Metal-based scaffolds of Schiff bases derived from naproxen: Synthesis, antibacterial activities, and molecular docking studies

Article abstract of DOI:10.3390/molecules24071237

We report here the synthesis, characterization, and antibacterial evaluation of transition metal complexes of Ni, Cu, Co, Mn, Zn, and Cd (6a–f), using a Schiff base ligand (5) derived from naproxen (an anti-inflammatory drug) and 5-bromosalicylaldehyde by a series of reactions. The ligand and the synthesized complexes were characterized by elemental analysis, UV-Visible, FTIR, and XRD techniques. The ligand 5 behaves as a bidentate donor and coordinates with metals in square planar or tetrahedral fashion. In order to evaluate its bioactivity profile, we screened the Schiff base ligand and its metal complexes (6a–f) against different species of bacteria and the complexes were found to exhibit significant antibacterial activity. The complexes showed more potency against Bacillus subtilis as compared to the other species. Moreover, we modeled these complexes’ binding affinity against COX1 protein using computational docking.

Full text of DOI:10.3390/molecules24071237

molecules
Article
Metal-Based Scaffolds of Schiff Bases Derived from
Naproxen: Synthesis, Antibacterial Activities,
and Molecular Docking Studies
Muhammad Ashraf Shaheen 1,2 , Shanshan Feng 1, Mehwish Anthony 2,
Muhammad Nawaz Tahir 3, Mubashir Hassan 4, Sung-Yum Seo 4, Saeed Ahmad 5,
Mudassir Iqbal 6 , Muhammad Saleem 7,
*
and Changrui Lu 1,
*
1
Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry,
Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China;
mashaheen@uos.edu.pk (M.A.S.); sandyfss@163.com (S.F.)
Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan;
mehwish.anthony.chemist@gmail.com
Department of Physics, University of Sargodha, Sargodha 40100, Pakistan; dmntahir_uos@yahoo.com
Collage of Natural science, Department of Biology, Kongju National University, Gongju,
Chungcheongnam 32588, Korea; 18817326450@163.com (M.H.); 18226212391@163.com (S.-Y.S.)
Department of Chemistry, College of Sciences and Humanities Prince Sattam bin Abdul Aziz University,
Al-Kharj 11942, Saudi Arabia; saeed_a786@hotmail.com
Department of Chemistry, School of Natural Sciences (SNS), National University of Sciences &
Technology (NUST), H-12, Islamabad 44000, Pakistan; mudassir.iqbal@sns.nust.edu.pk
Department of Chemistry, University of Sargodha, Sub-campus, Bhakkar 30000, Pakistan
Correspondence: saleemqau@gmail.com (M.S.); crlu@dhu.edu.cn (C.L.);
2
3
4
5
6
7
*
Tel./Fax: +86-21-67792740 (ext. 2310) (C.L.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Derek J. McPhee
Received: 4 March 2019; Accepted: 26 March 2019; Published: 29 March 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: We report here the synthesis, characterization, and antibacterial evaluation of transition
metal complexes of Ni, Cu, Co, Mn, Zn, and Cd (6a ), using a Schiff base ligand ( ) derived
–
f
5
from naproxen (an anti-inflammatory drug) and 5-bromosalicylaldehyde by a series of reactions.
The ligand and the synthesized complexes were characterized by elemental analysis, UV-Visible,
FTIR, and XRD techniques. The ligand
square planar or tetrahedral fashion. In order to evaluate its bioactivity profile, we screened the Schiff
base ligand and its metal complexes (6a ) against different species of bacteria and the complexes
5 behaves as a bidentate donor and coordinates with metals in
–
f
were found to exhibit significant antibacterial activity. The complexes showed more potency against
Bacillus subtilis as compared to the other species. Moreover, we modeled these complexes’ binding
affinity against COX1 protein using computational docking.
Keywords: naproxen; Schiff base; hydrazide; complexation; bioactivity
1. Introduction
The therapeutic usage of metal-based substances dates back to the ancient Greeks, Assyrians,
Egyptians, and Chinese, who have been known to use cinnabar and various compounds of gold,
silver, and bismuth to cure different diseases. In traditional Chinese medicine, arsenic drugs, such as
arsenic trioxide (ATO), were used as antiseptic and anticancer agents or in the treatment of rheumatoid
diseases, syphilis, and psoriasis. Past research has identified a large number of metal complexes for
their potential use as therapeutics and catalysts. Since the 16th century, transitions metal complexes
have shown effective therapeutic powers in treating cancer, diabetes, and arthritis. More recently,
Molecules 2019, 24, 1237; doi:10.3390/molecules24071237
www.mdpi.com/journal/molecules

Molecules 2019, 24, 1237
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studies have shown that metal complexes, such as cisplatin and its analogues, threaten various types
of cancer [1,2].
The ligand plays a vital role in determining the properties of the metal complexes for a specific
purpose. Therefore, a variety of ligands with different donor sites have formed metal-based scaffolds
for therapeutic and diagnostic agents [
chelation tendency toward several metal ions [
field, including diagnostics [ ]. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) and
their derivatives have shown structural and physicochemical diversity and biocompatibility as ligands,
forming transition metal complexes endowed with therapeutic effects [ 10]. Naproxen, ibuprofen,
3]. Among them, Schiff bases, with different donor sites with
4,5], proved to be versatile ligands used in the medical
6
7–
and aspirin are the most prominent NSAIDs that can form metal complexes as ligands due to their
medicinal effects and biocompatibility [8–11].
To obtain good drug candidates, the investigation of bioactivities of the well-known NSAIDs and
their hybridized compounds via Schiff base formation takes priority. Studies have shown that the
NSAID complexes with transition metals can reduce gastrointestinal mucosal disorders effectively [12].
Several NSAIDs metal complexes possess anti-oxidative features and anti-inflammatory activities, such
as organo-tin compounds [13–17]. Reports show that tolfenamic acid–Co (II) complex interacts with
albumin serum and DNA [16
,
18,19]. Meanwhile, the naproxen and diclofenac acid form complexes
with Cu (II) ions that exhibit antimicrobial and anti-tumor activities [20]. Ibuprofen forms complexes
with Cu (II) and Zn (II) ions and shows inhibitory growth and antibacterial effects [21–24].
Another class of organic molecules, the hydrazides, show diverse properties, such as anticonvulsant,
anti-inflammatory, antibacterial, antimalarial, antifungal, and anti-tuberculosis activities [25
The hydrazides and acyl-hydrazide complexes of naproxen have shown antimalarial [28 29], anti-tumor,
anti-inflammatory (Zn, Co, and Ca) [30 31], and anti-oxidative effects (Co complex) [32]. Consequently,
–27].
,
,
we synthesized Naproxen hydrazides and reacted them with salicylic aldehydes to obtain the Schiff
bases, which were then utilized to obtain the metal complexes. The resulting metal complexes were
characterized by different spectroscopic techniques and screened for antibacterial activity, yielding
several potential candidate compounds with antibacterial activity.
2. Results and Discussion
2.1. Synthesis and Structure of the Schiff Base (5)
Compound 5, the Schiff base of hydrazide, was prepared as illustrated in Scheme 1. Briefly,
sodium salt of naproxen was treated with HCl to form 2-(6-methoxynaphthalen-2-yl) propanoic acid
and was subsequently converted to methyl 2-(6-methoxynaphthalen-2-yl) propanoate. The formation
of ester was confirmed by the appearance of an IR absorbance peak at 1083.99 cm−1 for (OC
−
OCH3).
, was reacted with hydrazine to prepare the hydrazide, and then treated further with
5-Bromosalicylaldehyde to prepare the Schiff base ligand . The FTIR spectrum of the Schiff base
shows peaks for (N
H) at 3226.91 cm−1 for (C=N) at 1658.78 cm−1, for (NC=O) at 1614.42 cm−1
for (Ar
OH) at 3541.31cm−1, for (C
at 3049.46 cm 1, and for (C
Br) at 623.01 cm−1. The compound
Methyl ester,
3
5
−
,
−
−
O) at 1203.58 cm−1, for (Ar
−
OCH3) at 1271.09 cm−1, for (OH)
exhibits max at (C=N) 282.0 nm.
−
−
5
λ
The FTIR and UV data agree with the proposed structure of 5 [33–36].

Molecules 2019, 24, 1237
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Scheme 1. Synthesis of Schiff base metal complexes 6a–f; (i) MeOH, HCl, stirring, room temperature (rt);
(ii) MeOH, H2SO4, reflux 4–5 h; (iii) Hydrazine hydrate, MeOH, reflux 4–5 h; (iv) MeOH, Glacial acetic
−
acid, reflux 2–3 h; (v) 10% NaHCO3, MeOH, Ni(CH3COO )2
·
4H2O, reflux (6a); 10% NaHCO3, MeOH,
Mn(CH3COO−)2, re−flux (6b); 10% NaHCO3, MeOH, Cu(CH3COO−)2, reflux (6c); 10% NaHCO3,
−
MeOH, Zn(CH3COO )2, reflux (6d); 10% NaHCO3, MeOH, Co(CH3COO )2, reflux (6e); 10% NaHCO3,
MeOH, CdCl2·5H2O, reflux (6f).
2.2. Single Crystal XRD Analysis for the Schiff Base (5)
In compound 5, (N’-[(E)-(5-bromo-2-hydroxyphenyl)methylidene]-2-(6-methoxynaphthalen-2-yl)
propanehydrazide), the aldehyde moiety (C1-C7/O1/Br1), A and the naphthalene moiety (C11–C20),
B share the same plane with r.m.s. deviations of 0.0161 and 0.0131 Å, respectively. The hydrazidal
(C8/C9/N1/N2/O2), part C is roughly planar with a root-mean-square◦(r.m.s.) deviation of 0.2889 Å.
◦
◦
The dihedral angle between A/B, A/C, and B/C is 60.52 (11) , 49.88 (15) , and 45.42 (17) , respectively.
Figure 1 shows intramolecular H-bonding of O-H . . . N type with an S (6) loop. Intramolecular
interactions link the molecules due to N-H . . . O interactions between the imine and carbonyl groups
in the form of C (4) chains along the crystallographic a-axis. The molecules have pi-pi stacking between
the similar benzene rings in the range [3.131(2)–3.131(2) Å] and have the slippage range [3.572–3.786 Å]
(Figure 2). The entire crystal data have been tabulated in Table 1.
Figure 1. ORTEP diagram of the Schiff base (
5) with thermal ellipsoids drawn at the 50% probability
level. The H-atoms are shown as small circles of arbitrary radii.

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Figure 2. The packing diagram of the Schiff base (5) showing the infinite one-dimensional chains along
the a-axis.
Table 1. Experimental details.
SHELX
Crystal data
Chemical formula
C21H19BrN2O3
Mr
427.29
Crystal system, space group
Orthorhombic, P212121
Temperature (K)
a, b, c (Å)
V (Å3)
296
4.9129 (8), 16.732 (3), 22.570 (3)
1855.3 (5)
Z
4
Radiation type
Mo Kα
−1
2.24
µµ (mm
)
Crystal size (mm)
Data collection
0.44 × 0.22 × 0.20
Bruker Kappa APEXII CCD
Diffractometer
Diffractometer
Absorption correction
–
No. of measured, independent and observed
[I> 2σ(I)] reflections
13779, 4040, 1985
Rint
0.091
0.651
−1
(sin θ/λ)max (Å
)
Refinement
R[F2> 2σ(F2)], wR(F2), S
0.052, 0.105, 0.94
No. of reflections
4040
No. of parameters
249
H-atom treatment
H atoms treated by a mixture of independent and constrained refinement
−3
0.28, −0.28
∆ρmax, ∆ρmin (e Å
)
−
−
Flack x determined using 563 quotients [(I+) − (I )]/[(I+) + (I )] (Parsons,
Absolute structure
Flack and Wagner, ActaCryst. B69 (2013) 249-259).
Absolute structure parameter
0.026 (12)
Computer programs: SHELXL2014/7 (Sheldrick, 2014).

Molecules 2019, 24, 1237
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The crystal structure data have been deposited at the Cambridge Crystallographic Data Centre
under CCDC No. 1556675. These data can be obtained free of charge via http://www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK;
Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
2.3. Synthesis of Target Molecules 6a–f
The Schiff base ligand 5 solution was treated with a corresponding metal salt solution and colored
complexes were obtained as precipitates. The color change in the reaction mixture before and after
induction of metal ions indicates complex formation. Thin layer chromatography was used to verify
the formation of target molecules 6a
signal corresponding to the phenolic hydroxyl stretching vibration in ligand
–
f
. The FTIR spectral analysis registered the disappearance of the
, caused by the chelation
5
with corresponding metal ions. Moreover, the signal due to C=N stretching vibration shifted. Scheme 1
summarizes the synthetic protocol adopted to synthesize the target molecules 6a–f.
2.4. Anti-Bacterial Activity
We then screened all of the abovementioned compounds, i.e., Schiff bases and their metal
complexes, for their antibacterial activities [37], showing that the Schiff base ligand and its metal
complexes exhibited significant antibacterial activities. We selected four stains of different types of
bacterial species, Escherichia coli, Streptococcus aureous, Salmonella typhae, and Bacillus subtilis, for use
in evaluating antimicrobial potential by the diffusion method (Table 2). Briefly, autoclaved glass
plates were used for conducting bacterial activity. Distilled water was used for preparing a solution of
agar gel and Ciprofloxacin was used as a reference. Samples of all the derivatives of naproxen were
placed in bacterial medium for 24 h. The activity was measured in terms of inhibition zones in mm.
All compounds tested showed inhibition to bacteria growth, comparable with that of ciprofloxacin.
The complexes with Co, Cu, and Co in general showed improvements over the free ligand across all
four bacterial species.
Table 2. The results of anti-bacterial activity of naproxen derivatives 6a–f.
Escherichia
Coli
Streptococcus
Aureous
Salmonella
Typhae
Bacillus
Subtilus
Sr. No.
1.
2.
3
4.
5.
6.
7.
8.
Samples
Schiff Base (5)
12.7
14.5
11.9
15.3
11.5
11.3
14.1
14.2
11.8
13.0
12.3
15.3
11.3
16.3
13.2
13.9
12.1
16.0
14.2
12.3
13.3
14.1
15.3
13.4
12.2
16.8
13.4
14.3
16.5
13.1
14.1
13.8
Ni Complex (6a)
Mn Complex (6b)
Cu Complex (6c)
Zn Complex (6d)
Co Complex (6e)
Cd Complex (6f)
Reference
2.5. Computational Analysis of Synthesized Compounds Against COX1
2.5.1. Molecular Docking Analyses
Prostaglandin endoperoxide H synthases (PGHSs)-1 and -2 (also called cyclooxygenases (COXs)-1
and -2) catalyze the committed step in prostaglandin biosynthesis. In the pathway, NSAIDs target
COX1 and COX2 [38]. Human COX1 enzyme comprises two chains with 553 residues. The docked
complexes of synthesized compounds 6a
–f bound to COX1 were analyzed on the basis of the lowest
binding energy values (kcal/mol) and hydrogen/hydrophobic bonding analyses. The analysis showed
that all compounds bind to the enzyme with binding energy values around
to the reference structure energy value (−8.20 kcal/mol).
−
11.70 kcal/mol, compared

Molecules 2019, 24, 1237
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2.5.2. Structure Activity Relationship (SAR) Analyses of Synthesized Compounds and Target Protein
The SAR analyses showed that compounds (6a ) directly interact within the active region of
–
f
COX1. Results showed that compounds build hydrogen and hydrophobic interactions with active
site target residues with appropriate binding distances. In the 6a-docking results, we observed two
interactions at different binding residues. The carbonyl oxygen atom of 6a interacts with Asn122 and
forms a hydrogen bond having a length of 3.10 Å. Another hydrophobic interaction was observed
against Leu112 with bond length 4.26 Å. In 6b-docking complex, we observed two hydrophobic
interactions against target protein. In 6b-docking complex, we observed a weak binding interaction
at Arg79 and Tyr64 residues having the bond lengths 5.07 and 4.69 Å, respectively. In both docking
complexes, the metals containing ligands (6a and 6b) were different; therefore, our model shows little
variant binding interaction pattern.
As in 6a-docking, in 6c-docking complex two hydrophobic interactions and one hydrogen bond
were observed at different residues (Pro84, Arg79, and Lys532) of target protein. The ligand 6c
forms hydrophobic interactions having a bond length of 4.95 and 3.13 Å. Similarly, we show a weak
hydrogen bond with bond length 5.07 Å. In 6d-COX1 docking, a couple of hydrogen bonds were seen
at Asn122 and Ser126 at a bond length of 2.91 and 2.82 Å, respectively. In both 6c and 6d docking
complexes, the hydrogen bonds strengthen the docking complexes. In 6e and 6f complexes, we
observed hydrophobic interactions against the target protein residues Thr80, Arg120, Ile89, Tyr64,
and Ile46, with distances of 2.96, 3.91, 5.22, 5.06, and 4.37 Å, respectively (Figure 3). The comparative
results showed that the binding residues among standard compounds (5) and other derivatives
were similar in 6a and 6d, whereas little fluctuations in residues exist in other docking complexes.
A literature study also justified that these binding pocket residues are significant in downstream
signaling pathways [39–41].
Figure 3. Docking of synthesized compounds. The ligand structures (6a
–f) are justified in red, purple,
brown, green, light purple, and pink colors, respectively. The reference structure is highlighted in blue

Molecules 2019, 24, 1237
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color. The interactive residues are displayed in gray color in all complexes. In the center, all the
compounds are highlighted within the binding pocket of the target protein. The protein ribbon is
highlighted in yellow and cyan colors. The purple and dark green dotted lines represent hydrogen and
hydrophobic interactions in angstroms.
3. Materials and Methods
The chemicals used were of analytic grades, purchased from Sigma Aldrich, Pakistan, and used
without purification except where mentioned. Sodium salt of naproxen was received from Moringa
Pharma, Pakistan, as a gift. FTIR Prestige 21 (Shimadzu, Kyoto, Japan) was used for FTIR spectra of
−
the synthesized products. Elemental analyses were carried out with an Exeter Analytical Inc-CE-440
Elemental Analyzer. Melting points were determined by a Gallenkamp digital melting point apparatus
(MFB
1H-NMR and 13C-NMR spectra were recorded on a Varian Unity INOVA (300 MHz) spectrometer.
1H-NMR (300 MHz) and 13C-NMR (75 MHz) chemical shift values are reported as
using the residual
−
595
−
010M). Bruker (KAPPA Apex II) XRD was used for determination of crystalline structure.
δ
solvent signal as an internal standard. All NMR measurements were recorded in CDCl3 as a solvent
unless mentioned otherwise. Antibacterial activity was screened by using fresh cultures of different
species of bacteria by following the disc diffusion method [42].
3.1. Synthesis of 2-(6-Methoxynaphthalen-2-yl)propanoicacid (2)
Naproxen, (2) was prepared by treating equimolar amount of Naproxen-Na, (1) and HCl.
◦
Yield: 98%, mp. 152 C. v¯ cm−1: (C=O) 1718 cm−1, (C
−
O) 1174 cm−1; (O H) 3186 cm−1
,
−
(Ar−OCH3) 1265 cm−1. C14H14O3 (230.3): calcd. C, 73.03; H, 6.13; O, 20.85; found C, 72.93; H, 6.03.
3.2. Synthesis of 2−(6−Methoxynaphthalen−2−yl)propanehydrazide (4)
The hydrazide of the methyl ester (4), was prepared from naproxen (2), through a series of
reactions depicted in Scheme 1 according to reported [43] procedure with some modifications.
3.3. Synthesis of (N’-[(E)-(5-bromo-2-hydroxyphenyl) methylidene]-2-(6-methoxynaphthalen-2-yl)
propanehydrazide) (5)
A methanolic solution of naproxen hydrazide, (
methanolic solution of 5-bromosalicyladehyde (1.65g, 8.2 mmol) and the mixture was refluxed for
5 h. The reaction mixture was concentrated and filtered. The product was washed with pet. ether
repeatedly and recrystallized from methanol and n-hexane. Yield: 3.82g: 76%, mp. 138 ◦C. v¯ cm−1
(N O)
H) 3226.91 cm−1, (C=N) 1658.78 cm−1, (NC=O) 1614.42 cm−1, (Ar OH) 3541.31 cm−1, (C
1203.58 cm−1, (Ar OCH3) 1271.09 cm−1, (OH) 3049.46 cm−1, (C Br) 623.01 cm−1
max: (C=N)
4) (2.00g, 8.2 mmol) was added to the acidified
4
−
:
−
−
−
−
−
. λ
282.0 nm. C21H19BrN2O3 (427.3): calcd. C, 59.03; H, 4.48; Br, 18.70; N, 6.56; O, 11.23; found C, 58.73; H,
4.18; Br, 18.30; N, 6.16. H-NMR:
1
δ 1.41 (d, 3H, Me), 3.83 (s, 3H, -OMe), 3.53 (q, 1H, -CH), 3.76 (m, 2H,
-NH2), 6.41 (d, 1H, -ArH), 7.16–7.20 (m, 2H, -ArH), 7.37 (d, 1H, -ArH), 7.41–7.44 (m, 2H, -ArH), 7.81
(s, 1H, -ArH), 7.86–7.88 (m, 2H, -ArH), 8.68 (s, 1H, =CH). 13C-NMR:
15.2, 45.4, 55.8, 105.4, 110.8, 118.5,
δ
119.6, 120.8, 126.0, 126.7, 128.3, 128.9, 129.4, 132.3, 132.9, 133.4, 135.3, 146. 3, 169.7, 156.1, 177.7.
3.4. Synthesis of Metal Complexes 6a-f from Schiff Base Ligand (5)
Complexes 6a–f were prepared by the same general procedure. The methanolic solution of the
ligand ( ) and the metal salts were mixed in a 2:1 ratio in the presence of 10% Na2CO3 and refluxed
5
for 1–2 h. The reaction mixture was concentrated and filtered. The solid products were washed and
recrystallized with appropriate solvents.
3.4.1. Synthesis of Ni Complex (6a)
Schiff base ligand (5) (0.785 g, 1.8 mmol) was added to methanol (25 mL) in a round bottom
flask (100 mL) and heated for 30 min with continuous stirring. A 10% NaHCO3 (2 mL) solution was

Molecules 2019, 24, 1237
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added to the reaction mixture. The methanolic solution of Ni(CH3COO)2
·
4H2O (0.228 g, 0.91 mmol)
was added to the Schiff base mixture. The reaction mixture was refluxed for 2 h with continuous
stirring. The light green color ppt. was washed with distilled water repeatedly and dried. Yield
0.801g; 97%, mp. 298 ◦C FTIR Peaks: (N H) 3184 cm−1, (Ni N) 449 cm−1, (Ni O) 480 cm−1, (C=N)
1604 cm−1, (Ar OCH3) 1230 cm−1, (C Br) 565 cm−1, (CO) 1170 cm−1, (NC=O) 1749 cm−1
max:
:
−
−
−
−
−
. λ
(C=N) 394.0 nm. C42H36N4NiO6 (911.3): calc. C, 55.36; H, 3.98; N, 6.15; found C, 55.06; H, 3.68; N, 5.9.
3.4.2. Synthesis of Mn (II) Complex (6b)
The maroon color ppt. was rinsed with distilled water repeatedly: Yield: 0.275 g; 84%, mp.
◦
270 C FTIR Peaks: (N
(Ar
−
H) 3165 cm−1, (Mn
−
N) 428 cm−1, (Mn O) 480 cm−1, (C=N) 1604 cm−1
,
−
−
OCH3) 1219 cm−1, (C Br) 536 cm−1, (CO) 1174 cm−1, (NC=O) 1724 cm−1
. λ max: (C=N)
−
404.0 nm. C42H36Br2MnN4O6 (907.5): calcd. C, 55.59; H, 4.00; N, 6.17; found C, 55.39; H, 3.90; N, 6.07.
3.4.3. Synthesis of Cu Complex (6c)
The green ppt. was washed with distilled water several times: Yield: 0.277 g; 84%, mp.
◦
265 C FTIR Peaks: (N
(Ar
−
H) 3224 cm−1, (Cu
−
−
N) 470 cm−1, (Cu
−
O) 542 cm−1, (C=N) 1612 cm−1
,
−1
−
OCH3) 1276 cm−1, (C
Br) 648 cm−1, (CO) 1190 cm−1, (NC=O) 1879 cm
; λ max: (C=N) 316 nm.
C42H36Br2CuN4O6: calcd. C, 55.06; H, 3.96; N, 6.12; found C, 54.96; H, 3.76; N, 5.94.
3.4.4. Synthesis of Zn Complex (6d)
Pale yellow color ppt. was obtained after filtration and washing with water: Yield: 0.955 g: 89%,
mp. 300+ ◦C.FTIR Peaks: (N
(Ar
OCH3) 1244 cm−1, (C
C42H36Br2N4O6Zn (917.9): calcd. C, 54.95; H, 3.95; N, 6.10; found C, 54.75; H, 3.65; N, 5.90.
−
H) 3116 cm−1, (Zn
−
N) 457 cm−1, (Zn
−
O) 476 cm−1, (C=N) 1616 cm−1
−1
−
−
Br) 551 cm−1, (CO) 1165cm−1, (NC=O) 1739 cm
; λ max: (C=N) 301.0 nm.
3.4.5. Synthesis of Co Complex (6e)
After performing filtration, orange color ppt. was washed with distilled water thoroughly: Yield:
◦
0.733 g; 69%, mp. 279 C; FTIR Peaks: (N
−
H) 3138 cm−1, (Co
−
N) 460 cm−1, (Co
−
O) 470 cm−1, (C=N)
max:
1608 cm−1, (Ar
−
OCH3) 1286 cm−1, (C
−
Br) 551 cm−1, (CO) 1168 cm−1, (NC=O) 1816 cm−1
;
λ
(C=N) 300.0 nm. C42H36Br2CoN4O6 (911.5): calcd. C, 55.34; H, 3.98; N, 6.15; found C, 55.04; H, 3.78;
N, 6.01.
3.4.6. Synthesis of Cd Complex (6f)
After filtration, creamy white color ppt. was rinsed repeatedly with Pet. Ether: Yield: 0.130 g; 92%,
mp. 293 ◦C FTIR Peaks: (N
(Ar
OCH3) 1244 cm−1, (C
C42H36Br2CdN4O6 (965.0): calcd. C, 52.28; H, 3.76; N, 5.81; found C, 52.01; H, 3.46; N, 5.41.
FTIR spectra of the compounds can be obtained from the corresponding author free of cost
on request.
−
H) 3132 cm−1, (Cd
−
N) 555 cm−1, (Cd
−
O) 603−c1m−1, (C=N) 1612 cm−1
,
−
−
Br) 636 cm−1, (CO) 1170 cm−1, (NC=O) 1776 cm
; λ max: (C=N) 299 nm.
3.5. Anti-Bacterial Testing
Autoclaved glass plates were used for conducting bacterial activity. Distilled water was used
for preparing a solution of agar gel and Ciprofloxacin was used as a reference. Samples of all the
derivatives of naproxen were placed in bacterial medium for 24 h. The activity was measured in terms
of inhibition zones in mm.

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3.6. Molecular Docking
3.6.1. Retrieval of COX1 Structure from the Protein Data Bank (PDB)
The three-dimensional (3D) crystal structure of COX1 (PDBID: 3N8Z) was accessed from the PDB
(http://www.rcsb.org). The retrieved protein structure was further minimized by using a conjugate
gradient algorithm and amber force field in UCSF Chimera 1.10.1 [44].
3.6.2. Designing of Ligands and Molecular Docking
The synthesized ligands (6a
by UCSF Chimera 1.10.1. A docking experiment was used on all synthesized compounds (6a
COX1 using a PyRx docking tool [45]. In the docking experiment, grid box parametric dimension
values were adjusted as X = 25.6989, Y = 57.7957, and Z = 8.339, respectively. The default
–f) were sketched in the ACD/ChemSketch tool and minimized
–f)
−
exhaustiveness = 8 value was used to obtain the finest binding conformational pose of protein–ligand
docked complexes. The docked complexes were evaluated on lowest binding energy (Kcal/mol)
values, and the hydrogen/hydrophobic interactions pattern using Discovery Studio (4.1) and UCSF
Chimera 1.10.1. To check the validity of our docked complexes, a reference structure (Comp. 5) was
also docked to check their binding pattern against COX1.
4. Conclusions
In this study, we synthesized metal derivatives of Naproxen-based Schiff bases in acidic or basic
medium as required. We characterized the prepared compounds, namely naproxen acid from naproxen
salt, methyl ester, hydrazide, Schiff base, and metal complexes, by different spectroscopic techniques.
Subsequently, we screened these compounds for in vitro antibacterial activity, revealing that all
complexes possess such activity. Lastly, we proved antibacterial activity through a computational
approach. Our results suggest that these compounds inhibit Cyclooxygenase-1 through specific
binding to its active sites. We calculated their individual binding energy against the target protein.
Metal complexes with Co, Cu, and Co showed higher antibacterial activity than ciprofloxacin across
all four bacterial species.
Author Contributions: Investigation, M.A., M.N.T., M.H., S.-Y.S., S.A., and M.I.; writing—original draft,
M.A.S. and C.L.; writing—review and editing, S.F.; conceptualization, project administration, M.S. and M.A.S.;
supervision and resources, C.L.
Funding: This research was funded by the Program for Professor of Special Appointment (Eastern Scholar)
at Shanghai Institutions of Higher Learning (No.2012-28), the Fundamental Research Funds for the Central
Universities (15D110508, 15D110527, 13D110522, 17D210502, 17D310512, 18D210501, 18D310507, 2232014D3-39),
and the National College Student Innovation Experiment Program (14T10501).
Acknowledgments: We thank Chen Peiran for helpful discussions.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available at the moment but can be easily prepared and
provided by the authors on demand.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).