Synthesis of a new class of antimicrobial agents incorporating the indolin-2-one moiety

Article abstract of DOI:10.3109/14756366.2012.689298

New furanone derivatives incorporating the indolin-2-one moiety 3 were prepared via the Perkin reaction of isatins 1 with aroylpropionic acids 2 under conventional conditions or microwave irradiation. A series of functionally heterocyclic derivatives (e.g., pyridazines, pyrroles, and sulfonamides) incorporating the indolin-2-one moiety was achieved via reaction of 3 with different reagents under microwave irradiation conditions. The newly synthesized compounds were characterized on the basis of FTIR, ¹H, ¹³C NMR and mass spectral studies. Some of the new synthesized compounds were screened for antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus), Gram-negative bacteria (Escherichia coli and Shigilla flexneri) and antifungal activity against Aspergillus flavus and Candida albicans. Compound 8 j was equipotent to chloramphenicol in inhibiting the growth of E. coli minimum inhibitory concentration (MIC 2.5 μg/mL). Compound 8j may possibly be used as a lead compound for developing a new antibacterial agents. The antibacterial activity is expressed as the corresponding MIC (μg/mL) values.

Full text of DOI:10.3109/14756366.2012.689298

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; Early Online: 1–10
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2012.689298
ORIGINAL ARTICLE
Synthesis of a new class of antimicrobial agents incorporating
the indolin-2-one moiety
Nadia G. Kandile1, Howida T. Zaky1, Yassmin G. Saleh1, and Nashwa A. Ahmed2
1Department of Chemistry, Faculty of Women, Ain Shams University, Cairo, Egypt and 2Basic Science Department,
Faculty of Applied Medical Science, October 6th University, 6 October City, Egypt
Abstract
New furanone derivatives incorporating the indolin-2-one moiety 3 were prepared via the Perkin reaction of isatins 1
with aroylpropionic acids 2 under conventional conditions or microwave irradiation. A series of functionally heterocyclic
derivatives (e.g., pyridazines, pyrroles, and sulfonamides) incorporating the indolin-2-one moiety was achieved via
reaction of 3 with different reagents under microwave irradiation conditions. The newly synthesized compounds were
characterized on the basis of FTIR, 1H, 13C NMR and mass spectral studies. Some of the new synthesized compounds
were screened for antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus),
Gram-negative bacteria (Escherichia coli and Shigilla flexneri) and antifungal activity against Aspergillus flavus and
Candida albicans. Compound 8 j was equipotent to chloramphenicol in inhibiting the growth of E. coli minimum
inhibitory concentration (MIC 2.5 μg/mL). Compound 8j may possibly be used as a lead compound for developing a
new antibacterial agents. The antibacterial activity is expressed as the corresponding MIC (μg/mL) values.
Keywords: furanones, sulfonamides, antimicrobial agents, microwave irradiation
Introduction
kinase inhibitors6,12–16, a variety of 3-substituted indolin-
2-ones have been utilized as anticancer drugs or drug
candidates17–21. A representative member of this class is
Sunitinib(SU11248, SutentTM;Pfizer, Cairo, Egypt)which
iscurrentlyusedintheclinicsasamulti-targetingtyrosine
Among a wide variety of compounds that have been
explored for developing pharmaceutically important
antimicrobial agents, unsaturated γ-lactones have played
an important role. Moreover, furanone ring derivatives
have acquired a special place in natural chemistry and
in heterocyclic chemistry, as the furanone frequently
encountered structural motif in many pharmacologically
relevant compounds. ey are active constituents of many
natural and synthetic compounds exhibiting pronounced
biological activities, such as cytotoxic1,2, antifungal3,4, anti-
bacterial, anti-inflammatory, analgesic5–7, cardiotonic8,
cyclo-oxygenase-2 (COX-2) inhibitory9,10, antiviral11, and
antibiotic activity12.
kinase inhibitor with antiangiogenic activity Figure 122,23
.
Promoted by the above biological and chemical activities
and in connection with our synthetic program aimed
at the synthesis and bioassay of several poly-functional
heteroannulated ring systems of expected bioresponse,
samples of heterocycles incorporating indolin-2-one
moiety were synthesized and assayed.
As part of our ongoing studies concerning the prepa-
ration of potential biologically active compounds24–29 and
bioactive heterocycles based on oxindole moiety30–35, we
report herein a convenient microwave-enhanced, high
speed, fast, and economic way for the synthesis of new
2(3H)-furanones, for use as key intermediates for the
synthesis of new pyridazine, pyrrol, and sulfonamide
derivatives.We investigated their antimicrobial activity in
Indirubin identified as the active compound with
increased emergence of bacterial resistance to antibiotic
therapy, has created an urgent need for the development
of new antibacterial agents (Figure 1).
Since various kinases are involved in the growth
of microorganisms and because many oxindoles are
Address for Correspondence: Nadia G. Kandile, Department of Chemistry, Faculty of Women, Ain Shams University, Cairo, Egypt. Tel. and
Fax: +224157804. E-mail: nadiaghk@yahoo.com
(Received 24 March 2012; revised 24 April 2012; accepted 25 April 2012)
1

2
N. G. Kandile et al.
order to get new compounds that could be optimized as
potent antimicrobial agents.
(3a–l) were established on the basis of IR, mass spectrum,
1HNMR, and 13CNMR spectral data. e IR spectra of com-
pounds (3g–l) revealed absorption bands at 3,425–3,397
(NH), while compounds (3a–f) displayed no frequen-
cies for a NH group. e IR spectra of compounds (3a–l)
revealed absorption bands at 1,793–1,729 (lactone, C=O).
Results and discussion
Chemistry
1-Acetyl-3-[(5-(4-alkylphenyl)-2-oxofuran-3(2H)-
ylidene)]-5-alkyl-indolin-2-ones (3a–f
) were achieved
Structures
from the reaction of isatin derivatives (1a–c) with β-aroyl
propionic acids (2a,b) under conventional Perkin condi-
tions according to the method reported in our previous
work30. However, in some cases of microwave irradia-
tion, to afford the formation of 5-alkyl-3-[(2-oxo-5-(4-
alkylphenyl)furan-3(2H)-ylidene)]indolin-2-ones (3g–l)
was achieved. Compounds (3g–l) were also obtained by
the action of 6N HCl on compounds (3a–f). e synthetic
route used to synthesize compounds (3a–l) is outlined in
Scheme 1.
e syntheses of poly functionally heterocyclic (e.g., pyrid-
azine, pyrrole, and sulfonamide) derivatives incorporating
indolin-2-one moiety were achieved from investigating the
reactivity of compounds (3a–l), towards nucleophiles such
as hydrazine hydrate and benzylamine. When compounds
(3g–j,l) were stirred with hydrazine hydrate in ethanol
at room temperature, the products were 2-[(5-alkyl-2-
oxoindolin-3-ylidene)-4-oxo-4-(4-alkylphenyl)] butane-
hydrazides (4a–e). e structures of (4a–e) were established
Figure 1. Antibacterial agents containing the indolin-2-one moiety.
Scheme 1. Synthesis of the target compound 3.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of a new class of antimicrobial agents
3
from IR, mass, 1HNMR, and 13CNMR spectra. e 1HNMR
spectra of compounds (4a–e) displayed the NH protons
of the NH2 group which disappeared on addition of
D2O. Cyclization of 2-[(5-Alkyl-2-oxoindolin-3-ylidene)-
refluxing or by microwave irradiation for 3 min at 85°C
under the before mentioned conditions. All reactions
gave the same products, that is 2-[(1-acetyl-5-alkyl-2-oxo-
indolin-3-ylidene)]-N-benzyl-4-oxo-4(4-alkylphenyl)
butaneamide (6a–f) or N-benzyl-4-[(4-methoxyphenyl)-2-
(5-nitro-2-oxo-indolin-3-ylidene)]-4-oxo-butaneamide
(6g) respectively. Compounds (6a–g) were characterized
by their IR spectra of which showed absorption bands of
4-oxo-4-(4-alkylphenyl)]butane hydrazides (4a–e
) can
occurred with microwave irradiation in ethanol to give
5-alkyl-3-[(oxo-6-(4-alkylphenyl)-2,3-dihydropyridazin-
4-(5H)-ylidene)]indolin-2-ones (5a–d).e structures of
the products were confirmed by IR, mass,1HNMR, and
13CNMR spectra. e 1HNMR spectra of compounds
(5a–e) lack any absorption bands responsible for the NH2
group. Also, 5-methyl-3-[(oxo-6-(4-methoxyphenyl)-
2,3-dihydropyridazin-4(5H)-ylidene)] indolin-2-one (5a)
was formed from microwave irradiation of a mixture of
the furanone derivative (3g) and hydrazine hydrate in
alkaline ethanol Scheme 2.
e 13CNMR spectrum of 5-methyl-3-[(oxo-6-(4-
methoxyphenyl)-2,3-dihydro pyridazin-4(5H)-ylidene)]
indolin-2-one (5a) showed bands at 176.38, 160.19, 141.7,
137.54, 135, 130.09, 129.95, 127.64, 125.87, 125.15, 123.98,
116.02, 108.86, 102.02, 100.19, 35.82, 20.86 and 20.69.
e reaction of 1-acetyl-5-alkyl-3-[(2-oxo-5-(4-alkyl-
phenyl)furan-3(2H)-ylidene)] indolin-2-ones (3a–f) and
3-[(5-(4-methoxyphenyl)-2-oxofuran-3(2H)-ylidene)-
5-nitro] indolin-2-one (3k) with benzylamine were car-
ried out in ethanol by stirring at room temperature or by
1
the NH group at 3,293.82–3,291.89 cm−1. HNMR spectra
of (6a–g) showed the NH signal at 4.77-4.27 which disap-
peared by the addition of D2O. e amide derivatives
(6a,c,d) can be cyclized by refluxing for 3 h or by micro-
wave irradiation for 3 min at 120°C in acetic acid and
hydrochloric acid to yield the corresponding pyrrolones,
1-alkyl-3-[(1-benzyl-2-oxo)-5-(4-alkylphenyl)-1,2-
dihydropyrrol-3-ylidene)-5-alkyl]-indolin-2-one (7a–c).
1HNMR spectra of (7a,b) showed a lack of frequencies for
NH groups. e IR spectrum of (7c) revealed absorption
bands for C=O at 1,672.95 and 1,642.58 cm−1. Further sup-
port for the structure of these compounds was obtained
by IR, 13CNMR and mass spectra.
1-Acetyl-3-[(1-benzyl-2-oxo-5(4-tolyl)-1,2-
dihydropyrrol-3-ylidene)-5-chloro]indolin-2-one
(7a), was obtained in one step via reaction of 1-acetyl-
5-[chloro-3-(2-oxo-5-p-tolylfuran-3(2H)-ylidine)]
indolin-2-one (3c) with benzylamine in acetic acid and
Scheme 2. Synthesis of the target compounds 4, 5, 6, 7, and 8. Reagents and conditions: (i) NH2NH2,EtOH, Stirr.,(R.T.), (ii) EtOH, M.W., (iii)
NH2NH2, EtOH, M.W., (iv) Stirr, (R.T.) or M.W., NH2CH2Ph, EtOH, (v) CH3COOH, HCl reflux or M.W., (vi)NH2CH2Ph, CH3COOH, HCl, M.W.,
(vii) appreciate sulfonamide, CH3COOH, M.W.
© 2012 Informa UK, Ltd.

4
N. G. Kandile et al.
hydrochloric acid using microwave irradiation for 3 min
at 120°C. M.p and mixed m.p experiment confirmed suc-
cessive synthesis.
bromide pellets and frequencies are reported in cm−1.
e 1H NMR were measured on a Varian genini-300
MHZ spectrophotometer and chemical shifts (δ) are in
ppm. e mass spectra (m/z) values were measured on
mass spectrophotometer HP model GC MS-QPL000EX
(Shimadzu) at 70 eV. Elemental analyses were carried out
at the Microanalytical Centre, Cairo University, Egypt.
Antimicrobial activity evaluations were carried out at the
Basic Science Department, Faculty of Applied Medical
Science, October 6th University, October City, Egypt. An
Explorer Automated Microwave Synthesis Workstation
(CEM) was used for synthesis of new compounds.
A series of sulfonamide derivatives were synthesized
by the reaction of 3-[5-(4-alkylphenyl)-2-oxofuran-
3(2H)-ylidene]5-alkylindolin-2-ones (3i,k,l) with different
sulfonamides such as sulfanilamide, sulfaguanidine, and
(3g–i,k,l)with4-(2-aminoethyl)benzenesulfonamide,inthe
presence of acetic acid under microwave irradiation for
3minandat120°C,togivethecorrespondingsulfonamide
derivatives (8a–k). e IR spectra of compounds (8a–k) were
characterized by the presence of absorption bands of
SO2 at 1,402-1,300.75 cm−1, and lack of any absorption
bands corresponding to a lactone. Further support for
the structure of these compounds was obtained from IR,
1HNMR, and mass spectra.
General procedure for synthesis of
furanone derivatives via conventional Perkin reaction
conditions (3a–f
)
Furanone derivatives were prepared via condensation of
finely powdered β-aroylpropionic acid (0.01 mol), fused
sodium acetate (0.01 mol) and 5-alkylisatin (0.01 mol) in
acetic anhydride (10 ml) heated on a hot plate until a clear
solution was obtained. Heating was continued on a water
bath until a solid separated out. e reaction mixture
was cooled, filtered off and the precipitate was washed
with water, petroleum ether (b.p. 40–60°C) and the solid
product was crystallized from acetic acid to give (3a–f).
Biological evaluation (in vitro antimicrobial
measurement)
e in vitro antimicrobial potency of some of the newly
synthesized compounds was compared with broad spec-
trum antibiotic namely chloramphenicol and nystatin
against Gram-negative Escherichia coli (ATCC-25922)
and S. flexeniri, gram-positive Staphylococcus aureus
(ATCC-25923), Bacillus cereus, and fungi Aspergillus fla-
vus and Candida albicans (ATCC 10231) strains.
e antibacterial activity of the synthesized com-
pounds was tested using an agar well diffusion method36.
e agar-diffusion method was used for the determination
of the preliminary antibacterial and antifungal activity.
Chloramphenicol and nystatin were used as reference
drugs. e results were recorded for each tested com-
pound as the average diameter of inhibition zones (IZ)
of bacterial or fungal growth around the disks in mm.
Compounds inhibiting the growth of one or more of the
above microorganisms were further tested for their MIC
and were determined by broth dilution technique37. e
MIC (mg/mL) and inhibition zone diameters values are
recorded in Table 1. e IZ diameters values cited in
Table 1 between brackets are attributed to the tested orig-
inal concentration (1 mg/mL) as a preliminary test. e
results depicted in Table 1 revealed that most of tested
compounds displayed variable inhibitory effects on the
growth of the tested Gram-positive and Gram-negative
bacterial strains, and also against fungal strains. A close
investigation of the MIC values indicates that sulfon-
amide derivative 8j (MIC 2.5 μg/mL) against E.coli, was
equipotent with the reference and antifungal C. albicans,
also depicted (MIC 5 μg/mL).
1-Acetyl-3-[(5-(4-tolyl)-2-oxofuran-3(2H)-ylidine)]-5-
methylindolin-2-one (3a)
Reddish brown crystals, 74%, m.p. 262–264°C;
IR:CH(alicyclic) at 2,930.31, C=O(lactone) at 1,729.83, C=O(amide)
at 1,680.89, C=C at 1,618.95 cm−1; MS (EI) m/z 361 (M+ +
1
2), HNMR (DMSO, 300 MHz): δ 8.22-7.15 (m, 7H, 2Ar-
H), 6.44 (s, 1H, hetero CH), 3.30-3.19 (s, 3H, COCH3),
2.68-2.60 (s, 6H, 2CH3).
1-Acetyl-3-[(5-(4-tolyl)-2-oxofuran-3(2H)-ylidine)]-5-
nitroindolin-2-one (3b)
Reddish brown crystals, 72%, m.p. 272–274°C; IR:
CH(alicyclic) at 2,924.52, C=O(lactone) at 1,730.8, C=O(amide) at
1,687.81, C=C at 1,621.84 cm−1; MS(EI) m/z 390 (M+),
1HNMR (DMSO, 300 MHz): δ 8.31-7.01 (m, 7H, 2Ar-H),
6.90-6.87 (s, 1H, hetero CH), 3.75 (s, 3H, COCH3), 2.49-
2.36 (s, 3H, OCH3).
1-Acetyl-3-[(5-(4-tolyl)-2-oxofuran-3(2H)-ylidine)]-5-
chloroindolin-2-one (3c)
Reddish brown crystals, 69%, m.p. 252–254°C; IR:
CH(alicyclic) at 2,922.59, C=O(lactone) at 1,764.83, C=O(amide) at
1,714.41, C=C at 1,614.13 cm−1, MS(EI) m/z 378 (M+ − 1),
1HNMR (DMSO, 300 MHz): δ 8.13-7.28 (m, 7H, 2Ar-H),
6.44 (s, 1H, hetero CH), 3.35-2.65(s, 3H, COCH3), 2.60-
2.36 (s, 3H, OCH3).
Materials and methods
Chemistry
All melting points are uncorrected and were determined
on a Gallenkamp instrument. Infrared spectra of the
new compounds were measured on a Perkin-Elmer
spectrophotometer model 1430 using potassium
1-Acetyl-5-methyl-3-[(2-oxo-5-p-methoxyphenylfuran-3(2H)-
ylidin)]indolin-2-one (3d)
Reddish brown crystals,70%, m.p. 279–281°C; IR:
CH(alicyclic) at 2,916.63, C=O
at 1,776.12, C=O(amide) at
(lactone)
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of a new class of antimicrobial agents
5
Table 1. Minimal inhibitory concentrations (MIC, µg/mL) and inhibition zones (mm) of some new synthesized compounds.
MICa in μg/mL, and zone of inhibition (mm)
Bacteria
Gram-negative bacteria
Gram-positive bacteria
Fungi
Compound number
E. coli
15 (23)
15 (25)
10 (27)
5 (28)
S. flexeniri
S. aureus
15 (24)
10 (23)
10 (25)
5 (27)
B. cereus
A. flavus
20 (12)
15 (13)
10 (15)
15 (16)
20 (17)
10 (14)
15 (15)
20 (17)
15 (15)
20 (15)
10 (16)
15 (15)
15 (16)
15 (16)
10 (16)
10 (16)
15 (15)
10 (18)
15 (16)
C. albicans
2a
2b
3a
3b
3c
3d
3e
3f
8a
8b
8c
8d
8e
8f
8g
8h
20 (21)
15 (20)
10 (24)
5 (26)
15 (25)
10 (25)
10 (26)
5 (26)
20 (14)
15 (15)
10 (18)
15 (19)
20 (18)
10 (18)
15 (19)
20 (17)
15 (14)
15 (17)
10 (17)
15 (16)
15 (18)
15 (16)
10 (18)
10 (17)
15 (17)
5 (22)
10 (29)
10 (26)
5 (27)
10 (26)
10 (22)
10 (24)
10 (26)
10 (26)
10 (26)
5 (25)
10 (28)
10 (23)
10 (25)
10 (27)
10 (28)
10 (28)
5 (26)
10 (28)
10 (24)
10 (27)
10 (28)
10 (26)
15 (27)
10 (29)
10 (28)
10 (26)
10 (28)
15 (28)
5 (28)
10 (26)
5 (29)
5 (27)
5 (29)
10 (30)
10 (27)
10 (28)
10 (29)
2.5 (35)
10 (28)
2.5 (34)
10 (29)
10 (28)
10 (24)
10 (27)
15 (25)
10 (25)
10 (25)
5 (29)
10 (29)
15 (25)
10 (29)
10 (30)
5 (27)
8i
8j
8k
10 (27)
5 (32)
10 (27)
5 (31)
15 (26)
10 (30)
10 (30)
10 (18)
Reference drug
Chloramphenicol
Nystatin
2.5 (39)
—
2.5 (35)
—
2.5 (38)
—
2.5 (38)
—
—
—
2.5 (35)
2.5 (38)
1,707.66, C=C at 1,606.41 cm−1; MS(EI) m/z 376 (M+ + 1),
1HNMR (DMSO, 300 MHz): δ 8.72-7.10 (m, 7H, 2Ar-H),
6.99 (s, 1H, hetero CH), 3.87-3.85 (s, 3H, OCH3), 3.37-3.30
(s, 3H, COH3), 3.25-3.24 (s, 3H,CH3).
in acetic anhydride (10 ml) via microwave irradiation at
200°C for 2 min. e reaction mixture was cooled, filtered
off and the precipitate was washed with water and petro-
leum ether (b.p. 40–60°C). e solid product was crystal-
lized from acetic acid to give (3g–l).
1-Acetyl-5-nitro-3-[(2-oxo-5-p-methoxyphenylfuran-3(2H)-
ylidin)]indolin-2-one (3e)
5-Methyl-3-[(2-oxo-5-(4-tolyl)furan-3(2H)-ylidine)]indolin-2-
one (3g)
Reddish brown crystals, 72%, m.p. 290–292°C; IR:
CH(alicyclic) at 2,925.14, C=O(lactone) at 1,775.15, C=O(amide)
at 1,723.09, C=C at 1,609.31 cm−1; MS(EI) m/z 406 (M+),
1HNMR (DMSO, 300 MHz): δ 8.33-7.01 (m, 7H, 2Ar-H),
6.99 (s, 1H, hetero CH), 3.87-3.82 (s, 3H, OCH3), 3.81-
3.32(s, 3H, COCH3).
Reddish brown crystals,79%, m.p. 238–240°C; IR: NH
at 3,425, CH(alicyclic) at 2,973.1-2,916.8, C=O(lactone) at
1,779.5,C=O(amide) at 1,712.5, C=C at 1,698.8 cm−1; MS(EI)
1
m/z 314 (M+ − 3), HNMR (DMSO, 300 MHz): δ 10.75 (s,
1H, NH), 8.51-7.14 (m, 7H, 2Ar-H), 6.78 (s, 1H, hetero
CH), 3.32, 3.19 (s, 6H, 2CH3).
1-Acetyl-5-chloro-3-[(2-oxo-5-p-methoxyphenylfuran-3(2H)-
ylidin)]indolin-2-one (3f)
5-Nitro-3-[(2-oxo-5-(4-tolyl)furan-3(2H)-ylidine)]indolin-2-
one (3h)
Reddish brown crystals,75%, m.p. 280–282°C;
IR:CH(alicyclic) at 2,924.52, C=O(lactone) at 1,779.97, C=O(amide)
at 1,708.62, C=C at 1,604.48 cm−1; MS(EI) m/z 395 (M+),
1HNMR (DMSO, 300 MHz): δ 8.24-7.02 (m, 7H, 2Ar-H),
6.64 (s, 1H, hetero CH ), 3.88-3.82 (s, 3H, OCH3), 3.39-2.66
(s, 3H, COCH3).
Reddish brown crystals, 76%, m.p. 280–282°C; IR: NH
at 3,397.96, CH(alicyclic) at 3,031.55–2,923.56, C=O(lactone)
at 1,793.47, C=O(amide) at 1,722.12, C=C at 1,639.2 cm−1;
MS(EI) m/z 350 (M+ + 2),1HNMR (DMSO, 300 MHz): δ
9.62 (s, 1H, NH), 8.39-7.33 (m, 7H, 2Ar-H), 6.51 (s, 1H,
hetero CH ), 3.29 (s, 3H, CH3).
General procedure for the synthesis of furanone
derivatives via microwave irradiation under Perkin
5-Chloro-3-[(2-oxo-5-(4-tolyl)furan-3(2H)-ylidine)]indolin-2-
one (3i)
reaction conditions (3g–l
)
Furanone derivatives were prepared via condensation of
finely powdered β-aroyl propionic acid (0.01 mol), fused
sodium acetate (0.01 mol) and 5-alkylisatin (0.01 mol)
Reddish brown crystals, 80%, m.p. 270–272°C; IR: NH
at 3,418.21, CH(alicyclic) at 2,924.52–2,845.3, C=O(lactone) at
1,775.15, C=O(amide) at 1,711.51, C=C at 1,604.48 cm−1; MS(EI)
© 2012 Informa UK, Ltd.

6
N. G. Kandile et al.
m/z 339 (M+ + 2), 1HNMR (DMSO, 300 MHz): δ 10.01 (s, 1H,
NH), 8.21-7.31 (m, 7H, 2Ar-H), 6.42 (s, 1H, hetero CH), 3.30
(s, 3H, CH3), 13CNMR (DMSO, 300 MHz): 171.89, 163.48,
146.82, 146.40, 146.24, 138.40, 136.26, 130.09, 129.25,
129.04, 128.97, 127.24, 126.82, 124.58, 120.93, 112.72, 30.61.
2,971.77–2,926.45, C=O(ketone) at 1,647.88, C=O(amide) at
1,615.41, C=C at 1,558.2 cm−1; MS(EI) m/z 380 (M+),
1HNMR (DMSO, 300 MHz): δ 9.64 (s, 1H, NH), 9.24 (t, 1H,
NH), 7.65-7.05(m, 7H, 2Ar-H), 6.62 (d, 2H, NH2), 4.19 (s,
2H, CH2), 3.56-3.31 (s, 3H, CH3).
2-[(5-Chloro-2-oxoindolin-3-ylidine)]-4-oxo-4-(4-tolyl)
butanehydrazide (4c)
5-Methyl-3-[(2-oxo-5-(4-methoxyphenyl)furan-3(2H)-ylidine)]
indolin-2-one (3j)
Pale brown crystals,75%, m.p. 140–142°C; IR: NH2 at
3,410.49–3,317.4, NH at 3,222.2, CH(alicyclic) at 2,971.52–
2,962.45, C=O(ketone) at 1,647.48, C=O(amide) at 1,615.44, C=C
Reddish brown crystals, 85%, m.p. 252–254°C; IR: NH at
3,424.5, CH(alicyclic) at 2,924.8, C=O(lactone) at 1,773, C=O(amide)
at 1,694.3, C=C at 1,652.7 cm−1; MS(EI) m/z 330 (M+ + 2)
1HNMR (DMSO, 300 MHz): δ 10.71 (s, 1H, NH), 8.62-7.08
(m, 7H, 2Ar-H), 6.76 (s, 1H, hetero CH), 3.87-3.80 (s, 3H,
OCH3), 3.35 (s, 3H, CH3).
1
at 1,515.78 cm−1; MS(EI) m/z 369 (M+), HNMR (DMSO,
300 MHz): δ 10.22 (s, 1H, NH), 9.19 (t, 1H, NH),7.67-6.89
(m, 7H, 2Ar-H), 6.86 (d, 2H, NH2), 4.19 (s, 2H, CH2), 3.48
(s, 3H, CH3).
5-Nitro-3-[(2-oxo-5-(4-methoxyphenyl)furan-3(2H)-ylidine)]
indolin-2-one (3k)
2-[(5-Methyl-2-oxoindolin-3-ylidine)]-4-oxo-4-(4-
methoxyphenyl)-butane hydrazide (4d)
Reddish brown crystals, 80%, m.p. 256–258°C; IR: NH at
3,422.7, CH(alicyclic) at 3,008.2-2,840.7, C=O(lactone) at 1,769.3,
C=O(amide) at 1,720.1, C=C at 1,640.4 cm−1; MS(EI) m/z 363
(M+ − 1),1HNMR (DMSO, 300 MHz): 9.22 (s, 1H, NH), δ
7.91-7.00 (m, 7H, 2Ar-H), 6.41 (s, 1H, hetero CH), 3.86-
3.82 (s, 3H, OCH3).
Pale brown crystals,73%, m.p. 162–164°C; IR: NH2 at
3,315.7-3,283.6, NH at 3,186.1, CH(alicyclic) at 3,035.1-
2,839.3, C=O(ketone) at 1,702.6, C=O(amide) at 1,609.8, C=C
1
at 1,513.1 cm−1; MS(EI) m/z (M+), HNMR (DMSO, 300
MHz): δ 9.99 (s, 1H, NH), 9.63-9.31 (t, 1H, NH), 7.54-6.74
(m, 7H, 2Ar-H), 6.35 (d, 2H, NH2), 4.23 (s, 2H, CH2), 3.81-
3.69 (s, 3H, OCH3), 3.30-3.05 (s, 3H, CH3).
5-Chloro-3-[(2-oxo-(4-methoxyphenyl)furan-3(2H)-ylidine)]
indolin-2-one (3l)
2-[(5-Chloro-2-oxoindolin-3-ylidine)]-4-oxo-4-(4-
Reddish brown crystals, 82%, m.p. 230–232°C; IR: NH at
3,422.7, CH(alicyclic) at 3,065.2-2,839.1, C=O(lactone) at 1,787.9,
C=O(amide) at 1,715.7, C=C at 1,650.4 cm−1; MS(EI) m/z 355
methoxyphenyl)-butane hydrazide (4e)
Pale brown crystals, 75%, m.p. 180–182°C; IR: NH2 at 3,443.2-
3,348.7, NH at 3,261.58, CH(alicyclic) at 2,961.16, C=O(ketone) at
1,688.37, C=O(amide) at 1,617.02, C=C at 1,512.88 cm−1; MS(EI)
m/z 385 (M+), 1HNMR (DMSO, 300 MHz): δ10.2 (s, 1H, NH),
9.82 (s, 1H, NH), 7.27-6.88 (m, 7H, 2Ar-H), 6.56-6.53 (d, 2H,
NH2), 4.36 (s, 2H, CH2), 3.86-3.81 (s, 3H, OCH3).
1
(M+ + 2) HNMR (DMSO, 300 MHz): δ 10.02(s, 1H, NH),
8.00-6.99 (m, 7H, 2ArH), 6.40-6.39 (s, 1H, hetero CH),
3.85-3.81 (s, 3H, OCH3).
General procedure for (4a–e
Hydrazide derivatives were prepared via stirring (3g–j,l
(0.01 mol), (1 ml) of hydrazine hydrate in ethanol (20
ml) at room temperature until the color changed. e
reaction mixture was filtered off. e solid product was
crystallized from ethanol to give (4a–e).
)
General procedure for the synthesis of (5a–d
)
)
Pyridazine derivatives were prepared via reaction of
hydrazide derivatives (4a,b,d,e) (0.01 mol) and ethanol
(10 ml) by microwave irradiation at 150°C for 3 min. e
reaction mixture was cooled, filtered off and the precipi-
tate was crystallized from ethanol to give (5a–d).
2-[(5-Methyl-2-oxoindolin-3-ylidine)]-4-oxo-4-(4-tolyl)butane
hydrazide (4a)
5-Methyl-3-[(3-oxo-6-(4-tolyl)-2,3-dihydropyridazin-4(5H)-
ylidene)]indolin-2-one (5a)
Pale brown crystals, 75%, m.p. 210–212°C; IR: NH2 at 3,334.5-
3,272.9, NH at 3,187.6, CH (alicyclic) at 3,032-2,862.2, C=O(ketone)
at 1,712.5-1,682.5, C=O(amide) at 1,620.4, C=C at 1,520.66 cm−1
MS(EI) m/z 349 (M+), 1HNMR (DMSO, 300 MHz): δ 10.55 (s,
1H, NH), 10.19 (t, 1H, NH), 7.47-6.71 (m, 7H, 2Ar-H), 4.67-
4.54 (d, 2H, NH2), 4.16 (s, 2H, CH2), 3.48-3.30 (s, 6H, 2CH3),
13CNMR (DMSO, 300 MHz): 176.04, 168.98, 150.05, 140.67,
140.67, 140.48, 139.94, 136.73, 130.93, 129.40, 128.99, 126.92,
125.85, 121.15, 108.72, 48.19, 35.70, 20.75.
Orange crystals, 70%, m.p. 220–222°C; IR: NH(broad
band)
at 3,301-3,247.54, CH(aliphatic) at 3,021.91–2,849, C=O at
1,704.76–1,648.84, C=N at 1,549.52, C=C at 1,503.2 cm−1;
MS(EI) m/z 331 (M+),1HNMR (DMSO, 300 MHz): δ 10.28
(s, 1H, NH(oxindole)), 9.48 (s, 1H, NH(pyridazine)), 7.77-6.73 (m,
7H, 2ArH), 4.64 (s, 2H, hetero CH2), 3.42 (s, 6H, 2CH3),
13CNMR (DMSO, 300 MHz): 176.38, 160.19, 141.70,
137.54, 135.00, 130.09, 129.95, 127.64, 125.87, 125.15,
123.08, 116.03, 108.86, 102.02, 100.19, 35.82, 20.86, 20.69.
5-Nitro-3-[(3-oxo-6-(4-tolyl)-2,3-dihydropyridazin-4(5H)-
ylidene)]indolin-2-one (5b)
2-[(5-Nitro-2-oxoindolin-3-ylidine)]-4-oxo-4-(4-tolyl)
butanehydrazide (4b)
Pale brown crystals, 71%, m.p. 120–122°C; IR: NH(broad band) at
3,392.17,CH(aliphatic) at2,973.7-2,924.5,C=Oat1,653.66–1,600,
Pale brown crystals,70%, m.p. 110–112°C; IR: NH2
at 3,408.57–3,359.5, NH at 3,238.09, CH(alicyclic) at
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of a new class of antimicrobial agents
7
C=N at 1,545.96, C=C at 1,513.9 cm−1; MS(EI) m/z 363 (M+
1,629.55, C=O(amide) at 1,563.02, C=C at 1,538.26 cm−1;
1
1
+ 1), HNMR (DMSO, 300 MHz): δ 9.72 (s, 1H, NH(oxindole)),
MS(EI) m/z 486 (M+ + 2), HNMR (DMSO, 300 MHz): δ
9.21 (s, 1H, NH(pyridazine)), 7.92-6.60 (m, 7H, 2ArH), 4.48 (s,
2H, hetero CH2), 3.30 (s, 3H, CH3).
7.46-7.20 (m, 12H, 3ArH), 4.77 (t, 1H, NH(amide), 4.23 (d, 2H,
NHCH2), 3.73 (s, 2H, CH2CO), 2.51-2.5 (s, 3H, COCH3), 2.49
(s, 3H, CH3), 13CNMR (DMSO, 300 MHz):196.21, 171.21,
169.09, 165.09, 150.59, 149.03, 145.48, 140.19, 138.11,
137.79, 137.57, 137.41, 137.34, 137.01, 136.22, 135.79,
132.06, 130,121. 18,73.46, 63.08, 53.60, 49.76, 45.48.
5-Methyl-3-[3-oxo-(6-(4-methoxyphenyl)-2,3-
dihydropyridazin-4(5H)-ylidine)]indolin-2-one (5c)
Orange crystals, 70%, m.p. 220–222°C; IR: NH(broad band) at
3,375-3,217.8, CH(aliphatic) at 2,933.3-2,855.5, C=O at 1,655.4,
C=N at 1,608.6, C=C at 1,512.9 cm−1; MS(EI) m/z 347 (M+),
1HNMR (DMSO, 300 MHz): δ 9.99 (s, 1H, NH(oxindole), 9.31
(s, 1H, NH(pyridazine)), 7.70-6.35 (m, 7H, 2Ar-H), 4.34 (s, 2H,
hetero CH2), 3.83-3.78 (s, 3H, OCH3), 3.40-3.37 (s, 3H, CH3).
2-[(1-Acetyl-5-methyl-2-oxo-indolin-3-ylidene)]-N-benzyl-4-
(4-methoxyphenyl)-4-oxobutanamide (6d)
Pale brown crystals,90%, m.p. 120–121°C; IR: NH at
3,292.86, CH(aliphatic) at 3,064.33–2,895.98, C=O(ketone) at
1,630.52, C=O(amide) at 1,563.02, C=C at 1,533.26 cm−1;
MS(EI) m/z 481 (M+ − 1),1HNMR (DMSO, 300 MHz): δ
7.32-7.17 (m, 12H, 3ArH), 4.27 (t, 1H, NH(amide)), 4.12 (d,
2H, NHCH2), 3.88 (s, 3H, OCH3), 3.73 (s, 2H, CH2CO),
2.51-2.49 (s, 3H, COCH3), 2.49-2.45 (s, 3H, CH3).
5-Chloro-3-[3-oxo-(6-(4-methoxyphenyl)-2,3-
dihydropyridazin-4(5H)-ylidine)]indolin-2-one (5d)
Pale brown crystals, 71%, m.p. 118–220°C; IR: NH(broad
at 3,420.14–3,255.25, CH(aliphatic) at 2,922.59, C=O at
band)
1,654.6, C=N at 1,541.81, C=C at 1,515.8 cm−1; MS(EI)
m/z 367 (M+), 1HNMR (DMSO, 300 MHz): δ 10.21 (s, 1H,
NH(oxindole)), 9.62 (s, 1H, NH(pyridazine)), 7.97-7.01 (m, 7H,
2ArH), 4.22 (s, 2H, hetero CH2), 3.30 (s, 3H, OCH3).
2-[(1-Acetyl-5-nitro-2-oxo-indolin-3-ylidene)]-N-benzyl-4-(4-
methoxyphenyl)-4-oxobutanamide (6e)
Pale brown crystals, 89%, m.p. 118–120°C; IR: NH at
3,291.89, CH(aliphatic) at 3,061.44–2,896.54, C=O(ketone) at
1,628.59, C=O(amide) at 1,564.95, C=C at 1,539.73 cm−1;
General procedure for the synthesis of 2-[(1-acetyl-
5-alkyl-2-oxo-indolin-3-ylidene)]-N-benzyl-4-
oxo-4(4-alkylphenyl)butanamides (6a–f), and
N-benzyl-[4-(4-methoxyphenyl)-2-(5-nitro-2-oxo-
indolin-3-ylidene)]-4-oxo-butan amide (6g)
1
MS(EI) m/z 515 (M+), HNMR (DMSO, 300 MHz): δ 7.8-
7.20 (m, 12H, 3ArH), 4.77-4.47 (t, 1H, NH(amide)),4.25-4.12
(d, 2H, NHCH2), 3.92-3.81 (s, 3H, OCH3), 3.72 (s, 2H,
CH2CO), 2.51-2.49 (s, 3H, COCH3).
A mixture of (3a–c,k) (0.01 mmol) in ethanol (20 ml) and
benzyl amine (0.01 mmol) was refluxed for 3 h or stirred
at room temperature for 3 h or microwave irradiated for 3
min at 85°C, e products were filtered off and recrystal-
lized from ethyl alcohol to give the amide (6a–g).
2-[(1-Acetyl-5-chloro-2-oxo-indolin-3-ylidene)]-N-benzyl-4-(4-
methoxyphenyl)-4-oxobutanamide (6f)
Pale brown crystals, 88%, m.p. 100–102°C; IR: NH at
3,292.89, CH(aliphatic) at 3,063.48–2,898.12, C=O(ketone) at
1,629.59, C=O(amide) 1,565.92, C=C at 1,544.96 cm−1; MS(EI)
m/z 502 (M+),1HNMR (DMSO, 300 MHz): Δ7.32-7.18
(m, 12H, 3ArH), 4.65-4.32 (t, 1H, NH(amide)), 4.13 (d, 2H,
NHCH2), 3.80 (s, 3H, OCH3), 3.73 (s, 2H, CH2CO), 2,51-
2.49 (s, 3H, COCH3).
2-[(1-Acetyl-5-methyl-2-oxo-Indolin-3-ylidene)]-N-benzyl-4-
oxo-4(4-tolyl) butanamide (6a)
Pale brown crystals, 92%, m.p. 125–127°C; IR: NH at
3,292.86, CH(aliphatic) at 3,063.37–2,890.16, C=O(ketone) at
1,629.55, C=O(amide) at 1,563.06, C=C at 1,539.26 cm−1;
MS(EI) m/z 467 (M+), 1HNMR (DMSO, 300 MHz): δ 7.79-
7.20 (m, 12H, 3ArH), 4.77-4.49 (t, 1H, NH(amide)), 4.36-4.12
(d, 2H, NHCH2), 3.73 (s, 2H, CH2CO), 2.51-2.46 (s, 3H,
COCH3), 2.48-2.47 (s, 3H, CH3).
N-benzyl-4-[(4-methoxyphenyl)-2-(5-nitro-2-oxo-indolin-3-
ylidene)]-4-oxo-butan amide(6g)
Pale brown crystals, 90%, m.p. 100–102°C; IR: NH at
3,292.86, CH(aliphatic) at 3,063.37–2,894.15, C=O(ketone) at
1,631.48, C=O(amide) at 1,565.06, C=C at 1,538.2 cm−1; MS(EI)
1
2-[(1-Acetyl-5-nitro-2-oxo-indolin-3-ylidene)]-N-benzyl-4-
oxo-4(4-tolyl)butanamide (6b)
m/z 471(M+), HNMR (DMSO, 300 MHz):δ 7.47-7.18 (m,
12H, 3ArH), 4.77-4.65 (t, 1H, NH), 4.23 (s, 1H, NH), 4.13 (d,
2H, NHCH2), 3.73 (s, 2H, OCH3), 2.50 (s, 3H, CH2CO).
Pale brown crystals, 87%, m.p. 110–111°C; IR: NH at
3,292.86, CH(aliphatic) at 3,064.33–2,890.16, C=O(ketone) at
1,629.55, C=O(amide) at 1,563.02, C=C at 1,538.26 cm−1;
General procedure for the synthesis of 1-acetyl-
3[-(1-benzyl-2-oxo)-5-p-tolyl-1,2-dihydropyrrol-
3-ylidene)]-5-alkylindolin-2-one(7 )
1
MS(EI) m/z 497 (M+ − 2), HNMR (DMSO, 300 MHz):
Δ7.46-7.20 (m, 12H, 3ArH), 4.77 (t, 1H, NH(amide)), 4.23-
4.12 (d, 2H, NHCH2), 3.73 (s, 2H, CH2CO), 2.51-2.49 (s,
3H, COCH3), 2.48-2.47 (s, 3H, CH3).
and3-[(1-benzyl-5-(4-methoxyphean,byl)-2-oxo-1,2-
dihydropyrrol-3-ylidine)]-5-nitroindolin-2-one (7c)
Method 1
2-[(1-Acetyl-5-chloro-2-oxo-indolin-3-ylidene)]-N-benzyl-4-
oxo-4(4-tolyl) butanamide (6c)
Pale brown crystals, 85%, m.p. 110–112°C; IR: NH at
3,292.86, CH(aliphatic) at 3,064.41–2,931.27, C=O(ketone) at
A mixture of (6b,c,g) (0.01 mmol) and HCl/AcOH (1:1) was
refluxed for 3 h or microwave irradiated for 3 min at 120°C.
e solid product was filtered off and recrystallized from
acetic acid to give the pyrrolone derivatives (7a–c).
© 2012 Informa UK, Ltd.

8
N. G. Kandile et al.
Method 2: preparation of (7a)
4-[(3-(5-Naitro-2-oxindolin)-3-ylidene)-5-(4-methoxyphenyl)-
2-oxo-2,3-dihydro-pyrrol-1-yl)] benzene sulfonamide (8b)
Violet crystals, 72%, m.p. 268–269°C, IR: NH(broadband) at
3,417.24, CH(aliphatic) at 2,921.63, C=O(amide) at 1,673.51,
C=O(oxopyroline) at 1,608.34, and SO2 at 1,333.53 cm−1. MS(EI)
Benzylamine (0.01 mmol), (3c) (0.01 mmol) and HCl/
AcOH (1:1) were added together. e reaction mixture
was reacted via microwave irradiation for 3 min at 120°C.
e solid product was filtered off and recrystallized from
a suitable solvent to give the pyrrolone derivative (7a).
1
m/z 519 (M+) HNMR (DMSO, 300 MHz): δ 11.42 (s, 2H,
NH2), 10.32 (s, 1H, NH(oxindole)), 7.98-7.02 (m, 12H, 3Ar-H),
6.97-6.95 (s, 1H, CH(hetero)), and 3.85-3.77 (s, 3H, OCH3).
1-Acetyl-3-[(1-benzyl-2-oxo)-5-p-tolyl-1,2-dihydropyrrol-3-
ylidene)]-5-chloro indolin-2-one (7a)
White crystals, 82%, m.p. 286–288°C; IR: CH(aliphatic) at
3,000.69, C=O(ketone) at 1,676.68, C=O(amide) at 1,644.8, C=C
4-[(3-(5-Chloro-2-oxindolin-3-ylidene)-5-(4-methoxyphenyl)-
2-oxo-2,3-dihydro-pyrrol-1-yl)] benzene sulfonamide (8c)
Violet crystals, 70%, m.p. 220–222°C, IR: NH(broadband)
at 3,406.6, CH(aliphatic) at 2,929.3, C=O(amide) at 1,715.3,
C=O(oxopyroline) at 1,602.56 and SO2 at 1,302.6 cm−1, MS(EI)
m/z 508 (M+), 1HNMR (DMSO, 300 MHz): δ 10.88 (s, 2H,
NH2), 10.02 (s, 1H, NHoxindole), 7.98-7.02 (m, 12H, 3Ar-H),
6.98-6.82 (s, 1H, CH(hetero)), and 3.89-3.79 (s, 3H, OCH3).
1
at 1,593.88 cm−1; MS(EI) m/z 468 (M+), HNMR (DMSO,
300 MHz): δ 7.52-7.32 (m, 12H, 3ArH), 4.02 (s, 1H, hetero
CH), 3.97 (s, 2H, N-CH2), 3.95-3.93 (s, 3H, COCH3), 2.50-
2.49 (s, 3H, CH3).
1-Acetyl-3-[(1-benzyl-2-oxo)-5-p-tolyl-1,2-dihydropyrrol-3-
ylidene)]-5-nitro-indolin-2-one (7b)
White crystals, 80%, m.p. 280–282°C; IR: CH(aliphatic) at
2,999.73, C=O(ketone) at 1,770.33, C=O(amide) at 1,683.55,
4-[(3-(5-Chloro-2-oxindolin-3-ylidene)-5-(4-tolyl)-2-oxo-2,3-
dihydropyrrol-1-yl)] phenyl sulfonyl guanidine (8d)
1
C=C at 1,592.91 cm−1; MS(EI) m/z 474 (M+ − 5), HNMR
Violet crystal, 65%, m.p. 240–242°C, IR: NH(broadband)
at 3,433.6, CH(aliphatic) at 2,922.5, C=O(amide) at 1,734.08,
C=O(oxopyroline) at 1,712.48, C=N at 1,617.98 and SO2 at 1,402
(DMSO, 300 MHz): δ 7.54-7.34 (m, 12H, 3ArH), 4.22 s, 1H,
hetero CH), 3.98 (s, 2H, NH2), 3.40 (s, 3H, COCH3), 2.49 (s,
3H, CH3). 13CNMR (DMSO, 300 MHz):172.2, 163.8, 161.4,
151.6, 144.1, 142.08, 141.8, 139.4, 138.2, 134.05, 132.06,
129.86, 128.9, 128.41, 128.23, 126.2, 125.8, 124.8, 123.6,
120.50, 100.2, 42.04, 38.94, 38.66.
1
cm−1, MS(EI) m/z 535 (M+), HNMR: δ 10.84 (s, 2H, 2NH
of NHCNHNH2), 10.08 (s, 2H, NH2), 7.87-7.18 (m, 12H,
3Ar-H), 6.73 (s, 1H, CH(hetero), and 2.49-2.29 (s, 3H, CH3).
4-[(3-(5-Nitro-2-oxindolin-3-ylidene)-5-(4-methoxyphenyl)-2-
oxo-2,3-di-hydropyrrol-1-yl)] phenyl sulfonyl guanidine (8e)
Violet crystals, 64% , m.p. 273–274°C, IR: NH(broadband) at
3,433.64, CH(aliphatic) at 2,924.52, C=O(amide) at 1,721.52,
C=O(oxopyroline) at 1,692.4, C=N at 1,612.2, and SO2 at
3-[(1-Benzyl-5-(4-methoxyphenyl)-2-oxo-1,2-dihydropyrrol-3-
ylidine)]-5-nitro- indolin-2-one (7c)
White crystals, 87%, m.p. 270–272°C; IR: NH at 3,216.13,
CH(aliphatic) at 2,995.87, C=O(ketone) at 1,672.96, C=O(amide) at
1,642.58, C=C at 1,591.95 cm−1; MS(EI) m/z 450 (M+ − 3),
1HNMR (DMSO, 300 MHz): δ 7.52-7.36 (m, 12H, 3ArH),
4.02 (s, 1H, NH), 4.00 (s, 1H, hetero CH), 3.98-3.96 (s, 2H,
N-CH2), 3.45 (s, 3H, OCH3).
1
1,332.57 cm−1, MS(EI) m/z560 (M+), HNMR: δ 10.22 (s,
1H, NH(oxindole)), 10.19 (s, 2H, 2NH of NHCNHNH2), 9.99
(s, 2H, NH2), 7.93-6.79 (m, 12H, 3Ar-H), 6.69 (s, 1H,
CH(hetero)), and 3.83-3.77 (s, 3H, OCH3).
4-[(3-(5-Chloro-2-oxindolin-3-ylidene)5-(4-methoxyphenyl)-
2-oxo-2,3-dihydropyrrol-1-yl)]phenyl sulfonyl guanidine (8f)
Violet crystals, 60%, m.p. 200–202°C, IR: NH(broadband) at
3,376.75, CH(aliphatic) at 2,931.27, C=O(amide) at 1,734.07,
C=O(oxopyroline) at 1,712.48, C=N at 1,603.52 and SO2 at
General procedure for the synthesis of 4-[(3-(5-alkyl-
2-oxindolin-3-ylidene)-5-(4-alkyl-phenyl)-2-oxo-2,3-
dihydropyrrol-1-yl)] sulfonamides (8a–k
)
A mixture of (3g,h,i,k,l),(0.01 mol), of the appropriate sulfon-
amide (0.01 mol), and fused sodium acetate (0.01 mol) in
acetic acid (10 ml) were reacted via microwave irradiation
for 3 min at 120°C, the reaction mixture was cooled, filtered
off and the precipitate was washed with water, petroleum
ether (b.p. 40–60°C). e solid product was crystallized
from the suitable solvent to give (8a–i).
1
1,300.75 cm−1, MS(EI) m/z 550 (M+, HNMR): δ 10.88 (s,
1H, NH(oxindole)), 10.82 (s, 2H, 2NH NHCNHNH2), 10.02
(s, 2H, NH2), 7.95-6.84 (m, 12H, 3Ar-H), 6.48 (s, 1H,
CH(hetero)), and 3.86-3.84 (s, 3H, OCH3).
4-[(2-(3-(5-Methyl-2-oxindolin-3-ylidene)-5-(4-tolyl)-2-oxo-
2,3-di-hydropyrrol-1-yl) ethyl)]benzene sulfonamide (8g)
Violet crystals, 68%, m.p. 262–264°C, IR: NH of NH2 at
3,391.17–3,257.18, CH(aliphatic) at 2,925.48, C=O(amide) at
1,677.97, C=O(oxopyroline) at 1,584.24, and SO2 at 1,325.82
4-[(3-(5-Chloro-2-oxoindolin-3-ylidene)-5-(4-tolyl)-2-oxo-2,3-
dihydro-pyrrol-1-yl)]benzene sulfonamide (8a)
Violet crystals, 69%, m.p. 219–220°C, IR: amino group
NH(broadband) at 3,400-85 CH(aliphatic) at 2,924.5, C=O(amide) at
1,710.5, C=O(oxopyroline) at 1,601.5 and SO2 at 1,321.9 cm−1,
1
cm−1, MS(EI) m/z 498 (M+ + 1), HNMR: δ 10.60 (s, 1H,
NH(oxindole)), 9.28 (s, 2H, NH2), 7.65-7.13 (m, 11H, 3Ar-H),
6.75-6.72 (s, 1H, CH(hetero)), 3.94-3.37 (t, 4H, 2CH2), and
3.31-3.25 (s, 6H, 2CH3). 13CNMR (DMSO): δ169.99, 169.48,
152.79, 142.27, 142.14, 141.43, 140.09, 133.24, 132.46,
1
MS(EI) m/z 492 (M+), HNMR (DMSO, 300 MHz): δ 10.89
(s, 2H, NH2), 9.48 (s, 1H, NH(oxindole)), 7.85-7.20 (m, 12H, 3Ar-
H), 6.82 (s, 1H, CH(hetero)) and 2.49-2.39 (s, 3H, CH3).
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of a new class of antimicrobial agents
9
129.94, 129.56, 128.96, 127.97, 127.39, 125.91, 125.68,
121.53, 120.53, 109.32, 101.95, 41.61, 33.95, 20.99, 20.91.
a suspension of the corresponding species. en 0.1 mL
of the spore suspension was distributed on the surface of
sterile Sabouraud dextrose agar plates.
4-[(2-(3-(5-Nitro-2-oxindolin-3-ylidene)-5-(4-tolyl)-2-oxo-2,3-
dihydropyrrol-1-yl) ethyl)] benzene sulfonamide (8h)
Violet crystals, 73%, m.p. 255–256°C, IR: NH of NH2 at
3,405.67 (broad band), CH(aliphatic) at 2,925.48, C=O(amide)
at 1,687.41, C=O(oxopyrolene) at 1,613.16 and SO2 at 1,336.43
cm−1, MS(EI) m/z 532 (M+), 1HNMR: δ 12.22 (s, 1H,
NH(oxindole)), 11.41 (s, 2H, NH2), 8.24-7.02 (m, 11H, 3Ar-H),
6.99-6.63 (s, 1H, CH(hetero)), 4.09-3.76 (t, 4H, 2CH2) and
3.28-2.81 (s, 3H, CH3).
Six millimeter diameter wells were punched in the
agar media and filled with 100 μL (500 μg/mL in DMSO)
of the tested chemical compounds previously sterilized
through 0.45 sterile membrane filter38. e plates were
kept at room temperature for 1 h and then incubated at
37°C for 24 h for bacteria and 30°C for 4 days for fungi.
e antimicrobial activities were evaluated by mea-
suring the inhibition zone diameters (mm). Commercial
antibiotic discs were used as positive reference standard
to determine the sensitivity of the strains.
4-[(2-(3-(5-Chloro-2-oxindoline-3-ylidene)-5-(4-tolyl)-2-oxo-
2,3-dihyd-ropyrro-l-1-yl) ethyl)]benzene sulfonamide (8i)
Violet crystals, 70%, m.p. 232–334°C, I.R. NH of NH2 at
3,423.03 (broad band), CH(aliphatic) at 2,925.48, C=O(amide)
at 1,678.73, C=O(oxopyroline) at 1,612.2 and SO2 at 1,337.39,
MS(EI) m/z 520 (M+), 1HNMR: δ 11.88 (s, 1H, NH(oxindole)),
10.82 (s, 2H, NH2), 8.00-7.09 (m, 11H, 3Ar-H), 6.86 (s, 1H,
CH(hetero)), 4.09-3.68 (t, 4H, 2CH2), and 3.32 (s, 3H, CH3).
Determination of MIC of the synthesized compounds
Compounds inhibiting the growth of one or more of the
above microorganisms were further tested for their MIC
and were determined by broth dilution technique37. e
nutrient broth and the yeast extract broth media, which
contained 1 mL of different concentrations of the tested
compounds (2.5, 5, 10, 15, 20, 25 μg/mL) were inocu-
lated with the microbial strains. e bacterial cultures
were incubated for 24 h at 37°C, whereas the fungal ones
were incubated at 30°C for 48 h. e growth was moni-
tored spectrophotometrically. e lowest concentration
required to arrest the microbial growth was regarded as
MICs (μg/mL).
4-[(2-(3-(5-Nitro-2-oxindolin-3-ylidene)-5-
(4-methoxyphenyl)-2-oxo-2,3-di-hydro-pyrrol-1-yl) ethyl)]
benzene sulfonamide (8j)
violet crystal, 70%, m. p. 279–280°C, IR. NH of NH2 at
3,422.06 (broad band), CH(aliphatic) at 2,914.89, C=O(amide)
at 1,652.83, C=O(oxopyroline) at 1,609.3, and SO2 at 1,334.5,
1
MS(EI) m/z 548 (M+), HNMR: δ 11.4 (s, 1H, NHoxindole),
Conclusion
9.92 (s, 2H, NH2), 7.74-7.01 (m, 11H, 3Ar-H), 6.92 (s, 1H,
CH(hetero)), 4.09-3.82 (t, 4H, 2CH2), and 3.78-3.29 (s, 3H,
OCH3).
We have reported a convenient microwave-enhanced,
high speed, short, and economic way for the synthesis
of a new series of furanones and study their reactivity
towards some nucleophiles with the hope for preparing
new antimicrobial and antifungal agents. e data of
MICs of the in vitro antimicrobial evaluation of the aro-
ylpropionic acids 2a,b furanone derivatives 3a–f and the
sulfonamide derivatives 8a–f against several pathogenic
bacterial strains revealed that compound (8j) showed
significant activity against bacterial species. Its activity
was comparable to the reference chloramphenicol.
4-[(2-(3-(5-Chloro-2-oxindolin-3-ylidene)-5-(4-
methoxyphenyl)-2-oxo-2,3-dihydro-pyrrol-1-yl)ethyl)]
benzene sulfonamide (8k)
Violet crystals, 78%, m.p. 279–280°C, I.R. NH of NH2 at
3,437.49–3,347.82, CH(aliphatic) at 2,928.38, C=O(amide) at
1,715.56, C=O(oxopyroline) at 1,608.34, and SO2 at 1,376.93,
MS(EI) m/z 534 (M+ − 1), 1HNMR: δ 10.86 (S, 1H,
NH(oxindole)), 10.19 (s, 2H, NH2), 7.77-6.86 (m, 11H, 3Ar-H),
6.74-6.52 (s, 1H, CH(hetero)), 3.87-3.76 (t, 4H, 2CH2), and
3.31 (s, 3H, OCH3).
Declaration of interest
Antimicrobial evaluation
e authors declared no conflicts of interest.
Most of the newly synthesized compounds in addition to
the reference drugs Chloramphenicol and Nystatin were
screened for their antibacterial and antifungal activities
using the agar well diffusion technique36. e microor-
ganisms (reference and clinical isolates) used included
Gram-negative E. coli (ATCC-25922) and S. flexeniri,
Gram-positive Staphylococcus aureus (ATCC-25923),
Bacillus cereus, and fungi Aspergillus flavus and Candida
albicans (ATCC 10231). For the antibacterial assay, a
standard inoculum (105 CFU/mL) was distributed on
the surface of sterile nutrient agar plates by a sterile glass
spreader. For the antifungal assay a loopful of a particu-
lar fungal strain was transferred to 3 mL of saline to get
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