processes

Article
Preparation, Antimicrobial Activity and Docking Study of
Vanadium Mixed Ligand Complexes Containing
4-Amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol and
Aminophenol Derivatives
Doaa Domyati 1 , Sami A. Zabin 2 , Ahmed A. Elhenawy 2,3 and Mohamed Abdelbaset 2,4, *

1 Department of Chemistry, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia;
[email protected]
2 Chemistry Department, Faculty of Science, Albaha University, Abaha 65731, Saudi Arabia;
[email protected] (S.A.Z.); [email protected] (A.A.E.)
3 Chemistry Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt
4 Chemistry Department, Faculty of Science, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
* Correspondence: [email protected]

Abstract: The synthesis of mixed-ligand complexes is considered an important strategy for de-
veloping new metal complexes of enhanced biological activity. This paper presents the synthesis,
characterization, in vitro antimicrobial assessment, and theoretical molecular docking evaluation



for synthesized oxidovanadium (V) complexes. The proposed structures of the synthesized com-


pounds were proved using elemental and different spectroscopic analysis. The antimicrobial tests
Citation: Domyati, D.; Zabin, S.A.;
showed moderate activity of the compounds against the Gram-positive bacterial strains and the
Elhenawy, A.A.; Abdelbaset, M.
fungal yeast, whereas no activity was observed against the Gram-negative bacterial strains. The
Preparation, Antimicrobial Activity
performance of density functional theory (DFT) was conducted to study the interaction mode of the
and Docking Study of Vanadium
targeted compounds with the biological system. Calculating the quantitative structure-activity rela-
Mixed Ligand Complexes Containing
4-Amino-5-hydrazinyl-4H-1,2,4-
tionship (QSPR) was performed depending on optimization geometries, frontier molecular orbitals
triazole-3-thiol and Aminophenol (FMOs), and chemical reactivities for synthesized compounds. The molecular electrostatic potentials
Derivatives. Processes 2021, 9, 1008. (MEPs) that were plotted link the interaction manner of synthesized compounds with the receptor.
https://doi.org/10.3390/pr9061008 The molecular docking evaluation revealed that the examined compounds may possess potential
antibacterial activity.
Academic Editors: Yunfei Du, Kang
Hyun Park and Andrea Melchior Keywords: 1,2,4-triazole-3-thiol; vanadium (V) complexes; in silico pharmacokinetic; antimicrobial
activity; molecular docking
Received: 6 April 2021
Accepted: 4 June 2021
Published: 7 June 2021

1. Introduction
Publisher’s Note: MDPI stays neutral
Compounds having a 1,2,4-triazole ring-system represent an interesting class of hete-
with regard to jurisdictional claims in
published maps and institutional affil-
rocyclic compounds and are the focus of many researchers due to their ease of synthesis
iations.
and their application diversity, especially as therapeutic agents [1–4]. These compounds
have interesting physical properties such as solubility, dipole character, and hydrogen
bonding capacity; they act as important pharmacophores due to their interacting ability
with biological receptors [5]. Additionally, molecules with 1,2,4-triazole moiety along with
some adjacent donor groups are potential ligands used for designing interesting coordi-
Copyright: © 2021 by the authors.
nation compounds with interesting applications [6]. Molecules with 1,2,4-triazole moiety
Licensee MDPI, Basel, Switzerland.
are very strong N-atom donors towards d-metal ions and can be readily deprotonated [7].
This article is an open access article
distributed under the terms and
There is more focus on developing metal complexes as promising potential therapeutic
conditions of the Creative Commons
agents because researchers believe that the coordination of organic molecules with metal
Attribution (CC BY) license (https:// ions enhances their biological activity [8–11].
creativecommons.org/licenses/by/
4.0/).

Processes 2021, 9, 1008. https://doi.org/10.3390/pr9061008 https://www.mdpi.com/journal/processes

Processes 2021, 9, 1008 2 of 13

Vanadium coordination compounds are one of these compounds that have attracted
the interest of many research due to their involvement in several biological processes and
as they are also known as prospective inhibitors of various enzymes [12,13].
Oxidovanadium (IV and V) complexes have been reported to exhibit insulin-mimetic
activity, cell differentiation stimulatory and inhibitory actions, anti-microbial activity, tumor
growth inhibition, and prophylaxis against carcinogenesis [14]. Moreover, vanadium and
its compounds inhibit several ATPases, different phosphatases, and some enzymes like
ribonucleases, phosphodiesterases, and glucose-6-phosphatase [14].
Moreover, it is reported that Oxidovanadium (IV) and dioxidovanadium (V) com-
plexes exhibit comparable or larger anti-mycobacterium tuberculosis activities than the
free parent organic ligands [15].
The literature survey revealed that the strategy of designing metal complexes with
mixed ligands is a promising approach for developing new compounds bearing better
biological activity [16]. Complexes designed through combining ligands with biological
activity and metals having therapeutic potential proved to have enhanced biological
activity [11,12,16]. Vanadium mixed ligands complexes were reported as medicinal agents
for treating different diseases [15].
Keeping in view the significant bioactive nature of the ligand molecules with triazoles
nucleus as well as vanadium complexes, the present work aimed to synthesize vanadium (V)
mixed-ligand complexes involving the heterocyclic 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-
thiol as primary ligand and aminophenol derivatives as secondary ligands. To evaluate the
biological activities of the tested vanadium complexes, the docking calculations were run to
investigate the possibility of an interaction between these compounds and DNA gyrase. This
protein was selected due to their reported studies [17,18], which revealed that theses complexes
can bind to the DNA gyrase and could be considered as biologically active compound [19].
Additionally, the synthesized complexes were screened in vitro for antimicrobial activity and
were subjected to theoretical molecular docking evaluation [20–23].

2. Materials and Methods

2.1. Materials and Physical Measurements
The chemicals used in experimentation were purchased from Sigma-Aldrich (St. Louis,
MO, USA) and used as received. Melting points of the prepared compounds were deter-
mined using Electrothermal (Cat NO. TA9100) melting point apparatus. Molar conduc-
tivities of freshly prepared dimethyl formamide (DMF) solutions of the complexes at a
concentration of 0.001M were measured using Hanna instrument HI8633N Multi-range
conductivity meter.

2.2. Elemental Analysis and Spectroscopy

Elemental analysis for C, H, N, and S were carried out using Leco VTF-900 CHN-S-O
932 version 1.3× (ThermoFisher Scientific, Waltham, MA, USA) instrument. FT-IR spectra
were recorded on Nicolet IS50 FT-IR spectrophotometer in the range of 400–4000 cm−1 . UV–
visible spectra for the complexes in DMF solvent were recorded on Evolution 300 UV–vis
Spectrophotometer. Mass spectra were recorded on a Thermo Fisher Exactive + Triversa
Nanomate mass spectrometer. The 1 HNMR spectra were obtained using Varian Mercury-
400BB (400 MHz) spectrometer using TMS (1 H) as standard.

2.3. Preparation of Mixed-Ligand Oxidovanadium (V) Complexes

The targeted complexes were prepared using 1:1:1 (L1 :M:L2–4 ) molar ratio. To a
mixture of hot ethanolic solution of 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol (L1 )
(0.01 mol) and o-phenylenediamine (L2 ), or 2-aminophenol (L3 ), or 2-aminothiophenol (L4 )
(0.01 mol), an aqueous hot solution of ammonium metavanadate (NH4 VO3 ) or potassium
metavanadate (KVO3 ) (0.01 mol) was added slowly dropwise with continuous stirring and
refluxing for 4 h. The complexes precipitated out from the solution were filtered washed
with proper solvents and dried in open air. The purity of the compounds were checked
Processes 2021, 9, 1008 3 of 13

with TLC paper where one spot was observed confirming the formation of single complex.
All the synthesized complexes were colored solid powders with reasonable yield and
melting points above 300 ◦ C.

2.4. Computational Study

2.4.1. Preparation of Ligands and Protein
From protein data bank RCSB, the 3D structure of protein files was downloaded for
(ID: 4uro [24]) DNA Gyrase B and (ID: 1VJY [25]) transforming growth factor beta receptor
type I (TGFBR1). In order to mining data of proteins we used BLAST P tool for analysis
of FASTA sequence of proteins. Then, CLUSTALW package was utilized for multiple of
amino acids alignments as reported earlier [26–30].
All the Quantum chemical computations for (L1, L2 & 1–6) were performed, using the
DFT theory [31] with the Becke3-Lee-Yang-parr (B3LYP) level using 6-311++ G(d,p) basis.
The optimization Geometry for molecular structures was carried out to improve knowledge
of chemical structures.
The (1-6) were built then energy minimized based on DFT/VMP [31]. The Docking
process were completed by MOE 2015 package [32]. The error correction for structure
of catalytic sites were performed by supplemented hydrogens and partial charges using
(Amber12: EHT), then minimized by utilizing the same force field with RMSD = 0.100. The
catalytic site was identified and analyzed using Site Finder program that based on alpha
spheres as well as energy model [33]. The catalytic zone was predicted by the MOE-Site
finder [33].

2.4.2. Stepwise Docking Experiment

The Docking computations were completed by MOE 2015 package (Molecular Operat-
ing Environment (MOE)) [32]. The error correction for structure of catalytic sites into DNA
Gyrase B (ID: 4uro) were performed by supplemented hydrogens and partial charges using
(Amber12: EHT), then minimized through utilizing the same force field with RMSD = 0.100.
The catalytic site was identified and analyzed using Site Finder program method, which
is based on alpha spheres as well as energy model. The catalytic zone was predicted
using the MOE-Site finder. Water and inhibitors molecules were eliminated, then H-atoms
were supplemented to the obtained crystal structure. The charges were designed using
MMFF94x force field. The alpha-site spheres were added depending on site-finder module.
Afterwards the ligand was subjected to induced fit docking (IFD) for generating energy
poses and assigning final binding scores.

2.5. Assessment of Antimicrobial Capacity

The synthesized compounds were assessed against Staphylococcus aureus (ATCC 25923),
Streptococcus pneumoniae (ATCC 49619) as Gram-positive bacteria strains, Escherichia coli
(ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) Gram-negative bacteria strains, and
Candida albicans (ATCC 10231) as yeast. The reported Disc Diffusion Assay (DDA) method
was used as assessment methodology using Muller–Hinton agar as a microbiological
growth medium [33]. The stock solution of the compounds was prepared by dissolving
0.02 g of each compound in 5 mL dimethylformamide (DMF) solvent. After the incubation
period, the microbial susceptibility was measured by noting the zones (in mm) of complete
inhibition around each hole. Each experiment was repeated three times and results were
recorded as mean value.

3. Results
3.1. Synthesis of Oxidovanadium (V) Mixed Ligand Complexes
The designed oxidovanadium (V) mixed ligand complexes were prepared successfully
using 4-amino-5-mercapto-3-phenyl-1,2,4-triazole (L1 ) as primary ligand and o-aniline
derivatives (L2 –L4 ) as secondary ligands mixed with the vanadium salts in 1:1:1 stoichio-
metric ratio ((L1 :M:L2–4 )). The yields obtained were in reasonable yield with a range of
Processes 2021, 9, 1008 4 of 13

70–85%. The elemental analysis obtained (Table S1, Supplementary Material) were in
agreement with the proposed structure. The isolated solid compounds were dark-colored
powders with high melting points (>300 ◦ C) and were soluble in dimethyl formamide
(DMF) and dimethyl sulfoxide (DMSO).

3.2. Molar Conductivity

The measured molar conductivity values (Table S1, Supplementary Material) for the
prepared complexes with a concentration of 1 × 10−3 M in DMSO solution at room tem-
perature lie in the range (75–110.5 ohm−1 cm2 mole−1 ) indicating an electrolytic behavior
and of ionic nature [34,35].

3.3. IR Spectra
The important infrared frequencies exhibited by the ligand (L1 ) and the obtained
vanadium (V) complexes are listed in (Table S2 Supplementary Material). The ligand’s (L1 )
IR spectra showed characteristic absorption bands at 3270, 3200 cm−1 assigned for NH2
group, and 2910 cm−1 specified for SH group. In the IR spectra of the metal complexes, it
was observed that NH2 group bands were shifted their position indicating binding of NH2
group with the vanadium metal ion. The characteristic band for υ(SH) was not shown in
the spectra of the vanadium (V) complexes suggested deprotonation and hence binding to
the vanadium ion through S-atom [36,37].
The participation of oxygen, sulfur, and nitrogen in coordination with the metal
ion is further supported by the new band appearance at 450–480, 530–550, and 590–595
cm–1 assigned for v(V-S), v(V-N), and v(V-O), respectively [28,32]. In the IR spectra of
some complexes a strong band and in some others medium band appeared in the range
1440–1460 cm−1 which are due to the deformation modes of the δ(NH4+ ) ion [37,38]. The
presence of sharp band in the spectra of the vanadium complexes at 920–980 can be assigned
to (V=O) stretches [34,37]. A broad band at 3050–3405 cm−1 was observed in the spectra
of the metal complexes, which is an indication for the presence of hydrated water in the
complexes [39].
These observations suggesting that the obtained vanadium complexes have the general
formula [VO(NNS)(OX)] where X = N, O or S. The primary ligand (L1 ) coordinates to
the oxidovanadium (V) center in a tridentate (NNS) fashion while, the secondary ligands
(L2 , L3 , and L4 ) coordinates to the oxidovanadium (V) center in Bidendate (NN), (NO), or
(NS) [16].

3.4. UV–Visible Spectra

The electronic spectra of the vanadium (V) complexes in 10−3 M DMSO solution
at room temperature (Figure S2, Supplementary Material) showed peaks at the range
of 349–356 nm, which may be due to the intra-ligand charge transfer π→π* and n→π*
transitions, and other peaks in the range of 424–440 nm, which are assigned to ligand-to-
metal charge transfer (LMCT) transitions from the Pπ orbital on the nitrogen, oxygen, and
sulfur atoms to the empty orbital of the d0 vanadium centers [40–42].

3.5. 1 H-NMR Spectra

1 H-NMR spectra of the ligands and their vanadium (V) complexes (Figure S3, Sup-
plementary Material) have been recorded in DMSOd6 using tetramethyl silence (TMS)
as internal standard. The 1 H NMR spectra of the ligand (L1 ) showed the –SH proton
at 10.18 ppm, which was disappeared in the spectrum of the vanadium (V) complexes
indicating deprotonation and coordination through the thiol group with the vanadium
metal ion [43]. Furthermore, in the 1 H NMR Spectra the signals of NH2 protons appear at
δ5.14 ppm, shifted to high field in the spectra of the vanadium (V) complexes indicating
bonding through the nitrogen atom of the amine group to the central vanadium ion [44]. In
1 H-NMR spectrum of the vanadium (V) complexes did not show any signal in the region
 ppm, which was disappeared in the spectrum of the vanadium (V) complexes indicating
deprotonation and coordination through the thiol group with the vanadium metal ion
Processes 2021, 9, 1008 [43]. Furthermore, in the 1H NMR Spectra the signals of NH2 protons appear at δ5.145ppm,of 13
shifted to high field in the spectra of the vanadium(V) complexes indicating bonding
through the nitrogen atom of the amine group to the central vanadium ion [44]. In 1H-
NMR spectrum of the vanadium (V) complexes did not show any signal in the region
12.00–12.37
12.00–12.37suggesting
suggestingdeprotonation
deprotonationof
ofOH
OHgroup
group(in
(inco-ligand
co-ligandLL3 )3)and
andcoordinating
coordinatingtoto
the vanadium metal ion via oxygen atom [45].
the vanadium metal ion via oxygen atom [45].
3.6. Mass Spectra
3.6. Mass Spectra
The mass spectra were recorded in order to confirm the theoretically calculated molec-
The mass spectra were recorded in order to confirm the theoretically calculated mo-
ular weight according to the proposed structure (Figure S4, Supplementary Material). The
lecular weight according to the proposed structure (Figure S4, Supplementary Material).
observed peak for the complex NH4 [VO(L1 )(L2 )] 2.5H2 O(1) at 383.00 matches the theoreti-
The observed peak for the complex NH4[VO(L1)(L2)] 2.5H2O(1) at 383.00 matches the the-
cally calculated molecular weight of (383.3). The mass spectrum for K[VO(L1 )(L2 )] 1.5H2 O
oretically calculated molecular weight of (383.3). The mass spectrum for K[VO(L1)(L2)]
(2) showed a peak at 386.58 equivalent to the calculated M. Wt. (386.35). In case of the
1.5H2O (2) showed a peak at 386.58 equivalent to the calculated M. Wt. (386.35). In case of
complex NH4 [VO(L1 )(L3 )] 4H2 O(3) the observed peak at 410.08 is equivalent to the calcu-
the complex NH4[VO(L1)(L3)] 4H2O(3) the observed peak at 410.08 is equivalent to the
lated M. Wt. (409.29). The observed peak for NH4 [VO(L1 )(L4 )] H2 O (5) at 372.25 matches
calculated M. Wt. (409.29). The observed peak for NH4[VO(L1)(L4)] H2O (5) at 372.25
the calculated its M. Wt. (372.32), Finally for the complex K[VO(L1 )(L4 )] 2H2 O (6) the
matches the calculated its M. Wt. (372.32), Finally for the complex K[VO(L1)(L4)] 2H2O (6)
observed peak was at 410.17 matches the theoretical M. Wt. (411.39). These observations
the observed peak was at 410.17 matches the theoretical M. Wt. (411.39). These observa-
are in agreement with the proposed structures as shown in Scheme 1.
tions are in agreement with the proposed structures as shown in Scheme 1.

Scheme1.1.Proposed
Proposedstructure
structureofofthe
theM[VO(L
M[VO(L2))(L
(L2–4)] yH2O complexes.
Scheme 2 2–4 )] yH2 O complexes.

3.7.
3.7.Molecular
MolecularModeling
ModelingStudies
Studies
To
Toget
getclear
clearview
view ofof
the chemical
the chemical structure of the
structure complexes,
of the complexes, the the
optimization
optimizationgeometry
geom-
was
etryachieved
was achievedusing density functional
using density theory DFT/B3LYP/6-311G++(d,p)
functional theory DFT/B3LYP/6-311G++(d,p) basis set level
basis set
implemented
level implemented in materialstudio2017
in materialstudio2017workspace. The bond
workspace. Thelength and angle
bond length and for complexes
angle for com-
were
plexessummarized
were summarized in (TableinS3, Supplementary
(Table Material).
S3, Supplementary The optimization
Material). geometry
The optimization for
geom-
all tested ligands (1–6) showed that the triazoles were stabilized in
etry for all tested ligands (1–6) showed that the triazoles were stabilized in parallel modeparallel mode with
phenyl ring, and
with phenyl ring,atand
the at
same
the time
samethe
time triazoles arranged
the triazoles in perpendicularity
arranged in perpendicularityposition with
position
metal core centers
with metal (Figure
core centers S5). S5).
(Figure
The
Thefrontier
frontiermolecular
molecularorbitals
orbitalsFMOs
FMOsisiscircular
circularorbitals,
orbitals,whichwhichinclude
includeboth
bothvital
vital
orbitals (i) HOMO, highest occupied molecular orbital; and (ii) LUMO,
orbitals (i) HOMO, highest occupied molecular orbital; and (ii) LUMO, lowest unoccu- lowest unoccupied
molecular orbital.
pied molecular TheseThese
orbital. orbitals can judge
orbitals the interaction
can judge rout ofrout
the interaction the ofreactant speciesspecies
the reactant with
others. FMOs gap was characterized by the chemical reactivity and
with others. FMOs gap was characterized by the chemical reactivity and kinetic stability kinetic stability of the
molecule. The molecule possesses promising value of EHOMO
of the molecule. The molecule possesses promising value of EHOMO and has good ability and has good ability to
awarding electron, as well as easier for losing electron of valence to biological
to awarding electron, as well as easier for losing electron of valence to biological media, media, and
hence enhancing
and hence interactions
enhancing with awith
interactions receptor, and vice
a receptor, andversa
vice [46,47]. (HOMOs)/(LUMOs)
versa [46,47]. (HOMOs)/(LU-
have been figured in (Figure 1) for the (1–6) complexes
MOs) have been figured in (Figure 1) for the (1–6) complexes systems systems in the S0 states.
in the S0Figure 1
states.
indicates the distribution of molecular orbits over studied systems. The HOMO orbital was
Figure 1 indicates the distribution of molecular orbits over studied systems. The HOMO
distributed around phenyl rings for compounds 1 and 6. The complexes 2–5 were stabilized
orbital was distributed around phenyl rings for compounds 1 and 6. The complexes 2–5
by distributing HOMO orbitals between triazoles and phenyl rings. The LUMO orbital has
were stabilized by distributing HOMO orbitals between triazoles and phenyl rings. The
been covered in triazole and metal cores in all tested complexes, except V complex 6 the
LUMO orbital has been covered in triazole and metal cores in all tested complexes, except
LUMO cloud covered only upon metal ring. From HOMO and LUMO maps the electron
V complex 6 the LUMO cloud covered only upon metal ring. From HOMO and LUMO
cloud transfer from HOMO to LUMO zones, which means there is an intramolecular
maps the electron cloud transfer from HOMO to LUMO zones, which means there is an
electron flow from phenyl ring to metal and triazole rings in the investigated complexes.
All complexes showed good stability due to high stability of the energy gap.
Processes 2021, 9, x FOR PEER REVIEW 6 of 13

intramolecular electron flow from phenyl ring to metal and triazole rings in the investi-
gated complexes.
intramolecular All complexes
electron flow showed
from phenyl ring good stability
to metal due to high
and triazole ringsstability of the energy
in the investi-
Processes 2021, 9, 1008 6 of 13
gap.
gated complexes. All complexes showed good stability due to high stability of the energy
gap.
1 2 3
1 2 3

HOMO
4 5 6
HOMO
4 5 6

1 2 3
1 2 3

LUMO
LUMO 4 5 6
4 5 6

Figure 1. The HOMO and LUMO for complexes (1–6) at DFT theory based in B3LYP/6-
Figure 311G++(d,p).
1. The1.HOMO and LUMO for complexes (1–6)(1–6)
at DFT theory based in B3LYP/6-
Figure The HOMO and LUMO for complexes at DFT theory based in B3LYP/6-311G++(d,p).
311G++(d,p).
The voltage for the electrostatic map (EV) of complexes 1–6 is represented in Figure
The voltage for the electrostatic map (EV) of complexes 1–6 is represented in Figure 2.
2.
The From
Fromvoltage thefor
comparison ofEVtheof
the electrostatic
the comparison of the EVtheof(EV)
map the of
complexes,
complexes, it canitbe1–6
complexes can berepresented
is concluded
concluded that there
in Figure
that there is is dis-
distribu-
2. Fromtribution
tion the of positive
comparison
of positive of charges
charges the EV of
around around the triazole
thetriazole
the complexes, rings
ringsitincan
all beinconcluded
all complexes
complexes 1–6that 1–6
there
(shown (shown dis- in yel-
inisyellow to
low
tribution to green
greenofcolor).
positive color).
Thecharges The
electron electron
around
density,the density,
astriazole
shown in as shown
rings
red in in red color,
all complexes
color, is
is delocalized delocalized
1–6all
(shown all
in yel-
over the over the
skeleton
ofskeleton
low to green of theThe
color).
the molecular molecular
electronof
structure structure
density, of shown
as
the complexes the complexes
in red
1–6. The 1–6.
color,
metalThe metal
is core
delocalizedcoreall
centers, centers,
over the
having having
a large a
large
skeleton
bond bond
oforder, order,
the molecular
has a highhas a high
structure ability
abilityofofthe of attracting
complexes
attracting electrons,
1–6. The
electrons, metal
and and hence
corethe
hence the
centers, increasing
having
increasing a elec-
electron
tron
largedensity density
bond order, over
has metal
over the the metal
a highcores. cores. Therefore,
abilityTherefore,
of attractingthese these
electrons,
complexescomplexes
and(1–6)
hence (1–6) showed
the increasing
showed high
elec-electro-
high electrophilic
philic capacity
tron density
capacity over the
in the in the biological
metal
biologicalcores.
media media [48].
Therefore,
[48]. these complexes (1–6) showed high electro-
philic capacity in the biological media [48].

Figure
Figure 2. 2. Electrostatic
Electrostatic surface
surface Voltage
Voltage (VP)
(VP) for for complexes
complexes 1–61–6 at DFT/B3LYP/6-311G++(d,p)
at DFT/B3LYP/6-311G++(d,p) molec-
molecu-
Figure ular orbital
lar2.orbital calculations,
calculations,
Electrostatic yellow
surfaceyellow colors
colors
Voltage representing
(VP)representing
for complexes -ve
-ve1–6 regions,
regions, and blue colors indicating
and blue colors indicatingmolec-
at DFT/B3LYP/6-311G++(d,p) positive
positive re-
regions.
ular orbital
gions. calculations, yellow colors representing -ve regions, and blue colors indicating positive
regions.
3.8. Docking Studies
The docking study targeted (ID: 4uro) DNA Gyrase B Candida albicans lanosterol
14-α-demethylase, and (ID: 1VJY) was performed to examine the potential mode of the
complexes (1–6) as antimicrobial agents. The fingerprint for ligand–protein-interactions
were estimated based on the docking score through implementing function in the Molecular
Processes 2021, 9, 1008 7 of 13

Operating Environment MOE 2015.10 package (Figures 3 and 4; Figure S6, Supplementary
Materials). All calculated energies of the docking simulation via crystal-structures (PDB:
4uro and 1VJy) have been summarized in (Table S4, Supplementary Material). Bacterial
DNA-gyrase plays a vital role in the activity of the antibacterial agents, and acts by breaking
double-stranded DNA through catalyzing negative supercoiling, which is essential for
DNA replication, transcription, and recombination [49]. Analysis of the co-crystallized
DNA-gyrase cleavage complex with novobiocin, which is an effective antibacterial agent
that acts by cleaving DNA and restricting the ATPase binding site located on the vital
peptidoglycan of the bacterial cell wall (Ser 55, Ala64, Asn.65, Asp89, Thr164, Thr173,
and Val79). The inhibitory effect may be a result of the distinct structure of the cell wall
that characterizes the Gram-negative and Gram-positive bacteria. The cell wall of the
Gram-negative bacteria is composed of a thin peptidoglycan layer (7–8 nm) with an addi-
tional outer membrane. While the Gram-positive bacteria contain a thick peptidoglycan
layer (20–80 nm) outside the cell wall with no outer membrane. The peptidoglycan is a
mesh-like polymer consisting of sugars and amino acids. A peptidoglycan layer protects
microorganisms against antibacterial agents such as antibiotics, toxins, chemicals, and
Processes 2021, 9, x FOR PEER REVIEW
degradative enzymes [48,50]. In addition, the crystal structure of TGF of β-RI bound 8 of 13
with
naphthyridine (ligand 460) was obtained as PDB file (ID: 1VJY) with 2.0Å resolution.

4uro

1VJY

Figure
Figure3.3.Plotted
PlottedPLIF
PLIFhistogram which
histogram represented
which the the
represented interacted docked
interacted complexes
docked 1-6 with
complexes 1–6 resi-
with
dues of 4uro and 1VJY.
residues of 4uro and 1VJY.

1
2
Processes 2021, 9, 1008 8 of 13
Figure 3. Plotted PLIF histogram which represented the interacted docked complexes 1-6 with resi-
dues of 4uro and 1VJY.

1
2

3 4

Processes 2021, 9, x FOR PEER REVIEW 9 of 13

5 6

Figure 4. The binding mode of complexes (1–6) into the active site of DNA Gyrase, H-bond represented as blue dashed color.
Figure 4. The binding mode of complexes (1–6) into the active site of DNA Gyrase, H-bond represented as blue dashed
color.
The updated redocked technique has been used for 1–6 complexes into active sites in
the absence of the reference inhibitor. The 1–6 complexes were successfully capped into
From the above data, one can deduced that the hydrophobic residues of complexes
active zone of the enzymes. The docked poses of complexes were obtained and used for
played a circular pharmabiotic for binding to the DNA-gyrase pocket. Furthermore, the
energy-minimized by a molecular-mechanics (Amber12: EHT) force field, until reached
inhibition potency
0.05/kcal/mol of gradient
of the 1–6 complexes for bacterial
convergence. growth
The poses mayfiltered
were be duedepending
to the attacking-
on the
power against the peptidoglycan-naked cell-wall of bacteria [52,53]. Thus,
lowest binding free energy calculation ∆G with the lowest root means quart deviation the antibacte-
rial mechanism
(RMSD) betweenofthe
thepose
investigated complexes
before and include the
after refinement. Thealteration of the
∆G utilized thepermeability
AMBER force of
the bacterial membrane. As a result, the tested complexes may leak through
field combined with GB/VI solvation parameters, which considered the contributions of sugars and
proteins
the to deactivate
solvation in binding hydrogen
process respiratory
[51]. Finally,chain enzymes,
the highest MOEand scoring
subsequently, they
function forpro-
the
duce pits and gaps in the bacterial membrane (peptidoglycan layer) to induce
tested compounds was applied to evaluate the binding affinities of the tested compounds irregular
fragmentation
(Table of the bacterial
S4, Supplementary cells [54,55]. We therefore concluded that these indexes in-
Material).
dicate that these complexes may lead to suitable biological functions.
For (ID: 1VJY) transforming growth factor (TGF) for β-receptor type I (β-RI): All
complexes except five showed lower binding-score (ΔG = -5.0 Kcal/mol) than reference
ligand460 (ΔG = −4.81 Kcal/mol), (Table S3, Supplementary Material). The six complexes
showed significant binding-affinity (ΔG = −4.13 Kcal/mol). PLIF showed that the Leu.232
was bonded with 83.3% of complexes (2–6). Interestingly, the 1–6 complexes formed H-
bond with amino acid backbone (Gly.212, Lys.232, Asp.281, and Ala.350) for β-RI (Figure
S6, Supplementary Materials). The compounds interacted with important amino acids of
β-RI binding-site as 1 → (Glu 254 and His.283), 2 → (Lys 232 and Sre280), 3 → Ala → (230
and Lys 232); 4 →( Lys 232, Ser.280 and Ala.350), 5 → (Lys 232 and Val219), and 6 → (Lys
Processes 2021, 9, 1008 9 of 13

(ID: 4uro) DNA Gyrase B: The complex 1 exhibited the highest binding affinity
(−4.4 Kcal/mol.) compared with other 2–6 complexes. The other 2–6 complexes showed
nearly the same considerable binding potency as well as RMSD. The scores of the binding
energy were arranged as 3 > 4 > 2 > 5 > 6 with a trend for ∆G between ~−3.9 and −3.01
(Table S4, Supplementary Material). All compounds allowed H-bond formation with im-
portant amino acid residues (Glu.58, Pro.87, Ile.102, and Gly.125) at the DNA gyrase active
site (Figure S6, Supplementary Materials). The analysis of the protein ligand fingerprint
PLIF-consensus was graphed in Figure 3. Interestingly, PLIF showed the Glu.58 and pro.87
are combined with 50% of tested complexes.
All compounds were arranged in perpendicular mode with Pro.87 and Glu.58 (see
Figure 4). The hydrophobic residues and presence of ammonia and potassium in the outer
shell of complexes 1–6 played a stabilization factor for the receptors-conformation. The
variation in the complexes-conformations sensed the interactions with the hydrophilic
amino acid backbone at the 4uro binding site (Figure S6, Supplementary Materials).
From the above data, one can deduced that the hydrophobic residues of complexes
played a circular pharmabiotic for binding to the DNA-gyrase pocket. Furthermore, the
inhibition potency of 1–6 complexes for bacterial growth may be due to the attacking-
power against the peptidoglycan-naked cell-wall of bacteria [52,53]. Thus, the antibacterial
mechanism of the investigated complexes include the alteration of the permeability of
the bacterial membrane. As a result, the tested complexes may leak through sugars
and proteins to deactivate hydrogen respiratory chain enzymes, and subsequently, they
produce pits and gaps in the bacterial membrane (peptidoglycan layer) to induce irregular
fragmentation of the bacterial cells [54,55]. We therefore concluded that these indexes
indicate that these complexes may lead to suitable biological functions.
For (ID: 1VJY) transforming growth factor (TGF) for β-receptor type I (β-RI): All
complexes except five showed lower binding-score (∆G = −5.0 Kcal/mol) than reference
ligand460 (∆G = −4.81 Kcal/mol), (Table S3, Supplementary Material). The six complexes
showed significant binding-affinity (∆G = −4.13 Kcal/mol). PLIF showed that the Leu.232
was bonded with 83.3% of complexes (2–6). Interestingly, the 1–6 complexes formed H-
bond with amino acid backbone (Gly.212, Lys.232, Asp.281, and Ala.350) for β-RI (Figure
S6, Supplementary Materials). The compounds interacted with important amino acids of
β-RI binding-site as 1 → (Glu 254 and His.283), 2 → (Lys 232 and Sre280), 3 → Ala → (230
and Lys 232); 4 → (Lys 232, Ser.280 and Ala.350), 5 → (Lys 232 and Val219), and 6 → (Lys
232 and Ser 280). The binding-affinity for 2–4 exhibited nearby equal ∆G = ~−2 Kcal/mol.

3.9. Antimicrobial Tests

The prepared oxidovanadium (V) complexes were screened for antibacterial and
antifungal activity and the obtained results are presented in Table 1. It is observed that
the compounds are moderately active against both Gram-positive bacterial strains and the
fungal strains, whereas all compounds were inactive against the Gram-negative bacterial
strains. These observations suggest that the prepared vanadium mixed metal complexes
had similar activity compared to our reported work earlier on vanadium complexes with
triazole moiety [18,19]. It was reported that the biological activity of the used co-Ligands
(L2 , L3 , and L4 ) were moderate [56–58]. In our work it was observed the complexes with
the co-ligand (L4 ) containing thiol group showed better activity than the other complexes.
This may be due to the presence of two thiol groups which enhances the antimicrobial
activity [19].
Processes 2021, 9, 1008 10 of 13

Table 1. Antimicrobial activity of the ligand (L1) and its vanadium (V) complexes.

“Antifungal
“Antibacterial Activity 200 µg/disc”
Activity”

Ligand and “Gram-Positive Bacteria” Gram-Negative Bacteria Yeast

Complexes S.a S.p E.c P.a C.a
NH4 [VO(L1 )(L2 )]
0 20 0 0 12
2.5H2 O(1)
K[VO(L1 )(L2 )]
12 23 0 0 17
1.5H2 O (2)
NH4 [VO(L1 )(L3 )]
12 26 7 6 11
4H2 O(3)
K[VO(L1 )(L3 )] H2 O
16 21 0 0 14
(4)
NH4 [VO(L1 )(L4 )]
0 24 0 0 13
H2 O (5)
K[VO(L1 )(L4 )]2
15 21 9 7 18
H2 O (6)
Amoxicillin 28 35 21 23 0
S.a.: Staphylococcus aureus (ATCC 25923), S.p.: Streptococcus pneumoniae (ATCC 49619); E.c.: Escherichia coli (ATCC
25922); P.a.: Pseudomonas aeruginosa (ATCC 27853); C.a.: Candida albicans (ATCC 10231).

4. Conclusions
The synthesized mixed-ligand oxidovanadium (V) complexes containing tri and
bidentate ligands were of the general formulae NH4 [VO(L1 )(L2 -4 )]yH2 O or K[VO(L1 )(L2 -
4 )]yH2 O. The structures were proposed based on elemental analysis, mass spectra, IR,
UV–visible, molar conductance, and 1HNMR measurements. The synthesized mixed-
ligand oxidovanadium (V) complexes were monomeric with octahedral geometry. The
antimicrobial tests for the prepared compounds showed moderate activity against the
Gram-positive bacteria type and fungal yeast.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10

.3390/pr9061008/s1. Figure S1. IR spectrum for (1–6) complexes; Figure S2: The electronic spectrum
of (1 and 4) complex; Figure S3: 1 H NMR spectrum of complexes (1–3); Figure S4: Mass spectra for (1,
3, 5, 6) complexes; Figure S5: optimization geometry of tested complexes (1–6) at DFT/PM6; Figure S6:
Schematic interactions between ligands and proteins 4uro and 1VJY using protein–ligand interaction
fingerprint tools; Table S1: The elemental analysis data and molar conductance measurements of the
Vanadium (V) Complexes; Table S2: IR Spectroscopic data (cm−1 ) of the ligands and their vanadium
(V) complexes; Table S3: Docking energy scores (kcal/mol) derived from the MOE for investigated
complexes 1–6 and reference inhibitors Novobiocin & Naphthyridine.
Author Contributions: Conceptualization, M.A. and A.A.E.; methodology, M.A.; software, A.A.E.;
validation, M.A., S.A.Z., and D.D.; formal analysis, M.A.; investigation, D.D.; resources, D.D.; data
curation, M.A.; writing—original draft preparation, M.A. and D.D.; writing—review and editing,
A.A.E.; visualization, M.A.; supervision, M.A. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Albha university, and approved by the Institutional Review Board.
Informed Consent Statement: For studies not involving humans.
Data Availability Statement: Date of the compounds are available from the authors.
Conflicts of Interest: The authors declare no conflict of interest.
Processes 2021, 9, 1008 11 of 13

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