Synthesis of bis-Schiff bases of isatins and their antiglycation activity

Article abstract of DOI:10.1016/j.bmc.2009.09.028

Bis-Schiff bases 1-27 have been synthesized and their in vitro antiglycation potential has been evaluated. Compounds 21 (IC₅₀ = 243.95 ± 4.59 μM), 20 (IC₅₀ = 257.61 ± 5.63 μM), and 7 (IC₅₀ = 291.14 ± 2.53 μM) showed an exc

Full text of DOI:10.1016/j.bmc.2009.09.028

Bioorganic & Medicinal Chemistry 17 (2009) 7795–7801
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of bis-Schiff bases of isatins and their antiglycation activity
a
a
a
a
Khalid Mohammed Khan a, , Momin Khan , Muhammad Ali , Muhammad Taha , Saima Rasheed ,
*
Shahnaz Perveen b, M. Iqbal Choudhary a
a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University Karachi, Karachi 75270, Pakistan
b PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan
a r t i c l e i n f o
a b s t r a c t
Article history:
Bis-Schiff bases 1–27 have been synthesized and their in vitro antiglycation potential has been evaluated.
Received 13 August 2009
Revised 14 September 2009
Accepted 15 September 2009
Available online 19 September 2009
Compounds 21 (IC50 = 243.95 4.59
showed an excellent antiglycation activity better than the standard (rutin, IC50 = 294.46 1.50
study has identified a series of potential molecules as antiglycation agents. A structure–activity relation-
ship has been studied, and all the compounds were characterized by spectroscopic techniques.
Ó 2009 Elsevier Ltd. All rights reserved.
l
M), 20 (IC50 = 257.61 5.63
l
M), and 7 (IC50 = 291.14 2.53
lM)
l
M). This
Keywords:
Isatins
Bis-Schiff bases
Antiglycation
AGEPs
1. Introduction
As the unpleasant incident of type-2 diabetes is increasing, its
injurious effects are mostly attributed to the formation of sugar-
Schiff bases form an important class of organic compounds with a
wide variety of biological properties.1–5 Development of a new che-
motherapeutic Schiff bases is now attracting the attention of medic-
inal Chemist.6 Many studies have reported regarding the biological
activities of Schiff bases, including their anticancer,7 antibacterial,8
antifungal, and herbicidal activities.9,10 Schiff bases, derived from
various heterocycles, were reported to possess cytotoxic,11 anticon-
vulsant,12 antiproliferative,13 anticancer, and antifungal activities.14
A number of Schiff bases15–18 have been tested for antibacterial,19–22
antifungal,21–23 anticancer,24,25 and herbicidal26 activities.
Isatin and its analogs are versatile substrates, which can be used
for the synthesis of numerous heterocyclic compounds. Isatins also
have important pharmacological and biological activities.27
A variety of biological activities are associated with Schiff bases of
isatin including CNS activities as potentiation of pentobarbitone in-
duce nercosis,28 analgesic,29 anticonvulsant,30 antidepressant,31
antiinflammatory,32 antimicrobial, andeffects onthe central nervous
system.33 Isatins are capable of crossing the blood–brain-barrier.34
In the present study, in vitro antiglycation activity of a series of
bis-Schiff base derivatives 1–27 has been evaluated in continuation
of our previous study.35 Discovery of antiglycation agents is an
important approach for the treatment of late diabetic complica-
tions. Since currently number of effective antiglycating agents is
very small, the need of new antiglycating agents is still unmet.36
derived substances called advanced glycation end products (AGE-
Ps)37 which are important pathogenic mediators of almost all dia-
betic complications.38
Schiff bases are formed initially by reaction between protein
and glucose without any enzyme, whereas the rearrangement of
Schiff base intermediate to Amadori product takes number of days.
Extensive effort has been focused on the discovery of new inhibi-
tors of glycation, because of their therapeutic potential.39 Certain
molecules have been developed that can cleave AGEPs cross-links
and perhaps open the possibility of reversing the steady process
of diabetic complications.40 It has been found that aged garlic ex-
tract (AGE) inhibit the formation of AGEPs in vitro and prevents
the formation of glycation-derived free radicals. S-Allylcysteine is
a very important component of aged garlic extract that acts as a
potent antioxidant and thus inhibit the AGEPs formation.41,42
Aminoguanidine, an inhibitor of AGEPs formation was found to
prevent retinopathy in diabetic animals and protect them from
developments of diabetic vascular complications. However, amino-
guanidine has encountered some toxicity problems in phase III clin-
ical trials.43 Efforts have now been made to develop new and safe
synthetic antiglycation agents.44 It has been demonstrated that
polyamines, spermine and spermidine have potent antiglycation ef-
fects, comparable to those of aminoguanidine and carnosine.45
2. Chemistry
Bis-Schiff bases 1–27 were synthesized from commercially
* Corresponding author. Tel.: +92 214824910; fax: +92 214819018.
available isatins by refluxing with hydrazine hydrate and then
E-mail addresses: hassaan2@super.net.pk, khalid.khan@iccs.edu (K.M. Khan).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.09.028

7796
K. M. Khan et al. / Bioorg. Med. Chem. 17 (2009) 7795–7801
Table 1
condensing with different aromatic aldehydes in methanol in very
high yields (Scheme 1). In a typical reaction isatin (1 g) were dis-
solved in hydrazine hydrate (10 ml) and refluxed for 25 min to af-
ford hydrazone. Then condensation of these hydrazones with
different substituted aromatic aldehydes in equimolar amount in
methanol under reflux for 3 h, the progress of reaction was moni-
tored by TLC. After cooling and filtration the crystalline powder of
bis-Schiff bases was collected, then washed with methanol and
dried to afford compounds 1–27 in high yields. Recrystallization
from methanol afforded pure crystals. The structures of synthe-
sized compounds 1–27 were determined by employing different
spectroscopic techniques including 1H NMR, EI, IR, and UV
spectroscopy.
In vitro antiglycation activity of compounds 1–27
Compounds
R1
R2
R3
R4
IC50 SEMa
(lM)
1'
1'
OH
6'
5'
1
H
H
H
444.11 7.29
313.22 5.92
3'
4'
2'
3'
6'
5'
2
H
H
H
OH
1'
8'
7'
3. Bioactivity
3
4
5
Cl
H
H
H
H
H
Cl
H
H
416.00 15.82
6'
3'
4'
1'
5'
It is reported that a Schiff base adduct between aminoguanidine
and pyridoxal is responsible for inhibiting advanced glycation end
product (AGEPs) formation. Moreover, it has been found that the
inhibitory potential of adduct against advanced protein glycation
was similar/or more than that of aminoguanidine when assessed
by fluorometry and ELISA.46 By taking into account, we have pre-
pared bis-Schiff bases 1–27 of isatin to evaluate their antiglycation
potential.Recentlywe havereportedunsymmetricallydisubstituted
urea derivatives as a new class of potent antiglycating agents.47
Herein, we are reporting bis-Schiff bases 1–27 which were evaluated
for their in vitro antiglycation activity35 as a new class of antiglycat-
ing agents.47,48 Compounds 1–27 exhibited a varying degree of anti-
glycation activity IC50 values ranging between 243.95 and
8'
7'
NAb
3'
6'
4'
1'
5'
2'
6'
5'
311.81 12.62
Cl
4'
1'
OMe
6'
5'
6
7
H
H
H
H
H
H
458.38 7.55
291.14 2.53
3'
2'
4'
1'
634.05
1.50 M) (Table 1). Compounds 21 (IC50 = 243.95 4.59
(IC50 = 257.61 5.63 M), and 7 (IC50 = 291.14 2.53 M) showed
an excellent antiglycation activity better than the standard (rutin,
IC50 = 294.46 1.50 M). Compounds 5 (IC50 = 311.81 12.62 M),
(IC50 = 313.22 5.92 M), 14 (IC50 = 358.58 8.98 M), 11
(IC50 = 361.98 5.56 M), 18 (IC50 = 365.55 1.03 M), 9 (IC50
380.30 10.64 M), 13 (IC50 = 405.51 2.69 M), 19 (IC50 = 415.92
8.39 M), 3 (IC50 = 416.0 15.82
6 (IC50 = 458.38 7.55
l
M, and compared with standard rutin (IC50 = 294.46
l
l
M), 20
l
l
6'
5'
OH
l
l
OH
1'
2
l
l
l
l
=
l
l
2'
6'
5'
8
9
H
H
H
H
H
H
NAb
l
l
M), 1 (IC50 = 444.11 7.29 lM),
Cl
8'
l
M), and 27 (IC50 = 469.24 0.00
l
M) exhib-
ited a moderate antiglycation potential. Nevertheless, both com-
pounds 16 and 22 were found to possess an antiglycation activity
with the IC50 value of 634.05 3.39 lM, thus considered to be least
active among the series. Additionally compounds 4, 8, 10, 12, 15, 17,
and 23–26 showed less than 50% inhibition, therefore they were not
further evaluated for their IC50 values.
Compounds 20 and 21 are the most active analogs of the series
with IC50 values of 257.61 5.63 lM and 243.95 4.59 lM, having
Cl
7
'
2'
380.30 10.64
3'
6'
4'
1'
5'
2'
3'
6'
10
H
H
H
NAb
5'
R1
NH2
O
N
F
1'
R1
O
3
R2
4
3
R2
N2H4.H2O
2
2
+
R4CHO
5
O
F
F
N
6'
5'
Reflux, 25 min
1
N1
11
12
H
H
H
H
361.98 5.56
H
7
H
R3
3'
3'
R3
4'
1'
MeOH, Reflux, 3h
6'
5'
Cl
Cl
NAb
4'
1'
R4
R1
4
N
N
3
R2
2'
3'
6'
2
5
O
13
H
H
H
405.51 2.69
N 1
H
5'
7
R3
NMe2
Scheme 1. Synthesis of bis-Schiff bases from isatin.

K. M. Khan et al. / Bioorg. Med. Chem. 17 (2009) 7795–7801
7797
M)
Table 1 (continued)
Table 1 (continued)
Compounds
R1
H
R2
H
R3
H
R4
IC50 SEMa
(
lM)
Compounds
R1
H
R2
Cl
R3
H
R4
IC50 SEMa
469.24 1.7
(l
1'
1'
2'
OH
6'
6'
14
15
16
358.58 8.98
27
5'
5'
OH
OMe
4'
1'
OH
OH
Rutinc
294.46 1.50
6'
Cl
H
H
H
Cl
H
NAb
a
b
c
SEM is the standard error of the mean.
NA: not active.
Rutin standard inhibitor for antiglycation activity.
5'
OMe
4'
1'
2'
6'
5'
634.05 3.39
nitro groups at para- and ortho-position, respectively. It is expected
that nitro group has formed a Zwitter complex with carbonyl group
of methylglyoxal which resulted in potentially high antiglycation
activity. Similarly compound 7, a dihydroxy analog, was found to
be the third most active antiglycating agent with IC50 of
OH
4'
1'
2'
3'
6'
17
H
H
H
NAb
291.14 2.53 lM. Activity related to this compound might be
due to acetal formation by the reaction of dihydroxy analog 7
5'
OEt
1'
and the carbonyl group of methylglyoxal.
Compounds 2 and 1 are hydroxyl analogs of Schiff bases with IC50
values of 313.22 5.92 and 444.11 7.29 lM, respectively. para-
2'
6'
Hydroxyl group in compound 2 is suppose to be involved in hemiac-
etalformationwithmethylglyoxal, however, the orthoanalog, which
is relativelyhindered, showsa lowerIC50 value thanitspara analog 2.
18
19
20
Cl
H
H
H
H
H
Cl
H
H
365.55 1.03
415.92 8.39
257.61 5.63
5'
OMe
OEt
OMe
1'
On the other hand compound 14 (IC50 = 358.58 8.98 lM) has
ortho-hydroxyl group with a meta-methoxy group was found to be
moreactivethancompound1, thisprobablymightbe duetoelectron
donating effect of methoxy group.
Compounds 3, 9, 13, 18, and 19 is a group of compounds which
do not have any functional group, capable of reacting with methyl-
glyoxal, however, they exhibited a measurable amount of antigly-
cation potential. This may be due to electron-donating groups or
electron rich substituents such as naphthyl group.
A remarkable effect on the antiglycation activity due to presence
of electron withdrawing groups at isatin was observed. Compounds
12, 15, 24–27 with electron withdrawing groups at isatin moiety,
either showed extremely low antiglycation potential or complete
lack of activity. Surprisingly, compound 27 (IC50 = 469.24
6'
5'
3'
4'
1'
2'
3'
6'
5'
NO2
1'
NO2
6'
5'
21
22
H
H
H
H
H
H
243.95 4.59
634.05 3.39
3'
1'
4'
0.00
lated compound 7 showed an excellent activity (IC50 = 291.14
2.53 M). This variation in activity may be due to the presence of a
lM) showed a sharp decline in activity, whereas its closely re-
OH
6'
l
3'
chloro group at position 5 of isatin. Similarly, effect of chloro groups
at positions 4 and 7 can be seen in the compounds 11 and 12.
Cl
4'
1'
OH
6'
4. General experimental
23
24
H
H
H
H
H
NAb
3'
Me
Melting points were determined on a Büchi 434 melting point
apparatus and were uncorrected. NMR experiments were
performed on Avance Bruker AM 300 MHz CHN analysis was per-
formed on a Carlo Erba Strumentazion-Mod-1106, Italy. Ultraviolet
(UV) spectra were recorded on Perkin–Elmer Lambda-5 UV/vis
spectrometer in MeOH. Infrared (IR) spectra were recorded on JAS-
CO IR-A-302 spectrometer as KBr (disk). Electron impact mass
spectra (EI MS) were recorded on a Finnigan MAT-311A, Germany.
Thin layer chromatography (TLC) was performed on pre-coated sil-
ica gel aluminum plates (Kieselgel 60, 254, E. Merck, Germany).
Chromatograms were visualized by UV at 254 and 365 nm.
4'
2'
1'
6'
Cl
NAb
5'
OMe
OMe
1'
2'
6'
25
26
H
H
Cl
Cl
H
H
NAb
3'
5'
F
4.1. Assay for antiglycation
1'
OH
6'
5'
NAb
4.1.1. Chemicals
Bovine serum albumin (BSA) was purchased from the Research
Organics (Cleveland, USA), while other chemicals {glucose
3'
4'
(continued on next page)

7798
K. M. Khan et al. / Bioorg. Med. Chem. 17 (2009) 7795–7801
anhydrous, trichloroacetic acid (TCA) sodium azide (NaN3), di-
methyl sulfoxide (DMSO), sodium dihydrogen phosphate (NaH2-
PO4), sodium chloride (NaCl), disodium hydrogen phosphate
(Na2HPO4), potassium chloride (KCl), potassium dihydrogen phos-
phate (KH2PO4), and sodium hydroxide (NaOH) were purchased
from Sigma–Aldrich. Sodium phosphate buffer (pH 7.4), was pre-
pared by mixing Na2HPO4 and NaH2PO4 (67 mM) containing so-
dium azide (3 mM). Phosphate buffer saline (PBS) was prepared
by mixing NaCl (137 mM), Na2HPO4 (8.1 mM), KCl (2.68 mM),
and KH2PO4 (1.47 mM) and pH 10 was adjusted with NaOH
(0.25 mM). BSA (10 mg/ml) and glucoses anhydrous (50 mg/ml)
solutions were prepared in sodium phosphate buffer. Test samples
were prepared in DMSO (1 mM/ml).
This test was used to evaluate the ability of the candidate com-
pounds to inhibit the methyl glyoxal mediated development of
fluorescence of BSA. Activity was performed by using the reported
method48,49 with the following modifications:
Triplicate samples of BSA 100 mg/ml, 14 mM MGO, 0.1 M phos-
phate buffer (pH 7.4) containing NaN3 (30 mM) was incubated un-
der aseptic conditions at 37 °C for 9 days in the presence or
absence of various concentrations of the test compounds. After
9 days of incubation, each sample was examined for the develop-
ment of specific fluorescence (excitation, 330 nm; emission,
440 nm) on a microtitre plate spectrophotometer (Spectra Max,
Molecular Devices, USA). Rutin was used as a positive control
5.3. 2-Naphthaldehyde-N-(4,7-dichloro-2-oxo-1,2-dihydro-3H-
indol-3-ylidene)hydrazone (3)
Yield: 0.33 g, 98%; 1H NMR: (300 MHz, DMSO-d6): d 10.87 (s,
1H, –N@CH), 8.1 (s, 1H, C@H), 8.0 (s, 1H, H-10), 7.90 (m, 4H, H-
50–80), 7.65 (m, 2H, H-30,40), 7.21 (d 1H, J5,6 = 8.6 Hz, H-5), 7.00 (d,
1H, J6,5 = 8.6 Hz, H-6); EI MS: m/z (rel. abund.%), 367 (M+, 12),
339 (70), 229 (100), 172 (44), 138 (40), 127 (57), 75 (13).
5.4. 2-Naphthaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)hydrazone (4)
Yield: 0.26 g, 86%; 1H NMR: (300 MHz, DMSO-d6): d 11.23 (s,
1H, N–H), 8.74 (s, 1H, –N@CH), 8.41 (s, 1H, H-10), 8.00 (m, 4H, H-
50–80), 7.8 (d 1H, J4,5 = 7.6 Hz, H-5) 7.62 (m, 2H, H-30,40), 7.40 (t,
1H, J6,7,5 = 7.6 Hz, H-6), 7.04 (t, 1H, J5,4,6 = 7.6 Hz, H-5), 6.92 (d,
1H, J7,6 = 7.6 Hz, H-7); EI MS: m/z (rel. abund.%), 299 (M+, 8), 271
(100), 243 (18), 153 (11), 127 (42), 77 (6).
5.5. 3-Chlorobenzaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)hydrazone (5)
Yield: 0.24 g, 86%; 1H NMR: (300 MHz, DMSO-d6): d 11.1 (s, 1H,
N–H), 8.71 (s, 1H, –N@CH), 7.97 (br s, 1H, H-60), 7.93 (d, 1H,
J4 ,3 = 8.1 Hz, H-40), 7.80 (d, 1H, J7,6 = 7.5 Hz, H-7), 7.64 (m, 2H, H-
0
0
4/H-6), 7.40 (t, 1H, J3 ,2 ,4 = 8.1 Hz, H-30), 7.03 (t, 1H, J5,4,6 = 7.5 Hz,
0
0
0
(IC50 = 294
lM
1.50 SEM).
H-5), 6.90 (d, 1H, J2 ,3 = 8.1 Hz, H-20); EI MS: m/z (rel. abund.%),
0
0
The percent inhibition of AGE formation in the test sample ver-
sus control was calculated for each compound by using the follow-
ing formula:
284 (M+, 6), 225(29), 179 (65), 151 (25), 78 (97), 63 (100).
5.6. 2-Methoxybenzaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-
3-ylidene)hydrazone (6)
% inhibition ¼ ð1 ꢀ fluorescence of test sample=fluorescence
of the control groupÞ ꢁ 100
Yield: 0.23 g, 82%; 1H NMR: (300 MHz, DMSO-d6): d 11.05 (s,
1H, N–H), 8.81 (s, 1H, –N@CH), 8.10 (dd, 1H, J4,6 = 1.51 Hz,
J4,5 = 7.7 Hz, H-4), 7.97 (d, 1H, J6 ,5 = 7.2 Hz, H-60), 7.58 (td, 1H,
0
0
5. General procedure for the synthesis of compounds 1–27
J 4 ,2 ,6 = 1.6 Hz, J4 ,5 ,3 = 7.2 Hz, H-40), 7.39 (td, 1H, J6,7,5 = 7.7 Hz,
0
0
0
0
0
J6,4 = 1.1 Hz, H-6), 7.20 (d, 1H, J3 ,4 = 7.2 Hz, H-30), 7.14 (t, 1H,
0
0
The preparation of hydrazone’s was carried out by refluxing a
mixture of isatin (1 g) and hydrazine hydrate (10 ml). Then this
hydrazone (1 mmol) and different substituted aromatic aldehydes
(1 mmol) in methanol were refluxed for 3 h, the progress of reac-
tion was monitored by TLC. After cooling and filtration the crystal-
line powder of Schiff bases were collected, then washed with
methanol and dried to afford compounds 1–27 in high yields.
Recrystallization from methanol afforded pure crystals.
5,6,4, = 7.5 Hz, H-5), 7.03 (t, 1H, J5 ,6 ,4 , = 7.2 Hz, H-50), 6.90 (d, 1H,
0
0
0
J
J7,6 = 7.2 Hz, H-7); EI MS: m/z (rel. abund.%), 279 (M+, 3), 251
(100), 208 (20.1), 118 (32), 91 (25), 77 (19).
5.7. 3,4-Dihydroxybenzaldehyde-N-(2-oxo-1,2-dihydro-3H-
indol-3-ylidene)hydrazone (7)
Yield: 0.24 g, 86%; 1H NMR: (300 MHz, DMSO-d6): d 10.5 (s, 1H,
N–H), 8.51 (s, 1H, –N@CH) 8.09 (d, 1H, J4,5 = 7.5 Hz, H-4), 7.4 (s, 1H,
H-20), 7.38 (t, J6,7,5 = 7.5 Hz, 1H, H-6), 6.94 (t, 1H, J5,6,4, = 7.5 Hz, H-
5.1. 2-Hydroxybenzaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)hydrazone (1)
5), 6.9 (d, 1H J7,6 = 7.5 Hz, H-4), 6.88 (d, 1H, J6, 5 = 8.1 Hz, H-60),
0
0
6.86 (d, 1H, J5 ,6 = 8.1 Hz, H-50); EI MS: m/z (rel. abund.%), 281
0
0
Yield: 0.22 g, 83%; 1H NMR: (300 MHz, DMSO-d6): d 11.8 (s, 1H, N–
H), 11.27(s, 1H, O–H), 8.91(s,1H, –N@CH), 7.71(d, 1H, J4,5 =7.8 Hz, H-
(M+, 3), 253 (100), 226 (11), 118 (24).
4), 7.52 (d, 1H, J6 ,5 = 8.0 Hz, H-60), 7.41 (t, 2H J6,5,7/5 ,6 ,4 = 7.9 Hz, H-6/
0
0
0
0
0
5.8. 3,4-Dichlorobenzaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-
3-ylidene)hydrazone (8)
H-50), 7.08 (t, 1H, J4 ,3 ,5 = 8.0 Hz, H-40), 7.00 (d, 1H, J3 ,4 = 8.0 Hz, H-30),
6.88 (t, 1H, J5,4,6 = 7.8 Hz, H-5), 6.85 (d, 1H, J7,6 = 7.8 Hz, H-7),; EI MS:
m/z (rel. abund.%), 265 (M+, 37.3), 237 (100), 146 (9.5), 118 (65), 91
(18.4), 63 (28.1).
0
0
0
0
0
Yield: 0.28 g, 89%; 1H NMR: (300 MHz, DMSO-d6): d 10.89 (s, 1H,
´
N–H), 8.56 (s, 1H, –N@CH), 8.16 (s, 1H, H-2), 7.98 (dd, 1H,
J7,5 = 1.5 Hz, J7,6 = 8.3 Hz, H-7), 7.84(d, 1H, J4,5 = 8.3 Hz, H-4), 7.77(d,
1H, J5 ,6 = 7.7 Hz, H-50) 7.40 (t, 1H, J6,7,5 = 8.3 Hz, H-6), 7.02 (t, 1H,
5.2. 4-Hydroxybenzaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)hydrazone (2)
0
0
J5,6,4 = 8.3 Hz, H-5), 6.9 (d, 1H, J6´,5 = 7.7 Hz, H-60); EI MS: m/z (rel.
´
abund.%), 319 (M+, 4), 289 (100), 145 (24), 118 (74), 91 (17), 91 (17).
Yield: 0.23 g, 87%; 1H NMR: (300 MHz, DMSO-d6): d 10.99 (s,
1H, N–H), 10.79 (s, 1H, O–H), 8.59 (s, 1H, C@H), 8.02 (d, 1H,
5.9. 1-Naphthaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)hydrazone (9)
J4,5 = 7.5 Hz, H-4), 7.84 (d, 2H, J2 ,3 /6 ,5 = 8.6 Hz, H-20/H-60), 7.50
0
0
0
0
(d, 1H, J7,6 = 7.5 Hz, H-7), 7.00 (d, 2H, J3 ,2 /5 ,6 = 8.6 Hz, H-30/H-50),
6.9 (m, 2H, H-5/H-6); EI MS: m/z (rel. abund.%), 265 (M+, 4), 237
(100), 210 (8.9), 133 (11), 118 (30), 65.1 (10).
0
0
0
0
Yield: 0.25 g, 84%; 1H NMR: (300 MHz, DMSO-d6): d 10.90 (s,
1H, N–H), 9.26 (s, 1H, –N@CH), 8.27 (d, 1H, J8 ,7 = 6.87 Hz, H-80),
0
0

K. M. Khan et al. / Bioorg. Med. Chem. 17 (2009) 7795–7801
7799
8.18 (d, 1H, J4,5 = 8.1 Hz, H-4), 8.07 (d, 1H, J5 ,6 = 7.6 Hz, H-50), 7.94
5.16. 3-Hydroxybenzaldehyde N-(2-oxo-1,2-dihydro-3H-indol-
3-ylidene)hydrazone (16)
0
0
(d, 1H, J4 ,3 = 7.6 Hz, H-40), 7.67 (m, 4H, H-), 7.39 (dt, 1H, J5,7 = 0.90,
J5,4,6 = 8.1 Hz H-5), 6.99 (t, 1H, J6,7,5 = 8.1 Hz, H-6), 6.92 (d, 1H,
J7,6 = 8.1 Hz, Ar-H); EI MS: m/z (rel. abund.%), 299 (M+, 3.0), 271
(100), 244 (27), 154 (15), 127 (67), 77 (11).
0
0
Yield: 0.22 g, 81%; (1H NMR: (300 MHz, DMSO-d6): d 10.98 (s,
1H, N–H), 9.8 (s, 1H, O–H), 8.7 (s, 1H, –N@CH), 7.57 (d, 1H,
J4,5 = 7.5 Hz, H-4), 7.4(d, 1H, J6 ,5 = 8.2 Hz, H-60), 7.31 (t, 1H,
0
0
5.10. 4-Fluorobenzaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)hydrazone (10)
J5 ,4 ,6 = 8.2 Hz, H-50), 7.11 (d, 1H, J4 ,5 = 8.2 Hz, H-40), 7.0 (t, 1H,
J6,7,5 = 7.5 Hz, H-6), 6.9 (t, 1H, J5,6,4 = 7.5 Hz, H-5), 6.80 (s, 1H, H-
20), 6.72 (d, 1H, J7,6 = 7.5 Hz, H-7); EI MS: m/z (rel. abund.%), 265
(M+, 40), 234 (86), 144 (59.6), 118 (100).
0
0
0
0
0
Yield: 0.24 g, 88%; 1H NMR: (300 MHz, DMSO-d6): d 10.65 (s, 1H,
0
0
0
0
0
0
0
0
N–H), 8.63 (s, 1H, –N@CH), 8.06 (dd, 2H, J3 ,5 /5 ,3 = 5.7, J3 ,2 /5 ,6
=
8.7 Hz, H-3/5), 7.9 (d, 1H, J4,5 = 7.5 Hz, H-4), 7.40 (m, 3H, H-40/50/5),
7.03 (t, 1H, J6,5,7 = 7.50 Hz, H-6), 6.90 (d, 1H, J7,6 = 7.5 Hz, H-7); EI
MS: m/z (rel. abund.%), 267 (M+, 7), 239 (100), 212 (9), 118(76), 95
(71).
5.17. 4-Ethoxybenzaldehyde N-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)hydrazone (17)
Yield: 0.25 g, 86%; 1H NMR: (300 MHz, DMSO-d6): d 11.04 (s, 1H,
N–H), 8.85 (s, 1H, –N@CH), 8.10 (dd, 1H, J4,7 = 1.41 Hz, J 4,5, = 7.8 Hz
H-4), 8.00 (d, 2H, J6 ,5 /2 ,3 = 7.5 Hz, H-60/20), 7.55 (td, 1H, J6,4
=
0
0
0
0
5.11. 2-Fluorobenzaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)hydrazone (11)
1.54 Hz, J6,5,7 = 7.8 Hz, H-6) 7.39 (td, 1H, J5,7 = 1.40 Hz, J5,6,4 = 7.8 Hz
0
0
0
0
H-5), 7.18 (d, 1H, J7,6 = 7.8 Hz, H-7), 6.89 (d, 2H, J5 ,6 /3 ,2 = 7.5 Hz,
H-3/5), 4.15 (q, J = 7.0 Hz, 2H, OCH2), 1.38 (t, 3H, J = 7 Hz, CH3); EI
MS: m/z (rel. abund.%), 293 (M+, 4.09), 265 (97), 160 (27), 133 (90),
118 (100), 90 (77).
Yield: 0.21 g, 78%; 1H NMR: (300 MHz, DMSO-d6): d 10.55 (s,
0
0
1H, N–H), 8.86 (s, 1H, –N@CH), 8.15 (dt, 1H, J4 ,6 = 1.7 Hz,
J4 ,5 ,3 = 7.6 Hz, H-40), 7.89 (d, 1H, J4,5 = 7.2 Hz, H-4), 7.64 (m, 1H,
H-60) 7.42 (m, 3H, H-30/50/6), 7.03 (t, 1H, J5,4,6 = 7.2 Hz, H-5), 6.89
(d, 1H, J7,6 = 7.2 Hz, H-7); EI MS: m/z (rel. abund.%), 267 (M+, 7),
239 (100), 212 (7), 118(92), 75 (44).
0
0
0
5.18. 3,4-Dimethoxybenzaldehyde-N-(4,7-dichloro-2-oxo-1,2-
dihydro-3H-indol-3-ylidene)hydrazone (18)
5.12. 2-Florobenzaldehyde-N-(4,7-dichloro-2-oxo-1,2-dihydro-
3H-indol-3-ylidene)hydrazone (12)
Yield: 0.26 g, 68%; 1H NMR: (300 MHz, DMSO-d6): d 11.5 (s, 1H,
N–H), 8.75 (s, 1H, –N@CH), 7.85 (s, 1H, H-20), 7.75 (d, 1H,
J7,6 = 8.4 Hz, H-7), 7.72 (d, 1H, J6 ,5 = 7.5 Hz, H-60), 7.25 (d, 1H,
0
0
Yield: 0.28 g, 84%; 1H NMR: (300 MHz, DMSO-d6): d 11.97 (s,
1H, N–H), 8.5 (s, 1H, –N@CH), 7.31 (m, 4H, H-60,50,40,30), 7.25 (d,
1H, J6,5 = 8.4 Hz, H-6), 6.99 (d, 1H, J5,6 = 8.4 Hz, H-5); EI MS: m/z
(rel. abund.%), 335 (M+, 19), 307 (64), 229 (76), 186 (100), 122
(65) 75 (81).
J5,6 = 8.4 Hz, H-5), 7.10 (s, 1H, H-20), 6.99 (d, 1H, J5 ,6 = 7.5 Hz, H-
5), 3.8 (s, 3H, OCH3), 3.7 (s, 3H, OCH3); EI MS: m/z (rel. abund.%),
378 (M+, 19), 307 (64), 229 (75.89), 186 (100), 122 (65) 75 (81).
0
0
5.19. 2-Ethoxybenzaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)hydrazone (19)
5.13. 4-(Dimethylamino)benzaldehyde-N-(2-oxo-1,2-dihydro-
3H-indol-3-ylidene)hydrazone (13)
Yield: 0.25 g, 85%; 1H NMR: (300 MHz, DMSO-d6): d 11.09 (s,
1H, N–H), 8.85 (s, 1H, –N@CH), 8.10 (dd, 1H, J4,6 = 1.42 Hz,
Yield: 0.25 g, 86%; 1H NMR: (300 MHz, DMSO-d6): d 10.90 (s,
1H, N–H), 8.61 (s, 1H, –N@CH), 8.20 (d, 1H, J4,5 = 7.3 Hz, H-4),
J4,5 = 7.5 Hz, H-4), 8.00 (d, 1H, J6 ,5 = 8.2 Hz, H-60), 7.58 (td, 1H,
0
0
J4 ,6 = 1.6 Hz, J4 ,5 ,3 = 8.2 Hz, H-40), 7.39 (t, 1H, J6,7,5 = 7.5 Hz, H-6)
0
0
0
0
0
7.89 (d, 2H, J2 ,3 /6 ,5 = 9 Hz, H-2/6), 7.36 (t, 1H, J6,7,5 = 7.3 Hz, H-6),
7.2 (d, 1H, J3 ,4 = 8.2 Hz, H-30), 7.1 (t, 1H, J5,4,6 = 7.5 Hz, H-5), 7.0
0
0
0
0
0
0
7.3 (t, 1H, J5,6,4 = 7.3 Hz, H-5), 6.88 (d, 2H, J3 ,2 /5 ,6 = 9.0 Hz, H-30/
50), 6.84 (d, 1H, J7,6 = 7.3 Hz, H-7), 3.05 (s, 6H, N(Me)2); EI MS: m/
z (rel. abund.%), 292 (M+, 55), 264 (100), 147 (58), 118 (35), 77 (45).
(t, 1H, J5 ,4 6 = 8.2 Hz, H-50), 9.90 (d, 1H, J7,6 = 7.5 Hz, H-7), 4.15 (q,
2H, J = 6.9 Hz, OCH2), 1.38 (t, 3H, J = 6.9 Hz, CH3); EI MS: m/z (rel.
abund.%), 293 (M+, 4), 265 (92), 160 (28), 133 (100), 118 (98), 91
(69).
0
0
0
0
0
0
0
5.14. 2-Hydroxy-3-methoxybenzaldehyde-N-(2-oxo-1,2-
dihydro-3H-indol-3-ylidene)hydrazone (14)
5.20. 4-Nitrobenzaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-3-
ylidene)hydrazone (20)
Yield: 0.21 g, 71%; 1H NMR: (300 MHz, DMSO-d6): d 11.98 (s, 1H,
N–H), 11 (s, 1H, O–H), 9.00 (s, 1H, –N@CH) 7.6 (br d, 1H, J4,5 = 7.7 Hz,
Yield: 0.25 g, 86%; 1H NMR: (300 MHz, DMSO-d6): d 10.92 (s,
0
0
0
0
0
0
H-4), 7.4 (dt, 1H, J6,4 = 1.06 Hz, J6,5,7 = 7.7 Hz, H-6), 7.20 (dd, J6 ,4
=
1H, N–H), 8.67 (s, 1H, –N@CH), 8.39 (d, 2H, J3 ,2 /5 ,6 = 8.7 Hz, H-
1.15 Hz, J6 ,5 = 7.8 Hz, 1H, H-60), 7.1 (dd, 1H, J3 ,4 = 1.09 Hz,
J = 7.8 Hz, H-30), 7.0 (dt, 1H, J5,7 = 1.44 Hz, J5,6,4 = 7.7 Hz, H-5), 6.9 (t,
30/50), 8.21 (d, 2H, J2 ,3 /6 ,5 = 8.7 Hz, H-20/60), 7.74 (d, 1H,
J4,5 = 7.5 Hz, H-4), 7.4 (t, 1H, J6,7,5 = 7.5 Hz, H-6), 7.01 (t, 1H,
J5,4,6 = 7.5 Hz, H-5), 6.9 (d, 1H, J7,6 = 7.5 Hz, H-7); EI MS: m/z (rel.
abund.%), 294 (M+, 19), 266 (100), 220 (76), 118 (91), 91 (20).
0
0
0
0
0
0
0
0
1H, J5 ,6 ,4 = 7.8 Hz, H-50), 7.0 (br d, 1H, J7,6 = 7.7 Hz, H-7), 3.82 (s,
3H, OMe); EI MS: m/z (rel. abund.%), 295 (M+, 48), 267 (99), 252
(100), 135 (47), 118 (89).
0
0
0
5.21. 2-Nitrobenzaldehyde-N-(2-oxo-1,2-dihydro-3H-indol-3-
5.15. 2-Hydroxy,3-methoxybenzaldehyde-N-(4,7-dichloro-2-
oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazone (15)
ylidene)hydrazone (21)
Yield: 0.26 g, 87%; 1H NMR: (300 MHz, DMSO-d6): d 10.92 (s,
1H, N–H), 8.79 (s, 1H, –N@CH) 8.23 (d, 1H, J4,5 = 7.5 Hz, H-4),
Yield: 0.28 g, 77%; (1H NMR: (300 MHz, DMSO-d6): d 11.79 (s,
1H, N–H), 11.61 (s, 1H, O–H), 8.98 (s, 1H, –N@CH) 7.50 (d, 1H,
8.15 (d, 1H, J3 ,4 = 7.8 Hz, H-40), 7.93 (t, 1H, J4 ,5 ,3 = 7.8 Hz, H-40),
0
0
0
0
0
J6,5 = 8.7 Hz, H-6), 7.29 (d, 1H, J6 ,5 = 7.8 Hz, H-60), 7.18 (d, 1H,
7.84 (t, 1H, J3 ,2 ,4 = 7.8 Hz, H-30), 7.75 (d, 1H, J6 ,5 = 7.8 Hz, H-60);
7.41 (t, 1H, J6,7,5 = 7.5 Hz, H-6), 7.00 (t, 1H, J5,4,6 = 7.5 Hz, H-5),
6.90 (d, 1H, J7,6 = 7.5 Hz, H-7); EI MS: m/z (rel. abund.%), 294 (M+,
6), 264 (5), 159 (76), 131 (100), 103 (67), 91 (38).
0
0
0
0
0
0
0
J4 ,5 = 7.8 Hz, H-40), 7.12(d, J5,6 = 8.7 Hz, H-5), 6.94 (t, 1H,
0
0
J5 ,4 ,6 = 7.8 Hz, H-50), 3.82 (s, 1H, OMe); EI MS: m/z (rel. abund.%),
0
0
0
363 (M+, 54), 335 (49), 215 (52), 135 (73), 108 (82), 52 (100).

7800
K. M. Khan et al. / Bioorg. Med. Chem. 17 (2009) 7795–7801
5.22. 5-Chloro-2-hydroxybenzaldehyde-N-(2-oxo-1,2-dihydro-
3H-indol-3-ylidene)hydrazone (22)
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.09.028.
Yield: 0.27 g, 90%; 1H NMR: (300 MHz, DMSO-d6): d 11.86 (s,
1H, N–H), 10.99 (s, 1H, O–H), 8.95 (s, 1H, –N@CH) 7.78 (d, 1H,
J6 ,4 = 2.7 Hz, H-60), 7.63 (d, 1H, J4,5 = 7.5 Hz, H-4), 7.46 (m, 2H, H-
0
0
References and notes
6/40), 7.07 (t, 1H, J5,4,6 = 7.5 Hz, H-5), 7.03 (d, 1H, J3 ,4 = 8.7, H-30),
6.96 (d, 1H, J7,6 = 7.5 Hz, H-7); EI MS: m/z (rel. abund.%), 279 (M+,
94), 251 (100), 134 (28), 118 (89), 77 (27).
0
0
1. Lozier, R.; Bogomolni, R. A.; Stoekenius, W. J. Biophys. 1975, 15, 955.
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5.23. 2-Hydroxy-5-methylbenzaldehyde-N-(2-oxo-1,2-dihydro-
3H-indol-3-ylidene)hydrazone (23)
Yield: 0.24 g, 87%; 1H NMR: (300 MHz, DMSO-d6): d 11.67 (s,
1H, N–H), 10.96 (s, 1H, O–H), 8.95 (s, 1H, –N@CH) 7.62 (d, 1H,
0
0
J4,5 = 7.5 Hz, H-4), 7.43 (m, 2H, H-6/7), 7.3 (dd, J4 ,6 = 1.8 Hz,
J4 ,3 = 8.4 Hz, 1H, H-40), 7.06 (t, 1H, J5,4,6 = 7.5 Hz, H-5), 6.94 (d,
0
0
1H, J3 ,4 = 8.4 Hz, H-30), 2.26 (s, 3H, Me); EI MS: m/z (rel. abund.%),
0
0
299 (M+, 100), 271 (82), 118 (83), 91 (11).
5.24. 3,4-Dimethoxybenzaldehyde-N-(5-chloro-2-oxo-1,2-
dihydro-3H-indol-3-ylidene)hydrazone (24)
12. Kucukguzel, I.; Kucukguzel, S. G.; Rollas, S.; Sanis, G. O.; Ozdemir, O.; Bayrak, I.;
Altug, T.; Stables, J. II Farmaco 2004, 59, 839.
Yield: 0.24 g, 70%; 1H NMR: (300 MHz, DMSO-d6): d 10.97 (s,
1H, N–H), 8.67 (s, 1H, –N@CH), 8.09 (d, 1H, J4,6 = 1.8 Hz, H-4),
7.58 (br s, 1H, H-20), 7.53 (d, 1H, J7,6 = 8.4 Hz, H-7), 7.45 (dd, 1H,
13. Vicini, P.; Geronikaki, A.; Incerti, M.; Busonera, B.; Poni, G.; Kabras, C. A.; Colla,
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V. Y.; Pombeiro, A. J. L. Inorg. Chem. 2003, 42, 6024.
J6,4 = 1.8 Hz, J6,7 = 8.4 Hz, H-6), 7.17 (d, 1H, J6 ,5 = 8.4 Hz, H-60),
0
0
6.92 (d, 1H, J5 ,6 = 8.4 Hz, H-50), 3.87 (s, 6H, OMe); EI MS: m/z
0
0
(rel. abund.%), 343 (M+, 8), 315 (100), 245 (42), 152 (39), 79 (46.9).
18. (a) Mashaly, M.; Boyoumi, H. A.; Taha, A. Chem. Pap. 1999, 53, 299; (b) Chohan,
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5.25. 4-Florobenzaldehyde-N-(5-chloro-2-oxo-1,2-dihydro-3H-
indol-3-ylidene)hydrazone (25)
Yield: 0.17 g, 55%; (1H NMR: (300 MHz, DMSO-d6): d 10.9 (s, 1H,
0
0
0
0
0
0
0
0
N–H), 8.65 (s, 1H, –N@CH), 8.04 (dd, 2H, J3 ,5 /5 ,3 = 5.7 Hz, J3 ,2 /5 ,6
=
=
0
0
0
0
8.7 Hz, H-3/5), 7.84 (d, 1H, J4,6 = 2.4 Hz, H-4), 7.5 (d, 2H, J2 ,3 /6 ,5
8.7 Hz, H-20/60), 7.3 (d, 1H J6,7 = 8.4 Hz, H-6), 6.93 (d, 1H,
J7,6 = 8.4 Hz H-7); EI MS: m/z (rel. abund.%), 301 (M+, 4.80), 273
(87), 152 (55), 122 (37), 95 (100).
24. Desai, S. B.; Desai, P. B.; Desai, K. R. Heterocycl. Commun. 2001, 7, 83.
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5.26. 2-Hydroxybenzaldehyde-N-(5-chloro-2-oxo-1,2-dihydro-
3H-indol-3-ylidene)hydrazone (26)
28. Sarangapani, M.; Reddy, N. A.; Jayamma, Y.; Reddy, V. M. Indian Drugs 1998, 35,
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39. Monnier, V. M. Arch. Biochem. Biophys. 2003, 419, 1.
40. Vasan, S.; Foiles, P.; Founds, H. Arch. Biochem. Biophys. 2003, 419, 89.
41. (a) Hunt, J. V.; Bottoms, M. A.; Mitchinson, M. J. Biochem. J. 1993, 291, 529; (b)
Ahmed, N. Diabetes Res. Clin. Pract. 2005, 67, 3.
42. Ahmed, M. S.; Ahmed, N. Am. Soc. Nutr. 2006, 136, 796S.
43. (a) Gugliucci, A. J. Am. Osteopath. Assoc. 2000, 100, 621; (b) Singh, R.; Barden, A.;
Mori, T.; Beilin, L. Diabetologia 2001, 44, 129.
Yield: 0.25 g, 83%; 1H NMR: (300 MHz, DMSO-d6): d 11.80 (s,
1H, N–H), 10.96 (s, 1H, O–H), 9.01 (s, 1H, –N@CH), 7.7 (d, 1H
0
0
J6,7 = 8.4 Hz, H-6), 7.65 (s, 1H, H-4), 7.60 ((d, 1H, J6 ,5 = 8.1 Hz, H-
60), 7.46 (t, 1H J5 ,6 ,4 = 8.1 Hz, H-50), 7.3 (d, 1H J3 ,4 = 8.1 Hz, H-30),
7.00 (m, 2H, H-7/40), 6.92 (d, 1H, J = 8.4 Hz, Ar-H); EI MS: m/z
(rel. abund.%), 299 (M+, 75), 271 (100), 152 (81), 120 (33), 65 (50).
0
0
0
0
0
5.27. 3,4-Dihydroxybenzaldehyde-N-(5-chloro-2-oxo-1,2-
dihydro-3H-indol-3-ylidene)hydrazone (27)
Yield: 0.22 g, 69%; 1H NMR: (300 MHz, DMSO-d6): d 10.9 (s, 1H,
N–H), 9.6 (s, 1H, O–H), 8.57 (s, 1H, –N@CH), 7.4 (s, 1H, H-4), 7.38
(d, 1H J6,7 = 7.5 Hz, H-6), 7.25 (d, 1H, J6 ,5 = 7.8 Hz, H-60), 7.1 (s,
0
0
1H, H-20), 6.9 (d, 1H, J5 ,6 = 7.8 Hz, H-50), 6.86 (d, 1H, J7,6 = 7.5 Hz,
H-7); EI MS: m/z (rel. abund.%), 315 (M+, 5), 287 (100), 180 (32),
152 (85), 109 (36), 63 (40).
0
0
Acknowledgements
This work was supported by the Higher Education Commission
(HEC) Pakistan, under National Research Support Program for
Universities.

K. M. Khan et al. / Bioorg. Med. Chem. 17 (2009) 7795–7801
7801
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