Inclusion complexes of Schiff bases as phytogrowth inhibitors

Article abstract of DOI:10.1007/s10847-012-0161-5

This article details the preparation, characterization and phytotoxic evaluation of several Schiff base inclusion complexes obtained from β-cyclodextrin and p-sulfonic acid calix[6]arene. The inclusion complexes (1:1 molar ratio) were prepared by mixing a 5 mmol L^-1 aqueous solution (containing 1 % DMSO) of Schiff bases (guests) with aqueous solution (containing 1 % DMSO) of 5 mmol L^-1 of β-cyclodextrin or p-sulfonic acid calix[6]arene (hosts). The host-guest systems were characterized via a series of NMR experiments. The ability of the complexes to interfere with the radicle elongation of Sorghum bicolor (dicotyledonous species) and Cucumis sativus (monocotyledonous species) was evaluated. After 48 h, the inclusion complexes inhibited the radicle elongation of both species from 11 to 56 %. The formation of inclusion complexes was also investigated theoretically by molecular dynamics simulations in aqueous solution through implicit approach. Based on the experimental observation, the phytotoxic activity evaluated can be attributed to the formation of host-guest systems. This was supported by the theoretical findings based on stable interaction energy analyses for all the studied supramolecular systems.

Full text of DOI:10.1007/s10847-012-0161-5

J Incl Phenom Macrocycl Chem (2013) 75:197–204
DOI 10.1007/s10847-012-0161-5
ORIGINAL ARTICLE
Inclusion complexes of Schiff bases as phytogrowth inhibitors
•
Sergio Antonio Fernandes Eder do Couto Tavares Robson Ricardo Teixeira
•
•
´
Cleiton Moreira da Silva Ricardo Marques Montanari Angelo de Fatima
ˆ
•
•
•
´
•
Cleber Paulo Andrada Anconi Wagner Batista de Almeida
•
•
Helio Ferreira dos Santos Antonio Alberto da Silva
´
ˆ
Received: 10 January 2012 / Accepted: 19 April 2012 / Published online: 5 May 2012
Ó Springer Science+Business Media B.V. 2012
Abstract This article details the preparation, character-
ization and phytotoxic evaluation of several Schiff base
inclusion complexes obtained from b-cyclodextrin and
p-sulfonic acid calix[6]arene. The inclusion complexes (1:1
molar ratio) were prepared by mixing a 5 mmol L-1 aqueous
solution (containing 1 % DMSO) of Schiff bases (guests)
with aqueous solution (containing 1 % DMSO) of 5 mmol
L-1 of b-cyclodextrin or p-sulfonic acid calix[6]arene
(hosts). The host–guest systems were characterized via a
series of NMR experiments. The ability of the complexes to
interfere with the radicle elongation of Sorghum bicolor
(dicotyledonous species) and Cucumis sativus (monocoty-
ledonous species) was evaluated. After 48 h, the inclusion
complexes inhibited the radicle elongation of both species
from 11 to 56 %. The formation of inclusion complexes was
also investigated theoretically by molecular dynamics sim-
ulations in aqueous solution through implicit approach.
Based on the experimental observation, the phytotoxic
activity evaluated can be attributed to the formation of host–
guest systems. This was supported by the theoretical find-
ings based on stable interaction energy analyses for all the
studied supramolecular systems.
Electronic supplementary material The online version of this
article (doi:10.1007/s10847-012-0161-5) contains supplementary
material, which is available to authorized users.
S. A. Fernandes Á E. do Couto Tavares Á
Keywords Schiff base Á Calix[n]arenes Á Cyclodextrin Á
Phytotoxicity Á Host–guest systems Á Molecular dynamics
R. R. Teixeira Á R. M. Montanari Á A. A. da Silva
´
Grupo de Quımica Supramolecular e Biomimetica (GQSB),
Departamento de Quımica, Universidade Federal de Vic¸osa
´
´
(UFV), Vic¸osa, MG 36570-000, Brazil
S. A. Fernandes (&)
´
Departamento de Quımica, Universidade Federal de Vic¸osa
(UFV), Campus Universitario, Avenida P.H. Rolfs, s/n, Vic¸osa,
Introduction
´
Cyclodextrins (CD) are oligosaccharides made up of six
(a), seven (b), or eight (c) D-glupyranoses linked by
a-(1,4)-bonds [1–5]. In the pharmaceutical industry, these
host molecules are widely used to enhance water solubility,
chemical stability, bioavailability of insoluble or poorly
soluble drugs, as well as to reduce toxicity and control the
release rate of active compounds [6–9]. These effects are
related to high molecular recognition ability of a variety of
guest molecules including compounds of agrochemical
interest [10–26]. Calix[n]arenes are another class of oligo-
mer host molecules, constructed by linking phenol residues
via methylene groups. Calix[n]arenes with various cavity
sizes have been designed, each presenting conformation
MG 36570-000, Brazil
e-mail: santonio@ufv.br; sefernandes@gmail.com
ˆ
´
´
C. M. da Silva Á A. de Fatima Á W. B. de Almeida
ˆ
´
Grupo de Estudos em Quımica Organica e Biologica (GEQOB),
Departamento de Quımica, Universidade Federal de Minas
´
Gerais (UFMG), Belo Horizonte, Pampulha,
MG 31270-901, Brazil
C. P. A. Anconi
Departamento de Quımica, Universidade Federal de Lavras,
´
Lavras, MG 37200-000, Brazil
H. F. dos Santos
Departamento de Quımica, Universidade Federal de Juiz de
´
Fora, Juiz de Fora, MG 36036-330, Brazil
123

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J Incl Phenom Macrocycl Chem (2013) 75:197–204
isomers, with frequently modified phenolic hydroxy groups.
As a result, calix[n]arenes have been used as platforms for
the design and synthesis of biological active compounds
[27–32].
Materials and methods
Chemicals and reagents
Schiff bases are aldehyde- or ketone-like compounds in
which the carbonyl group is replaced by an imine or azo-
methine group. They are widely used industrially, exhib-
iting a broad range of biological activities, such as
antifungal, antibacterial, anti-malarial, anti-proliferative,
anti-inflammatory, anti-viral, and anti-pyretic properties
[33]. Despite the pharmacological properties of Schiff
bases, only one study on their potential agrochemical
properties has been reported. Huneck et al. [34] found that
only a few Schiff bases inhibited wheat, rye, and barley
seedlings. Although they presented varied biological
activities, a limiting factor was insolubility or poor stability
in water [35, 36].
All reagents were of analytical grade. b-Cyclodextrin
(99 %) and D2O (99.75 %) were purchased from Aldrich;
p-sulfonic acid calix[6]arene (2) was synthesized as pre-
viously described [44, 45].
Preparation of inclusion complexes
Inclusion complexes 1/3–6 or 2/3–6 in a 1:1 molar ratio
were obtained by mixing a 5 mmol L-1 aqueous solution
(containing 1% DMSO) of compounds 3, 4, 5, or 6 with
aqueous solution (containing 1 % DMSO) of 5 mmol L-1
of host 1 or 2. Solutions with the following guest–host
ratios were prepared: 15:0; 12:3; 10.5:4.5; 9:6; 7.5:7.5; 6:9;
4.5:10.5 and 3:12. In these solutions, the total number of
moles of the species was kept constant while the mole
fraction of each species varied. Each system was stirred for
24 h at room temperature. The ideal mixing time to equi-
librium was determined for each system (data not pre-
sented). For each solution, NMR spectra were recorded as
described in the NMR spectroscopy section.
Our group has studied compounds with phytotoxic
activity and the host–guest chemistry of cyclodextrins and
calix[n]arenes [37–43]. A natural extension of our study
would be to evaluate the use of b-cyclodextrin and p-sul-
fonic acid calix[6]arene to increase the water solubility of
Schiff bases as well as assess the phytotoxic activity of the
resulting inclusion complexes. Thus, the aim of this study
was to prepare and investigate the inclusion complex
formed by b-cyclodextrin (1), p-sulfonic acid calix[6]arene
(2) and Schiff bases 3–6 (Fig. 1). The phytotoxic effects of
the host–guest systems on Sorghum bicolor and Cucumis
sativus were investigated. In addition, theoretical investi-
gation through molecular dynamics (MD) was carried out
for all possible inclusion complexes to estimate relative
stabilization energies and discuss host–guest formation.
NMR spectroscopy
All experiments were performed at 298 K in D2O con-
taining 1 % DMSO-d6. Routine 1D 1H spectra were
acquired in a MERCURY-300 Varian spectrometer oper-
1
ating at 300.069 MHz for H (64 k data points, 30° exci-
tation pulse duration of 2.2 ls, spectral width of 6 kHz,
OH
Fig. 1 Structures of
b-cyclodextrin (1), p-sulfonic
acid calix[6]arene (2) and the
Schiff bases:
N-benzylideneaniline (3),
4-(phenylimino)methyl)phenol
(4), 4-(benzylideneamino)
phenol (5) and 3-(phenylimino)-
methyl)phenol (6)
O
O
HO
O
OH
HO
OH
O
OH
HO
HO
O
OH
SO3H
SO3H
SO3H
SO3H
SO3H
SO3H
O
O
OH
O
OH
HO
OH
O
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH O
O
O
OH
(2)
O
OH
HO
O
(1)
OH
OH
HO
N
N
(3)
N
N
HO
(4)
(5)
(6)
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J Incl Phenom Macrocycl Chem (2013) 75:197–204
199
(a)
(b)
Fig. 2 1H NMR spectra (300.069 MHz; D2O containing 1 % DMSO-d6;dHDO 4.67; 298 K, 5 mmol L-1 each) of the pure compound 4 (a) and 2/4
complex (b)
acquisition time of 3.3 s and relaxation delay of 10 ms) in
a 5 mm probe with inverse detection mode at room tem-
perature, unless stated otherwise. The chemical shifts were
calibrated considering the dHDO signal (4.67) as reference.
1 or 2, or inclusion complexes 1/3–6 and 2/3–6 (molar ratio
1:1) were prepared as previously described to adsorb acid-
washed sand (0.125 mL g-1) in Petri dishes (id = 9 cm and
height = 3 cm). Groups of seven germinated S. bicolor or C.
sativus seeds were placed on each plate. The Petri dishes
were sealed with parafilmÒ and incubated at 301 1 K, in
the dark at 75o inclination. After 24 h and 48 h, root length
was measured to the nearest millimeter. All treatments were
replicated four times in a completely randomized design.
The percentage of radicle growth inhibition or stimulation
was calculated in relation to the radicle length of the control,
treated with distilled water containing 1 % DMSO. The
results were analyzed by ANOVA and Scott–Knott’s mul-
tiple-range tests at P B 0.05 by using the software GENES
(Genetics and Statistical Analysis. Version 2007.0.0—Uni-
versidade Federal de Vic¸osa, Vic¸osa—MG, Brazil).
Determination of complexation stoichiometry
Job plots were prepared with 5 mmol L1- stock solutions
of compounds (1), (2), (3), (4), (5), and (6) [46].
Synthesis of Schiff bases
Schiff bases 3–6 were prepared by the condensation of the
appropriate amines with benzaldehydes in toluene using a
Dean Stark apparatus as previously described [35]. The
solvent was evaporated, and the compounds purified by
crystallization.
Theoretical calculations
Phytotoxic evaluation: radicle elongation assay on sand
with S. bicolor and C. seeds
Molecular dynamics (MD) simulations in aqueous media
were carried out for the Schiff bases and all possibly host–
guest systems using the GAFF (Generalized AMBER force
field) as implemented in the AMBER 10 package [47].
Cutoff radii for van der Waals and Coulombic electrostatic
Sorghum bicolor and C. sativus seeds were placed on ger-
mination paper imbibed with distilled water in a germination
chamber with a saturated relative humidity, at 301 1 K
for 24 h. Solutions containing 5 9 10-4 mol L-1 of compounds
˚
interactions were 8 and 20 A, respectively. All C–H and
123

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J Incl Phenom Macrocycl Chem (2013) 75:197–204
Table 1 1H NMR chemical shifts (d) and chemical shift differences
(Dd = d4 free - d4 complex) of the pure compound 4 and its complexes
with b-cyclodextrin 1/4 (5 mmol L-1 samples, 298 K)
0,022
0,020
0,018
0,016
0,014
0,012
0,010
1 : 1
9
8
6
N
7
3
5
2
4
HO
1
Hydrogens
4
d
1/4
d
1/4
Dd = dfree - dcomplex
0,2
0,3
0,4
0,5
0,6
0,7
0,8
[4]/[4] + [2]
H-2 and H-9
H-7
6.74
6.93
7.12
7.78
9.64
6.78
6.94
7.16
7.80
9.56
-0.04
-0.01
-0.04
-0.02
0.08
Fig. 3 Job plots for the complex formed between Schiff base 4 and p-
sulfonic acid calix[6]arene (2)
H-8
H-3
H-5
crystallographic data from which hydration water mole-
cules were removed, prior to MD simulations [50]. Other
starting geometries were constructed using appropriate
molecular modeling software. The aqueous MD interaction
energy (DE) of each host–guest system formed with
b-cyclodextrin (1) or p-sulfonic acid calix[6]arene (2) was
evaluated from the differences in the average total potential
energy of the complexes and isolate host and guest mole-
cules. For all studied host–guest systems, two distinct guest
orientations were investigated.
Table 2 1H NMR chemical shifts (d) and chemical shift differences
(Dd = d4free - d4complex) of the pure compound 4 and its complexes
with p-sulfonic acid calix[6]arene 2/4 (5 mmol L-1 samples, 298 K)
9
8
6
N
7
3
5
2
4
Results and discussion
HO
1
The Schiff bases 3–6 were prepared by condensing
appropriate amines with benzaldehydes in toluene using a
Dean Stark apparatus according to our previous publica-
tion [35]. The synthesized compounds were fully char-
acterized by IR and NMR spectroscopy and elemental
analysis.
Hydrogens
4
d
2/4
d
2/4
Dd = dfree - dcomplex
H-2 and H-9
H-7
6.74
6.93
7.12
7.78
9.64
6.78
6.83
7.12
7.74
9.56
-0.04
0.10
0.00
0.04
0.09
H-8
H-3
The inclusion complexes between b-cyclodextrin (1),
p-sulfonic acid calix[6]arene (2) and the Schiff bases 3–6
were prepared by stirring appropriate amounts of the host
compounds and the Schiff bases in aqueous solution con-
taining 1 % DMSO for 24 h. Clear solutions were obtained
in all cases. The degree of complexation between
b-cyclodextrin (1) or p-sulfonic acid calix[6]arene (2) and
Schiff bases 3–6 was determined by NMR in aqueous
solutions.
H-5
O–H bond lengths were fixed using the SHAKE algorithm.
Based on our previous work [48] all MD runs were initi-
ated at 5 K and warmed up to 50 K during 10 ps and
equilibrated for 100 ps. Subsequently, five similar con-
secutive MD steps were executed. In each step, the struc-
tures were warmed up to 50 K along 10 ps and equilibrated
during 100 ps. All MD simulations with length of 1,000 ps
had a time step of 1.5 fs and were performed at 298.15 K.
The solvent effect was included within the Born solvation
model, as currently implemented in AMBER 10 package
[49]. b-Cyclodextrin starting geometry was obtained from
We started our investigation by analyzing the com-
plexation-induced hydrogen chemical shifts (Dd), in the 2/4
complex and comparing these values with those for the free
Schiff base 4 (Fig. 2). The host hydrogens were observed
as a single resonance due to the fast exchange between a
free guest and a complexed one on the NMR time scale.
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J Incl Phenom Macrocycl Chem (2013) 75:197–204
201
Table 3 Effect of
b-ciclodextrin (1), p-sulfonic
0.125 mL g-1
Compound/complex
S. bicolor
acid calix[6]arene (2) and Schiff
24 h
48 h
base inclusion complexes 1/3–6
and 2/3–6 on radicle growth of
Sorghum bicolor seedlings after
Radicle length (cm)a
Inhibition (%)
Radicle length (cm)a
Inhibition (%)
1
1.76a
1.55b
2.00a
1.17d
1.07d
1.85a
1.43c
1.61b
1.12d
1.55b
1.93a
9
5.83a
4.81b
5.03b
2.41e
4.82b
5.61a
4.34c
4.49c
3.22d
4.24c
5.43a
No inhibition
24 and 48 h
2
20
11
1/3
1/4
1/5
1/6
2/3
2/4
No inhibition
7
39
45
4
56
11
No inhibition
26
17
42
20
0
20
17
41
22
0
a
2/5
Means followed by same
letter in the columns do not
differ by the Scott–Knott’s test
at P B 0.05
2/6
Control
Table 4 Effects of
Compound/complex
0.125 mL g-1
C. sativum
b-cyclodextrin (1), p-sulfonic
acid calix[6]arene (2) and Schiff
base inclusion complexes 1/3–6
and 2/3–6 on radicle growth of
Cucumis sativum seedlings after
24 and 48 h
24 h
48 h
Radicle length (cm)a
Inhibition (%)
Radicle length (cm)a
Inhibition (%)
1
2.16b
2.39b
1.85c
2.26b
2.19b
2.15b
1.92c
2.22b
1.77c
2.19b
2.83a
24
16
35
20
23
24
32
22
37
23
0
4.89a
5.70a
4.33b
5.28a
5.18a
4.98a
4.13b
5.23a
4.17b
4.57b
5.84a
16
2
2
1/3
1/4
1/5
1/6
2/3
2/4
2/5
2/6
Control
26
10
11
15
29
10
29
22
0
a
Means followed by same
letter in the columns do not
differ by the Scott–Knott’s test
at P B 0.05
The analysis of chemical shifts revealed that the
hydrogens of Schiff base 4 presented a small variation of
chemical shifts in the presence of p-sulfonic acid
calix[6]arene (B0.1 ppm), as well as in the presence of
b-cyclodextrin (B0.08 ppm), as it can be seen in Tables 1
and 2.
Table 5 Interaction energies evaluated for all host–guest systems
formed with the Schiff base guests 3, 4, 5, or 6 and b-cyclodextrin (1)
or p-sulfonic acid calix[6]arene (2) hosts
Host–guest complex
Interaction energy (DEa)
in kcal mol-1
1/3
1/4
1/5
1/6
2/3
2/4
2/5
2/6
a
-17
-15
-16
-16
-16
-16
-14
-15
9
9
9
9
8
8
8
8
The stoichiometries for the 1/4 and 2/4 complexes were
found to be 1:1, determined by Job plot’s method. Figure 3
shows a Job’s plot for the complex 2/4.
The trends described above concerning complexes 1/4
and 2/4 were similar to the other inclusion complexes.
The biological effects of the host compounds 1 and 2, as
well as the complexes (1/3–6) and 2/3–6 screened for
phytotoxicity are summarized in Tables 3 and 4.
Based on the data, dicotyledonous S. bicolor species
presented a slight radicle reduction when treated with host
Average data evaluated from 1,000 ps MD simulation at 298.15 K
within the Born solvation model
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J Incl Phenom Macrocycl Chem (2013) 75:197–204
Fig. 4 Final MD geometries obtained after 1,000 ps of simulation at 298.15 K. The solvent effect has been included within the Born solvation
model, as currently implemented in AMBER 10 package
compound 2, while no effect was observed with compound 1.
Radicle growth of monocotyledonous C. sativus species was
initially (24 h) affected by both compounds 1 and 2, but this
effect was no longer noticeable after 48 h. Therefore, these
compounds can be considered good candidates for active
carrier systems in herbicide formulations. It should be
mentioned that such studies are very important for both
pharmaceutical and agrochemical applications [51].
phytotoxic activities (see Tables 3, 4), it can be stated that the
active compounds correspond to the host–guest systems
depicted in Fig. 4. Furthermore, it must be mentioned that, in
the study by Huneck and co-workers, the Schiff bases 3, 4 and
5 were inactive against wheat, rye, and barley [34]. Although
the plant species used in this study to evaluate the phytotox-
icity of the inclusion complexes were different, improved
biological activity of the Schiff bases was demonstrated.
Focusing on the host–guest systems, complex 1/4 pro-
moted the highest radicle reduction in S. bicolor (56 %
inhibition after 48 h), followed by complex 2/5 (about
41 % inhibition) (Table 3). According to Table 4, the
species C. sativus was more affected by the complexes 1/3,
2/3 and 2/5 (about 30 % inhibition).
Conclusion
In this paper, we have investigated the formation of inclusion
complexes between b-cyclodextrin (1), p-sulfonic acid
calix[6]arene (2) and Schiff bases 3–6. Due to the low
activity of compounds 1 and 2 and very low solubility of the
Schiff bases studied, the observed phytotoxic activity was
ascribed to host–guest systems formed between the aldi-
mines and host molecules 1 and 2. This is supported by
theoretical investigation identifying favorable interaction
energies for all the studied host–guest systems through MD
simulations. This inclusion complexation should be regarded
as an important step in the design of novel formulations of
Schiff bases for agrochemical purposes.
The data in Tables 3 and 4 suggest that complex 2/5 can
be an unspecific phytotoxic combination, acting indis-
criminately in S. bicolor and C. sativus. The complexes
containing compound 3 (1/3 and 2/3) appear to be more
selective to C. sativus, whereas complex 1/4 was more
selective to S. bicolor. The complexes containing com-
pound 6 showed the lowest activities (about 20 %). In
general, all the treatments were less effective on C. sativus.
To support the experimental evidence on the formation of
host–guest systems, all possible inclusion compounds were
theoretically investigated. Two distinct guest orientations
were tested and no significant differences were found con-
cerning guest orientation within the MD approach. The
simulation data has been summarized in Table 5.
Acknowledgments This work was supported by FAPEMIG, CNPq,
CAPES and FUNARBE.It is a collaboration research project of Rede
´
Mineira de Quımica (RQ-MG) also supported by FAPEMIG.
In light of the approximations of the model used, it can
be stated, based on Table 5 data, that all the associations
studied form stable host–guest systems. In addition,
according to the average values, no host–guest system can
be identified as the most stable one.
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