Synthesis, antibacterial, antifungal and antiviral activity evaluation of some new bis-Schiff bases of isatin and their derivatives

Article abstract of DOI:10.3390/12081720

Twelve new bis-Schiff bases of isatin, benzylisatin and 5-fluoroisatin 3a-3l were prepared by condensation of isatin, benzylisatin and 5-fluoroisatin with primary aromatic amines. The chemical structures of the products were confirmed by ¹H- and ¹³CNMR, IR and mass spectral data. The compounds were screened for antiviral activity against a panel of DNA and RNA viruses. Minimum cytotoxic and minimum virusinhibitory concentrations of these compounds were determined. Compounds 3c and 3i were the most cytotoxic in HEL cells. These newly synthesized bis-Schiff bases were also tested for their antibacterial and antifungal activities. They did not display activity against S. cerevisiae (ATCC 28383) or C. albicans (CIP 1180-79).

Full text of DOI:10.3390/12081720

Molecules 2007, 12, 1720-1730
molecules
ISSN 1420-3049
© 2007 by MDPI
www.mdpi.org/molecules
Full Paper
Synthesis, Antibacterial, Antifungal and Antiviral Activity
Evaluation of Some New bis-Schiff Bases of Isatin and Their
Derivatives
Aliasghar Jarrahpour 1,*, Dariush Khalili 1, Erik De Clercq 2, Chanaz Salmi 3 and Jean Michel
Brunel 3
1
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
2
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-
3000 Leuven, Belgium
3
Laboratoire SESNAB, Faculté de St Jérôme, Case 342, Université Paul Cézanne, Av. Escadrille
Normandie Niémen, 13397 Marseille cedex 20, France
* Author to whom correspondence should be addressed. e-mail: jarrah@susc.ac.ir or
aliasghar6683@yahoo.com
Received: 11 April 2007; in revised form: 13 May 2007 / Accepted: 15 May 2007 / Published: 7
August 2007
Abstract: Twelve new bis-Schiff bases of isatin, benzylisatin and 5-fluoroisatin 3a-3l
were prepared by condensation of isatin, benzylisatin and 5-fluoroisatin with primary
aromatic amines. The chemical structures of the products were confirmed by ¹H- and 13C-
NMR, IR and mass spectral data. The compounds were screened for antiviral activity
against a panel of DNA and RNA viruses. Minimum cytotoxic and minimum virus-
inhibitory concentrations of these compounds were determined. Compounds 3c and 3i
were the most cytotoxic in HEL cells. These newly synthesized bis-Schiff bases were also
tested for their antibacterial and antifungal activities. They did not display activity against
S. cerevisiae (ATCC 28383) or C. albicans (CIP 1180-79).
Keywords: Isatin, bis-Schiff base, antibacterial, antiviral, antifungal.

Molecules 2007, 12
1721
Introduction
Isatin has been known for about 150 years and has been recently found, like oxindole and
endogenous polyfunctional heterocyclic compounds, to exhibit biological activity in mammals [1].
Isatin also is a synthetically versatile substrate that can be used to prepare a large variety of
heterocyclic compounds, such as indoles and quinolines, and as a raw material for drug synthesis [2].
Isatin is further known to be a color reagent for the amino acid proline, forming a blue derivative [3].
This property has been exploited for the determination of this amino acid in pollens [4] and other
vegetable materials [5] using paper chromatography or for the detection of polymer-bound compounds
possessing proline residues [6]. Some isatin derivatives exhibit antiplasmodial activity [7]. Schiff
bases and Mannich bases of isatin are known to possess a wide range of pharmacological properties
including antibacterial, [8-10] anticonvulsant, [11,12] anti-HIV, [13-16] antifungal [17-20] and
antiviral activity [21]. Bis-Schiff bases are characterized by their capacity to completely co-ordinate a
metal ion, forming chelate rings [22]. The Schiff bases of isatin have also been used as ligands for
complexation of metals such as copper II [23]. These complexes catalyzed the oxidation of
carbohydrates. Bis-Schiff bases can act as inhibitors of human α-thrombin [24]. Recently it has been
reported that a bis-imine of isatin has antimicrobial properties [25] and affects cell viability [26]. Here
we report the synthesis and characterization of new bis-Schiff bases of isatin, benzylisatin [27] and
5-fluoroisatin, which could be considered as potential biologically active compounds.
Results and Discussion
The desired bis-Schiff bases of isatin and its derivatives were prepared by the reactions of isatin,
5-fluoroisatin and benzylisatin with commercially available aromatic diamines in the presence of
catalytic amounts of glacial acetic acid in EtOH under reflux condition (Scheme 1). The physico-
chemical properties of bis-Schiff bases thus prepared are summarized in Table 1.
Scheme 1
Y
Y
Z
X
Z
Y
Y
O
R2
Z
X
Z
EtOH
reflux
N
O
N
R2
N
R2
W
O
W
O
NH2
R1
NH2
W
W
N
N
R1
R1
3a-k
2
1
O
EtOH
reflux
N
N
O
H2N
NH2
N
O O
H
N
N
H
H
2'
3l

Molecules 2007, 12
1722
Table1. Physico-chemical properties of compounds 3a-3l.
Position of
Compd.
X
Y
Z
W
R1
R2
C=N
relative to X
3,3΄
m.p. (˚C)
color
time(h) Yield (%)
3a
3b
3c
3d
CH2
CH2
CH2
CH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
>260
248-250
>260
ochre
17
20
0.5
5
77
70
99
68
3,4΄
4,4΄
3,3΄
light ochre
ochre
F
>260
light brown
orange-
3e
CH2 Cl
Et Et
H
H
4,4΄
>260
15
74
yellow
3f
CH2
CH2
H
H
H
H
H
H
Bn
Bn
H
H
4,4΄
3,3΄
180-182
204-206
orange
8
3
98
82
3g
oval-yellow
canary-
3h
3i
O
O
H
H
H
H
H
H
H
H
H
F
3,4΄
4,4΄
>260
>260
28
91
87
yellow
brown-
0.5
yellow
3j
3k
3l
O
CO
-
H
H
-
H
H
-
H
H
-
Bn
H
-
H
H
-
4,4΄
4,4΄
-
204-206
242-244
>260
dark orange
yellow
1
88
70
80
0.5
19
brick-red
Derivatives 3a-3l were evaluated for their in vitro biological properties against several human
pathogens [28] (Table 2).
Table 2. Antimicrobial activities of derivatives 3a-3l.
Antimicrobial activity (MIC) (μg/mL)
Sample CIP
S. cerevisiae (28383)a
S. aureus (4.83)
C. albicans (1180-79)
E. coli (54127)
3a
3b
3c
3d
3e
3f
<50
<50
<50
<50
<50
<50
<50
<50
<50
<50
<50
<100
<50
<50
<50
<50
<50
<50
<50
<50
<50
<50
<50
<50
<100
<50
<50
<50
<50
<50
<50
<50
<50
<50
<50
<50
<100
<50
<50
<50
<50
<50
3g
3h
3i
<50
<50
<50
3j
<50
<50
3k
3l
<100
a ATCC Number

Molecules 2007, 12
1723
The compounds were also evaluated for their cytotoxicity (Table 3) and antiviral activity (Table 4)
in human embryonic lung (HEL) and human epithelial (HeLa) cells and African green monkey kidney
(Vero) cells, according to well-established procedures [29-31]. Derivatives 3a-3l were found to
possess no antifungal activities against S. cerevisiae (ATCC 28383) and C. albicans (CIP 1180-79).
Moreover, no antibacterial activities against Gram-positive and Gram-negative bacteria were noted, as
is shown in Table 2. The minimum cytotoxic concentration of the compounds varied from 8 µg/mL to
≥ 400 µg/mL, compounds 3c and 3i being the most cytotoxic (at 8 and 16 µg/mL) in HEL cells (Table
3).
Table 3: The minimum cytotoxic concentration of compounds 3a-3l.
Minimum cytotoxic concentration(µg/mL)*
compound
HEL
Vero
HeLa
3a
80
80
80
80
≥16
≥16
80
3b
3c
16
≥16
80
3d
80
80
3e
80
16
16
3f
40
40
200
200
≥16
≥16
80
3g
3h
200
400
8
200
400
40
3i
3j
400
80
≥80
≥16
400
500
>500
-
3k
80
3l
400
>500
>500
>500
>100
-
≥400
>500
>500
-
Brivudin
Ribavirin
Acyclovir
Ganciclovir
(S)-DHPA
-
-
500
>500
The results of antiviral activity of the new Schiff bases of isatin and 5-flouroisatin are shown in
Table 4. None of the compounds exhibited specific antiviral activity, which means that they did not
inhibit the replication (induction of viral cytopathogenicity) of any of the viruses tested at a
concentration that was ≥ 5-fold lower than the minimum cytotoxic concentration.

Molecules 2007, 12
1724
Table 4. Antiviral activity of compounds 3a-3l.
Minimum virus-inhibitory concentration* (µg/mL)
HEL
Compound
Herpes simplex
virus-1 KOS
ACVr (TK-)
Herpes simplex Herpes simplex
Vesicular
stomatitis virus
Vaccinia virus
virus-1(KOS)
virus-2(G)
3a
>16
>16
>3.2
>16
>16
>8
>16
>16
>3.2
>16
>16
>8
>16
>16
>3.2
>16
9.6
>16
>16
>3.2
>16
>16
>8
>16
>16
>3.2
>16
>16
>8
3b
3c
3d
3e
3f
>8
3g
3h
>40
>80
>1.6
>80
>16
>80
0.16
500
2.4
>40
>80
>1.6
>80
>16
>80
>500
>500
20
>40
>80
>1.6
>80
>16
>80
60
>40
>80
>1.6
>80
>16
>80
>500
>500
>500
>100
-
>40
>80
>1.6
>80
>16
16
3i
3j
3k
3l
Brivudin
Ribavirin
Acyclovir
Ganciclovir
(S)-DHPA
500
>500
300
12
300
>500
>100
-
0.48
-
4
-
-
Vero
Compound
Para-influenza-
3 virus
Coxsackie virus
B4
Reovirus-1
Sindbis virus
PuntaToro virus
3a
>16
>16
≥16
>16
>3.2
>8
>16
>16
>16
>16
>3.2
>8
>16
>16
>16
>16
>3.2
>8
>16
>16
>16
>16
>3.2
>8
>16
>16
>16
>16
>3.2
>8
3b
3c
3d
3e
3f
3g
3h
>40
>80
>8
>40
>80
>8
>40
>80
>8
>40
>80
>8
>40
>80
>8
3i
3j
>80
>16
>80
>100
300
-
>80
>16
>80
>100
300
-
>80
>16
>80
>100
300
-
>80
>16
>80
>100
>500
-
>80
>16(80)
>80
>100
60
3k
3l
Brivudin
Ribavirin
Acyclovir
Ganciclovir
(S)-DHPA
-
-
-
-
-
-
>100
300
>100
>100

Molecules 2007, 12
1725
Table 4. Cont.
Minimum virus-inhibitory concentration*
(µg/mL)
HeLa
Compound
Vesicular
stomatitis
virus
Coxsackie
virus B4
Respiratory
syncytial virus
3a
9.6
3.2
>16
>16
>16
>16
>3.2
>40
>40
>16
>16
>16
>16
>400
>500
>500
-
>16
>16
>16
>16
>3.2
>40
>40
>16
>16
>16
>16
>400
>500
60
3b
3c
>16
9.6
3d
3e
>3.2
>40
>40
>16
>16
>16
48
3f
3g
3h
3i
3j
3k
3l
>400
>500
60
Brivudin
Ribavirin
Acyclovir
Ganciclovir
(S)-DHPA
-
-
-
-
-
500
>500
>500
*Required to reduce virus- induced cytopathogenicity by 50%.
Experimental
General
Chemical materials and solvents were obtained from Merck, Fluka and Aldrich chemical
companies. Melting points were determined in open capillary tubes in Buchi 530 circulating oil
apparatus and are not corrected. FT-IR spectra (KBr) were run on a Shimadzu FTIR-8300
spectrophotometer. NMR spectra were recorded on a Bruker Avance DPX-250 spectrometer (1H-NMR
13
250 MHz, C-NMR 62.9 MHz) in CDCl3 or DMSO-d6 solvents using TMS as an internal standard.
Mass spectra were obtained on a Shimadzu GCMS-QP 1000 EX instrument at 70 ev. The
determination of the prepared products and reaction monitoring were carried out on silica gel 254
analytical sheets obtained from Fluka. Column chromatography was carried out by silica gel 60 Merck
(230-270).

Molecules 2007, 12
1726
General procedure for preparation of bis-Schiff bases of isatin and its derivatives
Isatin, benzylisatin [27] or 5-fluoroisatin (13.6 mmol) and the aromatic diamines (6.8 mmol) were
dissolved in warm ethanol (20 mL) containing glacial acetic acid (0.45 mL). The reaction mixture was
refluxed for several hours. After standing at room temperature, the resulting solid was separated by
filtration and vacuum dried.
3,3´-[Methylenebis(3,1-phenylenenitrilo))bis[1,3-dihydro)-2H-indol-2-one (3a): IR (cm-1): 1652
(C=N), 1726 (C=O), 3168 (N-H); 1H-NMR (DMSO-d6) δ (ppm): 4.07 (2H, s, CH2), 6.29-7.43 (16H, m,
13
ArH), 10.96 (2H, s, N-H); C-NMR (DMSO-d6) δ (ppm): 44.40 (CH2), 115.63-155.53 (aromatic
carbons), 159.76 (C=N), 168.29 (C=O); MS (m/z, %): 458 (12.5), 457 (34.9), 456 (100.0), 327 (64.2),
312 (39.2), 299 (53.5), 284 (29.9), 283 (27.1), 200 (18.5), 180 (29.9), 165 (48.5), 44 (15.7).
3,3´-[Methylenebis[(3,1)-(4´,1´)phenylenenitrilo))bis[1,3-dihydro)-2H-indol-2-one (3b): IR (cm-1):
1612 (C=N), 1732 (C=O), 3213 (N-H); 1H-NMR (DMSO-d6) δ (ppm): 4.02 (2H, s, CH2), 6.37-7.56
13
(16H, m, ArH), 10.97 (2H, s, N-H); C-NMR (DMSO-d6) δ (ppm): 40.74 (CH2), 111.84-151.01
(aromatic carbons), 155.31(C=N), 163.85 (C=O); MS (m/z, %): 456 (23.9), 326 (6.0), 312 (28.5), 299
(100.0), 198 (20.2), 182 (11.4), 180 (50.9), 166 (21.7), 44 (27.5).
3,3´-[Methylenebis(4,1-phenylenenitrilo))bis[1,4-dihydro)-5-fluoro-2H-indol-2-one (3c): IR (cm-1):
1
1618 (C=N), 1739 (C=O), 3261 (N-H); H NMR (DMSO-d6) δ (ppm): 4.03 (2H, s, CH2), 6.09-7.41
13
(14H, m, ArH), 11.01 (2H, s, N-H); C-NMR (DMSO-d6) δ (ppm): 44.30 (CH2), 113.23-153.68
(aromatic carbons), 159.16 (C=N), 164.38 (C=O); MS (m/z, %): 492 (1.4), 467 (2.8), 439 (2.1), 368
(52.8), 339 (10.0), 313 (22.8), 236 (28.5), 83 (50.7), 57 (100.0).
3,3´-[Methylenebis(3,1-phenylenenitrilo))bis[1,3-dihydro)-5-fluoro-2H-indol-2-one (3d): IR (cm-1):
1622 (C=N), 1733 (C=O), 3290 (N-H); 1H-NMR (DMSO-d6) δ (ppm): 4.06 (2H, s, CH2), 6.78-7.48
(14H, m, ArH), 10.86 (2H, s, N-H); 13C-NMR (DMSO-d6) δ (ppm): 40.50 (CH2), 112.02-150.67
(aromatic carbons), 150.67 (C=N), 163.73 (C=O); MS (m/z, %): 493 (1.4), 492 (0.7), 368 (7.1), 313
(10.7), 178 (22.1), 147 (22.1), 91 (24.2), 43 (100.0).
3,3´-[Methylenebis(2-chloro-3,5-diethyl-4,1-phenylenenitrilo))bis[1,3-dihydro)-2H-indol-2-one (3e):
1
IR (cm-1): 1614 (C=N), 1735 (C=O), 3247 (N-H); H-NMR (DMSO-d6) δ (ppm): 0.86-1.05 (12H, t,
13
4CH3), 4.19 (CH2), 6.66-7.70 (10H, m, ArH), 10.98 (2H, s, N-H); C-NMR (DMSO-d6) δ (ppm):
13.21-13.73 (2CH3), 23.02-23.77 (2CH2), 37.50 (CH2), 112.10- 147.13 (aromatic carbons), 156.83
(C=N), 163.42 (C=O); MS (m/z, %): 637 (0.7), 603 (2.1), 577 (4.2), 555 (9.2), 368 (34.2), 339 (7.8),
313 (15.0), 236 (15.0), 97 (34.2), 96 (56.4), 43 (100.0).
3,3´-[Methylenebis(4,1-phenylenenitrilo))bis [1,3-dihydro)-1-phenylmethylene-2H-indol-2-one (3f):
IR (cm-1): 1604 (C=N), 1732 (C=O); 1H-NMR (CDCl3) δ (ppm): 4.06 (2H, s, CH2), 5.00 (4H, s, CH2),
6.41-7.70 (26H, m, ArH); 13C-NMR (DMSO-d6) δ (ppm): 44.40 (CH2), 110.04-148.83 (aromatic

Molecules 2007, 12
1727
carbons), 154.57 (C=N), 163.78 (C=O); MS (m/z, %): 636 (3.5), 442 (2.8), 417 (100.0), 388 (12.8),
326 (27.8), 207 (20.0), 180 (17.8), 106 (37.8), 91 (35.7), 43 (13.5).
3,3´-[Methylenebis(3,1-phenylenenitrilo))bis[1,3-dihydro)-1-phenylmethylene-2H-indol-2-one
(3g):
IR (cm-1): 1604 (C=N), 1732 (C=O); 1H-NMR (CDCl3) δ (ppm): 4.01 (2H, s, CH2), 4.96 (4H, s, CH2),
6.53-7.67 (26H, m, ArH); 13C-NMR (CDCl3) δ (ppm): 44.36 (CH2), 110.06-150.90 (aromatic carbons),
154.58 (C=N), 163.67 (C=O); MS (m/z, %): 636 (1.4), 417 (100.0), 326 (32.1), 285 (14.2), 198 (40.0),
180 (43.5), 165 (27.1), 106 (17.1), 91 (35.0), 44 (5.0).
3,3´-[Oxybis[(3,1)-(4´,1´)phenylenenitrilo))bis[1,3-dihydro)-2H-indol-2-one (3h): IR (cm-1): 1620
(C=N), 1733 (C=O), 3195 (N-H). 1H NMR (DMSO-d6) δ (ppm): 6.16-7.77 (16H, m, ArH), 10.94 (2H,
13
s, N-H); C NMR (DMSO-d6) δ (ppm): 111.27-155.49 (aromatic carbons), 158.91 (C=N), 163.69
(C=O); MS (m/z, %): 458 (3.8), 330 (14.6), 329 (56.3), 302 (17.9), 301 (48.8), 234 (10.8), 200 (44.4),
171 (14.3), 128 (18.3), 108 (53.2), 92 (33.8), 66 (100.0), 44 (53.9).
3,3´-[Oxybis(4,1-phenylenenitrilo))bis[1,3-dihydro)-5-fluoro-2H-indol-2-one (3i): IR (cm-1): 1618
(C=N), 1739 (C=O), 3261 (N-H); 1H-NMR (DMSO-d6) δ (ppm): 6.25-7.43 (14H, m, ArH), 11.07 (2H,
s, N-H); 13C-NMR (DMSO-d6) δ (ppm): 111.27-154.00 (aromatic carbons), 155.41 (C=N), 163.66
(C=O); MS (m/z, %): 495 (2.8), 494 (2.1), 426 (22.1), 396 (9.2), 368 (14.2), 313 (31.4), 264 (22.1),
236 (28.5), 168 (30.0), 97 (43.5), 69 (65.0), 43 (100.0).
3,3´-[Oxybis(4,1-phenylenenitrilo))bis[1,4-dihydro)-1-phenylmethylene-2H-indol-2-one
(3j):
IR
(cm-1): 1604 (C=N), 1732 (C=O); 1H-NMR (CDCl3) δ (ppm): 5.01 (4H, s, CH2), 6.72-7.71 (26H, m,
13
ArH); C-NMR (CDCl3) δ (ppm): 44.42 (CH2), 110.03-154.65 (aromatic carbons), 155.33 (C=N),
163.76 (C=O); MS (m/z, %): 638 (0.7), 577 (3.5), 551 (5.0), 419 (100.0), 328 (20.0), 288 (6.4), 237
(12.8), 207 (20.7), 180 (7.1), 146 (7.1), 91 (27.1), 43 (26.4).
3,3´-[Methanonebis(4,1-phenylenenitrilo))bis[1,4-dihydro)-2H-indol-2-one (3k): IR (cm-1): 1593
1
(C=N), 1735 (C=O, amide), 1660 (C=O, ketone), 3222 (N-H); H-NMR (DMSO-d6) δ (ppm): 6.25-
7.58 (16H, m, ArH), 10.99 (2H, s, N-H); 13C-NMR (DMSO-d6) δ (ppm): 119.74-134.76 (aromatic
carbons), 164.20 (C=N), 197.53 (C=O); MS (m/z, %): 470 (5.3), 341 (27.7), 313 (35.4), 221 (14.6),
212 (7.8), 180 (4.3), 120 (98.5), 104 (14.6), 92 (36.1), 76 (30.8), 44 (100.0), 43 (99.0).
3,3΄-[(2-Methyl-1,3-phenylene)dinitrilo)bis[1,3-dihydro)-2H-indole-2-one (3l): IR (cm-1): 1616 (C=N),
1
1716 (C=O), 3209 (N-H); H-NMR (DMSO-d6) δ (ppm): 2.50 (3H, s, CH3), 6.57-7.06(11H, m, ArH),
10.42 (1H, s, N-H); 13C-NMR (DMSO-d6) δ (ppm): 18.88 (CH3), 117.84-152.52 (aromatic carbons),
163.35 (C=N), 167.51 (C=O); MS (m/z, %):380 (0.7), 368 (13.5), 339 (2.8), 313 (8.5), 285 (5.0), 264
(5.0), 236 (11.4), 129 (9.2), 97 (28.5), 69 (42.8), 43 (100.0).

Molecules 2007, 12
1728
Acknowledgements
We gratefully acknowledge the financial support of this study by Shiraz University Research
Council (85-GR-SC-23).
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