Antimicrobial activity of aroylhydrazone-based oxido vanadium(v) complexes: In vitro and in silico studies

Article abstract of DOI:10.1039/c5nj02594j

A tridentate Schiff base ligand (E)-N′-((2-hydroxynaphthalen-1-yl)methylene)benzohydrazide (H₂L) and its oxido-vanadium(v) complexes with formulae [VO(L)(MeOH)(OMe)] (1), [VO(L)(OEt)] (2), and [VO(L)(OPr)] (3) have been synthesized and fully ch

Full text of DOI:10.1039/c5nj02594j

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Page 1 of 28
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Antimicrobial activity of arylhydrazone-based oxido vanadium(V) complexes:
in-vitro and in silico studies
a,
a
b
c
S. Yousef Ebrahimipour *, Iran Sheikhshoaie , Jim Simpson , Hadi Ebrahimnejad , Michal
d
a
d
Dusek , Nima Kharazmi , Vaclav Eigner
a
Department of Chemistry, Faculty of Science, Shahid Bahonar University of Kerman, Kerman,
Iran
b
c
d
Department of Chemistry, University of Otago, PO Box 56, Dunedin 9054, New Zealand
Department of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran
Institute of Physics ASCR, v.v.i., Na Slovance 2, 182 21 Praha 8, Czech Republic
*
Corresponding author:
Dr. S. Yousef Ebrahimipour
Department of Chemistry, Faculty of Science
Shahid Bahonar University of Kerman, 76169-14111 Kerman, Iran.
Tel./fax: +98 34 3132 2143
Email: ebrahimipour@uk.ac.ir, Ebrahimipour@ymail.com
1

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Abstract
A tridentate Schiff base ligand (E)-N'-((2-hydroxynaphthalen-1-yl)methylene)benzohydrazide
(
H L) and its oxido-vanadium(V) complexes with formulae [VO(L)(MeOH)(OMe)] (1),
2
[
VO(L)(OEt)] (2), and [VO(L)(OPr)] (3) have been synthesized and fully characterized by
1
physicochemical and spectroscopic methods including elemental analysis, FT-IR, HNMR and
molar conductivity. The solid state structures of H L and complexes 1-3 have been also
2
investigated using single crystal X-ray analysis. It was concluded that H L crystallized in keto
2
form in solid state, however in all complexes, the ligand appears in the enol form. The
coordination geometry of complex 1 was found to be distorted octahedral while complexes 2 and
3
adopt a square pyramidal geometries. The antimicrobial activity of these compounds was also
evaluated against Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 33591 and
9213) bacteria and the results showed that all three complexes have significant antibacterial
2
activities. In order to determine the potential of these complexes as antimicrobial agents,
molecular docking of the complexes with GlcN-6-P synthase was also investigated.
Keywords: Schiff base, Oxido-vanadium(V) complex, antimicrobial activity, X-ray crystal
structure
2

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1
.
Introduction
Hydrazone-based Schiff base ligands have received considerable attention due to the ease with
1
, 2
which they are synthesised and their wide range of applications.
Schiff bases can coordinate a
wide variety of transition metal ions in different oxidation states forming complexes with
3
, 4
interesting properties, architectures and applications.
Among the transition metals, vanadium
has attracted considerable attention due to its important role in bioinorganic chemistry as well as
5
in other fields. For the different oxidation states of vanadium, only V(III), V(IV), and V(V) are
6
involved in physiological systems. As a biocompatible element, vanadium has a wide variety of
7
biochemical and physiological functions. Many of these are due to the inhibition or stimulation
of enzymes that participate in phosphate metabolism.
8
, 9
A variety of different enzymes, including nitrogenases, haloperoxidases,
phosphate-
1
0
11
metabolizing enzymes and phosphomutases , involve vanadium. Furthermore, vanadium is
able to replace other transition metal ions in enzymes due to its compatibility with a variety of
potential ligand systems. In addition, vanadium complexes are well documented to have
1
2
therapeutic applications
mechanisms of several biochemical processes.
One of the most interesting properties of metal complexes, including those of vanadium, is their
and have also been used as model compounds to clarify the
1
3, 14
1
5
antimicrobial activity.
Various methods have been reported to evaluate this activity.
Glucosamine-6-phosphate synthase (GlcN-6-P synthase) has been recently considered as a new
target in antimicrobial studies because the GlcN-6-P produced by this enzyme is crucial for the
1
6, 17
survival of the cell.
It has been demonstrated that inactivation of GlcN-6-P synthase, even
for a short-time, results in morphological changes, agglutination and lysis and is therefore lethal
18
for pathogenic microorganisms.
Any compounds that can inhibit the action of this enzyme is a potential antimicrobial agent.
Molecular docking procedures provide important insights into the binding mechanism, affinity
and potential activity of drug candidates such as metal complexes with protein targets such as
1
9
GlcN-6-P synthase.
In a continuation of our search for biologically potent molecules
1
5, 20-22
, a tridentate hydrazine-
based ligand (E)-N'-((2-hydroxynaphthalen-1-yl)methylene)benzohydrazide (H L) and three of
2
its oxido-vanadium(V) complexes, [VO(L)(MeOH)(OMe)] (1) and [VO(L)(OR)] R = Et, (2); Pr,
(3) have been synthesized and fully characterized. The antimicrobial activities of these
3

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compounds are also investigated against various microorganisms. Molecular docking studies
were also performed in order to gain a better understanding of the drug-receptor interactions with
these complexes.
2
.
Results and discussion
(
IV)
During the reaction of the ligand H L with the same equivalent of [V O(acac) ] in alcoholic
2
2
solvent (ROH; R=CH , C H , C H ) under ambient conditions, V(IV) center is oxidized to
3
2
5
3
7
V(V). Moreover, the coordinated acac molecules are replaced by the ligand and corresponding
alkoxy groups resulted in the production of [V(V)O(OMe)(MeOH)(L)] or [V(V)O(OR)(L)]
(
R=C H or C H ). Here, the ligand acts as an ONO tridentate coordinating agent through its N–
2 5 3 7
imine and O–phenolate moieties. The resulting complexes were stable in air. They are soluble in
most common organic solvents except n-hexane and diethyl ether. Prior to complexation, the
ligand adopts the enol tautomeric form and is doubly deprotonated to give the (1Z,N'E)-N'-(2-
oxidonaphthalen-1-yl)methylenebenzohydrazonate dianion (Scheme 1). The molar conductivities
-1
2
-1
of the complexes are in the range of 2.7-3.1 Ω cm mol which confirms their behaviour as
2
3
non-electrolytes.
Scheme 1: schematic diagram of the complexation process.
.1 Spectral characterizations
2
-1
The infrared spectrum of the ligand displays absorption bands at 3297 and 1623 cm assigned to
NH and C=O vibrations respectively. Absence of these vibrations in the spectra of the complexes
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confirms that, while the uncomplexed ligand favours the keto-tautomer in the solid state, it
adopts the enol-form prior to deprotonation and coordination. In the spectrum of H L, stretching
2
-1
21
and out of plane bending vibrations of the OH group appear at 3395 and 698 cm respectively.
Disappearance of these peaks upon complexation (for 2 and 3), confirms the coordination of the
-1
deprotonated phenolic oxygen to vanadium. In the ligand, the intense band at 1601 cm is can be
assigned to the stretching vibration of azomethine moiety. In the complexes however, these
-1
24
bands shift to lower wave number by 5, 3 and 7 cm for 1 , 2 and 3 respectively . These shifts
imply the coordination of the azomethine nitrogen to the vanadium atom in complexes. The ca.
-1
3
4 cm reduction in wavenumber of the ν(C-O) vibration in the spectra of the complexes, is
25
evidence for coordination of the phenolic oxygen to the central metal atom. The characteristic
-1
26
V=O vibrations in the complexes are found as sharp peaks in the range 971-974 cm . The
1
HNMR spectra of the compounds were recorded in DMSO-d at the ambient temperature. The
6
2
7
spectrum of H L shows a singlet at 12.8 ppm for the OH proton resonance . Disappearance of
2
this peak in the spectra of the complexes confirms coordination of the deprotonated phenolic
2
1
oxygen to the central metal atom. In H L, a singlet at 12.2 ppm was assigned to the NH
2
2
8
proton. The absence of this peak in the specta of the complexes again provides a strong
evidence for the adoption of the enol form of ligand in the complexes. The exchangeability of
this proton in the ligand was confirmed by addition of D O to the DMSO-d solution. In the
2
6
spectra of complexes, the azomethine signal shows a significant downfield in comparison to the
4
,22
free ligand, supporting the fact azomethine nitrogen is bound to the vanadium atom.
The
4
1
protons of the aromatic rings lie between in 7.2-8.4 ppm as multiplet signals. H NMR spectra
of 1 and 2 in solution of DMSO-d are almost identical to each other, except for the proton
6
1
signals of the alkoxide chain,. In the HNMR of [VO(L)(MeOH)(OMe)], 1, the signal for methyl
group of the coordinated methanol molecule and of the methoxy group both appear at 3.1 ppm.
The hydroxyl resonance proton of coordinated methanol can be found at 5.3 ppm. In spectrum of
2
, the CH and CH resonances of the ethyl group of the ethoxide appear at 3.4 ppm as a quartet
2 3
and 1.1 ppm as a triplet respectively. In the case of 3, the protons of the propoxide ligand
resonate in the classic triplet, multiplet, triplet pattern with peaks at 3.3 ppm OCH , 1.4 ppm
2
OCH CH and 0.8 ppm, CH .
2
2
3
2
.2 X-ray structure determinations
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Selected bond distances and angles for H L and the complexes 1-3 are listed in Table 1. The
2
structure of the free ligand molecule is shown in Fig. 1 and clearly reveals the adoption of the
keto-tautomeric form in the solid state with C12=O2 = 1.2324(16) Å, N2—C12 = 1.3523(19) Å
and the hydrogen atom on N2 readily located in a difference Fourier map and refined with a
restrained bond length N2—H1n2 of 0.920(9) Å.
Fig. 1. The molecular structure of H L showing the atom numbering scheme with ellipsoids
2
drawn at the 50% probability level. An intramolecular hydrogen bond is drawn as a dotted line.
The entire molecule is not completely planar with an rms deviation of 0.2373 Å from the best fit
plane through all 22 non-hydrogen atoms. This is despite the intramolecular hydrogen bond
formed between the hydroxyl substituent on the naphthalene ring and the N1 atom, Fig. 1, Table
2
0
. The central C11, N1, N2, C12, O2 portion of the molecule is certainly planar, rms deviation
.0365 Å, and subtends angles of 18.22(3)° and 31.46° respectively to the naphthalene
(C1…C10) and phenyl (C13…C18) ring systems. Bond distances and angles in the molecule are
2
9
not unusual and agree well with those found in the structure of a hydrate of the same molecule
3
0
.
6

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Table 1. Selected bond lengths, (Å), and angles, (°), for H L and complexes 1, 2 and 3.
2
H L
1
2
3
2
V1—O1v
V1—O1
V1—O2
V1—N1
V1—O3
V1—O4
O1—C2
C1—C11
C11—N1
N1—N2
N2—C12
C12—O2
C12—C13
O4—C22
O4—C22'
1.5926(10)
1.8704(10)
1.9675(10)
2.1158(10)
1.7790(9)
2.2832(10)
1.582(3)
1.856(2)
1.927(3)
2.094(3)
1.752(2)
1.586(2)
1.8501(19)
1.933(2)
2.091(2)
1.748(2)
1.3505(18) 1.3309(15)
1.455(2) 1.439(2)
1.2857(19) 1.2971(16)
1.3815(18) 1.3944(16)
1.3524(19) 1.3165(15)
1.2324(16) 1.2999(15)
1.335(4)
1.435(5)
1.297(4)
1.392(4)
1.311(4)
1.306(4)
1.472(5)
1.335(3)
1.428(4)
1.301(4)
1.389(3)
1.303(4)
1.308(3)
1.477(4)
1.491(2)
1.4826(19)
1.402(2)
1.400(3)
O1v—V1—O1
O1v—V1—O2
O1v—V1—O3
O1v—V1—N1
O1v—V1—O4
O1—V1—O2
O1—V1—O3
O1—V1—N1
O1—V1—O4
O2—V1—O3
O2—V1—N1
O2—V1—O4
O3—V1—N1
O3—V1—O4
99.15(5)
97.66(5)
101.87(4)
94.77(4)
174.90(5)
152.43(4)
101.84(4)
82.43(4)
82.72(4)
95.87(4)
74.52(4)
78.70(4)
161.84(5)
82.28(4)
105.10(13)
103.85(13)
109.02(14)
98.88(13)
105.96(10)
103.30(10)
109.22(10)
98.58(10)
144.89(13)
98.11(12)
82.03(11)
144.75(8)
98.87(9)
82.26(8)
90.79(12)
74.24(11)
89.55(9)
74.29(8)
150.89(14)
150.50(9)
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Table 2. Hydrogen bond distances (Å), angles (°) for H L and complexes 1-3.
2
Compound D—H…A
D—H
0.860(13)
0.920(9)
0.96
0.96
0.96
H…A
1.778(11) 2.5652(17)
1.941(11) 2.8345(15)
2.54
2.46
2.70
D…A or
‹ D—H…A
149(2)
163.2(13)
132
156
136
H L
2
O1—H1o1…N12
L(i)
N2—H1n2…O2
L(i)
C11—H1c11…O2
C14—H1c14…O1
C15—H1c15…O2
3.2523(18)
3.360(2)
3.4456(19)
L(ii)
L(ii)
1
(i)
1
2
3
O4—H1o4…N2
0.860(5)
0.96
0.96
0.96
0.96
1.915(4)
2.42
2.51
2.71
2.94
2.7718(14)
3.3740(19)
3.453(2)
3.422(2)
3.775(2)
173.7(16)
173
171
132
148
1(ii)
C5—H1c5…O1v
U1iii)
1
C7—H1c7…O2
(i)
C14—H1c14…O4
1(ii)
C3—H1c3…Cg4
C4—H1c4…Cg3
1(ii)
0.96
2.97
3.7263(19)
137
2
(ii)
C3—H1c3…O1V
C19—H1c19…O1V
C4—H1c4…Cg5
C8—H1c8…Cg4
C16—H1c16…Cg3
C17—H1c17…Cg4
0.96
0.96
0.96
0.96
0.96
0.96
2.61
2.68
2.65
2.93
2.71
2.97
3.527(5)
3.244(6)
3.417(4)
3.692(4)
3.472(4)
3.628(4)
163
116
137
137
137
127
2(iii)
2(iv)
2(v)
2
2
(vi)
(vi)
3
(ii)
C3—H1c3…O1V
C19—H1c19… O1V
C4—H1c4…Cg5
C8—H1c8…Cg4
C15—H1c15…Cg4
C16—H1c16…Cg3
0.96
0.96
0.96
0.96
0.96
0.96
2.66
2.70
2.65
2.93
2.95
2.65
3.582(4)
3.57(2)
3.428(3)
3.684(3)
3.595(3)
3.426(3)
164
147
139
137
126
138
W(iii)
3(iv)
3(v)
3
3
(vi)
(vi)
Symmetry codes: L(i) x+1/2, −y+1/2, z+1/2; L(ii) x, y, z+1; 1(i) −x+1, −y+2, −z; 1(ii) −x+3/2, y+1/2,
−
−
−
z−1/2; 1(iii) x−1/2, −y+3/2, z−1/2; 2(ii) x, y−1, z; 2(iii) −x+1, −y+1, −z. 2(iv) x, −y−1/2, z−1/2; 2(v)
x+2, y+1/2, −z+1/2; 2(vi) x, −y+1/2, z−3/2; 3(ii) x, y−1, z; 3(iii) −x+2, y, −z+1/2; 3(iv) −x+1/2, y+1/2,
z+1/2; 3(v) x+1, −y, z−1/2; 3(vi) −x+1/2, y+3/2, −z−1/2.Cg3, Cg4 and Cg5 are the centroids of the C1,
C2, C3, C4, C9, C10; C5, C6, C7, C8, C9, C10 and C13, C14, C15, C16, C17, C18 rings respectively.
3
1
The Cambridge Structural Database, CSD , also reveals 20 closely related molecules with a
wide variety of different substituents on the benzene ring. These include the m- and p-tolyl
3
2
33
derivatives and an unusual bis(2-hydroxy-1-naphthaldehyde)-1,3-benzenedicarbohydrazone ,
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with two 2-hydroxynapthaldehyde units as substituents on the benzene ring. Crystal packing in
the ligand is stabilised by one classical N—H…O and three non-classical C—H…O hydrogen
bonds Table 2. A reasonably strong offset π…π stacking interaction also occurs between the
phenyl ring and the hydroxyl substituted ring of the naphthalene system with a centroid to
3
4
centroid distance of 3.6412(9) Å. This is augmented by a second π…π contact between the
C=N double bond and the phenyl ring at a distance of 3.440(1) Å and these contacts combine to
stack the molecules along the a axis direction, Fig S1.
In the V(V) complex, [VO(L)(MeOH)(OMe)], the oxovanadium(V) cation is coordinated to the
-2
doubly deprotonated tridentate L ligand and a methoxide anion but there is also an additional
coordination site occupied by a neutral methanol molecule, rendering the V atom six-coordinate
Fig. 2.
Fig. 2. The molecular structure of [VO(L)(MeOH)(OMe)] showing the atom numbering scheme
with ellipsoids drawn at the 50% probability level. For clarity, only the major disorder
component of the methyl group of the methanol ligand is shown.
3
5
This structure has been briefly reported previously , from data collected at ambient
temperature, but is included in the discussion here for completeness and to allow comparisons of
both its molecular and crystal structures with those of complexes 2 and 3. The coordination
geometry of the V(V) atom is distorted octahedral with the equatorial plane occupied by the O1,
N1, O2 and O3 atoms with an rms deviation of 0.0079 Å from that plane. The V1 atom lies
0
.2908(8) Å out of this plane in the direction of O1V with the second axial site occupied by the
O4 atom of the additional methanol ligand. V=O (O N) complexes abound with 285 hits on the
4
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3
5
CSD. However, in addition to the previous report , only four other structures containing
3
6
variants of the 2-oxidonaphthalen-1-yl)methylenebenzo-hydrazonateligand are found.
Crystal packing for [VO(L)(MeOH)(OMe)] differs significantly from that for [VO(L)(OEt)]
and [VO(L)(OPr)]. In particular, the presence of the additional methanol ligand occupying the
sixth position in the coordination sphere of the metal obviates any close contact between the
metal atom and any of the aromatic rings. Classical O4—H1o4…N2 hydrogen bonds form
2
inversion dimers and generate R (10) rings. These contacts are strengthened by both C14-
2
H1c14…O4 hydrogen bonds and offset π…π stacking interactions between the phenyl ring and
the O1 bound ring of the naphthalene ring system, Fig. 3, with Cg3…Cg5 = 3.6359(12) Å (Cg3
and Cg5 are the centroids of the C1, C2, C3, C4, C9, C10 and C14…C19 rings respectively).
In addition C—H…O and C—H…π contacts, Table 2, further stabilise the structure and these
interactions combine to generate a three-dimensional network of molecules stacked along the b
axis direction, Fig S2.
Fig.3.Inversion dimers of [VO(L)(MeOH)(OMe)]. π …π contacts are shown as green dotted
lines with ring centroids represented by coloured spheres.
The molecular structures of the two five-coordinate vanadium(V) complexes, 2 and 3 reported
here, Fig. 4 and Fig. 5 are sufficiently similar to be discussed together.
1
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Fig. 4.The molecular structure of [VO(L)(OEt)] showing the atom numbering scheme with
ellipsoids drawn at the 50% probability level.
Fig. 5. The molecular structure of [VO(L)(OPr)] showing the atom numbering scheme with
ellipsoids drawn at the 50% probability level. For clarity, only the major disorder component in
the alkyl chain of the propoxide ligand is shown
They differ only in the nature of the alkoxide, either ethoxide, 2, or propoxide, 3, that acts as the
third anionic ligand species. Both complexes comprise an oxovanadium(V) cation in a slightly
distorted square pyramidal coordination environment bound to the two O atoms and the N1
1
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hydrazone
atom
of
the
doubly
deprotonated
(2-oxidonaphthalen-1-
yl)methylenebenzohydrazonate dianion. The fifth coordination site is occupied by the O atoms
of ethoxide for 2 or propoxide for 3. The hydrazonate and alkoxide ligands lie in the square
plane with the oxido, O1v, atoms axial with the O1 and O2 or O3 and N1 atoms mutually trans
in each case. The best fit equatorial plane through the four ligand donor atoms has an rms
deviation of 0.0160 Å with the V1 atom lying 0.4765 (15) Å out of that plane in the direction of
O1v. The corresponding plane for 3 has an rms deviation of 0.0192 Å with V1 out of the plane
by 0.2915(10) Å in the same direction. The extent of distortion from trigonal bipyramidal
geometry can be determined by calculating the trigonality index, τ , described by Addison et al
5
3
7
.
τ = 0 for an ideal square–pyramid and τ = 1 for an ideal trigonal bipyramid. For 2, τ =
5 5 5
0
.099 while for 3τ = 0.096 confirming that both complexes can quite reasonably be described as
5
3
+
square pyramidal with only minimal distortion. Five coordinate VO complexes with a
V=O(O N) coordination sphere are again quite common registering 181 hits on the CSD .
3
However, narrowing the search to include a tridentate ligand similar to H L shows only two
2
closely
methylbenzenecarbohydrazonato)-methoxo-oxo-vanadium(V)
naphthaldehyde isonicotinylhydrazone)-vanadium(V) trihydrate .
related
complexes,
(N-(1-(2-(hydroxy)-1-naphthyl)ethylidene)-4-
3
6b
and cis-dioxo-(2-hydroxy-1-
3
8
Comparison of equivalent bond distances in the coordination spheres of these related complexes
show that the V=O (1.596 and 1.629 Å) and V—N (2.186 and 2.120) Å distances are
considerably longer than those reported here, Table 1; the variation would seem to be too great to
be explained simply by the fact that these data for these two related structures were obtained at
ambient temperature.
In the crystal structure of 2 C4—H1c4…Cg5 contacts link molecule into rows in an obverse
fashion along c. These rows are interconnected by C19—H1c19…O1v hydrogen bonds that form
2
39
inversion dimers and generate R (10) rings, Fig 6(a), Table 2 , forming layers of molecules in
2
the ac plane. There are clear similarities between the crystal packing of 2 and 3. For 3, inversion
dimers also form through C19—H1c19…O1v contacts, although in this case the dimers are
linked into parallel chains along c by C4—H1c4…Cg5 contacts, also generating layers of
molecules in the ac plane, Fig. 6(b).
1
2

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Fig. 6. Layers of molecules of (a) complex 2 and (b) 3. In these and subsequent Figures,
hydrogen bonds are drawn as dashed lines. C—H…π contacts are shown as green dotted lines
with ring centroids represented by coloured spheres.
A second series of C3—H1c3…O1v hydrogen bonds link molecules of complex 2 into C(6)
3
9
chains along b. Interestingly, these C—H…O hydrogen bonds are seemingly augmented by an
1
3

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2
i
unusually close ring to metal interaction Cg5…V1 at a distance of 3.797 Å (2i = x,y+1,z)
shown in Fig. 7(a).
A closely similar situation exists for complex 3, again with the C3—H1c3…O1v derived C(6)
3
i
31
chain along b bolstered by an almost identical Cg5…V1 contact at a distance of 3.793 Å (3i =
x,y+1,z), Fig. 7(b) Such contacts, while presumably weak, are not unprecedented and are
related to the cation…π interactions that have previously been suggested to contribute to the
4
0
overall stabilisation of structures in both small molecule and protein systems .
Fig. 7. C(6) chains of molecules of (a) [VO(L)(OEt)] and (b) [VO(L)(OPr)] along b. The
unusual V…π contacts are shown as green dashed lines.
Similar close contacts have also been observed in the crystal structures of other transition metal
21, 41,42
complexes where the metal presents with a vacant coordination site
. Interestingly, the
database reveals six similar close V…π contacts in square pyramidal V(V) complexes with
4
3-46
VO N coordination spheres with metal…centroid distances under 4.0 Å
. However, the
4
possibility or potential significance of such contacts is not mentioned in the reports of these
related structures. In these other examples, the V…centroid distances lie in the range 3.859 to
3
.967 Å, suggesting that the contact observed here is relatively strong.
Chains of molecules of complex 2 also form along c as a result of C16—H1c16…Cg3 and
C17—H1c17…Cg4 contacts, Fig. 8a, while C16—H1c16…Cg3 and C17—H1c15…Cg4
1
4

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contacts also form chains of complex 3 molecules also along c, Fig. 8b. These contacts combine
with the previously described interactions to generate an extensive three dimensional network of
molecules stacked along the b axis direction (Figs. S3 and S4).
Fig. 8. Additional C—H…π chains of molecules of (a) [VO(L)(OEt)] and (b) [VO(L)(OPr)]
along the c axis direction.
1
5

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2
.3 Antibacterial activity
Table 3 shows the MIC ranges of the ligand and the complexes; [VO(L)(MeOH)(OMe)],
VO(L)(OEt)] and [[VO(L)(OPr)] against gram-positive (Staphylococcus aureus) and gram-
negative (Escherichia coli) bacteria generated by agar dilution. Not surprisingly, the ligand
[
(H2L) did not exhibit a distinct antimicrobial effect per se against Staphylococcus aureus (ATCC
-1
3
3591 and 29213) and Escherichia coli (ATCC 25922) (MIC: 5000 µg mL <) whereas its
complexes demonstrated different antimicrobial properties against these bacteria.
Table 3. Minimum inhibitory concentration (MIC) of the compounds against gram-positive and
gram-negative bacteria via the agar dilution method.
-1
minimum inhibitory concentration (µg mL )
Compounds
Ligand
1
2
Escherichia coli Staphylococcus aureus
Staphylococcus aureus
(MRSA , ATCC 33591)
1
(
ATCC 25922)
(ATCC29213)
5000<
5000<
5000<
<19.53
78.13
<19.53
<19.53
39.06
39.06
3
39.06
39.06
39.06
Negative control
-
-
-
(
DMSO)
1
methicillin-resistant Staphylococcus aureus
Zone of antibacterial inhibition against Escherichia coli shown by [VO(L)(OEt)], determined by
the agar well diffusion method is shown in fig. 9.
Fig. 9. Zone of antibacterial inhibition against Escherichia coli shown by [VO(L)(OEt)],
determined by agar well diffusion method.
1
6

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Despite the resistance displayed by methicillin-resistant S. aureus (MRSA) against different
antibiotics, the complexes [VO(L)(OEt)], [VO(L)(OPr)] and especially [VO(L)(MeOH)(OMe)],
showed explicit anti-MRSA activity. Furthermore, [VO(L)(MeOH)(OMe)] inhibited the growth
-1
of S. aureus and E. coli at relatively low concentration, 19.53 µg mL .
Antimicrobial activity of the compounds was also evaluated based on the diameters of the clear
inhibition zones surrounding the wells. 500 and 1000 µg of complexes 1-3 provided effective
inhibition of the growth of S. aureus (ATCC 29213 and 33591) and E. coli (ATCC 25922)
(Table 4). Here, the anti-MRSA activity of 500 and 1000 µg of the [VO(L)(MeOH)(OMe)] was
also associated with 28 and 30.5 millimeters of zone of inhibition respectively.
The higher activity of the metal complexes may be due to the changes occurred in the properties
of the metal ions after chelation. According to Tweedy’s chelation theory, polarity of the central
metal ion reduces due to partial sharing of its positive charge with donor groups of ligands
resulting in electron delocalization over the entire ring. Accordingly, penetration of the
complexes into the lipid membranes will be improved and as will blockage of the metal-binding
4
7
sites in the the enzymes of the microorganism .
Table 4. Antimicrobial activity of the compounds against gram-positive and gram-negative
bacteria determined by the agar well diffusion method.
Compounds
3
2
1
Bacteria
Ligand
-
1
-1
-1
(
µg well )
(µg well )
(µg well )
1
000 500 1000 500 1000 500 1000 500
5
15
0
100
0
Escherichia coli
ATCC 25922)
Staphylococcus aureus
ATCC 29213)
1
1.5
9
14
13
30
27
20
0
0
0
0
19.5
(
1
3
12
13 11.5 26
12.5
12
20
0
0
(
Staphylococcus
aureus(MRSA, ATCC
7.5
7
12
11 30.5 28
0
0
15.5
33591)
a, b: Positive controls, c: Negative control
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2
.4 Molecular docking studies
GlcN-6-P synthase was used as a target for the antimicrobial activity of complexes 1—3 as
potential inhibitors. The orientation of the inhibitors bound to the active site of the enzyme was
determined using automated docking. Binding energy and inhibition constants for all of the
compounds together with those of the standard drugs Cefixime and Azithromycin for comparison
are listed in Table 5.
-1
Table 5. Binding energy (kcal mol ) and inhibition constant of the complexes 1-3, cefixime and
Azithromycin.
-1
Compound
Complex 1
Complex 2
Complex 3
Cefixime
Binding energy (Kcal mol )
Inhibition constant (µM)
-5.33
-5.21
-5.19
-4.82
-4.27
123.33
151.03
157.32
294.21
744.28
Azithromycin
Docked images for title compounds and standard drugs are shown in Fig. 10. Docking of
cefixime, azithromycin and the compounds synthesized here with the enzyme showed that all of
the inhibitors can bind to one or more amino acids in the active site. In addition, the theoretical
binding energies of the tested compounds were obtained in the range of -4.27 kcal/mol -5.33
kcal/mol respectively. Results obtained revealed that all of the vanadium complexes bind less
strongly to GlcN-6-P synthase than the standards. However, for complex 1 a docking energy and
a binding energy of -8.46 kcal/mol and -5.33 kcal/mol were obtained respectively suggesting that
it may be a good inhibitor of GlcN-6-P synthase and subsequently a good antimicrobial agent.
1
8

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Fig 10. The docked complexes, cefixime and azitomycine in the active pocket of GlcN-6-P.
1
9

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3
. Conclusion
Three oxido-vanadium(V) complexes have been prepared by the reaction of tridentate ligand
H L and VO(acac) in 1:1 molar ratio in appropriate solvents. All of the compounds were
2
2
1
characterized by standard methods including X-ray crystal structure, FTIR, HNMR, molar
conductivity and elemental analysis. In all of the complexes the V(V) centre is coordinated to
ONO donor atoms of the deprotonated Schiff base ligand, an oxo group and the oxygen donor(s)
of alkoxide ligands and in one instance a coordinated methanol molecule. In-vitro antimicrobial
activities of title compounds revealed that complexation enhanced the biological activities of the
ligand. All three vanadium complexes showed an in-vitro antimicrobial characteristic to gram-
positive and gram negative bacteria, particularly towards methicillin-resistant S. aureus that is
resistant to numerous antibiotics. In particular [VO(L)(MeOH)(OMe)], showed explicit anti-
MRSA activity and further in vivo or in-situ testing of these complexes are planned. Docking
studies also suggested that complex 1, with a minimum binding energy should be a good
inhibitor of GlcN-6-P synthase.
4
. Experimental
4
.1 Materials and instrumentation
All chemicals and solvents used were of analytical reagent grade and were used as received. C,
H, N microanalyses were determined on a Thermo Finnigan Flash Elemental Analyzer 1112EA.
Melting points were measured on an Electrothermal-9100 apparatus and are uncorrected. FT-IR
-1
spectra were recorded on a FT-IR 8400-Shimadzu as KBr discs in the range 400-4000 cm .
Molar conductance measurements were made using a Metrohm 712 Conductometer in MeOH.
1
H-NMR spectra were recorded at 25 °C on a Bruker AVANCE 400 spectrometer.
4
.1.1 Synthesis of (E)-N'-((2-hydroxynaphthalen-1-yl)methylene)benzohydrazide
(
H L)
2
An ethanolic solution (4 mL) of benzohydrazide (0.14 g, 1 mmol) was added dropwise to 4 mL
of an ethanolic solution of 2- hydroxynaphthaldehyde (0.17 g, 1 mmol) with constant stirring.
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0

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The yellow solution so obtained was left undisturbed at room temperature. Single crystals
suitable for X-ray analysis appeared in the solution after 1 day; they were separated and dried in
a desiccator over anhydrous CaCl2.
-1
Yield: 65%. m.p.: 156 °C. Anal. Calc. for C H N O (290.32 g mol ): C, 74.47; H, 4.86; N,
18
14
2
2
-
1
9
1
.65. Found: C, 74.38; H, 4.81; N, 9.63%. FT-IR (KBr) cm : ν(OH) 3395, ν(NH) 3297, ν(C=O)
1
623, ν(C=N) 1601, ν(C=C ) 1453, ν(CO) 1351, ν(NN) 1155.ν (OH) 698. H-NMR (400 MHz,
ring
DMSO-d , 25 ºC, ppm): δ = 12.8 (s, 1H; OH), 12.2 (s, 1H; NH), 9.50 (s, 1H; CH=N), 7.24 (d,
6
j=8.9 Hz, 1H, Ar-H), 7.41 (t, j=7.4 Hz, 1H, Ar-H), 7.56-7.66 (m, 4H, Ar-H), 7.89(d, j=8.0 Hz,
1
H, Ar-H), 7.93(d, j=9.0 Hz, 1H, Ar-H), 7.99 (d, j= 7.0 Hz, 2H, Ar-H), 8.22 (d, j=8.5 Hz, 1H,
Ar-H)
4
.1.2 Synthesis of the complexes 1-3
The three vanadium complexes were each prepared by the following method: 0.1 mmol of
VO(acac) (0.03 g) was added to equimolar quantities of H L (0.1 mmol, 0.03 g) in the
2
2
appropriate solvent (methanol for 1 and ethanol and propanol for 2 and 3 respectively) and the
resulting clear solution was refluxed for 10 min at 90°C. After cooling, the solution was left
exposed to air and crystallization took place by slow evaporation at room temperature. After 2
days, single crystals suitable for X-ray diffraction were extracted and dried in a desiccator over
anhydrous CaCl2.
Methanol-(2-oxidonaphthalen-1-yl)methylene)benzohydrazonato-methoxido-oxido-
vanadium(V) [VO(L)(MeOH)(OMe)] (1)
-3
-1
2
-1
Yield: 65%. m.p.: >300 °C. Molar Conductance (10 M, MeOH): 3.1 Ω cm mol . Anal. Calc.
-1
for C H N O V (418.32 g mol ): C, 57.42; H, 4.58; N, 6.70. Found: C, 57.37; H, 4.51; N,
2
0
19
2
5
-1
6
.72%. IR (KBr) cm : ν(OH) 3442, ν(C=N) 1596, ν(C=C ) 1441, ν(C-O) 1289, ν(NN) 1140,
ring
1
ν(V=O)971, ν(VO)558, ν(VN)524. H-NMR (400 MHz, DMSO-d , ppm): δ = 9.8 (s, 1H;
6
HC=N), 7.2-8.4 (m, 11H; rings), 5.3 (q, 1H; OH), 3.1 (m, 6H; 2CH3).
(2-oxidonaphthalen-1-yl)methylene)benzohydrazonato-ethoxido-oxido-vanadium(V)
[VO(L)(OEt)] (2)
2
1

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-3
-1
2
-1
Yield: 63%. m.p.: >300 °C. Molar Conductance (10 M, MeOH): 2.7 Ω cm mol . Anal. Calc.
-1
for C H N O V (400.30 g mol ): C, 60.01; H, 4.28; N, 7.00. Found: C, 60.09; H, 4.34; N,
2
0
17
2
4
-1
6
.93%. IR (KBr) cm : ν(C=N) 1598, ν(C=C ) 1447, ν(C-O) 1317,ν(NN) 1141, ν(V=O) 974,
ring
1
ν(VO) 588, ν(VN) 530. H-NMR (400 MHz, DMSO-d , ppm): δ = 9.8 (s, 1H; HC=N), 7.2-8.4
6
(
m, 11H; rings), 3.4 (q, 2H; CH ), 1.1 (t, 4H; CH ).
2 3
(
2-oxidonaphthalen-1-yl)methylene)benzohydrazonato-propoxido-oxido-vanadium(V)
VO(L)(OPr)] (3)
Yield: 68%. m.p.: 208 °C. Molar Conductance (10 M, MeOH): 2.9 Ω cm mol .Anal. Calc.
[
-3
-1
2
-1
-1
for C H N O V (414.33 g mol ): C, 60.88; H, 4.62; N, 6.76. Found: C, 60.87; H, 4.71; N,
2
1
19
2
4
-1
6
.70%. IR (KBr) cm : ν(C=N) 1594, ν(C=C ) 1443, ν(C-O) 1317,ν(NN) 1136, ν(V=O)971,
ring
1
ν(VO)556, ν(VN)526. H-NMR (400 MHz, DMSO-d , ppm): δ = 9.8 (s, 1H; HCH=N), 7.2-8.4
6
(
m, 11H; rings), 3.3 (t, 2H; CH ), 1.4 (m, 2H; CH ), 0.8 (t, 3H; CH ).
2
2
3
4
.2 Crystal structure determination
The structures were measured using a Gemini diffractometer with an ATLAS CCD detector.
Mirror collimated Cu-Kα radiation was used for the ligand H L and complexes 2 and 3, while
2
data for complex 1 was collected with graphite monochromated Mo-Kα radiation. Data
4
8
integration and absorption correction were performed with CrysAlis pro software . The
4
9
50
51
structures were solved using Superflip software and refined with Jana2006 . MCE software
was used for visualization of the electron density. All hydrogen atoms attached to fully occupied
atoms were discernible in difference Fourier maps and could be refined to reasonable geometry.
The positions of hydrogen atoms attached to disordered atoms were derived geometrically.
According to common practice H atoms bonded to C were kept in ideal positions with C–H =
0
.96 Å while positions of H atoms bonded to N and O were refined with restrained bond lengths.
In both cases U (H) was set to 1.2U (C,N,O). All non-hydrogen atoms were refined using
iso
eq
harmonic refinement. The disordered solvent molecules were refined with restrained bond
lengths. The occupancies of the disorder components were refined with an occupancy sum
constrained to 1 for each solvent molecule. For further information on data collection and
structure refinement see Table 6.
2
2

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Table 6. Crystal data and structure refinement for H L and its V(V) complexes.
2
Compound
Formula
Mr
H L
1
2
3
2
C H N O
C H N O V
418.3
C H N O V
400.3
C H N O V
414.3
1
8
14
2
2
20 19
2
5
20 17
2
4
21 19 2 4
290.3
Crystal system
Space group
Radiation
λ (Å)
Monoclinic
Monoclinic
Monoclinic
Monoclinic
C2/c
Cu-Kα
1.5468
120
P2 /n
P2 /n
P2 /c
1
1
1
Cu-Kα
1.54184
120
Mo-Kα
0.71073
121
Cu-Kα
1.54184
120
T (K)
a (Å)
b (Å)
c (Å)
6.9512 (4)
29.5028 (18)
7.4215 (5)
108.876 (6)
1440.15
4
12.7970 (8)
7.8400 (4)
19.3207 (13)
104.308 (5)
1878.3 (2)
4
17.8457 (18)
5.9203 (5)
18.1622 (13)
110.679 (8)
1795.2 (3)
4
34.6714 (16)
6.0918 (3)
17.8955 (5)
97.143 (3)
3750.4 (3)
8
β (°)3
V (Å )
Z
-
3
ρ (g cm )
μ (mm )
1.339
0.72
1.479
0.56
1.481
4.86
1.468
4.69
-
1
θ , θ (°)
6.5, 66.7
4356
2471, 0.026
205, 2
0.043, 0.104
0.036, 0.096
1.21
3.1, 29.2
27921
4751, 0.025
260, 3
0.038, 0.101
0.032, 0.097
1.83
4.9, 67.2
9573
3113, 0.068
244, 0
0.070, 0.132
0.051, 0.118
1.28
5.0, 67.0
10825
3292, 0.056
263, 6
0.060, 0.100
0.039, 0.089
1.14
min max
Meas. relfns
Uniq. Reflns, Rint
Params., Restr.
Rall, wR2all
Robs, wR2obs
GOF
-3
Δρ , Δρ (e Å ) -0.18, 0.14
-0.36, 0.33
-0.37, 0.63
-0.23, 0.25
min
max
4
.3 Antimicrobial assays
The antimicrobial activities of the ligand [H L] and the complexes; [VO(L)(MeOH)(OMe)],
2
[
VO(L)(OEt)] and [VO(L)(OPr)] against gram-positive and gram-negative bacteria were
evaluated using the agar-well diffusion method. The minimum inhibitory concentrations of all
the compounds were also assayed via an agar dilution technique.
4
.4 Determination of minimum inhibitory concentration (MIC)
In order to determine the MIC of each compound, an agar dilution assay was performed as
5
2
described previously . Each compound was dissolved in DMSO and mixed well with sterilized,
molten Mueller-Hinton agar (45°C) at a 2-fold dilution. Each solution was poured onto a sterile
-1
Petri plate to obtain the desired final concentrations (between 19.53 and 5000 µg mL ) of each
compound. Negative (DMSO) control plates with the Mueller-Hinton agar were also prepared.
2
3

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The surface of the set agar plates was air-dried under a laminar airflow hood for 30 minutes. One
μL of the overnight broth culture of Escherichia coli (ATCC 25922) and Staphylococcus aureus
(ATCC 33591 and 29213), which had been adjusted to 0.5 McFarland-turbidity, was inoculated
onto the surface of the plates with different dilutions of the compounds and the inoculum spots
allowed to dry at room temperature. All plates were inverted and incubated appropriately for 16-
2
0 hours at 37°C. Each experiment was carried out in triplicate. The minimum inhibitory
concentration was defined as the lowest concentration able to inhibit visible bacterial growth on
the plates.
4
.5 Agar well diffusion assay
Separate samples of cation-adjusted Mueller-Hinton II broth (90922 Fluka) was inoculated with
Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 33591 and 29213) and
incubated at 37°C overnight. The microbial turbidity was adjusted equivalent to a 0.5 McFarland
turbidity standard. Thereafter, Mueller-Hinton agar plates (Merck, 105437) were swabbed
uniformly with the standardized inoculums. Once the surfaces of agar plates were dried
aseptically, 6 mm wells were bored using a sterile cork-borer about two cm apart. The bottom of
each well was coated with sterilized Mueller-Hinton agar at 45°C. For each microorganism,
separate 100 μL samples of the ligand [H L], or the V(V) complexes 1, 2, and 3 dissolved in
2
DMSO were added into the wells, to provide 500 and 1000 µg of the compound per well, and
allowed to diffuse at room temperature for 2 hours. Negative control (DMSO) and positive
controls (cefiximetrihydrate, 18588 Fluka, and azithromycin dihydrate, PZ0007 Sigma, 5 and 15
µg/well respectively) were also placed in wells. The plates were incubated face upwards at 37ºC
5
3
for 24 hours . The diameters of the zones of inhibition were evaluated using a microscope scale.
Each experiment was carried out in triplicate.
4
.6 Molecular docking
The crystal structure of GlcN-6-P synthase was obtained from the Protein Data Bank
54
(
http://www.pdb.org/pdb/home/home.do), PDB ID 2VF5, at a resolution of 2.90 Å . The
binding site of the target was selected based on the amino acid residues involved in binding to
the glucosamine-6-phosphate of GlcN-6-P synthase as obtained from PDB with ID 2VF5. This
would be considered to be the most accurate active region revealed by the experimental
crystallographic data. Accordingly, the grid was centered at the region including all the 12 amino
2
4

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acid residues surrounding the active site (Ala602, Val399, Ala40 0, Gly301, Thr302, Ser303,
Cys300, Gln348, Ser349, Thr352, Ser347 and Lys603). The coordination sphere of
ciprofloxacine, as a standard antimicrobial agent and the synthesized ligand and complexes were
generated from their X-ray crystal structure as a CIF file. Mercury software
5
5
(
http://www.ccdc.cam.ac.uk/) was then used to convert the CIF files to PDB format . Finally,
5
6
molecular docking studies were carried out using Autodock 4.2.5 software with the grid box
size set at 70, 64, and 56 Å for x , y and z, respectively, and the grid center set at 30.59, 15.822
and 3.497 for x , y and z, respectively. All molecular images and animations were produced
using the Discovery Studio Visualizer 4.5 package.
5. Supplementary data
CCDC 1062415, 1062606, 1062416, and 1062417 contains the supplementary crystallographic
data for H L, 1, 2 and 3 respectively. A copy of this information may be obtained free of
2
charge from The Director, CCDC, 12 Union Road, Cambridge, Cb2 1EZ, UK (fax: +44
1
223 336 033); web page: http://www.ccdc.cam.ac.uk/cgibin/catreq.cgi
6. Acknowledgements
Authors gratefully acknowledge the financial support provided for this work by the Shahid
Bahonar University of Kerman. JS thanks the Chemistry Department, University of Otago for
support of his work. The crystallographic part was supported by the project 15-12653S of the
Czech Science Foundation using instruments of the ASTRA lab established
within
the
Operation
program
Prague
Competitiveness
-
project
CZ.2.16/3.1.00/24510
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0.
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DOI: 10.1039/C5NJ02594J
Antimicrobial activity of arylhydrazone-based oxido vanadium(V) complexes:
in-vitro and in silico studies
S. Yousef Ebrahimipour*, Iran Sheikhshoaie, Jim Simpson, Hadi Ebrahimnejad, Michal Dusek,
Nima Kharazmi, Vaclav Eigner
A series of oxido vanadium(V) complexes have been synthesized and evaluated
from the point of experimental and theoretical antimicrobial activity.