18
12
14
29
30
26
28
22
24
32
32
35
–
1
2
2
3
1
1
1
1
2
2
1
1
2
1
1
22
24
19
21
15
17
31
32
29
30
25
26
35
34
36
–
2
1
1
1
2
3
3
3
2
3
2
2
1
2
2
24
28
22
23
18
20
34
34
31
33
29
30
39
40
38
–
3
1
2
2
1
1
1
3
3
2
3
2
3
3
3
8
9
10
11
12
13
14
15
16
17
18
19
20
Ketoconazole
Control (DMSO)
structures of all the compounds were further established
by IR, 13C NMR spectral data, and elemental analysis.
The minimum inhibitory concentration (MIC), mini-
mum bactericidal concentration (MBC), and minimum
fungicidal concentration (MFC) values of the compounds
tested are listed in Table 3. MIC is the lowest concentra-
tion of an antimicrobial that will inhibit the visible growth
of a microorganism. (But it is not sure that the microor-
ganisms are completely killed.). The MBC/MFC is the
lowest concentration of antibiotic required to kill a par-
ticular bacterium/fungus. The MBC/MFC involve an
additional set of steps performed once the MIC is deter-
mined. The antimicrobials are usually regarded as bacte-
ricidal/fungicidal if the MBC/MFC is not greater than four
times the MIC (French, 2006). The compounds 19 and 20
exhibited low MIC values when compared with 13 and 14.
In addition, MBC value is 2 9 MIC in case of P. aeru-
ginosa and MFC value is 2 9 MIC in case of P. chrys-
ogenum. However, the other compounds showed
bactericidal and fungicidal effects greater than 2 9 MIC.
The chloro-substituted sulfonamido pyrrole derivative 20
exhibited strong antibacterial activity against P. aeruginosa
with an inhibition zone of 32 mm at 100 lg and MIC and
MBC of 6.25 and 12.5 lg, respectively. The compound 20
also displayed strong antifungal activity against P. chrys-
ogenum with an inhibition zone of 40 mm at 100 lg and
MIC and MFC of 12.5 and 25 lg, respectively. In general,
it was noticed that compounds having chloro and fluoro
substitutions on pyrimidine ring and chloro substitution on
phenyl ring displayed comparatively higher antimicrobial
Biological evaluation
In vitro antimicrobial activity
The compounds 7–20 were evaluated for antibacterial and
antifungal activities at four different concentrations 12.5,
25, 50, and 100 lg/well. The results of antibacterial
activity data presented in Table 1 revealed that the com-
pounds 19 and 20 displayed higher antibacterial activity
than the standard drug Chloramphenicol particularly
toward Pseudomonas aeruginosa. On the other hand, the
compounds 13 and 14 exhibited an antibacterial activity
almost equal to the standard drug particularly against P.
aeruginosa at 100 lg/well. However, the compounds 9–12
displayed no activity against Gram-positive and the least
activity against Gram-negative bacteria at 100 lg/well. All
the tested compounds 7–20 inhibited the spore germination
against the fungi Aspergillus niger and Penicillium chrys-
ogenum. In fact all the compounds displayed slightly
higher antifungal activity toward P. chrysogenum than A.
niger. The compounds 19 and 20 exhibited greater anti-
fungal activity particularly toward P. chrysogenum at
100 lg/well when compared to the standard drug Keto-
conazole (Table 2).
123

Med Chem Res
Table 3 MIC, MBC, and MFC of compounds 17, 18, 11, and 12
Compound
MIC
MIC (MBC/MFC) (lg/well)
S. aureus
B. subtilis
P. aeruginosa
K. pneumonia
A. niger
P. chrysogenum
13
100 ([200)
50 ([100)
25 (100)
12.5 (50)
6.25
50 ([100)
25 (100)
50 (100)
12.5 (25)
6.25
6.25 (25)
6.25 (25)
6.25 (12.5)
6.25 (12.5)
6.25
50 ([100)
100 ([200)
50 (100)
25 (50)
12.5
25 (100)
25 (50)
12.5 (50)
12.5 (25)
–
12.5 (50)
12.5 (50)
12.5 (25)
12.5 (25)
–
14
19
20
Chloramphenicol
Ketoconazole
–
–
–
–
6.25
12.5
activity than those with methoxy and unsubstituted com-
pounds. Moreover, sulfonamide-linked pyrroles are com-
paratively more active than amido-linked pyrroles.
Phenyl- and furyl-substituted pyrrolyl carboxamide were
prepared as per the literature procedure (Pavri and Trudell,
1997)
General procedure for the synthesis of 4-phenyl-1H-
pyrrole-3-carboxylic acid (5)/4-(furan-2-yl)-1H-
pyrrole-3-carboxylic acid (6)
Conclusion
A new series of pyrrolyl carboxamides, pyrrolyl sulfona-
mides, and pyrrolyl pyrimidine derivatives were prepared
from simple starting compounds—ethyl 3-phenylacrylate
and ethyl 3-furanylacrylate under ultrasonication and
screened for their antimicrobial activity. Among the tested
compounds pyrrolyl pyrimidine derivatives and chloro-
substituted pyrroles displayed excellent activity when
compared to the other compounds. The chloro-substituted
pyrrolyl sulfonamides are the potent antimicrobial agents
particularly against P. aeruginosa and P. chrysogenum.
To a solution of compound 3/4 (650 mg, 3.17 mmol) in
THF (5 ml) and water (5 ml), dilute NaOH (7 ml) was
added and stirred at 90 °C for 12–15 h. The reaction
mixture was poured onto crushed ice and acidified with
2 N HCl and extracted with dichloromethane. The organic
layer was washed with brine solution and dried over an
Na2SO4. The solvent was removed under reduced pressure
and the resultant solid was recrystallized from ethanol.
4-Phenyl-1H-pyrrole-3-carboxylic acid (5)
Experimental protocols
m. p. 151–153 °C, yield 79 %; IR (KBr) (cm-1): 3,417
(OH), 3,367 (NH), 1,685 (C=O); 1H NMR (400 MHz,
CDCl3): d 6.90 (s, 1H, C5–H), 7.19–7.56 (m, 6H, Ar–H,
C2–H), 11.42 (br, 1H, NH), 11.60 (s, 1H, OH); 13C NMR
(100 MHz, CDCl3): d 106.5 (C-3), 114.5 (C-5), 120.1 (C-
2), 126.8, 128.4, 130.2, 131.8 (aromatic carbons), 136.5 (C-
4), 167.1 (CO) ppm; MS (m/z): 187.19 [M?ꢀ]. Anal. Calcd.
for C11H9NO2: C, 70.58; H, 4.85; N, 7.48 %; Found: C,
70.81; H, 4.92; N, 7.65 %.
All the chemicals were purchased from commercial sour-
ces and used without further purification. Ultrasonication
was performed in a Bandelin Sonorex RK 102H ultrasonic
bath operating at frequency of 35 kHz. Melting points were
determined in open capillaries on a Mel–Temp apparatus
and are uncorrected. The purity of the compounds was
checked by TLC (silica gel H, BDH, ethyl acetate/hexane,
1:3). The IR spectra were recorded on a Thermo Nicolet IR
200 FT-IR spectrometer as KBr pellets and the wave-
4-(Furan-2-yl)-1H-pyrrole-3-carboxylic acid (6)
numbers are given in cm-1. The H NMR spectra were
1
recorded in CDCl3 on
a
Bruker–400 spectrometer
m. p. 175–177 °C, yield 84 %; IR (KBr) (cm-1): 3,432
(400 MHz). The 13C NMR spectra were recorded in CDCl3
on a Bruker spectrometer operating at 100 MHz. All the
chemical shifts are reported in d (ppm) using TMS as an
internal standard. The mass spectra were recorded on Jeol
JMS–D 300 and Finnigan Mat 1210 B at 70 eV with an
emission current of 100 lA. The microanalyses were per-
formed on a Perkin–Elmer 240C elemental analyzer.
(OH), 3,392 (NH), 1,684 (C=O); 1H NMR (400 MHz,
0
0
CDCl3): d 6.42, 7.02, 7.17 (3H, Furanyl, C4 –H, C3 –H,
0
C5 –H), 7.41 (s, 1H, C5–H), 7.56 (s, 1H, C2–H), 11.58 (br,
1H, NH), 11.79 (s, 1H, OH); 13C NMR (100 MHz, CDCl3):
d 108.2 (C-3), 110.4 (C-30), 111.7 (C-40), 115.8 (C-5),
120.5 (C-2), 138.2 (C-4), 141.2 (C-50), 149.4 (C-20), 168.7
(CO); MS (m/z): 177.16 [M?ꢀ]. Anal. Calcd. for C9H7NO3:
123

Med Chem Res
C, 61.02; H, 3.98; N, 7.91 %; Found: C, 61.09; H, 4.02; N,
8.09 %.
temperature and sonicated for 20 min. Then 4-methoxy-
aniline (2.0 mmol) was added and sonicated for 20 min
followed by DIPEA (0.52 ml, 3.0 mmol). The reaction
mixture was further sonicated for 23–25 min and then
saturated NaCl solution was added. The separated precip-
itate was isolated by vacuum filtration over sintered glass,
washed with deionized water, and recrystallized from
2-propanol.
General procedure for the synthesis of N-(4-
chlorophenyl)-4-phenyl-1H-pyrrole-3-carboxamide (7)/
4-(furan-2-yl)-N-(4-chlorophenyl)-1H-pyrrole-3-
carboxmide (8)
The compound 5/6 (1.0 mmol) was dissolved in dry DMF
(10 ml). To this, HATU (0.38 g, 1.0 mmol) was added at
room temperature and sonicated for 10 min. Then 4-chlo-
roaniline (2.0 mmol) was added and sonicated for 20 min
followed by DIPEA (0.52 ml, 3.0 mmol). The reaction
mixture was further sonicated for 20–22 min. After the
completion of the reaction saturated NaCl solution was
added. The separated precipitate was isolated by vacuum
filtration over sintered glass, washed with deionized water,
and recrystallized from 2-propanol.
N-(4-Methoxyphenyl)-4-phenyl-1H-pyrrole-3-carboxamide
(9)
m. p. 120–122 °C, yield 63 %; IR (KBr) (cm-1): 3,169
1
(NH), 1,664 (C=O); H NMR (400 MHz, CDCl3): d 3.68
(s, 3H), 6.52 (s, 1H, C5–H), 6.99–7.42 (m, 10H, (C2–H),
Ar–H), 9.23 (br, 1H, CONH), 11.41 (br, 1H, NH); 13C
NMR (100 MHz, CDCl3): d 55.9 (CH3), 110.3 (C-5), 114.6
(C-3), 119.2 (C-2), 122.4, 124.1, 125.7, 126.2, 127.8,
128.4, 128.9, 129.4 (aromatic carbons), 130.5 (C-4), 165.3
(CO); MS (m/z): 292.34 [M?ꢀ]. Anal. Calcd. for
C18H16N2O2: C, 73.96; H, 5.52; N, 9.58 %; Found: C,
74.06; H, 5.50; N, 9.79 %.
N-(4-Chlorophenyl)-4-phenyl-1H-pyrrole-3-carboxamide (7)
m. p. 128–130 °C, yield 60 %; IR (KBr) (cm-1): 3,170
1
(NH), 1,671 (C=O); H NMR (400 MHz, CDCl3): d 6.96
(s, 1H, C5–H), 7.01–7.39 (m, 10H, (C2–H), Ar–H), 9.14
(br, 1H, CONH), 11.29 (br, 1H, NH); 13C NMR (100 MHz,
CDCl3): d 113.2 (C-5), 116.1 (C-3), 120.7 (C-2), 123.5,
124.7, 125.2, 125.9, 126.4, 127.1, 128.5, 129.6 (aromatic
carbons), 131.2 (C-4), 167.4 (CO); MS (m/z): 296.75
[M?ꢀ]. Anal. Calcd. for C17H13ClN2O: C, 68.81; H, 4.31;
N, 9.44 %; Found: C, 68.93; H, 4.43; N, 9.70 %.
4-(Furan-2-yl)-N-(4-methoxyphenyl)-1H-pyrrole-3-
carboxamide (10)
m. p. 110–112 °C, yield 73 %; IR (KBr) (cm-1): 3,172
1
(NH), 1,682 (C=O); H NMR (400 MHz, CDCl3): d 3.71
0
0
0
(s, 3H), 6.40, 6.55, 7.39 (3H, Furanyl, C4 –H, C3 –H, C5 –
H), 6.50 (s, 1H, C5–H), 7.02–7.42 (m, 5H, (C2–H), Ar–H),
9.26 (br, 1H, CONH), 11.46 (br, 1H, NH); 13C NMR
(100 MHz, CDCl3): d 56.3 (CH3), 109.6 (C-5), 111.6 (C-
40), 113.2 (C-30), 117.2 (C-3), 121.4 (C-2), 125.8, 126.2,
127.9, 129.4, (aromatic carbons), 134.8 (C-4), 137.8 (CO),
140.7 (C-50), 146.5 (C-20); MS (m/z): 282.29 [M?ꢀ]. Anal.
Calcd. for C16H14N2O3: C, 68.07; H, 5.00; N, 9.92 %;
Found: C, 68.15; H, 5.05; N, 10.07 %.
N-(4-Chlorophenyl)-4-(furan-2-yl)-1H-pyrrole-3-
carboxamide (8)
m. p. 118–120 °C, yield 75 %; IR (KBr) (cm-1): 3,317
1
(NH), 1,682 (C=O); H NMR (400 MHz, CDCl3): d 6.42
0
0
(s, 1H, C5–H), 6.48, 7.14, 7.42 (3H, Furanyl C4 –H, C3 –H,
0
C5 –H), 7.29–7.64 (m, 5H, C2–H, Ar–H), 9.19 (br, 1H,
CONH), 11.37 (br, 1H, NH); 13C NMR (100 MHz,
CDCl3): d 110.9 (C-40), 112.6 (C-30), 114.6 (C-5), 116.8
(C-3), 121.2 (C-2), 125.1, 126.2, 127.1, 125.9, (aromatic
compounds), 132.4 (C-4), 140.1 (C-50), 145.2 (C-20), 168.2
(CO); MS (m/z): 286.71 [M?ꢀ]. Anal. Calcd. for
C15H11ClN2O2: C, 62.84; H, 3.87; N, 9.77 %; Found: C,
62.94; H, 3.90; N, 9.93 %.
General procedure for the synthesis of N-(3,4,5-
trimethoxyphenyl)-4-phenyl-1H-pyrrole-3-
carboxamide (11)/4-(furan-2-yl)-N-(3,4,5-
trimethoxyphenyl)-1H-pyrrole-3-carboxamide (12)
The compound 5/6 (1.0 mmol) was dissolved in dry DMF
(10 ml). To this, HATU (0.38 g, 1.0 mmol) was added at
room temperature and sonicated for 10 min. Then 3,4,5-
trimethoxyaniline (2.0 mmol) was added and sonicated for
20 min followed by DIPEA (0.52 ml, 3.0 mmol). The
reaction mixture was further sonicated for 24–26 min.
After the completion of the reaction saturated NaCl solu-
tion was added. The separated precipitate was isolated by
vacuum filtration over sintered glass, washed with deion-
ized water, and recrystallized from 2-propanol.
General procedure for the synthesis of N-(4-
Methoxyphenyl)-4-phenyl-1H-pyrrole-3-carboxamide
(9)/4-(Furan-2-yl)-N-(4-methoxyphenyl)-1H-pyrrole-3-
carboxamide (10)
To a solution of compound 5/6 (1.0 mmol) in dry DMF
(10 ml), HATU (0.38 g, 1.0 mmol) was added at room
123

Med Chem Res
1H, CONH), 12.10 (br, 1H, NH); 13C NMR (100 MHz,
CDCl3): d 114.2 (C-5), 116.2 (C-3), 120.8 (C-2), 126.2,
127.8, 128.4, 128.9 (aromatic carbons), 129.6 (C=C–Cl)
131.6 (C-4), 151.7 (C=N), 160.9 (C=C–Cl), 165.2 (C=C–
F), 173.2 (CO); MS (m/z): 316.72 [M?ꢀ]. Anal. Calcd. for
C15H10ClFN4O: C, 56.95; H, 3.41; N, 17.84 %; Found: C,
56.88; H, 3.18; N, 17.69 %.
N-(3,4,5-Trimethoxyphenyl)-4-phenyl-1H-pyrrole-3-
carboxamide (11)
m. p. 137–140 °C, 65 %; IR (KBr) (cm-1): 3,354 (NH),
1,649 (C=O); 1H NMR (400 MHz, CDCl3): d 3.61 (s, 3H),
3.71 (s, 6H), 6.91 (s, 1H, C5–H), 6.98–7.46 (m, 8H, C2–H,
Ar–H), 9.53 (br, 1H, CONH), 11.36 (br, 1H, NH); 13C
NMR (100 MHz, CDCl3): d 56.2 and 57.6 (CH3), 114.7
(C-5), 116.2 (C-3), 121.1 (C-2), 131.9 (C-4), 127.8, 128.4,
128.9, 129.2, 136.5, 139.5, 145.9, 149.4 (aromatic car-
bons), 168.2 (CO); MS (m/z): 352.38 [M?ꢀ]. Anal. Calcd.
for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95 %; Found: C,
68.10; H, 5.71; N, 8.07 %.
N-(5-Chloro-4-fluoropyrimidin-2-yl)-4-(furan-2-yl)-1H-
pyrrole-3-carboxamide (14)
m. p. 148–150 °C, yield 64 %; IR (KBr) (cm-1): 3,385
1
(NH), 1,689 (C=O); H NMR (400 MHz, CDCl3): d 6.65,
0
0
0
7.21, 7.85 (3H, Furanyl, C4 –H, C3 –H, C5 –H), 6.75 (s, 1H,
C5–H), 7.41–8.10 (s, 1H, C2–H, 8.10 (s, 1H, Pyrimidine),
12.14 (br, 1H, NH), 9.65 (br, 1H, CONH); 13C NMR
(100 MHz, CDCl3): d 114.7 (C-40), 116.6 (C-3), 117.8 (C-
30), 120.2 (C-5), 121.4 (C-2), 129.9 (C=C–Cl), 132.3 (C-4),
143.4 (C-50), 150.6 (C-20), 153.2 (C=N), 161.5 (C=C–Cl),
166.3 (C = C–F), 175.5 (CO); MS (m/z): 307.69 [M?ꢀ].
Anal. Calcd. for C13H8ClFN4O2: C, 50.79; H, 3.15; N,
18.51 %; Found: C, 50.75; H, 2.95; N, 18.21 %.
4-(Furan-2-yl)-N-(3,4,5-trimethoxyphenyl)-1H-pyrrole-3-
carboxamide (12)
m. p. 129–131 °C; yield 60 %; IR (KBr) (cm-1): 3,358
1
(NH), 1,684 (C=O); H NMR (400 MHz, CDCl3): d 3.62
(s, 3H), 3.75 (s, 6H), 6.43 (s, 1H, C5–H), 6.53, 6.84, 7.61
0
0
0
(3H, Furanyl, C4 –H, C3 –H, C5 –H), 7.14–7.64 (m, 3H, C2–
H, Ar–H), 9.55 (br, 1H, CONH), 11.47 (br, 1H, NH); 13C
NMR (100 MHz, CDCl3): d 55.2 & 60.5 (CH3), 97.9 (C-
40), 106.7 (C-30), 111.6 (C-50), 114.9 (C-20), 116.8 (C-5),
118.7 (C-3), 122.8 (C-2), 136.4, 140.7, 150.1, 153.0 (aro-
matic carbons), 133.6 (C-4), 163.5 (CO); MS (m/z): 342.35
[M?ꢀ]. Anal. Calcd. for C18H18N2O5: C, 63.15; H, 5.30; N,
8.18 %; Found: C, 63.26; H, 5.35; N, 8.04 %.
General procedure for the synthesis of N-(4-phenyl-1H-
pyrrole-3-carbonyl)benzenesulfonamide (15)/N-(4-
furan-2-yl-1H-pyrrole-3-carbonyl)benzenesulfonamide
(16)
The compound 5/6 (1.0 mmol) was dissolved in dry DMF
(10 ml). To this, HATU (0.38 g, 1.0 mmol) was added at
room temperature and sonicated for 10 min. Then phe-
nylsulfonamide (2.0 mmol) was added and sonicated for
20 min followed by DIPEA (0.52 ml, 3.0 mmol). The
reaction mixture was further sonicated for 26–28 min.
After the completion of the reaction saturated NaCl solu-
tion was added. The separated precipitate was isolated by
vacuum filtration over sintered glass, washed with deion-
ized water, and recrystallized from 2-propanol.
General procedure for the synthesis of N-(5-chloro-4-
fluoropyrimidin-2-yl)-4-phenyl-1H-pyrrole-3-
carboxamide (13)/N-(5-chloro-4-fluoropyrimidin-2-yl)-
4-(furan-2-yl)-1H-pyrrole-3-carboxamide (14)
To a solution of compound 5/6 (1.0 mmol) in dry DMF
(10 ml), HATU (0.38 g, 1.0 mmol) was added at room
temperature and sonicated for 20 min. Then 5-chloro-4-
fluoropyrimidine (2.0 mmol) was added and sonicated for
20 min followed by DIPEA (0.52 ml, 3.0 mmol). The
reaction mixture was further sonicated for 20–23 min and
then saturated NaCl solution was added. The separated
precipitate was isolated by vacuum filtration over sintered
glass, washed with deionized water, and recrystallized
from 2-propanol.
N-(4-Phenyl-1H-pyrrole-3-carbonyl)benzenesulfonamide
(15)
m. p. 130–132 °C, yield 62 %; IR (KBr) (cm-1): 3,346
(NH), 1,664 (C=O), 1,305, 1,109 (SO2); 1H NMR
(400 MHz, CDCl3): d 6.56 (s, 1H, C5–H), 7.13–7.84 (m,
11H, C2–H, Ar–H), 9.38 (br, 1H, CONH), 12.27 (br, 1H,
NH); 13C NMR (100 MHz, CDCl3): d 110.9 (C-5), 115.9
(C-3), 120.6 (C-2), 126.7, 127.2, 128.3, 128.9, 129.7,
131.5, 132.7, 133.1 (aromatic carbons), 130.8 (C-4), 170.3
(CO); MS (m/z): 326.37 [M?ꢀ]. Anal. Calcd. for
C17H14N2O3S: C, 62.56; H, 4.32; N, 8.58 %; Found: C,
64.62; H, 4.40; N, 8.71 %.
N-(5-Chloro-4-fluoropyrimidin-2-yl)-4-phenyl-1H-pyrrole-
3-carboxamide (13)
m. p. 136–138 °C, yield 67 %; IR (KBr) (cm-1): 3,368
1
(NH), 1,678 (C=O); H NMR (400 MHz, CDCl3): d 6.70
(s, 1H, C5–H), 7.35–7.95 (m, 7H, C2–H, Ar–H), 9.57 (br,
123

Med Chem Res
12.49 (br, 1H NH); 13C NMR (100 MHz, CDCl3): d 56.9
(CH3), 111.9 (C-5), 113.2 (C-40), 115.8 (C-30), 117.5 (C-3),
120.1 (C-2), 128.9, 129.8, 131.8, 132.5 (aromatic carbons),
132.6 (C-4), 142.3 (C-50), 147.1 (C-20), 173.2 (CO); MS
(m/z): 346.36 [M?ꢀ]. Anal. Calcd. for C16H14N2O5S: C,
55.48; H, 4.07; N, 8.09 %; Found: C, 55.62; H, 4.14; N,
8.30 %.
N-(4-Furan-2-yl-1H-pyrrole-3-
carbonyl)benzenesulfonamide (16)
m. p. 148–150 °C, yield 65 %; IR (KBr) (cm-1): 3,352
(NH), 1,677 (C=O), 1,314, 1,120 (SO2); 1H NMR
0
(400 MHz, CDCl3): d 6.50, 6.86, 7.52 (3H, Furanyl, C4 –H,
0
0
C3 –H, C5 –H), 6.61 (s, 1H, C5–H), 7.09–7.61 (m, 6H, C2–
H, Ar–H), 9.40 (br, 1H, CONH), 12.35 (br, 1H, NH); 13C
NMR (100 MHz, CDCl3): d 111.4 (C-5), 112.9 (C-40),
114.3 (C-30), 115.7 (C-3), 120.8 (C-2), 125.2, 126.7, 127.2,
129.5 (aromatic carbons), 131.7 (C-4), 141.1 (C-50), 146.2
(C-20), 170.9 (CO); MS (m/z): 316.33 [M?ꢀ]. Anal. Calcd.
for C15H12N2O4S: C, 56.95; H, 3.82; N, 8.86 %; Found: C,
56.08; H, 3.86; N, 9.06 %.
General procedure for synthesis of N-(4-phenyl-1H-
pyrrole-3-carbonyl)-4-chlorobenzenesulfonamide (19)/
N-(4-furan-2-yl-1H-pyrrole-3-carbonyl)-4-
chlorobenzenesulfonamide (20)
The compound 5/6 (1.0 mmol) was dissolved in dry DMF
(10 ml). To this, HATU (0.38 g, 1.0 mmol) was added at
room temperature and sonicated for 10 min. Then
4-chlorophenylsulfonamide (2.0 mmol) was added and
sonicated for 20 min followed by DIPEA (0.52 ml,
3.0 mmol). The reaction mixture was further sonicated for
26–28 min. After the completion of the reaction, saturated
NaCl solution was added. The separated precipitate was
isolated by vacuum filtration over sintered glass, washed
with deionized water, and recrystallized from 2-propanol.
General procedure for the synthesis of N-(4-phenyl-1H-
pyrrole-3-carbonyl)-4-methoxybenzenesulfonamide
(17)/N-(4-furan-2-yl-1H-pyrrole-3-carbonyl)-4-
methoxybenzenesulfonamide (18)
To a solution of compound 5/6 (1.0 mmol) in dry DMF
(10 ml), HATU (0.38 g, 1.0 mmol) was added at room
temperature and sonicated for 20 min. Then 4-methoxy-
phenylsulfonamide (2.0 mmol) was added and sonicated
for 20 min followed by DIPEA (0.52 ml, 3.0 mmol). The
reaction mixture was further sonicated for 28–30 min and
then saturated NaCl solution was added. The separated
precipitate was isolated by vacuum filtration over sintered
glass, washed with deionized water, and recrystallized
from 2-propanol.
N-(4-Phenyl-1H-pyrrole-3-carbonyl)-4-
chlorobenzenesulfonamide (19)
m. p. 126–128 °C, yield 68 %; IR (KBr) (cm-1): 3,255
(NH), 1,676 (C=O), 1,320, 1,121 (SO2); 1H NMR
(400 MHz, CDCl3): 6.74 (s, 1H, C5–H), 7.20–7.89 (m,
10H, (C2–H), Ar–H), 9.51 (br, 1H, CONH), 12.43 (br, 1H,
NH); 13C NMR (100 MHz, CDCl3): d 114.7 (C-5), 115.8
(C-3), 123.4 (C-2), 124.2, 125.6, 126.1, 126.6, 127.5,
128.9, 129.4, 130.1 (aromatic carbons), 130.9 (C-4), 172.4
(CO); MS (m/z): 360.81 [M?ꢀ]. Anal. Calcd. for
C17H13ClN2O3S: C, 56.59; H, 3.63; N, 7.76 %; Found: C,
56.51; H, 3.66; N, 7.95 %.
N-(4-Phenyl-1H-pyrrole-3-carbonyl)-4-
methoxybenzenesulfonamide (17)
m. p. 139–141 °C; yield 72 %; IR (KBr) (cm-1): 3,360
(NH), 1,650 (C=O), 1,318, 1,126 (SO2); 1H NMR
(400 MHz, CDCl3): d 3.51 (s, 3H), 6.60 (s, 1H, C5–H),
7.12–7.79 (m, 10H, C2–H, Ar–H), 9.43 (br, 1H, CONH),
12.42 (br, 1H NH); 13C NMR (100 MHz, CDCl3): d 56.5
(CH3), 111.7 (C-5), 116.3 (C-3), 119.7 (C-2), 122.9, 123.6,
124.8, 125.4, 128.5, 129.4, 130.1, 130.8 (aromatic car-
bons), 131.9 (C-4), 171.6 (CO); MS (m/z): 356.42 [M?ꢀ].
Anal. Calcd. for C18H16N2O4S: C, 60.66; H, 4.53; N,
7.86 %; Found: C, 60.75; H, 4.55; N, 7.99 %.
N-(4-Furan-2-yl-1H-pyrrole-3-carbonyl)-4-
chlorobenzenesulfonamide (20)
m. p. 140–142 °C, yield 76 %; IR (KBr) (cm-1): 3,264
(NH), 1,680 (C=O), 1,345, 1,137 (SO2); 1H NMR
0
(400 MHz, CDCl3): 6.49, 6.96, 7.59 (3H, Furanyl, C4 –H,
0
0
C3 –H, C5 –H), 6.81 (s, 1H, C5–H), 7.22–7.76 (m, 5H, (C2–
H), Ar–H), 9.53 (br, 1H, CONH), 12.48 (br, 1H NH); 13C
NMR (100 MHz, CDCl3): d 113.1 (C-40), 115.2 (C-5),
116.2 (C-3), 117.5 (C-30), 124.5 (C-2), 125.5, 126.9, 127.6,
128.3 (aromatic carbons), 130.7 (C-4), 142.6 (C-50), 148.3
(C-20), 172.9 (CO); MS (m/z): 350.78 [M?ꢀ]. Anal. Calcd.
for C15H11ClN2O4S: C, 51.36; H, 3.16; N, 7.99 %; Found:
C, 51.46; H, 3.10; N, 8.06 %.
N-(4-Furan-2-yl-1H-pyrrole-3-carbonyl)-4-
methoxybenzenesulfonamide (18)
m. p. 145–147 °C, yield 66 %; IR (KBr) (cm-1): 3,371
(NH), 1,659 (C=O), 1,341, 1,132 (SO2); 1H NMR
(400 MHz, CDCl3): d 3.55 (s, 3H), 6.56, 7.01, 7.70 (3H,
0
Furanyl, C4 –H, C3 –H, C5 –H) 6.72 (s, 1H, C5–H),
0
0
7.18–7.67 (m, 5H, C2–H, Ar–H), 9.48 (br, 1H, CONH),
123

Med Chem Res
Antimicrobial testing
PDA (for fungi) by streaking. Plates inoculated with bac-
teria and fungi were incubated at 37 °C for 24 h and at
28 °C for 48 h, respectively. After incubation, the lowest
concentration that kills the tested organisms was noted as
MBC (for bacteria) or MFC (for fungi).
The compounds 7–20 were dissolved in DMSO at different
concentrations of 12.5, 25, 50, and 100 lg/well.
Cells
Acknowledgments One of the authors A. Padmaja is grateful to
CSIR, New Delhi, India for financial assistance under major research
project. The authors are also thankful to Prof. D. V. R. Sai Gopal,
Department of Bio-Chemistry (SVU), for Biological Activity.
Bacterial strains Staphylococcus aureus, Bacillus subtilis,
P. aeruginosa, Klebsiella pneumoniae; and fungi A. niger,
P. chrysogenum were obtained from Department of
Microbiology, S.V. University, Tirupati.
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