Microwave synthesis, characterization, and antimicrobial activity of some novel isatin derivatives

Article abstract of DOI:10.1155/2015/716987

Three series of isatin derivatives [3-hydrazino, 3-thiosemicarbazino, and 3-imino carboxylic acid derivatives] were synthesized employing microwave irradiation. The prepared compounds were characterized by FT-IR, NMR, elemental analysis, and X-ray crystal

Full text of DOI:10.1155/2015/716987

Hindawi Publishing Corporation
Journal of Chemistry
Volume 2015, Article ID 716987, 8 pages
http://dx.doi.org/10.1155/2015/716987
Research Article
Microwave Synthesis, Characterization, and Antimicrobial
Activity of Some Novel Isatin Derivatives
Ayman El-Faham,1,2 Wael N. Hozzein,3 Mohammad A. M. Wadaan,3 Sherine N. Khattab,2
Hazem A. Ghabbour,4 Hoong-Kun Fun,4,5 and Mohammed Rafiq Siddiqui1
1 Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
2Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt
3Bioproducts Research Chair, Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
4Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
5X-Ray Crystallography Unit, School of Physics, Universiti Sains Malaysia (USM), 11800 Penang, Malaysia
Correspondence should be addressed to Ayman El-Faham; aymanel faham@hotmail.com
Received 27 June 2015; Accepted 5 August 2015
Academic Editor: Artur M. S. Silva
Copyright © 2015 Ayman El-Faham et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
ree series of isatin derivatives [3-hydrazino, 3-thiosemicarbazino, and 3-imino carboxylic acid derivatives] were synthesized
employing microwave irradiation. e prepared compounds were characterized by FT-IR, NMR, elemental analysis, and X-ray
crystallography for derivatives 5b. e synthesized compounds were screened for antimicrobial activity against selected bacteria
and fungi. e results revealed that the N-alkyl isatin derivatives were biologically active with different spectrums activity. Most of
the 3-hydrazino and 3-thiosemicarbazino isatin derivatives were biologically inactive and generally the active derivatives showed
weak to moderate activity mainly against Gram-positive bacteria. e imino isatin carboxylic acid derivatives (2-[4-(1-benzyl-5-
bromo-2-oxoindolin-3-ylideneamino) phenyl]acetic acid, 5d) showed promising activity against all tested Gram-positive bacteria
and against fungal pathogens.
1. Introduction
smallpox [15] and GAL3 receptor antagonist capabilities
[16]. Isatin derivatives reported to show antiviral [17], anti-
inflammatory, analgesic [18], and anticonvulsant activities
[19]. Isatin-ꢀ-thiosemicarbazone derivatives were found to
demonstrate a range of chemotherapeutic activities [20–
26]. e literature survey revealed that thiocarbohydrazide
is an irreversible inhibitor of catalase, which inhibits the
degradation of serotonin and also possesses anticonvulsant
activity [27].
We report here the synthesis of three different series
of isatin derivatives (hydrazone, thiosemicarbazone, and
imino carboxylic acid derivatives) employing microwave
irradiation. e prepared compounds were subjected to in
vitro screening for their antimicrobial activities against rep-
resentatives of pathogenic Gram-positive and Gram-negative
bacteria and fungi.
e development of new therapeutic agents is one of the
essential goals in medicinal chemistry. In the recent years
there has been a spectacular increase in the use of microwave
heating within the pharmaceutical industry, because it facil-
itates the synthesis of new chemical entities with reduced
reaction time [1]. Microwave irradiation is considered as an
alternate source of heating and it has been proven recently
that microwave heating improves the efficiency of the reac-
tion and reduces the reaction time [2–7].
It was reported that the biological properties of isatin
derivatives include different effects on the brain and offer pro-
tection against some types of infections [8–11]. Isatin is con-
sidered as important class of bioactive compounds exhibiting
caspase inhibitor [12, 13], antibacterial, and antiproliferative
activity [14]. Schiff bases of isatin analogous have anti

2
Journal of Chemistry
2. Experimental Section
(3) 1-Benzyl-5-bromoisatin (1d; Supporting Information Page
2 in Supplementary Material Available Online at http://dx
.doi.org/10.1155/2015/716987). e product was obtained as
red orange crystals in 93% yield; mp 149–151∘C [Lit. [29] mp
2.1. Chemistry
152-153∘C, in 95% yield]. 1H NMR (CDCl ): ꢁ = 4.91 (s, 2H,
2.1.1. Materials. e solvents used were of HPLC reagent
grade. Melting points were determined with a Mel-Temp
apparatus and are uncorrected. Fourier transform infrared
spectroscopy (FTIR) spectra were recorded on a Nicolet 560
spectrometer. Nuclear magnetic resonance spectra (1H NMR
and 13C NMR) were recorded on a JEOL 400 MHz spectrom-
eter with chemical shif values reported in ppm (ꢁ units) rel-
ative to an internal standard. e microwave irradiation was
conducted using a multimode reactor (Synthos 3000, Anton
Paar GmbH, and 1400 W maximum magnetron). Reactions
were performed in teflon vessels (capacity 10 mL). e target
temperature was set and fixed during the irradiation. Settings
and readings for power (W) and pressure were taken from
the instrument. Elemental analyses were performed on a
Perkin-Elmer 2400 elemental analyzers, and the values found
were within 0.3% of the theoretical values. Follow-up of
the reactions and checks of the purity of the compounds
were done by thin layer chromatography (TLC) on silica gel-
protected aluminum sheets (GF254, Merck), and the spots
were detected by exposure to UV-lamp at ꢂ 254 nm for a
few seconds. e compounds were named using Chem. Draw
Ultra version 11, Cambridge Sof Corporation. e X-ray
diffraction measurements of compound 5b were performed
using Bruker APEX-II D8 Venture diffractometer.
3
C H CH ), 6.69 (d, J = 8.1 Hz, 1H, Ar), 7.24–7.32 (m, 5H, Ar),
6
5
2
7.45 (dd, 1H, J = 8.1 Hz, 2.2 Hz, Ar), 7.56 (d, 1H, J = 2.2 Hz, Ar)
ppm.
(4) 1-Benzyl-5-chloroisatin (1e; Supporting Information Page
3). e product was obtained as orange crystals in 86%
yield; mp 136∘C (Lit. [29] mp 134∘C, in 65% yield]. 1H NMR
(CDCl ): ꢁ = 4.94 (s, 2H, C H CH ), 6.69 (d, J = 8.1 Hz, 1H,
3
6
5
2
Ar), 7.28–7.34 (m, 5H, Ar), 7.45 (dd, 1H, J = 8.1 Hz, 2.3 Hz, Ar),
7. 56 (d, 1H, J = 2.3 Hz, Ar) ppm.
(5) 1-(2-Bromoethyl)isatin (1f ; Supporting Information Page
4). e product was obtained as red orange crystals in 89%
yield; mp 130-131∘C (Lit. [29] mp 131-132∘C; in 80% yield). 1H
NMR (CDCl ): ꢁ = 3.60 (t, 2H, J = 6.6 Hz, CH ), 4.16 (t, 2H,
3
2
J = 6.6 Hz, CH ), 7.00 (d, 1H, J = 8.1 Hz, Ar), 7.16 (t, 1H, J =
2
7.3 Hz, Ar), 7.60–7.63 (m, 2H, Ar) ppm.
2.1.3. Microwave Method for the Synthesis of (3a–3n). A mul-
timode reactor (Synthos 3000 Anton Paar, GmbH, 1400 W
maximum magnetron) was used. e initial step was con-
ducted with 4-Teflon vessels rotor (MF 100) that allows
the reactions to process under the same conditions. Isatin
derivatives 1a–1f and hydrazine hydrate 2a, thiosemicar-
bazide 2b, or 4-aminobenzamide 2c were mixed together in
a small portion of ethanol and then subjected to microwave
irradiation (400 watt). e vessels were heated for 5 min at
100∘C and held at the same temperature for another 5 min.
cooling was accomplished by a fan (5 min). e final product
was washed with cold ethanol and then dried under vacuum
to afford the products 3a–3n in high yield and purity.
2.1.2. Synthesis of Isatin Derivatives (1b–1f) . A mixture of
isatin (5 mmol) and potassium carbonate (8 mmol) in DMF
(10 mL) was stirred for 10 minutes at room temperature. Alkyl
halides (6 mmol; benzyl bromide for preparation of 1c, 1d,
and 1e; CH I for preparation of 1b; and 1,3-dibromoethane for
3
preparation of 1f) were added dropwise to the reaction mix-
ture and then the reaction was microwave irradiated using
a multimode reactor (Synthos 3000, Anton Paar GmbH,
Graz, Austria) (1,400 W maximum magnetron). e vessels
were heated for 5 minutes at 80∘C and held at the same
temperature for a further 5 minutes (400 W). Cooling was
accomplished by a fan (5 minutes). e final product was
dried and recrystallized from ethanol. All the spectral data
for the products obtained were in good agreement with the
reported data.
(1) 3-Hydrazinoisatin (3a; Supporting Information Pages 5 and
6). e product was obtained as yellow crystals from ethanol,
in 91% yield; mp 240–242∘C (Lit. [30] 242∘C). 1H NMR (d -
6
DMSO): ꢁ = 6.86 (d, J = 8.1 Hz, 1H, Ar), 6.98 (t, J = 7.3 Hz, 1H,
Ar), 7.14 (t, J = 7.3 Hz, 1H, Ar), 7.35 (d, J = 8.1 Hz, 1H, Ar), 9.55
(d, J = 14.0 Hz, 1H, NH), 10.54 (d, J = 14.0 Hz, 1H, NH), 10.75
(brs, 1H, NH) ppm. 13C NMR (d -DMSO): ꢁ = 110.5, 118.01,
6
121.9, 122.8, 126.8, 127.6, 139.2, 163.3 ppm.
(2) 1-Methyl-3-hydrazinoisatin (3b; Supporting Information
Pages 7 and 8). e product was obtained as yellow crystals
(1) 1-Methylisatin (1b). e product was obtained as orange
red crystals in 90% yield; mp 126-127∘C [Lit. [28] mp 126-
127∘C; in 73% yield]. 1H NMR (CDCl ): ꢁ = 3.36 (s, 3H, CH ),
from ethanol in 93% yield, mp 95–97∘C. 1H NMR (d -
6
3
3
DMSO): ꢁ = 3.66 (s, 3H, CH ), 6.96–7.05 (m, 2H, Ar), 7.23
3
3
6.78 (d, J = 7.8 Hz, 1H, Ar), 7.12 (t, J = 7.4 Hz, 1H, Ar), 7.47 (t,
J = 8.1 Hz, 1H, Ar), 7.61 (d, J = 8.1 Hz, 1H, Ar) ppm.
(t, J = 8.0 Hz, 1H, Ar), 7.41 (d, J = 7.3 Hz, 1H, Ar), 9.64 (d,
J = 8.8 Hz, 1H, NH), 10.58 (d, J = 10.3 Hz, 1H, NH) ppm.
13C NMR (d -DMSO): ꢁ = 25.7, 109.8, 117.7, 121.9, 122.4, 125.9,
6
(2) 1-Benzylisatin (1c). e product was obtained as orange
127.6, 140.5, 161.3 ppm. C H N O (175.19): Calcd. C, 61.70; H,
9
9
red crystals in 88% yield; mp 134–136∘C. [Lit. [28] mp 134–
5.18; N, 23.99; found: C, 61.87; H, 5.33; N, 24.19.
136∘C; 88% yield]. 1H NMR (CDCl ): ꢁ = 4.93 (s, 2H,
3
C H CH ), 6.77 (d, J = 7.7 Hz, 1H, Ar), 7.08 (t, J = 7.4 Hz, 1H,
(3) 1-Benzyl-3-hydrazinoisatin (3c; Supporting Information
Pages 9 and 10). e product was obtained as yellow crystals
from ethanol in 93% yield; mp 114-115∘C (Lit. [30] 114-115∘C).
6
5
2
Ar), 7.33 (s, 5H, Ar), 7.47 (t, J = 8.1, 1H), 7.61 (d, J = 8.1, 1H, Ar)
ppm.

Journal of Chemistry
3
1H NMR (d -DMSO): ꢁ = 4.97 (s, 2H, CH ), 6.96 (d, J =
8.1 Hz, 1H, Ar), 7.20–7.50 (m, 5H, Ar), 7.82 (s, 1H, Ar), 8.89
(s, 1H, 1NH), 9.19 (s, 1H, NH), 12.25 (s, 1H, 1NH) ppm.
6
2
8.0 Hz, 1H, Ar), 7.02 (t, J = 7.3 Hz, 1H, Ar), 7.17 (t, J = 8.0 Hz,
1H, Ar), 7.32 (s, 5H, Ar), 7.43 (d, J = 7.3 Hz, 1H, Ar), 9.77 (d, J =
14.0 Hz, 1H, NH), 10.58 (d, J = 14.0 Hz, 1H, NH) ppm. 13C
13C NMR (d -DMSO) ꢁ = 43.2, 112.4, 121.1, 122.0, 127.9,
6
128.0, 128.2, 129.3, 130.3, 130.8, 136.0, 141.7, 161.1, 179.3 ppm.
C H ClN OS (344.82): Calcd. C, 55.73; H, 3.80; N, 16.25;
NMR (d -DMSO): ꢁ = 42.8, 109.8, 117.9, 122.13, 122.6, 125.6,
6
16 13
4
127.5, 127.8, 127.9, 129.2, 137.3, 139.5, 161.3 ppm.
found: C, 56.00; H, 3.89; N, 16.01.
(4)1-Benzyl-5-bromo-3-hydrazinoisatin (3d; Supporting Infor-
mation Pages 11 and 12). e product was obtained as yellow
crystals from ethanol in 95% yield; mp 134–136∘C. 1H NMR
(d -DMSO): ꢁ = 4.97 (s, 2H, CH ), 6.96 (d, 1H, J = 8.1 Hz, Ar),
(10) 1-(2-Bromoethyl)isatin-3-thiosemicarbazone (3j; Support-
ing Information Pages 19 and 20). e product was obtained as
yellow crystals from ethanol in 88% yield; mp 246∘C (dec). 1H
NMR (d -DMSO): ꢁ = 3.77 (t, 2H, J = 6.4 Hz, CH ), 4.21 (t,
6
2
6
2
7. 19 (d, 1H, J = 8.1 Hz, Ar), 7.24–7.33 (m, 5H, Ar), 8.15 (s, 1H,
2H, J = 6.4 Hz, CH ), 7.18 (t, 1H, J = 7.3 Hz, Ar), 7.28 (d, 1H, J =
2
Ar), 9.98 (brs, 1H, 1NH), 10.35 (brs, 1H, NH) ppm. 13C NMR
8.0 Hz, Ar), 7.43 (t, 1H, J = 7.3 Hz, Ar), 7.21 (d, 1H, J = 7.3 Hz,
(d -DMSO): ꢁ = 40.3, 111.3, 117.4, 123.9, 126.7, 127.0, 127.8, 128.0,
Ar), 8.77 (s, 1H, NH), 9.12 (s, 1H, NH), 12.36 (s, 1H, NH) ppm.
6
129.2, 136.9, 138.0, 161.1 ppm. C H BrN O (329.02): Calcd.
13C NMR (d -DMSO) ꢁ = 30.1, 40.5, 110.9, 119.8, 121.3, 131.3,
15 12
3
6
C, 54.56; H, 3.66; N, 12.73; found: C, 54.78; H, 3.54; N, 12.98.
131.8, 142.9, 161.3, 179.2 ppm. C H BrN OS (327.20): Calcd.
11 11
4
C, 40.38; H, 3.39; N, 17.12; found: C, 40.66; H, 3.54; N, 17.40.
(5) 1-Benzyl-5-chloro-3-hydrazinoisatin (3e). e product was
obtained as yellow crystals from ethanol in 93% yield; mp
105–107∘C. 1H NMR (d -DMSO-): ꢁ = 4.97 (s, 2H, CH ), 6.96
ꢀ
(11)4-Amino-ꢃ -(2-oxoindolin-3-ylidene)benzohydrazide (3k;
Supporting Information Pages 21 and 22). e product was
obtained as a yellowish brown solid in 82% yield; mp > 250∘C.
1H NMR (d -DMSO): ꢁ = 6.00 (brs, 2H, NH ), 6.64 (d, 2H,
6
2
(d, J = 8.1 Hz, 1H, Ar), 7.19 (d, J = 8.1 Hz, 1H), 7.24–7.33 (m, 5H,
C H ), 8.15 (s, 1H, Ar), 9.98 (brs, 1H, 1NH), 10.35 (brs, 1H,
6
5
6
2
NH) ppm; 13C NMR (d -DMSO): ꢁ = 40.2, 111.3, 117.4, 123.9,
J = 8.8 Hz, Ar), 6.92 (d, 1H, J = 8.8 Hz, Ar), 7.11 (t, 1H, J =
8.1 Hz, Ar), 7.38 (t, 1H, J = 8.1 Hz, Ar), 7.76 (d, 2H, J = 8.1 Hz,
Ar), 7.88 (d, 1H, J = 7.3 Hz, Ar), 10.80 (s, 1H, NH), 11.33 (s,
6
127.0, 127.8, 128.0, 129.2, 137.0, 138.0, 161.1 ppm. C H ClN O
15 12
3
(285.73): Calcd. C, 63.05; H, 4.23; N, 14.71; found: C, 63.31; H,
4.44; N, 14.98.
1H, NH) ppm. 13C NMR (d -DMSO): ꢁ = 111.1, 113.3, 116.5,
6
118.9, 122.4, 127.0, 131.0, 132.8, 142.2, 144.1, 153.7, 165.5 ppm.
C H N O (280.28): Calcd. C, 64.28; H, 4.32; N, 19.99;
(6) Isatin-3-thiosemicarbazone (3f ). e product was
15 12
4
2
obtained as yellow crystals in 89% yield; mp 246∘C (dec) (Lit.
found: C, 64.13; H, 4.19; N, 20.14.
[29] 245-246∘C). 1H NMR (d -DMSO): ꢁ = 6.85–7.00 (m, 2H,
6
ꢀ
(12) 4-Amino-ꢃ -(1-methyl-2-oxoindolin-3-ylidene)benzohy-
Ar), 7.10 (brs, 2H, Ar), 7.50 (brs, 2H, NH ), 8.05 (s, 1H, NH),
2
drazide (3l; Supporting Information Pages 23 and 24). e
12.65 (brs, 1H, NH) ppm.
product was obtained as a yellow powder from ethyl acetate
in 88% yield; mp > 250∘C. 1H NMR (d -DMSO): ꢁ = 3.26 (s,
(7) 1-Benzyl isatin-3-thiosemicarbazone (3g; Supporting Infor-
mation Pages 13 and 14). e product was obtained as yellow
6
3H, CH ), 6.01 (brs, 2H, NH ), 6.64 (d, 2H, J = 8.4 Hz, Ar),
3
2
solid from ethanol in 93% yield; mp 246-247∘C. 1H NMR (d -
7. 12 (d, 1H, J = 8.0 Hz, Ar), 7.16 (d, 1H, J = 7.6 Hz, Ar), 7.38 (t,
6
DMSO): ꢁ = 4.98 (s, 2H, CH ), 7.02 (d, J = 8.1 Hz, 1H, Ar),
1H, J = 7.6 Hz, Ar), 7.74 (d, 2H, J = 8.8 Hz, Ar), 7.88 (d, 1H, J =
2
7.6 Hz Ar), 11.34 (s, 1H, NH) ppm. 13C NMR (d -DMSO): ꢁ
7.19 (t, J = 8.1 Hz, 1H, Ar), 7.24–7.39 (m, 5H, Ar), 7.72 (d, J =
6
8.1 Hz, 1H, Ar), 8.77 (s, 1H, 1NH), 9.12 (s, 1H, NH), 12.42 (s,
= 26.0, 109.2, 112.7, 113.1, 115.2, 118.3, 122.2, 126.1, 131.1, 132.2,
1H, 1NH) ppm. 13CNMR (d -DMSO): ꢁ = 43.1, 110.9, 120.1,
139.1, 144.5, 153.7, 163.6 ppm. C H N O (294.31): Calcd. C,
6
16 14
4
2
121.4, 123.6, 128.0, 128.2, 129.3, 131.5, 131.6, 136.3, 143.2, 161.4,
65.30; H, 4.79; N, 19.04; found: C, 65.45; H, 4.85; N, 19.31.
179.3 ppm. C H N OS (310.37): Calcd. C, 61.92; H, 4.55; N,
16 14
4
ꢀ
(13) 4-Amino-ꢃ -(1-benzyl-2-oxoindolin-3-ylidene)benzohy-
18.05; found: C, 62.13; H, 4.68; N, 18.31.
drazide (3m; Supporting Information Pages 25 and 26). e
product was obtained as yellowish brown solid in 87% yield;
mp 198–200∘C. 1H NMR (d -DMSO): ꢁ = 4.99 (s, 2H, CH ),
(8) 1-Benzyl-5-bromoisatin-3-thiosemicarbazone (3h; Sup-
porting Information Pages 15 and 16). e product was
obtained as yellow solid from ethanol in 91% yield; mp 246-
247∘C. 1H NMR (d -DMSO): ꢁ = 4.98 (s, 2H, CH ), 6.98 (d,
6
2
6.04 (brs, 2H, NH ), 6.67 (d, 2H, J = 8.0 Hz, Ar), 7.00 (d, 1H,
2
J = 7.3 Hz, Ar), 7.14 (t, 1H, J = 7.3 Hz, Ar), 7.27–7.41 (m, 5H,
Ar), 7.65 (d, 1H, J = 8.8 Hz, Ar), 7.76 (d, 2H, J = 8.0 Hz, Ar),
7. 95 (d, 1H, J = 7.3 Hz, Ar), 11.39 (s, 1H, NH) ppm. 13C NMR
6
2
J = 8.0 Hz, 1H, Ar), 7.24–7.38 (m, 5H, Ar), 7.52 (d, J = 8.0 Hz,
1H), 7.96 (s, 1H, Ar), 8.90 (s, 1H, 1NH), 9.18 (s, 1H, NH), 12.23
(s, 1H, 1NH) ppm. 13C NMR (d -DMSO): ꢁ = 43.2, 112.9,
(d -DMSO) ꢁ = 43.9, 110.3, 113.3, 113.7, 116.0, 123.0, 126.9, 127.7,
6
6
115.5, 122.4, 123.9, 122.4, 123.9, 128.0, 128.2, 129.3, 130.1, 133.5,
128.0, 128.1, 128.2, 129.3, 130.0, 131.2, 132.6, 142.3, 144.0, 153.8,
164.3 ppm. C H N O (370.41): Calcd. C, 71.34; H, 4.90; N,
136.0, 142.1, 161.0, 179.3 ppm. C H BrN OS (389.27): Calcd.
16 13
4
22 18
4
2
C, 49.37; H, 3.37; N, 14.39; found: C, 49.53; H, 3.61; N, 14.66.
15.13; found: C, 71.60; H, 5.01; N, 15.41.
ꢀ
(9) 1-Benzyl-5-chloroisatin-3-thiosemicarbazone (3i; Support-
ing Information Pages 17 and 18). e product was obtained
as yellow solid from ethanol in 91% yield; mp 242∘C (dec).
1H NMR (d -DMSO): ꢁ = 4.98 (s, 2H, CH ), 7.02 (d, J =
(14) 4-Amino-ꢃ -(1-benzyl-3-bromo-2-oxoindolin-3-ylide-
ne)benzohydrazide (3n; Supporting Information Pages 27 and
28). e product was obtained as brown solid in 83% yield;
mp 260–263∘C. 1H NMR (d -DMSO): ꢁ = 4.99 (s, 2H, CH ),
6
2
6
2

4
Journal of Chemistry
6.04 (brs, 2H, NH ), 6.67 (d, 2H, J = 8.04 Hz, Ar), 7.00 (d, 1H,
CH ), 6.64 (d, 1H, J = 7.3 Hz, Ar), 6.90–7.11 (m, 3H, Ar), 7.29–
2
2
J = 7.3 Hz, Ar), 7.14 (t, 1H, J = 7.3 Hz, Ar), 7.27–7.41 (m, 5H,
Ar), 7.65 (d, 1H, J = 8.8 Hz, Ar), 7.76 (d, 2H, J = 8.1 Hz, Ar),
7. 95 (d, 1H, J = 7.3 Hz, Ar), 11.39 (s, 1H, NH), 11.33 (s, 1H, NH)
7.48 (m, 8H, Ar) ppm. 13C NMR (d -DMSO): ꢁ = 40.3, 43.4,
6
114.3, 117.7, 117.9, 127.9, 128.0, 128.1, 129.2, 129.3, 131.2, 136.1,
136.8, 146.5, 148.9, 154.6, 162.9, 173.2 ppm. C H BrN O
23 17
2
3
ppm. 13C NMR (d -DMSO): ꢁ = 43.9, 110.3, 113.3, 113.7, 116.0,
(449.30): Calcd. C, 61.48; H, 3.81; N, 6.23; found: C, 61.73; H,
6
123.0, 126.9, 127.7, 128.0, 128.1, 128.2, 129.3, 130.0, 131.2, 132.6,
142.3, 144.0, 153.8, 164.3 ppm. C H N O (449.30): Calcd.
3.99; N, 6.51.
22 18
4
2
C, 71.34; H, 4.90; N, 15.13; found: C, 71.60; H, 5.01; N, 15.41.
2.2. Biology
2.2.1. Antimicrobial Activities of the Prepared Compounds.
e antimicrobial activities of the prepared compounds
were tested against representative pathogenic Gram-positive,
Gram-negative, and filamentous fungus test strains by using
the paper disc diffusion method [31]. In this method, three
agar media, nutrient agar [32] for bacteria, Sabouraud agar
[33] for the yeast strain, and Czapek Dox agar for the
fungus strain [34], were prepared and sterilized by auto-
claving at 120∘C and 1.5 atm for 20 min. e agar plates
were poured, lef to cool down and afer solidification
they were inoculated with the bacterial and fungal strains
by streaking. e synthesized compounds were dissolved
in dimethylsulfoxide (DMSO) at a final concentration of
10 mg/mL and 5 ꢄL of each compound was loaded on a sterile
filter paper disc (5 mm diameter; 50 ꢄg per disc). e filter
paper disc was then transferred aseptically into the inoculated
agar plates along with commercially available tetracycline
and erythromycin discs as positive controls and DMSO as
the negative control for comparison. e plates were then
incubated at 37∘C for 24 h for bacteria and at 30∘C for 48–72 h
for fungi. Afer incubation, diameters of the inhibition zones
around the paper discs were measured in mm as an indication
of the antimicrobial activities of the compounds.
2.1.4. Microwave Method for the Synthesis of (5a–5d). Isatin
derivatives 1a–1d and 4-aminophenyl acetic acid 4 were
mixed in small amount of ethanol as a solvent in the presence
of glacial acetic acid (2-3 drops). e individual vessels were
heated for 5 min at 100∘C and held at the same temperature
for another 5 min; cooling was accomplished by a fan (5 min).
e final product was washed with cold methanol and then
dried under vacuum to afford products 5a–5d in a pure state,
as observed from their spectral data.
(1) 2-[4-(2-Oxoindolin-3-ylideneamino)phenyl]acetic Acid
(5a; Supporting Information Pages 29 and 30). e product
was obtained as brown crystals from ethyl acetate in 88%
yield; mp: 210–212∘C. 1H NMR (d -DMSO): ꢁ = 3.63 (s, 2H,
6
CH ), 6.43 (d, 1H, J = 7.3 Hz, Ar), 6.72 (t, 1H, J = 7.3 Hz,
2
Ar), 6.90 (d, 1H, J = 8.1 Hz, Ar), 6.98 (d, 2H, J = 8.1 Hz, Ar),
7.32–7.40 (m, 3H, Ar), 10.88 (s, 1H, NH) ppm. 13C NMR
(d -DMSO): ꢁ = 40.2, 112.1, 116.3, 117.9, 119.9, 122.2, 125.8,
6
129.8, 131.1, 132.3, 135.0, 147.5, 149.5, 155.4, 164.0, 173.3 ppm.
C H N O (280.28): Calcd. C, 68.56; H, 4.32; N, 9.99;
16 12
2
3
found: C, 68.78; H, 4.49; N, 10.08.
(2) 2-[4-(1-Methyl-2-oxoindolin-3-ylideneamino)phenyl]ace-
tic Acid (5b; Supporting Information Pages 31 and 32). e
product was obtained as brown crystals from ethyl acetate in
88% yield; mp 198–200∘C. 1H NMR (d -DMSO): ꢁ = 3.19 (s,
3. Results and Discussion
6
3H, CH ), 3.62 (s, 2H, CH ), 6.45 (d, 1H, J = 8.0 Hz, Ar), 6.78
3
2
3.1. Chemistry. N-alkyl isatin derivatives 1b–1f were prepared
from isatin derivatives according to the reported method
employing microwave irradiation [30]. e spectral data of
1b–1f were in good agreement with the reported data [28–
30, 35–38]. Isatin derivatives3a–3n were prepared by conden-
sation of 1a–1f either with hydrazine hydrate 2a, thiosemi-
carbazide 2b, or 4-aminobenzhydrazide 2c following the
reported procedure using microwave irradiation (Scheme 1)
[30]. e products 3a–3n were obtained in excellent yields
(85–95%; Section 2) and their spectral data were in good
agreement with their proposed structures.
(t, 1H, J = 8.0 Hz, Ar), 6.92 (d, 2H, J = 8.0 Hz, Ar), 7.08 (d,
1H, J = 8.0 Hz, Ar), 7.34 (d, 2H, J = 8.0 Hz, Ar), 7.43 (t, 1H, J =
8.0 Hz, Ar) ppm. 13C NMR (d -DMSO) ꢁ = 26.1, 40.0, 110.2,
6
115.1, 117.3, 119.4, 122.2, 124.9, 130.6, 131.9, 134.4, 147.9, 148.8,
154.1, 162.2, 172.8 ppm. C H N O (294.30): Calcd. C, 69.38;
17 14
2
3
H, 4.79; N, 9.52; found: C, 69.54; H, 4.86; N, 9.78.
(3) 2-[4-(1-Benzyl-2-oxoindolin-3-ylideneamino)phenyl]ace-
tic Acid (5c; Supporting Information Pages 33 and 34). e
product was obtained as reddish brown crystals from ethyl
acetate in 86% yield; mp 180–182∘C. H NMR (d -DMSO):
1
6
e IR spectra of 3a–3e showed absorption bands in the
regions 3398 to 3217 cm−1 corresponding to (NH), a band
at 1688 cm−1 corresponding to the C=O group, and a peak
around 1584 cm−1 that reveals the formation of the C=N
bond. e NMR spectra of all the products 3a–3e are in a
good agreement with their structures [28–30].
ꢁ = 3.64 (s, 2H, CH ), 4.99 (s, 2H, CH ), 6.50 (d, 1H, J =
2
2
7.3 Hz, Ar), 6.78 (t, 1H, J = 8.0 Hz, Ar), 6.96–7.07 (m, 3H, Ar),
7.29–7.46 (m, 8H, Ar) ppm. 13C NMR (d -DMSO): ꢁ = 40.3,
6
43.4, 111.2, 114.3, 115.9, 117.9, 122.9, 125.7, 127.9, 128.1, 129.2, 130.3,
131.2, 132.5, 134.8, 136.4, 147.4, 149.3, 154.4, 162.9, 173.3 ppm.
C H N O (370.40): Calcd. C, 74.58; H, 4.90; N, 7.56; found:
23 18
2
3
e IR spectra of the series 3f–3j showed absorption
C, 74.74; H, 5.05; N, 7.42.
bands in the region 3453 cm−1 related to the asymmetric (N–
H) vibration of the terminal NH group. e other bands
(4) 2-[4-(1-Benzyl-5-bromo-2-oxoindolin-3-ylideneamino)phe-
nyl]acetic Acid (5d). e product was obtained as reddish
brown crystals from ethylacetate in 89% yield; mp 179-180∘C.
1H NMR (d -DMSO): ꢁ = 3.65 (s, 2H, CH ), 4.99 (s, 2H,
2
at 3336 and 3256 cm−1 may be due to the symmetric (N–
H) vibrations of the amide and amino groups. e peaks
at 1680 and 1588 cm−1 correspond to C=O and C=N group,
6
2

Journal of Chemistry
5
H
N
Y
Y
N
NH2NH
2a–2c
O
X
O
X
X
O
RX
DMF
O
O
EtOH/MW
N
N
H
N
10min
R
3a–3n
K2CO3
R
1a–1f
MW
X = H; 1a
X = Br, or Cl
X = R = Y = H; 3a
X = H, R = CH3, Y = H; 3b
X = R = H; 1a
10min
X = H, R = CH3; 1b
X = H, R = Bn; 1c
X = Br, R = Bn; 1d
X = Cl, R = Bn, 1e
X = H, R = Bn, Y = H; 3c
X = Br, R = Bn, Y = H; 3d
X = Cl, R = Bn, Y = H; 3e
X = R = H, Y = -CS-NH2; 3f
X = H, R = CH2CH2Br, 1f
X = H, R = Bn, Y = -CS-NH2; 3g
X = Br, R = Bn, Y = -CS-NH2; 3h
X = Cl, R = Bn, Y = -CS-NH2; 3i
X = H, R = CH2CH2Br, Y = -CS-NH2; 3j
X = R = H, Y = 4-NH2-C6H4-CO-; 3k
X = H, R = CH3, Y = 4-NH2-C6H4-CO-; 3l
X = H, R = Bn, Y = 4-NH2-C6H4-CO-; 3m
X = Br, R = Bn, Y = 4-NH2-C6H4-CO-; 3n
Scheme 1: Synthesis of 3-hydrazino and 3-thiosemicarbazino isatin derivatives.
COOH
COOH
N
O
X
X
O
EtOH/MW
O
+
N
5–10min
N
R
5a–5d
R
1a–1f
NH2
X = Y = H; 1a
4
X = Y = H; 5a
X = H, R = CH3; 1b
X = H, R = Bn; 1c
X = Br, R = Bn; 1d
X = H, R = CH3, 5b
X = H, R = Bn, 5c
X = Br, R = Bn, 5d
Scheme 2: Synthesis of isatin-3-iminocarboxylic acid derivatives.
respectively. e NMR of all the products 3f–3j are in good
agreement with their proposed structures (Section 2).
e IR spectra of 3k–3n reveal absorption bands in the
regions 3406, 3325, and 3225 cm−1 which can be assigned to
e IR spectra of the compounds derived from 4-
aminophenylacetic acid 5a–5d reveal broad absorption bands
in the region 3432-2632 cm−1 which can be assigned to
the hydroxyl group of the carboxylic group. e peaks at
1729, 1645, and 1602 cm−1 are related to the (C=O) of the
carboxylic, carbonyl, and imino groups, respectively. e 1H
NMR and 13C-NMR spectra of the products 5a–5d are also in
good agreement with their structures. e 1H NMR spectrum
of compound 5b as a prototype displayed two singlet peaks
the asymmetric (N–H) vibration of the terminal NH group
2
and the amide groups. e peaks at 1712, 1642, and 1592 cm−1
correspond to two C=O and C=N groups, respectively. NMR
spectra of all the obtained products 3k–3n are in good
agreement with their proposed structures (Section 2).
e imino isatin carboxylic acid derivatives 5a–5d were
prepared by condensation of isatin derivatives 1a–1d with 4-
aminophenylacetic acid 4 using microwave irradiation and
ethanol as a solvent (Scheme 2).
at ꢁ 3.19 and ꢁ 3.62 corresponding to CH and the benzylic
3
protons (C H CH ), respectively. Six peaks corresponding to
6
5
2
the 8 aromatic protons were observed at ꢁ = 6.45, 6.78, 6.92,
7.08, 7.34, and 7.43 ppm. e 13C-NMR spectrum confirmed

6
Journal of Chemistry
C3
C4
C2
02
03
C16
C5
C1
C6
C11
C14
C10
C15
C17
C12
N1
C7
C8
C13
C9
N2
01
Figure 1: ORTEP diagram of compound 5b (CCDC-1004251) drawn at 50% ellipsoids for nonhydrogen atoms.
its structure, where two signal were observed at ꢁ = 26.1
and 40.0 ppm assigned to the methyl and benzylic protons,
respectively. e observed peak at ꢁ = 154.1, 162.2, and
172.8 ppm is related to the C=N, C=O, and the carbonyl of
the carboxylic groups, respectively.
spectrum activity to be active against Bacillus subtilis and
two Gram-negative tested bacteria and against the fungal
pathogens in study.
Differently, most of the 3-hydrazino and 3-thiosem-
icarbazino isatin derivatives 3a–3n were biologically inactive
and generally the active derivatives showed weak to moderate
activity against at least two of the tested Gram-positive test
bacteria. Interestingly, the activity was associated with the
presence of the bromine or chlorine in the isatin moieties 3d,
3e, and 3n; however, their effect cannot be confirmed in the
activity of 3h and 3i because 3f was originally active.
Among the imino isatin carboxylic acid derivatives, 5d
which has bromine at position 5 showed good to high
antimicrobial activity compared to the positive control (ery-
thromycin and tetracycline) against the Gram-positive and
fungal test organisms. e presence of the methyl group in
5b was associated with the activity against the Gram-negative
bacteria and, similarly as in the N-alkyl isatin derivatives,
compound 5c, having a benzyl group, showed antimicrobial
activity against Bacillus subtilis and Candida albicans. ese
results obtained are similar to the reported results by Singh et
al. and Patel et al. [28, 39].
Single crystal X-ray crystallography is without doubt a
decisive analytical tool which confirms the configuration
of the imine double bond in the target compounds 5a–5d.
Fortunately, we have succeeded in getting single crystals of
compound 5b that was suitable for X-ray crystallography.
e solved structure is a representative example for the
synthesized target compounds 5a–5d. e assigned (E)-
configuration of compound 5b was established via its single
crystal X-ray structure (Figure 1).
Molecular formula of 5b is as follows: C H N O ,
17 14
2
3
Molecular weight: 294.30, Monoclinic, P21/c, a = 10.3860
∘
˚
˚
˚
(8) A, b = 8.5519 (7) A, ꢅ = 16.0149 (11) A, ꢀ = 96.604 (2) ,
3
−3
˚
V = 1413.01 (19) A , ꢆcalc = 1.383 Mg m , orange plate with
0.69 × 0.35 × 0.08 mm. A total of 28282 reflections were
measured, of which 3241 were independent. ꢇint = 0.163,
2
dataset (ℎ; ꢈ; ꢉ) = −13, 13; −11, 11; −20, 20. Refinement of ꢊ
2
2
2
against all reflections, led to [ꢊ > 2(ꢊ )] = 0.073, ꢋꢇ(ꢊ ) =
0.204, and ꢌ = 1.07.
Crystallographic data have been deposited with the
Cambridge Crystallographic Data Center (supplementary
publication number CCDC-1004251). Copies of the data may
be obtained free of charge from the Director, CCDC, 12 Union
Road, Cambridge, UK.
4. Conclusions
ree series of isatin derivatives (3-hydrazino, 3-thiosem-
icarbazino, and 3-imino carboxylic acid derivatives) were
synthesized by employing microwave irradiation in good
yields and purities. e prepared compounds were evaluated
for their antimicrobial activity against Gram-positive and
Gram-negative bacteria and fungal pathogenic organisms. In
general, the N-alkyl isatin derivatives were biologically active,
while some of the 3-hydrazino and 3-thiosemicarbazino
isatin derivatives were active against at least two of the three
used Gram-positive test organisms. It was found that the
activity was associated with the presence of the bromine or
chlorine in the isatin moiety of the prepared compounds. e
highest activity was achieved with one of the imino isatin
carboxylic acid derivatives that showed good to high activity
towards the three Gram-positive bacteria and the two fungal
tested microorganisms.
3.2. Biology. e antimicrobial activities of the prepared
compounds against a panel of pathogenic tested organisms
are collected in Table 1. e results revealed that all the N-
alkyl isatin derivatives 1b–1f were biologically active with
different spectrum activity. e isatin itself 1a exhibited
average antibacterial activities against the Gram-negative
test organisms only, but the activity decreased with the
presence of the methyl group in 1b. On the other hand, the
introduction of a benzyl group in 1c decreased the activity
against Gram-negative bacteria and confers activity against
Gram-positive bacteria, namely, Bacillus subtilis. However,
the presence of ethyl bromide group in 1f expands the

Journal of Chemistry
7
Table 1: e antimicrobial activities of the synthesized isatin derivatives expressed as inhibition zones of growth in mm against the tested
pathogenic organisms.
Test organisma
Compound
B.s.
—
M.l.
—
M.p.
—
E.c.
P.v.
S.t.
C.a.
—
Ph.i.
—
1a
14 0.33
14 0.66
15 0.33b
1b
—
—
—
9
0.33
9
0.33
9
0.33
—
—
1c
1f
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
7
8
0.33
0.66
—
—
—
0.66
0.33
0.66
—
0.66
0.66
—
—
—
—
—
—
—
—
—
—
—
—
—
10 0.33
—
10 0.66
—
—
0.66
—
0.33
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
8
8
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
9
9
7
15 0.33
15 0.66
15 0.33
—
10 0.66
10 0.33
—
10 0.33
—
—
—
—
—
9
7
—
—
—
—
—
—
—
—
11 0.33
—
13 0.66
—
17 0.33
—
—
—
5a
5b
5c
5d
—
—
—
—
—
23 0.66
16 0.66
15 0.66
17 0.66
—
—
13 0.33
22 0.33
11 0.33
—
10 0.66
18 0.33
28 0.33
24 0.66
10 0.33
18 0.33
—
20 0.66
18 0.33
20 0.33
—
—
15 0.66
Erythromycinc
Tetracyclined
14 0.33
18 0.66
11 0.66
20 0.66
—
—
—
aAll the results were obtained in DMSO; “—”, no activity; B.s., Bacillus subtilis; M.l., Micrococcus luteus; M.p., Mycobacterium phlei; E.c., Escherichia coli;
P.v., Proteus vulgaris; S.t., Salmonella Typhi; C.a., Candida albicans; and Ph.i., Phytophthora infestans. bZone of inhibition in mm (mean S.D., ꢁ ꢂ 3). ce
concentration was 15 ꢃg. de concentration was 30 ꢃg.
Conflict of Interests
[4] M. de Rosa and A. Soriente, “A combination of water and
microwave irradiation promotes the catalyst-free addition of
pyrroles and indoles to nitroalkenes,” Tetrahedron, vol. 66, no.
16, pp. 2981–2986, 2010.
e authors declare no conflict of interests.
[5] G.-R. Qu, J. Wu, Y.-Y. Wu, F. Zhang, and H.-M. Guo, “Synthesis
of novel 6-[N,N-bis(2-hydroxyethyl)amino]purine nucleosides
under microwave irradiation in neat water,” Green Chemistry,
vol. 11, no. 6, pp. 760–762, 2009.
Acknowledgment
e authors thank the King Abdul-Aziz City for Science and
Technology (KACST) in the Kingdom of Saudi Arabia for
funding this work through project “SGP-34-55.”
[6] D. Dallinger and C. O. Kappe, “Microwave-assisted synthesis in
water as solvent,” Chemical Reviews, vol. 107, no. 6, pp. 2563–
2591, 2007.
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