Synthesis of 1-(α-aminoalkyl)-2-naphthol and α-aminonitrile derivatives with molybdenum Schiff base complex covalently bonded on silica-coated magnetic nanoparticles and DNA interaction study of one type of derivatives using computational and spectroscopi

Article abstract of DOI:10.1016/j.bioorg.2019.01.022

An air- and moisture-stable molybdenum Schiff base complexes immobilized on magnetic iron oxide nanoparticles with a core-shell structure was developed for utilization as a new heterogeneous catalyst. The surface, structural and magnetic characteristics o

Full text of DOI:10.1016/j.bioorg.2019.01.022

Accepted Manuscript
Synthesis of 1-(α-aminoalkyl)-2-naphthol and α-aminonitrile derivatives with
molybdenum Schiff base complex covalently bonded on silica-coated magnetic
nanoparticles and DNA interaction study of one type of derivatives using com-
putational and spectroscopic methods
Jamshid Rakhtshah, Behrooz Shaabani, Sadegh Salehzadeh, Neda Hosseinpour
Moghadam
PII:
S0045-2068(18)31026-5
DOI:
https://doi.org/10.1016/j.bioorg.2019.01.022
YBIOO 2726
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 September 2018
3 January 2019
9 January 2019
Please cite this article as: J. Rakhtshah, B. Shaabani, S. Salehzadeh, N. Hosseinpour Moghadam, Synthesis of 1-
(α-aminoalkyl)-2-naphthol and α-aminonitrile derivatives with molybdenum Schiff base complex covalently
bonded on silica-coated magnetic nanoparticles and DNA interaction study of one type of derivatives using
computational and spectroscopic methods, Bioorganic Chemistry (2019), doi: https://doi.org/10.1016/j.bioorg.
2019.01.022
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Synthesis of 1-(α-aminoalkyl)-2-naphthol and α-aminonitrile derivatives with molybdenum Schiff
base complex covalently bonded on silica-coated magnetic nanoparticles and DNA interaction
study of one type of derivatives using computational and spectroscopic methods
Jamshid Rakhtshaha, Behrooz Shaabania,*,shaabani.b@gmail.com, Sadegh Salehzadehb, Neda Hosseinpour
Moghadamb
aDepartment of Inorganic Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran
bFaculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
*Corresponding author.
Graphical abstract
Highlights
Design and synthesis of immobilized molybdenum Schiff-base complex supported on Fe3O4 as a
green, mild and efficient heterogeneous nanostructure catalyst.
Synthesis of 1-(α-aminoalkyl)-2-naphthol and α-aminonitrile derivatives catalyzed by
immobilized molybdenum Schiff-base complex supported on Fe3O4.
This method has the ability to tolerate a wide variety of substitutions.
This reaction was the requirement lower catalytic amount.
High yields were achieved on ultrasonication in the presence of mentioned nanocatalyst.
Easy recovery and reusability of magnetic nanostructure heterogeneous catalyst.
This method has the high yield, the shorter reaction times, and compliance with the green
chemistry protocols.
The binding interaction of a new derivative with various types of rigid DNA and HSA has been
investigated by molecular modeling study.
In vitro studies under physiological conditions showed that the derivative interacts with calf-
thymus DNA (ct-DNA) via an intercalative binding mode.
Abstract
An air- and moisture-stable molybdenum Schiff base complexes immobilized on magnetic iron
oxide nanoparticles with a core-shell structure was developed for utilization as a new
heterogeneous catalyst. The surface, structural and magnetic characteristics of the nanomaterials

were characterized by using Fourier transform infrared (FT-IR) spectroscopy, X-ray powder
diffraction (XRD), vibrating sample magnetometry (VSM), scanning electron microscopy (SEM),
energy dispersive X-ray (EDX) and inductively coupled plasma atomic emission spectroscopy
(ICP-AES). In application point of view, an ultrasonic assisted one-pot multicomponent protocol
for the synthesis of 1-(α-aminoalkyl)-2-naphthol derivatives have been demonstrated under mild
condition with short reaction times, high yields and TON values up to 570. To survey the generality
of the procedure, we studied the synthesis of α-aminonitrile derivatives with different aldehydes,
trimethylsilyl cyanide (TMSCN) and aniline under the same conditions. Additionally, binding
interaction of 1-(phenyl(pyridin-2-ylamino)methyl)naphthalen-2-ol (AMAN-1) with various types
of rigid DNA and HSA has been investigated by molecular modeling study. In vitro studies under
physiological conditions showed that the desired derivative interacts with calf-thymus DNA (ct-
DNA) via an intercalative binding mode.
Keywords: Immobilized complexes; 1-(α-aminoalkyl)-2-naphthol; Ultrasonication; Molecular
docking; DNA interaction.
1. Introduction:
From an environmental friendly and cost-effective point of view, facile recovery and recycling of
the catalyst are the two most important features in catalytic processes [1]. Due to easier recovery,
a lot of research work is focused on the synthesis of new heterogeneous catalysts [2-4]. However,
these catalysts are not completely recoverable via filtration or centrifugation after catalytic
reactions which lead to loss of solid catalysts in the separation process [5-6]. Hence there is a need
to design clean catalysts with high reusability and stability which can overcome these drawbacks.

To overcome such limitations, magnetite nanoparticles, especially Fe3O4 nanoparticles, have
attracted significant interest as the support materials due to their unique physical properties
including large surface-to-volume ratio, magnetism and low toxicity. Iron magnetic nanoparticles
can be easily synthesized and functionalized and they can be recycled from the reaction medium
by an external magnetic field [8].
Homogenous transition metal Schiff base complexes have been extensively studied in the field of
catalysis reactions [9-10]. The Schiff base complexes used in these reactions are generally ease of
preparation and they are nontoxic, air, thermally and moisture stable [11-12]. It should be noted
that the mentioned catalysts exhibit high catalytic activity in a wide range of reactions such as
epoxidation of olefins, asymmetric ring opening of terminal epoxides, hydrogenation of organic
substrates, oxidation reactions and coupling reactions [13-15]. However, these systems have
several drawbacks related to the difficulty of catalyst recycling. In order to overcome the aforesaid
concerns, various organic/inorganic solid materials have been frequently applied as insoluble
support for these complexes [16-20]. In comparison with the other supports, the silica-coated iron
oxide particles offer pronounced advantages, like facilitating the grafting of various coupling
agents such as linkers, ligands, metals or complexes on their surface through the silanol groups,
better dispersion of the catalyst in solvents, great resistance to organic solvents, thermal resistance
and better performance in different chemical trans-formations [21].
The Mannich reaction is one of the most important multicomponent reactions in organic chemistry
for the one-pot synthesis of 1-(α-aminoalkyl)-2-naphthols, the so-called Betti bases [22].
Preparation of substituted Betti base derivatives with 1,3-aminooxygenated functional groups are
important and attractive due to their interesting catalytic [23], pharmaceutical and biological
properties [24]. They are the key precursors for the synthesis of a variety of biologically significant

natural products including antibiotics and HIV protease inhibitors [25]. In addition, this type of
compounds has showed a high level of catalytic activity as chiral catalysts in the enantioselective
alkylation or arylation of benzaldehyde [26]. The three-component typical Betti reaction is a
condensation reaction between an aldehyde, ammonia or urea and β-naphthol [27-28]. Recently, a
modified method via a three-component condensation of aromatic aldehydes, 2 or 4-aminopyridine
and β-naphthol in the presence of MNP-PhSO3H [29] and {[1,4-DHPyrazine] [C(NO2)3]2} [30] as
catalyst has been reported. Also, there are a couple of papers, which possessed our consideration
on the feasibility to dominate the use of catalysts. In the first one, the reaction was performed in
the absence of solvents by heating the mixture at 125 ºC to generate the corresponding products
with good yields [31]. The second one remarked the effect of H2O as solvent on the reaction at
room temperature [32].
To the best of our knowledge, no report has been made so far about the synthesis of 1-(α-
aminoalkyl)-2-naphthols catalyzed by supported Schiff base complexes by ultrasonic irradiation.
With this view in mind and our studies using a variety of immobilized Schiff base complexes [33-
35], we have developed a mild, efficient and environmentally friendly procedure for the one-pot
Mannich synthesis of 1-(α-aminoalkyl)-2-naphthols derivatives from the coupling of β-naphthol
(1), various aromatic aldehydes (2) and 2, 3 or 4-aminopyridine (3) using molybdenum Schiff base
complex immobilized on silica coated Fe3O4 as a reusable catalyst (Scheme 1). This novel
synthetic method is especially favored because it provides a synergy between immobilized
complex on magnetic support and ultrasound irradiation which offers the more advantages
compared to the conventional methods reported in the literature. In addition, binding interaction
of one selected derivative with various types of rigid DNA and HSA has been investigated by

molecular modeling study and also we study DNA interaction of this derivative with calf-thymus
DNA (ct-DNA) using spectroscopic methods.
2. Experimental:
2.1. General Information:
All the commercially available reagents and solvents in the present study were used without further
purification. IR spectra were recorded with a Jusco 300 FT-IR instrument in the range 400–4000
cm-1, using KBr pellets. Powder X-ray diffraction patterns were collected with a Bruker
D8ADVANCE diffractometer with Cu Kα radiation (λ=1.5406 Å) at a rate of 0.05º/min from 10º
to 90º of 2θ. Field emission scanning electron microscope (FESEM) was carried out on Philips
XL30. Magnetic measurement of materials was investigated with a vibrating sample magnetometer
(VSM) (4 inch, Daghigh Meghnatis Kashan Co., Kashan, Iran) at room temperature. The ICP
analyses were carried out by Perkin-Elmer optima 7300 DV spectrometer. Reaction progress and
1
purity of derivatives were checked by TLC using silica gel SIL G/UV 254 plates. The H NMR
(400.13) and 13C NMR (100.62 MHz) spectra were obtained in DMSO-d6 using a Bruker Avance
spectrometer.
A schematic representation for the synthesis of molybdenum Schiff base complex immobilized on
silica-coated Fe3O4 nanoparticles is shown in Scheme 2.
2.2. Synthesis of iron oxide nanoparticles (Fe3O4):
Fe3O4 nanoparticles were synthesized by chemical precipitation technique [36]. Aqueous solution
of FeCl3.6H2O and FeCl2.6H2O salts were mixed in deionized water in 2:1 ratio at 80 ◦C with rapid
addition of NH4OH under ultrasonication condition to yield a black powder. The precipitate was
washed three times with ethanol and deionized water and dried at 60 ◦C.

2.3. Synthesis of silica coated iron oxide nanoparticles (Fe3O4@SiO2):
For synthesis of silica-coated Fe3O4 nanoparticles [37], 2 g of Fe3O4 NPs were added to a solution
of 100 mL ethanol. The mixture sonicated for 10 min, and then 10 mL of deionized water, 2.5 mL
of 25 wt% concentrated aqueous ammonia solution and tetraethylorthosilicate (TEOS) were added
in turn. The mixture was stirred for 4 h at room temperature. The brown silica-coated nanoparticles
were collected from the solution using a magnet and thoroughly washed with ethanol and
deionized water, followed by drying under vacuum overnight.
2.4. Coating iron oxide nanoparticles with chlorosilane coupling agent (Fe3O4@SiO2@Cl):
1 g of silica coated nanoparticles was suspended in a 100 mL xylene solution of 3-
chloropropyltrimethoxysilane (CPTMS) (2 ml) under dry nitrogen atmosphere. The mixture was
refluxed for 3 h. The precipitate was collected and the nanoparticles were washed with two portions
of xylene (20 mL), and one portion of ethanol (20 mL), before drying under vacuum.
2.5. Synthesis of molybdenum Schiff base complex (MoSB):
The homogeneous Schiff base ligand was synthesized as follows. 2-Formylpyridine (1 mmol) was
dissolved in ethanol. Then, a mixture of 4-aminophenol (1 mmol) in ethanol was added, and the
mixture was refluxed for 3 h. The mixture was cooled and the resultant solid was separated and
washed with ethanol and dried under vacuum. yield: 90%. Then a solution of MoO2(acac)2 (1
mmol) in absolute ethanol (10 mL) was added to a mixture of the prepared Schiff base ligand (1
mmol) in absolute ethanol (10 mL). The mixture was stirred at 60 ◦C for 3h, then filtered, and the
precipitate was washed well with absolute ethanol (3×10 mL).
2.6. Synthesis of immobilized Mo complexes on silica-coated Fe3O4 nanoparticles
(Fe3O4@SiO2@MoSB):

The nanoparticles coated with chlrosilane coupling agent were first dispersed with ultrasonication
in ethanol, for 10 min and then MoSB (0.5 g) was added to reaction medium and the contents of
the flask were refluxed for 12 h. The solid was collected with external magnet, dried at 60 ºC, and
washed three times with ethanol.
2.7. General procedure for the synthesis of 1-(α-aminoalkyl)-2-naphthol derivatives:
A mixture of aromatic aldehydes (1 mmol), β-naphthol (1 mmol; 0.144 g), 2-, 3- or 4-
aminopyridine (1 mmol; 0.094 g), and catalyst (6 mg) was exposed to ultrasound irradiation at
room temperature for an appropriate time (Table. 2). The reaction was monitored by TLC (n-
hexane/ethyl acetate: 5/2), and ethyl acetate (10 mL) was added to mixture and stirred for 10 min.
The catalyst was collected with magnet and washed with ethanol three times, dried in vacuum and
reused. The solvent was evaporated under reduced pressure and the crude product was purified by
recrystallization from hot ethanol. The products were characterized by IR, 1H and 13C NMR.
1-((2,4-Dichlorophenyl)(pyridin-2-ylamino)methyl)naphthalen-2-ol (Table 5, entry 5): FT-IR
(KBr): υ 3388, 3064, 1613,1511, 1344, 1234 cm-1; 1H NMR (400 MHz, DMSO-d6) δppm 13.93 (s,
1H, −OH), 8.23 (s, 1H, −NH), 8.05 (d, J = 8.5 Hz, 1H, ArH), 7.99 (d, J = 9.2 Hz, 1H, ArH), 7.95
(d, J = 5.4 Hz, 1H, ArH), 7.91 (d, J = 8.8 Hz, 1H, ArH), 7.57 (d, J = 5.8 Hz, 1H, ArH), 7.55 (d, J
= 8.5 Hz, 1H, ArH), 7.48 (d, J = 8.8 Hz, 1H, ArH), 7.39 (t, J = 8.0 Hz, 1H, ArH), 7.24 (d, J = 5.8
Hz, 1H, ArH), 7.14 (t, J = 7.4 Hz, 1H, ArH), 7.02 (t, J = 8.6 Hz, 1H, ArH), 6.85 (t, J = 8.5 Hz, 1H,
13
ArH), 6.19 (s, 1H, −CH aliphatic); C NMR (101 MHz, DMSO-d6) δppm 143.9, 142.8, 135.6,
132.4, 131.0, 130.6, 130.4, 130.1, 130.0, 128.7, 127.4, 124.8, 124.3, 123.3, 122.6, 118.5, 117.5,
116.4, 114.7, 113.4, 112.0, 35.3.
2.5. Molecular docking

The three-dimensional (3D) structure of 1-(phenyl(pyridin-2-ylamino)methyl)naphthalen-2-ol
(AMAN-1) was built, and its geometry was optimized through Hyper Chem version 8 program
[38]. The optimized structure of desired derivative was used for the molecular docking simulation
(Fig. 1). The crystal structures of the pdb DNAs and HSA used in molecular docking were
extracted from Protein Data Bank (http://www.rcsb.org/pdb/home/home.do) and listed in Table 1.
The binding interactions of AMAN-1 with all of the pdb DNA structures and HSA were simulated
by molecular docking method using AutoDock 4.0 program [39]. All of the water molecules were
removed from the pdb structures and then the polar hydrogen atoms were added. The grid maps of
dimensions 60 × 60 × 60 ˚A and 126 × 126 × 126 ˚A with a grid-point spacing of 0.375 ˚A were
created respectively for five DNA structures and HSA to ensure an appropriate size for X-
accessible space. The values of the centers of grid boxes are shown in Table 1. Other miscellaneous
parameters were assigned to the default values given by the Autodock program. Finally, we
obtained the dominating configuration of the AMAN-1 derivative with six DNA structures and
HSA having minimum binding free energy (ΔG).
2.6. DNA binding experiments
2.6.1. UV-visible absorption spectral measurements
Absorbance spectra were recorded in the range (200–400 nm) with a spectrophotometer
(Analytikjena specord 210) using a 1.0 cm quartz cell. Absorption titration experiments were
carried out by keeping the concentration of AMAN-1 constant (3×10-5 M) while varying the DNA
concentration from 0 to 3.69×10-5 M at room temperature.
2.6.2. Viscosity measurements

Viscosity measurements were made using a viscometer (SCHOT AVS 450) maintained at 25°C in
a constant temperature bath. The DNA concentration was fixed at 5 × 10−5 M and flow time was
measured with a digital stopwatch; the mean values of three measurements were used to evaluate
the viscosity (η) of the samples. The values for relative specific viscosity (η/η0)1/3, where η0 and η
are the specific viscosity contributions of DNA in the absence (η0) and in the presence of the
AMAN-1 (η), were plotted against 1/R (R = [AMAN-1]/[DNA] = 0.0–1.2).
3. Results and discussion:
3.1. Characterization of molybdenum Schiff base complex immobilized on Fe3O4
nanoparticles:
The most possible way for immobilization of molybdenum complex on the surface of chloro-
modified magnetic nanoparticles are investigated. The hybrid materials obtained by mentioned
method were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction
(XRD), electron microscopy techniques (FESEM with EDS), vibrating sample magnetometer
(VSM) and inductively coupled plasma (ICP).
The FT-IR spectra of Fe3O4 nanoparticles, Fe3O4@SiO2, Fe3O4@SiO2@MoSB and Mo Schiff base
are shown in Fig. 2. The observation of broad bonds at around 470–740 cm-1 indicates the presence
of Fe-O bond in Fe3O4 nanoparticles. The comparison of FT-IR spectra in Fig 2, indicates the
differences between uncoated and coated magnetic nanoparticles with silica. The bands appearing
at 1064 cm-1 should be attributed to the stretching vibrations of the Si-O groups on the silica-coated
nanoparticle. The weak bands at around 2915–2930 cm-1, which are not present in IR spectrum of
Fe3O4@SiO2, assign to the stretching mode of the CH2 groups of chlorosilane coupling agent.
Also, the peak appeared at 1630 cm-1 in the IR spectrum of Mo Schiff base complex are related to
C=N bond and confirm the synthesis of desired complex. In IR spectrum of final product,

Fe3O4@SiO2@MoSB, the vibration band at 1630 cm-1 is the typical IR absorbance for imine band
[16].
The purity and crystalline structure of Fe3O4 nanoparticles and Fe3O4@SiO2@MoSB were
determined by powder X-ray diffraction (Fig. 3). The XRD pattern of Fe3O4 show eight peaks at
2θ = 18.3, 30.5, 35.9, 43.3, 53, 57, 62 and 74.5º, corresponding to Miller index values {h k l} of
(111), (220), (311), (400), (422), (511), (440) and (533). As shown in Fig. 2b, the characteristic
peaks of raw nanoparticles did not changed, revealing that the structure of Fe3O4 is well
maintained, after being coated with Mo Schiff base complex. A broad peak at 2θ=20-30°
representing the amorphous silica was also found besides the characteristic peaks of the Fe3O4
nanoparticles, which also indicated that magnetic nanoparticles had been successfully
encapsulated by silica-layered systems. The average crystal size of the final nanoparticles is
calculated using the Scherrer equation for immobilized Schiff base complexes which is found to
be approximately 18 nm [35].
The morphology of the synthesized Fe3O4@SiO2@MoSB was studied by scanning electron
microscopy technique. SEM images of the catalyst at two different magnifications with the scale
bar of 500 nm (Fig. 4a) and 100 nm (Fig. 4b) were recorded. These images clearly show that
nanoparticles have been formed and are well-defined spherical particles. The size of synthesized
nanomaterials was in the range of 10-30 nm.
The elemental composition was determined using Energy-dispersive X-ray (EDX) analysis. Fig.4c
shows the EDX pattern of catalyst, indicating that it is composed of iron, carbon, silicon, nitrogen,
oxygen and chlorine elements. In addition to the mentioned peaks, the characteristic peaks of
molybdenum support the possible complexation of molybdenum with Schiff base moieties. This

result confirms the successful immobilizing of the Schiff base sites on the surface of magnetic
nanoparticles.
Magnetic properties of prepared materials have been investigated at room temperature by means
of vibrating sample magnetometry (VSM). According to Fig. 5, it can be seen that all samples
show excellent superparamagnetic properties, indicating the retaining of the nanostructural nature
of Fe3O4 during immobilizing presses. The saturation magnetization values for Fe3O4 and
Fe3O4@SiO2@MoSB nanocomposites are 48 and 38 emug-1, respectively. Compared with neat
nanoparticles, a decrease of about 10 emug-1 in saturation magnetization value was observed for
supported nanoparticles which can be attributed to the coating of the magnetite particles with silica,
organic groups and Schiff base complex. However, the catalyst could still be separated
comfortably from the reaction mixture by using an external magnet.
Finally, the amount of Mo in the supported catalyst, determined by ICP, was about 0.29 mmol g-
1
.
3.2. Application of molybdenum complex immobilized on Fe3O4 as a heterogeneous catalyst
The catalytic activity of the Mo complex immobilized on nanoparticles as a mild and efficient acid
catalyst was applied in the one-pot three component condensation of aromatic aldehydes, 2-, 3- or
4-aminopyridine and β-naphthol for the synthesis of 1-(α-aminoalkyl)-2-naphthol derivatives
under ultrasonic irradiation. At the first stage, to find out the optimum parameters including the
quantity of catalyst, solvent and temperature, we studied the reaction of β-naphthol (1),
naphthalene-1-carbaldehyde (2) and 2-aminopyridine (3) as a model reaction in various conditions.
We try to screen the effect of catalyst amount on the reaction and yields. As shown in Table 2, the
result shows that in the absence of catalyst a trace amount of product was observed over a period

of 45 min and the best result was achieved when we carried out the model reaction in the presence
of 6 mg of catalyst. In order to check the effect of temperature on the reaction, the range of 25-100
◦C was screened. It was observed that in the presence of 6 mg of catalyst the yield of product has
no change when we increase the reaction temperature up to 100 ºC (Table 2, entries 7-10). To
verify the effect of ultrasound irradiation on this procedure, the synthesis of 1-(α-aminoalkyl)-2-
naphthols was done in the presence of varying amount of the nanocatalyst with and without
ultrasound irradiation (Table 3). It is clear that, reactions under ultrasonic irradiation led to shorter
reaction times and higher yields. It continued to optimize the model reaction by detecting the effect
of various solvents as the medium by using nanocatalyst at room temperature. The represented
data in Table 4, showed the reaction without any solvent was very successful with good high yields.
Therefore, the best results from the model reaction were obtained in the presence of 6 mg of
nanocatalyst at room temperature, solvent-free and ultrasonic irradiation conditions.
Having established the remarkable results, and in order to show the generality of these conditions
to other substrates, a variety of 1-(α-aminoalkyl)-2-naphthols derivatives were synthesized from
the three component reaction of different kinds of aromatic aldehydes containing electron-donating
or electron-withdrawing functionalities (1 mmol), 2-, 3- or 4-aminopyridine (1 mmol) and β-
naphthol (1 mmol) employing combined ultrasonic/Mo Schiff base complex immobilized on Fe3O4
nanoparticles (6 mg) as the heterogeneous acid catalyst under solvent-free reaction condition. The
results have been summarized in Table 5. According to the results, all the reactions proceeded
equally smooth and afforded the desired products in excellent yields and short reaction time
irrespective of the nature of the substituents. It should be noted that, aldehydes with electron-
withdrawing group and cinnamaldehyde were rather faster than electron donating groups and
worked well under these conditions. According to the ICP results for metal content, (6 mg of

catalyst is equivalent to 0.17 mol% of catalyst), turn over number (TON) and turn over frequency
(TOF) of the catalyst were calculated. The amount of metals loaded on magnetic support
determined by atomic absorption spectrophotometer.
To explore the scope and generality of this combined catalytic system, different kinds of aldehydes
(1) reacted with TMSCN (2) and aniline (3) to produce a library of α-aminonitrile derivatives (4)
under the same conditions. As can be seen from Table 6, the progress of this reaction was checked
by TLC and the corresponding compounds were obtained in excellent yields. Therefore, the
important role of the catalyst and ultrasonic irradiation in the reaction was verified.
Due to the lack of research articles on the synthesis of 1-(α-aminoalkyl)-2-naphthol derivatives
with aforementioned substrates, a limited comparison between the efficiency of our method and
other reported procedures in the synthesis of the same titled products was possible. The results for
the preparation of 1-(p-Chlorophenyl(2-pyridinylamino)methyl)naphthalene-2-ol were
represented in Table 7. We can conclude that our procedure is in the first rank among all methods
in terms of the reaction time and yield and also this fact that it avoids the use of volatile organic
solvents in the reaction. So it shows that use of the ultrasound irradiation improves the rate of
reaction and also yields of products formed.
In addition, the reusability of our catalyst was investigated for the condensation of β-naphthol and
naphthalene-1-carbaldehyde with 2-aminopyridine. After completion of the reaction, the catalyst
was separated with magnet in hot condition, after washing with ethanol, dried at 60 ºC and reused
for a similar reaction. The recovered catalyst could be reused at least eight times without significant
loss of activity (Fig. 6). Furthermore, the FT-IR spectrum and XRD pattern of the reused catalyst
after eight cycles revealed that the structure of the catalyst maintains during the reactions.

A proposed mechanism for synthesis of 1‐aminoalkyl‐2‐naphthol derivatives in the presence of
the Mo Schiff base complex immobilized on Fe3O4 nanoparticles has been presented in Scheme 3.
In this mechanism, at first, the nanocatalyst activates the carbonyl group of the aromatic aldehyde
to give intermediate (I). In the second step, β-naphthol attacks the intermediate (I) by the
nucleophilic addition affording the corresponding intermediate II as an ortho-quinone methide (o-
QM). The mechanism ends with the reaction of o‐quinone methide with amines to form the
aminoalkyl naphthol derivatives [29, 41].
3.3. In vitro mechanism action study of one type of derivatives with DNA
Generally, drug molecules can bind with DNA by means of either covalent or non-covalent
interactions. For these interactions, there are different binding sites in the DNA molecule: (i)
between any two nitrogen base pairs (intercalation binding), (ii) in the major or minor groove
(groove binding), (iii) on the exterior side of the helix (electrostatic binding) [42]. In the present
study, to attain a better understanding of mechanism action of 1-(phenyl(pyridin-2-
ylamino)methyl)naphthalen-2-ol (AMAN-1) with ct-DNA, UV-visible absorption spectroscopy
and viscosity measurement was investigated.
3.3.1. UV-vis absorption studies
In UV-Vis absorption spectroscopy technique, hyperchromism and hypochromism are the
generally meaningful spectral properties, which are used to discriminate against the variations in
the structure of DNA double-helix. Hypochromism is observed when there is a close proximity
interaction between the electronic levels of the interacting chromophore and those of the nitrogen
atoms of DNA base pairs [43]. Fig. 7 shows the UV-Vis absorption spectra of AMAN-1 (5×10-5
M) in the absence and presence of different concentrations of ct-DNA (0 to 3.69×10-5 M). The
absorption peak of AMAN-1 showed a gradual decrease with the increasing of different

concentrations of ct-DNA. Furthermore, in order to obtain a more quantitative determination of
the interaction strength between AMAN-1 and ct-DNA, intrinsic binding constant, Kb, was
determined using spectroscopic titration data at 260 nm. Then the data were fitted to equation (1)
to obtain the binding constant [44]:
1
2kb2Ct
2kbCt

DNA

b  (b2 
)
2
a   f
b   f
s

(1)
kb

DNA

b 1 kbCt 
2s
where εa is the extinction coefficient observed for AMAN-1 absorption band at a given DNA
concentration, εf is the extinction coefficient of the free derivative in solution, εb is the extinction
coefficient of the derivative when fully bound to DNA (it is assumed when further addition of
DNA does not change the absorbance, all the AMAN-1 molecule is bound and εb can be calculated
from Beer’s Law), Kb is the equilibrium binding constant, Ct is the total AMAN-1 concentration
in nucleotide, and s is the binding site size. The plots of (εa- εf)/(εb- εf) versus [DNA] is shown in
Fig. 8. The calculated Kb value was 2.9 ×105 M-1.
3.3.2. Viscosity measurements
To further verify the interaction binding mode between the AMAN-1 and ct-DNA, viscosity
measurements were carried out. Generally, the classical intercalator compounds cause an increase
in the DNA viscosity (separates base pairs of DNA in order to accommodate the binding ligand).
Non-classical compounds (such as groove binding and electrostatic) cause the reduction or no
change in the DNA viscosity [45]. The effect of the AMAN-1 on the viscosity of DNA is illustrated
in Fig. 9. As can be seen, the viscosity of DNA increased slightly or remained constant with
increasing different amounts of AMAN-1. This behavior may reveal the existence of groove

binding mode between DNA and the AMAN-1. This result is consistent with molecular docking
results (section 3-4.).
3.4. Molecular docking study of one type of derivatives with different type of DNAs
3.4.1. Molecular docking study with DNA
Molecular docking is a well-established computational method to identify the drug–
macromolecule (such as DNA and HSA) interactions for designing the modern drugs and to predict
the specific binding site available at the molecular target [46-50]. In the present study, molecular
docking studies of AMAN-1 with different types of DNA were performed in an attempt to
ascertain the preferred orientation of this derivative inside the DNA sequence (Fig. 10). The
AMAN-1 molecule was docked into various types of rigid DNA and the results were listed in
Table 8. The values of electrostatic forces between the drug candidate and DNAs is much lower
than the sum of the hydrogen bonding energy, van der Waals energy and desolvation free energy
in the binding process of DNA sequence and AMAN-1, and from this result, it can be concluded
that the main binding mode between the desired derivative and DNAs is not electrostatic.
3.4.2. Molecular docking study with HSA
To determine the binding ability of the AMAN-1 with the HSA (PDB ID: 1AO6), molecular
docking studies were performed. Generally, crystal structure descriptions of the 3D structure of
HSA showed that a single polypeptide chain of 585 amino acid residues contains three structurally
homologous domains (I–III): I (residues 1–195) II (196–383) and III (384–585); each domain has
two subdomains (A and B) [51]. In addition, the drug binding sites of HSA are located in
tryptophan residue (Trp-214) of HSA in subdomain IIA and hydrophobic cavities in subdomain
IA and IIA respectively. The molecular docking pattern of AMAN-1 and HSA indicated that

HSA/AMAN-1 complex was located in the subdomains IIA of HSA and also hydrogen binding
and hydrophobic interactions play an important role in the stability of this complex (Fig. 11).
Conclusions
In conclusion, we have synthesized and characterized a heterogeneous catalyst by immobilizing a
Mo Schiff base complex onto silica-coated magnetic Fe3O4 nanoparticles to overcome the leaching
of the complex in reaction medium. A new synthetic method for the synthesis of
1‐aminoalkyl‐2‐naphthol derivatives using the aforesaid catalyst in room temperature and solvent-
free condition have been developed. Then, to establish the generality of this procedure, we have
also extended this protocol for the synthesis of α-aminonitriles. The nanocatalyst synthesized here
is stable to the reaction conditions and can be recycled without significant loss of activity.
Comparison of the procedure efficiency of our combined method with other catalysts and reaction
conditions used in previous works indicates that our reaction condition have merits over other
reactions in several aspects. Finally, we tried to have a new viewpoint of the mechanism of
interaction between one type of aminoalky naphthol derivatives with DNA, that helps us to design
new molecular models of both novel and more efficient drug molecules which treat DNA. The
results of UV-vis absorption spectroscopy and viscosity measurements indicated that the selected
aminoalkynaphthol derivative interacts with ct-DNA in an intercalative binding mode, and the
binding constant is 2.9 ×105 M-1. Also, the result of molecular modeling was in approximate
correlation with our experimental results.
Acknowledgements
We would like to thank University of Tabriz and Iran National Science Foundation (INSF) (Grant
Number: 95014554) for financial support to our research group.
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Fig. 1. The optimized structure of AMAN-1.
Fig. 2. FT-IR Spectra of Fe3O4 (blue), Fe3O4@SiO2 (red), Fe3O4@SiO2@MoSB (green) and Mo Schiff base (dashed
line).
Fig. 3. Wide angle XRD patterns of the different samples. Different planes are indexed.
Fig. 4. FE-SEM micrograph with the scale bar of 500 nm (a), 100 nm (b) and EDX spectrum of Fe3O4@SiO2@MoSB
(c).
Fig. 5. Magnetic hysteresis curves measured at room temperature for Fe3O4 (a, blue) and Fe3O4@SiO2@MoSB (b,
green).
Fig. 6. Reusability of Fe3O4@SiO2@MoSB as a heterogeneous catalyst in model reaction.
Fig. 7. Absorption spectra of AMAN-1 in the presence of ct-DNA at different concentrations. Conditions: c(AMAN-
1)=5.0×10−5mol L−1. c(DNA)(×10−5mol L−1): 0.53, 1.06, 1.60, 2.12, 2.64 and 3.69 pH=7.4.
Fig. 8. Plots of (εa- εf)/(εb- εf) versus [DNA] for the titration of AMAN-1 with ct-DNA.
Fig. 9. Effect of increasing the concentration of AMAN-1 on the relative viscosity of ct-DNA at 25 ºC.
Fig 10. Molecular docking of the interactions of 1BNA (a), 1D32 (b), 1K2J (c), 1DNE (d), 104D (e) and 1ZNA (f)
as a type of DNA with AMAN-1.
Fig 11. Molecular docking of the interaction of HSA with AMAN-1.
Scheme 1. The synthesis of 1-(α-aminoalkyl)-2-naphthols derivatives using molybdenum complex supported on functionalized
Fe3O4 magnetite nanoparticles.

Scheme 2. The sequence of events in the preparation of Fe3O4@SiO2@MoSB.
Scheme 3. Proposed mechanism for the synthesis of 1‐aminoalkyl‐2‐naphthol using molybdenum complex supported
on functionalized Fe3O4 magnetite nanoparticles containing Schiff base ligand.
Table 1. Five DNA sequences and HSA used for molecular dockinga.
ID
PDB ID
Sequences
Unit Cell constants
Centers of grid
boxes
1
2
1BNA
1D32
D(CGCGAATTCGCG)2
D(CGCG)2
a= 24.87 Å, b = 40.39Å, c = 66.20 Å
α=90 ˚, β=90 ˚, γ=90 ˚
14.719, 20.979, 8.824
a=16.88 Å, b=26.88 Å, c=82.60 Å
α=90 ˚, β=90 ˚, γ=90 ˚
26.699, 13.011,
10.343
3
1DNE
D(CGCGATATCGCG)
a=25.48 Å, b=41.26 Å, c=66.88 Å
α=90 ˚, β=90 ˚, γ=90 ˚
15.259, 21.297,
75.998
2
4
5
1K2J
D(CGTACG)2
D(CGCG)2
No data
0.218, 1.887, 7.463
1ZNA
a=31.27 Å, b=64.67 Å, c=19.50 Å
18.079, -8.217, 8.853
α=90 ˚, β=90 ˚, γ=90 ˚
6
1AO6
HSA
a=59.68 Å, b=96.98 Å, c=59.72 Å
29.535, 31.826, 23.5
α=91.07 ˚, β=103.50 ˚, γ=75.08 ˚
aThese data were extracted from Protein Data Bank (http://www.rcsb.org/pdb/home/home.do).
Table 2. Effects of catalyst concentration and temperature on the synthesis of 1-(α-aminoalkyl)-2-naphthols
derivatives under solvent-free conditionsa
NH2
N
CHO
2
N
3
Amount of nano cat. (g)
HN
HO
+
Solvent-free, Temperature o
C
OH
1
Entry
Amount of catalyst (mg) Reaction temperature (oC)b Reaction time (min)
Yieldc (%)
1
2
3
4
5
6
7
8
9
—
—
2
2
4
4
6
6
6
r.t.
100
r.t.
100
r.t.
100
r.t.
50
45
45
45
45
45
45
20
20
20
20
20
20
30
30
45
50
75
77
94
94
94
94
94
94
75
100
r.t.
10
11
12
6
8
8
50

13
14
15
16
8
8
10
10
75
100
r.t.
20
20
20
20
94
94
95
95
100
aReaction conditions: naphthalene-1-carbaldehyde (1 mmol), β-naphthol (1 mmol) and 2-aminopyridine (1 mmol)
under ultrasonic irradiation;
bThis is the temperature of oil bath and not inside the reaction medium;
c Isolated yield.
Table 3. Effect of amounts of catalyst with or without sonication for synthesis of 1-(α-aminoalkyl)-2-naphthol
derivatives under solvent-free conditionsa
With sonication
Without sonication
Entry
Amount of catalyst (mg)
Yield (%)
Time (min)
Yield (%) Time (min)
1
2
3
4
5
2
4
6
8
10
30
75
94
94
94
45
45
20
20
20
16
50
65
65
65
70
55
40
40
40
aReaction conditions: naphthalene-1-carbaldehyde (1 mmol), β-naphthol (1 mmol) and 2-aminopyridine (1 mmol);
bThis is the temperature of oil bath and not inside the reaction medium;
cIsolated yield.
Table 4. Effects of solvent on the synthesis of 1-(α-aminoalkyl)-2-naphthols derivatives using 6 mg catalyst at room
temperaturea
NH2
N
CHO
2
N
3
Nano cat. (6 mg)
HN
+
Solvent, Room Temp. oC
OH
HO
1
Solvent-free
94
H2O
35
C2H5OH
CH3CN
60
CH2Cl2
50
Toluene
30
n-Hexane
Yield (%)b
70
45
35
Reaction
time (min)
20
40
40
35
50
60
anaphthalene-1-carbaldehyde (1 mmol), β-naphthol (1 mmol) and 2-aminopyridine (1 mmol) by under ultrasonic
irradiation under room temperature;
bIsolated yield.

Table 5. The three-component synthesis of 1-(α-aminoalkyl)-2-naphthols derivatives using 6 mg of nanocatalysta
O
H
OH
+
Nano Cat (6 mg)
Solvent-free, r. t.
R
OH
NH
Ar
ArNH2
R
Ar: 2, 3 or 4 Pyridyl
Name
R
Ar
Time (min) Yieldb (%) TONc
TOF (min-1)d
M.p (oC) [Ref.]
AMAN-1
AMAN-2
AMAN-3
AMAN-4
AMAN-5
AMAN-6
H
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
12
10
10
15
10
20
20
20
20
10
15
25
15
10
15
15
12
25
30
96
97
96
90
95
88
85
94
87
92
88
90
96
96
90
89
90
88
91
564.70
570.58
564.70
529.41
558.82
517.64
500.00
552.94
511.76
541.17
517.64
529.41
564.70
564.70
529.41
523.52
529.41
517.64
535.29
47.05
57.05
56.47
35.29
55.88
25.88
25.00
27.64
25.58
54.11
34.50
21.17
37.64
56.47
35.29
34.90
44.11
20.70
17.74
170-172[29]
192-194[30]
188-190[27]
210-212[27]
177-179[e]
172-174[27]
168-170[30]
220-222[30]
166-168[31]
200-202[31]
182-184[31]
211-213[31]
285-287[30]
223-225[30]
218-220[30]
257-259[30]
260-262[30]
200-202[29]
232-234[29]
4-NO2
4-Cl
4-Br
2,4-Cl
4-CH3
AMAN-7 4-OCH3 2-Pyridyl
AMAN-8 1-Naphtyl 2-Pyridyl
AMAN-9
H
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
4-Pyridyl
4-Pyridyl
4-Pyridyl
AMAN-10 4-NO2
AMAN-11
AMAN-12
4-Cl
4-Br
AMAN-13 4-NO2
AMAN-14 4-Cl
AMAN-15 4-CH3
AMAN-16 4-OCH3 4-Pyridyl
AMAN-17 1-Naphtyl 4-Pyridyl
AMAN-18
H
Ph
Ph
AMAN-19 3-NO2

AMAN-20
AMAN-21
4-Cl
4-Br
Ph
Ph
30
40
87
86
511.76
505.88
17.05
12.64
183-185[29]
190-192[29]
aReaction conditions: Aldehyde (1 mmol), β-naphthol (1 mmol), 2, 3 or 4 aminopyridine (1 mmol), room temperature,
solvent-free; ultrasonic irradiation;
bIsolated yield;
cTurnover numbers (TONs);
dTurnover frequencies (TOFs);
eNew derivative.
Table 6. The three-component synthesis of α-aminonitriles derivatives using 6 mg of nano catalysta
O
3
N
1
4
2
NH2
Ar
H
H3C
Si
Nano Cat (6 mg)
Solvent-free, r. t.
Ar
+
HN
R
H3C
N
H3C
Entry
Ar
C6H5
Time (min)
Yieldb (%)
TONc
500.00
TOF (min-1)d
M.p (oC) [Ref.]
1
2
3
4
5
6
25
20
20
30
30
25
85
89
90
85
88
90
20.00
26.17
26.47
16.66
17.25
21.17
80-83[40]
117-119[40]
Oil[40]
4-ClC6H5
4-NO2C6H5
4-CH3C6H5
4-CH3OC6H5
4-CNC6H5
523.52
529.41
500.00
517.64
529.41
78-80[40]
93-95[40]
105-107[40]
aReaction conditions: Aldehyde (1 mmol), aniline (1 mmol), TMSCN (1 mmol), room temperature, solvent-free,
ultrasonic irradiation;
bIsolated yield;
cTurnover number (TON);
dTurnover frequency (TOF)
Table 7. Comparison of the Fe3O4@SiO2@MoSB catalytic activity with those of reported proceduresa
Catalyst
Solv.
Temp (C)
Time (min)
Yieldb (%)
[Ref.]
MNP-PhSO3H
{[1,4-DHPyrazine][C(NO2)3]2}
Absence of catalyst
-
120
r.t.
125
r.t.
15
15
5
40
8
85
96
90
98
96
[29]
[30]
[31]
-
-
H2O
-
Absence of catalyst
Fe3O4@SiO2@MoSB
[27]
r.t.
This work
aModel reaction:4-chlorobenzaldehyde, β-naphthol and 2-aminopyridine;
bIsolated yield.

Table 8. The various energies and the hydrogen bonding interactions in the formation process of DNAs/AMAN-1 and
HAS/AMAN-1 complexes.
ΔG0
PDB ID
ΔE1(b)
ΔE2(c)
Hydrogen bonding
Binding site
(a)
kcal mol–1
kcal mol–1
kcal mol–1
DNA
aman
Bond length
(Å)
1BNA
1D32
-7.17
-8.66
-9.21
-0.10
-0.09
DT7:O4
(Chain A)
DT7:O4
(Chain A)
C7:O4*
(Chain B)
G6:H3
(Chain B)
G6:O4*
O1:H13
N1:H8
O1:H13
O1
2.194
Major groove
Intercalation
1.196
2.121
1.939
1.907
2.162
2.00
-7.72
N1:H8
N2
(Chain B)
G6:O4*
(Chain B)
T18:O3*
(Chain B)
G12:O3*
(Chain B)
G6:O1P
(Chain B)
DT17:O4
(Chain B)
SER480(OG) O1:H13
(Chain A)
SER480(OG) N1:H8
(Chain A)
1DNE
1K2J
-8.84
-6.47
-7.45
-6.57
-7.82
-10.33
-7.96
-8.94
-8.06
-9.31
-0.19
-0.05
-0.09
-0.10
-0.02
N1:H8
N2
Minor groove
Major groove
Major groove
Major groove
IIA
2.01
1ZNA
104D
1AO6
N1:H8
N1:H8
2.10
2.22
1.878
2.094
IIA
(a) ΔG0 is the binding free energy change in the binding process. (b) ΔE1 denotes intermolecular interaction energy,
which is a sum of van der Waals energy, hydrogen bonding energy, desolvation free energy and electrostatic energy.
(c) ΔE2 is the electrostatic energy