2022 Applied Organometallic Chemistry

Adam Mohamed (Orcid ID: 0000-0002-1757-0689)
Shaaban Saad (Orcid ID: 0000-0002-7835-6926)

El-Metwaly Nashwa (Orcid ID: 0000-0002-0619-6206)
Full paper
Two ionic oxo-vanadate and dioxo-molybdate complexes of dinitro-aroylhydazone

derivative: effective catalysts towards epoxidation reactions, biological activity, ctDNA
binding, DFT and silico investigations
Running Title
O=V4+ and O=Mo6+=O complexes, as effective catalysts and bio-reagents
Mohamed Shaker S. Adam1,2* | Saad Shaaban1,3 | Nashwa M. El-Metwaly3,4
1
Department of Chemistry, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa 31982, Saudi
Arabia.
2
Department of Chemistry, Faculty of Science, Sohag University, Sohag-82534, Egypt.
3
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt.
4
Department of Chemistry, Faculty of Applied Science, Umm Al Qura University, Makkah 24230, Saudi Arabia.
Tel. +966505669287, Fax. +966920002366
*Corresponding authors: madam@kfu.edu.sa; mohamed.shaker@science.sohag.edu.eg (M.S.S. Adam)
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/aoc.6763
This article is protected by copyright. All rights reserved.

Abstract
According to the ecological demand for synthesis of ecofriendly metallated organic
compounds, two new green dinitro-aroylhydazone derivative (HLZNa) was used for the
synthesis of vanadate (IV) and cis-molybdate (VI) complexes (VOLZNa and MoO2LZNa). The
N,O-bidentate ligand and its M-pincer chelates were characterized based on various
spectroscopic tools. IR spectra displayed high shift of the CH=N band with disappearance of
O—H band of HLZNa after its coordination to V4+ and Mo6+ in VOLZNa and MoO2LZNa,
respectively. 1HNMR spectra supported the above observation for HLZNa compared to that of
MoO2LZNa for the spectral signal of CH=N and O-H groups. In UV-Vis. spectra, VOLZNa
showed an additional spectral band at 741 nm for the d→d transition, which accomplished such
complexation. Catalytically, VOLZNa showed slightly more catalytic action, with 92% yield
after 2 h, compared to that MoO2LZNa catalyst (4 h with 92% yield) in the oxygenation of 1,2-
cyclooctene, i.e. epoxidation, at 90 °C. A strong reversible electrochemical behavior of
VOLZNa (V4+/V5+redox couple) enhanced the catalytic action of VOLZNa over MoO2LZNa,
which is supported by spectroscopic analysis. The biological behavior of HLZNa, VOLZNa
and MoO2LZNa was examined through their binding ability to ctDNA via UV–Visible
spectroscopy and hydrodynamic measurements. Spectroscopically, the derived binding
constant for VOLZNa and MoO2LZNa (Kb = 4.45 and 5.01 × 108 mol-1 dm3, respectively) were
higher than that of the free ligand (HLZNa, 2.88 × 108 mol-1 dm3), which referred to their
reactivity towards ctDNA. Also, the Gibbs’ free energy values (∆𝐺𝑏≠ ) for such interaction
illustrated their high potential against ctNDA over their ligand (-31.14, -32.22 and -32.52 kJ
mol-1, for HLZNa, VOLZNa and MoO2LZNa, respectively). The metal ions (V4+ and Mo6+) in
VOLZNa and MoO2LZNa, respectively, improved their antioxidant, antimicrobial and
antitumor activities over the free ligand. The structures of the current compounds were further
elucidated by the DFT/B3LYP method, which confirmed the mode of bonding depending on
the distribution of coordinating functional groups. Some physical parameters were estimated
to evaluate the probability of these compounds’ reactivity biologically and catalytically. The
catalytic role of MoO2LZNa complex was confirmed computationally. The in-vitro obtains
regarding the antimicrobial activity of the M-chelates were tested by silico approaches. The
outcomes reflected the high conformity of VOLZNa as an effective antimicrobial reagent.
Keywords: dinitro-aroylhydazone, complexes, epoxidation, ctDNA interaction, in vitro, silico

examinations, DFT study.

1 | Introduction
Owing to the highly attractive coordination chemical features of aryl/aroylhydrazones towards
transition metals and their interesting structural and isomeric features,[1] they were the subject
of numerous reports in prospective applicable fields, e.g. biology[2] and catalysis.[3]
Considerably, the vanadium- and molybdenum-aroylhydrazone, as oxometallated organic
frameworks, represent an exciting topic in coordination chemistry with various donor centers
of N,O-chelating of di-, tri- and multi-dentate hydazones.[4,5] Oxo- and dioxovandium(IV)/(V)
complexes are significantly formed with square pyramidal or octahedral geometry,[4] whereas,
dioxomolybdenum(VI) complexes possess octahedral geometries.[5] Many oxidation processes
of organic substrates are promoted catalytically with vanadium catalysts.[6] Vanadium is
considered reactive metal ion, among the most effective transition metals, due to its alternative
valents in the electron/oxygen transfer reactions.[7] Hence, vanadium complexes are
documented as sufficient catalysts for the catalytic functionalized oxidation of hydrocarbons,
e.g. alkanes and alkenes, as well as carbonyl compounds (alcohols and ketones) and thiols.[8]
Moreover, molybdenum compounds of +6 charge, as oxido-peroxido catalysts were also
developed in many oxidative catalytic protocols with high reactivity and efficiency.[9]
Considerably, oxo- or peroxo-metallated organic catalysts of high valence are preferable
catalysts for most selective redox systems of organic compounds.
Recently, aryl/aroylhydrazone vanadium complexes were represented as highly favoured
catalysts for various oxidation reactions. Additionally, V(V)-diacetyl resorcinol
aroylhydrazone complexes displayed an obvious improving role in oxidative bromination of
thymol with KBr using HClO4 or H2O2 and in the oxygenation of styrene, cyclohexenone, 1,2-
cyclooctene, cyclohexene, 1-octene, 1-hexene and stilbene.[10] Vanadyl(V)-hydrazone chelates
were explored as selective homogeneous catalysts for the hydrocarbons and sulfides oxidation
with H2O2.[11] A new V+5O-hydrazone complex with anti-coplanar geometry was studied as a
sufficient catalyst for the alkenes epoxidation, which reported recently by Mirdarvatan et al.[12]
Similarly, dioxomolybdenum aroylhydrazone complexes were explored as a homogeneous
catalyst via various oxidation processes of alkenes. Maurya et al. reported the new trinuclear
dioxidomolybdenum aroylhydrazone complexes as high selective catalysts in alkenes
epoxidation.[13] Also, some new tetranuclear molybdenum(VI) aroylhydrazone chelates were
probed as (pre)catalysts in the oxygenation of cyclohexene and cyclooctene under green
atmosphere.[14] Furthermore, molybdenum(VI) aroylhydrazone complexes of phloroglucinol
and resorcinol were reported by Avecilla et al.,[15] which exhibited high potential as

homogeneous catalysts for the alkenes (ep)oxidation with H2O2 (30% in water) supporting by
NaHCO3.
Accordingly, the epoxidation of olefins was achieved catalytically by numerous transition
metal complex catalysts (e.g. significantly with Mo6+ and V4+/5+ ions) is the most common
method for epoxides formation in various industrial proposes.[16] For that, the development of
effective and eco-friendly Mo(VI) and VO(IV)/(V)-complexes, as homogeneous catalysts, for
such redox systems, is a fundamental demand in scientific research and manufactories.[17] The
facile oxygen accessible of Mo(VI) and V(IV)-complexes gave additional advantages as
suitable catalysts with optimized conversion and selectivity for the oxygenation of olefins.[18]
Various terminal involved oxidants with an alternative reactivity, e.g. hydroperoxides,[18] urea
hydrogen peroxide, peroxysulfates, hypochlorites, periodates,[19] O2 air[5] and hydrogen
peroxide,[5] were also considered active towards olefins epoxidation, whereas, H2O2 is the most
eco-friendly one due to water and oxygen gas liberation as a green side product.[5,6] H2O2 is a
very active oxidant in a high polar system, whereas tert-butylhydroperoxide is represented as
more effective in the less polar oxygenation systems.[20] Therefore, the choice of a suitable and
effective oxidant depends mainly on the oxygenation system components.
Vanadium compounds with an observable antidiabetic behavior, assigned high potential in
cancer therapeutics.[21] Within this regard, various vanadium therapeutic reagents are proposed
as effective drugs for many diseases treatment.[22] Furthermore, molybdenum compounds are
studied widely as enzymatic reagents in the organisms,[23] which assigned as effective
bioinorganic enzymes.[24] Biologically, aroylhydrazones are abundantly represented in the
fundamental and applicable research as antimycobacterial, pharmacological, analgesic,
anticonvulsant, anti-inflammatory, antituberculosis, antiplatelet and antitumoral reagents.[25]
New nicotinoyl hydrazine derivatives were examined as effective drugs against diseases of the
overdoses of iron treatment.[26] Additionally, transition metal aroylhydrazone complexes are
the most attractive class in bioinorganic chemistry.[20-22] Numerous transition metal hydrazones
are considered effective bio-reagents, e.g. antitumor, antimicrobial and antituberculosis
drugs.[27] VVO-aroylhydrazone complexes (pyridine derivatives) assigned respectable urease
inhibitory activity, which was recently explored.[28] Also, trinuclear VO2+ and VO3+-complexes
of arylhydrazone derivatives have been reported as peroxidase mimicking potential by Pessoa
et al.[29] Vanadium (III-V)-Schiff base hydrazone complexes, which derived from pheny-
lacetic acid, documented a valuable inhibiting reactivity of human tyrosine phosphatases
through cytotoxicity investigation.[30] Furthermore, the insulin-like action of some synthesized
VO-aroylhydrazone chelates was studied with some normal and streptozotocin-diabetic

mice.[31] Moreover, dioxidovanadium (V)-nicotinoylhydrazone complexes showed high
antidiabetic activity, which has been also intensively studied.[32] The cytotoxicity and protein
reactivity of various V-chelates with inter-conversion in solutions of different oxy-modes of
aroylhydrazone derivatives were studied and reported.[33] Within the in vitro and silico
examinations, the antimicrobial potential of vanadyl(V)-aroylhydrazone complexes was also
investigated.[34] The high reactivity of MoO2-arylhydrazone complexes in vitro cytotoxicity
was evaluated currently by Asha and Kurup.[35] The antiproliferative and DNA interaction
potentials of new MoO2-complexes of ONO-aroylhydrazone derivatives were examined and
reported by Dinda et al.[36]
Aroylhydrazones are commonly less soluble in the greenest solvent (H2O), such refer to the
probability of their aqueous hydrolysis.[37] Consequently, the attachment of a neutralized
sodium sulfonate group in the synthesized aroylhydrazones would form new eco-friendly
aroylhydrazone derivatives with high solubility and stability in aqueous solution.[20]
Based on the above findings, the catalytic and biological properties of two new ionic complexes
of oxovanadium (IV) and dioxomolybdenum (VI)-complexes (VOLZNa and MoO2LZNa,
respectively) of bis-bidentate aroylhydrazone sodium sulfonate ligand (HLZNa) are studied.
The geometry of each structure was elucidated by DFT/B3LYP method. Also, to give depth
for in vitro study, different silico ways as Swiss-ADME, Pharmacophore and Molecular
Operating Environmental module (MOE), were utilized.
2 | Experimental
2.1 | Reagents and methodology
They are reported in the supplementary materials
2.2 | Synthesis
2.2.1 | Synthesis of the dinitro-aroylhydrazone ligand (HLZNa)
HLZNa ligand, 3-((2-(2,4-dinitrophenyl)hydrazineylidene)methyl)-4-hydroxybenzene sodium
sulfonate, was obtained in 81% yield (0.32 g) by refluxing a mixture of 2,4-
dinitrophenylhydrazine (0.20 g, 1.0 mmol) in 30 ml methanol and 3-formyl-4-hydroxybenzene
sodium sulfonate (0.22 g, 1.0 mmol) in 40 mL water for 2 h with continuous stirring at 90 °C.
The solvents were removed, and the obtained precipitate was washed 3 times with Et2O and
dried in an oven at 50 ºC. The solid obtained was re-crystallized from a mixture of H2O: MeOH
(1 : 1) to give an orange solid.

1
H NMR δ = 7.41 (s, 1 H), 7.57 (s, 1 H), 7.72 (d, 3J = 8.0 Hz, 1 H), 7.90 (s, 1 H), 8.20 (d, 3J =
7.8 Hz, 1 H), 8.68 (s, 1 H), 9.37 (s, 1 H, ―CH=N―) and 10.53 ppm (s, 1 H, NH) (Fig. S1a).
13
C NMR δ = 118.88 (CH), 120.10 (Cq), 121.64 (CH), 126.01 (CH), 131.45 (Cq), 133.53 (CH),
137.23 (Cq), 149.55 (CH), 155.01 (Cq), 159.17 (Cq), 161.81 (CH), 166.28 (Cq) and 173.22 ppm
(CH=N) (Fig. S1b). Also, the microelement CHN analyses of HLZNa are C: 39.01 (38.62), H:
2.00 (2.24) and N: 13.45 (13.86), m.p. is 289 °C.
2.2.2 | Synthesis of VO2+- and MoO22+-aroylhydrazone complexes

A general procedure for the synthesis of VO2+- and MoO22+-aroylhydrazone complexes was
followed: a mixture of HLZNa (0.81 g, 2.0 mmol) and the corresponding metal acetylacetonate
(1.0 mmol), i.e. bis(acetylacetonato)oxovanadium(IV) (VO(acac)2) or bis(acetylacetonato)
dioxomolybdenum (VI) (MoO2(acac)2, in 40 mL H2O was refluxed for 3 h at 90 °C. The
resulted solutions were cold down gradually to room temperature and water was removed under
reduced pressure. The residue was washed with diethyl ether and then dried in a vacuum to
afford a crystalline solid. The obtained solid complex was re-crystallized in a 40 mL methanol:
water mixture (1: 1) and dried in an oven at 70 ºC. Then corresponding complexes were
obtained with good yields, i.e. 69% (0.60 g) of VOLZNa and 74% (0.69 g) of MoO2LZNa.
1
H NMR δ = 7.28 (s, 1 H), 7.39 (s, 1 H), 7.48 (s, 1 H), 7.74 (s, 1 H), 8.82 (s, 1 H), 9.89 (s, 1
H), 11.61 (s, 1 H, NH) and 12.32 ppm (s, 1 H, ―CH=N―) (Fig. S2a). 13C NMR δ = 117.68
(CH), 119.99 (CH), 123.32 (Cq), 129.97 (CH), 136.88 (CH), 143.56 (CH), 146.96 (CH), 151.02
(Cq), 153.17 (Cq), 161.24 (Cq), 166.38 (Cq), 179.10 and 192.52 ppm (CH=N) (Fig. S2b).
The microelement CHN analyses for VOLZNa are C: 36.10 (35.75), H: 1.54 (1.85) and N:
13.16 (12.83), and for MoO2LZNa are C: 33.05 (33.42), H: 1.99 (1.73) and N: 9.88 (10.27),
m.p. of VOLZNa and MoO2LZNa is > 300 °C.
2.3 | Catalytic epoxidation of alkenes

For the accomplishment of the catalytic epoxidation of alkene, a three necks round bottom flask
of 100 mL capacity was connected with a water circulation condenser was loaded with 1.0
mmol of 1,2-cyclooctene (as the standard model of cycloalkenes), 3.50 mmol of hydrogen
peroxide (30% in H2O in water) and 0.02 mmol of VOLZNa or MoO2LZNa catalysts in 10.0
mL acetonitrile (AN). The redox reaction was kept with continuous stirring and heating at
various reaction temperatures from 50 to 100 °C for 6 h under a homogenous and aerobic
atmosphere. The progress of the reaction was monitored by gas-chromatography mass-spectra
(GC-MS) by the determination of the yielding percentages of the selective epoxide products.

Kinetic control of the catalytic processes was carried out by withdrawing about 10.0 μL sample
from the mother reaction mixture and treated with solid MnO2 (0.2 g) to quench excess H2O2
and then with anhydrous Na2SO4 to extract water from the sample solution. After that, the
resulting sample was filtrated through 0.3 g celite with dilution using AN (2 mL). A 1.0 µL
sample was delivered from the filtrate to the GC-MS device. For the catalytic system in H2O,
as a solvent, the products of the epoxidation reaction were extracted by diethyl ether (Et2O).
The GC-MS device model was QP2010 SE and supplied with Rxi-5 Sil MS capillary column
of 30 m length × 0.25 mm ID × 0.25 um film thickness. Within the GC parameters, the analysis
of the formed products was accomplished at injector temperature 25 °C of the oven with
gradual temperature increase to 200 °C by temperature rate of 10 °C min −1. The oven
temperature was held at 40 °C for 1 min. With the splitless mode, the inlet was operated. The
mass spectra transfer line temperature was held at 200 °C. The carrier gas was Helium with
99.999% purity, which fluid with a rate of 1 mL per min. The obtained analytical results of the
detected products were investigated by using LabSolution software with system control.
2.4 | Antimicrobial studies

2.4.1 | The antibacterial potential
The antibacterial properties of HLZNa ligand and its VOLZNa and MoO2LZNa complexes
were evaluated versus three bacterial strains namely, Escherichia coli and Serratia marcescens
as Gram-negative bacteria and Staphylococcus aureus as Gram-positive bacteria. Briefly, stock
solutions (20 μM) of HLNZa, VOLZNa and MoO2LZNa were prepared in DMSO. The
respective antibacterial potential was estimated using the known agar well dilution method.[20]
The bacterial strains' growth was performed in nutrient agar with sterile Petri plates. Wells
were made in agar with sterile cork borers. Paper discs were saturated with 20 μM of the
compounds and placed in the wells. Plates were then incubated for 24 h at 37 °C.[38] Negative
(DMSO) and positive (Gentamicin) controls were also included. It is worth noting that, there
was no influence of the DMSO against the bacterial strains. The applied DMSO concentration
was ˂ 0.1% and doesn't cause any growth inhibition against the bacterial strains.
2.4.2 | The antifungal potential

The antibacterial properties of HLZNa ligand and its VOLZNa and MoO2LZNa complexes
were also estimated against three fungal strains namely, Aspergillus flavus, Candida albicans,
and Trichophyton rubrum following the same method applied for the antibacterial assay.[38]
Fungi were isolated from the infected plant, extracted and mixed with the potato dextrose agar

which in turn was poured into Petri dishes. Plates were treated with the test compounds (20
μM) and incubated at 37 °C for 72 h. DMSO and Fluconazole were included as the negative
and positive controls, respectively. Indeed, DMSO concentration was ˂ 0.1% and did not
display any observable activity against the growth of the fungi.
2.4.3 | Minimal Inhibitory Concentration (MIC) and activity index (A)

With respect to the above antimicrobial studies, minimal inhibitory concentration (MIC) was
determined for the least HLNZa, VOLZNa or MoO2LZNa concentrations, which showed the
highest effective microbial growth inhibition. Activity index (A) was also calculated from the
inhibition zones (mm) of HLNZa, VOLZNa or MoO2LZNa compared to the inhibition zones
of the Gentamicin and Fluconazole standard drugs using Eq. 1:[20]
𝐼𝑛ℎ𝑖𝑏𝑖𝑡𝑖𝑜𝑛 𝑧𝑜𝑛𝑒 (𝑚𝑚)

𝐴= × 100 (1)
𝐼𝑛ℎ𝑖𝑏𝑖𝑡𝑖𝑜𝑛 𝑧𝑜𝑛𝑒 𝑜𝑓 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑑𝑟𝑢𝑔 (𝑚𝑚)
2.4.4 | Antioxidant potential

2.4.4.1 | DPPH screening
The free radical scavenging potential of VOLZNa and MoO2LZNa complexes was
preliminarily investigated employing the DPPH method.[38] Briefly, DPPH solution (0.1 mM
in 2.40 mL methanol) was added dropwisely to 100 µM aqueous solution of VOLZNa or
MoO2LZNa complex, and the resulting mixture was kept in the dark for a half-hour at 27 °C.
The decaying of the methanolic DPPH purple to the pale-yellow color was followed
spectrophotometrically and the molar absorptivity was measured at λ = 517 nm. Vitamin C was
used as the positive control,[39] whereas methanol and a blank sample (without DPPH) were
employed as the negative controls. The DPPH radical screening percentages were determined
following Eq. 2: [39]
𝐴𝑜 −𝐴𝑠
Radical scavenging % = ( ) × 100 (2)
𝐴𝑜
where, Ao is the control absorption and As is the sample absorption.
2.4.4.2 | SOD screening

The superoxide dismutase antioxidant-like potential of VOLZNa or MoO2LZNa was estimated
spectrophotometrically according to the reported method.[40] The complexes' potential to

inhibit phenazine methosulphate-mediated reduction was investigated using the nitro blue
tetrazolium dye at 560 nm of the absorption band and the shifts were recorded for more than 5
min.[40]
2.4.5 | Anticancer potential

The anticancer potential of the free hydrazone for HLZNa and its VOLZNa and MoO2LZNa
complexes were examined against three human cancer cell lines namely, hepatocellular
carcinoma (HepG-2), breast adenocarcinoma (MCF-7) and colon carcinoma (HCT-116) using
the reported method.[38] Cancer cells were mixed with sulforhodamine-B-stain (SRB) and the
absorbance was measured at λmax = 564 nm of SRB using ELISA microplate reader.[20] The
cancer cells were cultured within 104 cells well-1 in 96-multiwell plates and treated with serial
dilution concentrations of the current compounds (i.e. HLZNa, VOLZNa or MoO2LZNa). The
Sulfo-Rhodamine-B-stain (SRB) was applied, and plates were then incubated under inert
conditions (15% (v/v) CO2) for 48 h at 37 °C. Vinblastine was employed as the positive control.
The cytotoxicity was deduced from obtained IC50 concentrations (µM), which in turn is
determined by applying Eq. 3:[38]
𝐶𝑜𝑛𝑡𝑟𝑜𝑙𝑂𝐷 −𝐶𝑜𝑚𝑝𝑜𝑢𝑛𝑑𝑂𝐷
𝐼𝐶50 (µM) = × 100 (3)
𝐶𝑜𝑛𝑡𝑟𝑜𝑙𝑂𝐷
It is worth noting that, the applied DMSO concentration was ˂ 0.1% and didn't cause any
proliferation inhibition against the cancer cells.
2.4.6 | ctDNA interaction nature

A stock solution of ctDNA was prepared by dissolving ctDNA in fresh DMSO with a solution
of 50 mM NaCl and 5.0 mM tris-HCl for the pH control and then was kept at 4 °C. The molar
absorptivity was checked spectroscopically at λmax (260 nm) giving ~ 6600 mol-1 cm-1 and the
absorbance (A260/A280) ratio was also checked at 260 and 280 nm for the solution of ctDNA to
give 1.86, which in turn proofed the ctDNA stock solution purity.[20] The ethidium bromide
(EB) standard concentration was examined in the same study at (480 nm) giving ƹ = 5860 mol-
1
cm-1. HLZNa, VOLZNa and MoO2LZNa stock solutions were prepared in DMSO at ambient
temperature. Stock solutions were diluted to the given concentrations using buffering 1.0 × 10-
3
mol dm-3 solution of ctDNA with tris-HCl (5.0 mM) and NaCl (50 mM) and examined at pH
7.5.

2.4.6.1 | UV-Visible spectrophotometric investigations
Variable concentrations of ctDNA (μM, in DMSO) were mixed with HLZNa, VOLZNa or
MoO2LZNa (5.0 μM, in DMSO) and the UV-Vis. spectral changes of the characteristic
absorption bands were investigated according to the reported procedure.[38] At λmax, the marked
changes in the absorbance could be used to determine the binding constant (Kb), which refers
to the degree of interaction between these reagents and ctDNA. Applying Eq. 4, Kb could be
obtained by plotting of the ratio of [DNA]/(εa - εb) against the concentrations of ctDNA, as
reported elsewhere:[38]
[𝐷𝑁𝐴] [𝐷𝑁𝐴] 1
=𝜀 + [𝐾 (4)
𝜀𝑎 −𝜀𝑓 𝑏 −𝜀𝑓 𝑏 (𝜀𝑏 −𝜀𝑓 )]
since, εf represents the extinction coefficient of free ctDNA solution in absence of any studied
compound, εa represents the extinction coefficient of the mixed ctDNA solution with HLZNa,
VOLZNa or MoO2LZNa, and εb represents the coefficient at the end of the reaction between
the ctDNA and HLZNa, VOLZNa or MoO2LZNa. The extinction coefficients εa, εa and εb were
obtained from the plots of the absorbance Aabs against the concentrations of HLZNa, VOLZNa
or MoO2LZNa and alternative ctDNA concentrations, at room temperature. The intercept of
plots gave the value of Kb. Also, ∆𝐺𝑏≠ values (the standard Gibbs free energy) for the reaction
of ctDNA with the current compounds were elucidated from the Kb values by applying Eq.
5:[38]
∆𝐺𝑏≠ = −𝑅𝑇𝑙𝑛𝐾𝑏 (5)
Through Eq. 6, the percentages of the derived chromism for ctDNA interaction with the
compounds were deduced and evaluated:
𝐴𝑓𝑟𝑒𝑒 −𝐴𝑏𝑜𝑛𝑑𝑖𝑛𝑔
Chromism, % = (6)
𝐴𝑓𝑟𝑒𝑒
For the unreacted compounds, its absorbance is Afree, while, for the interacted ones with ctDNA
solutions, the absorbance is Abonding, at the characteristic maximum absorption wavelength
(λmax) for the solution of HLZNa, VOLZNa or MoO2LZNa.

2.4.6.2 | Viscosity investigations
Using Oswald micro-viscometer, the changes in the viscosity of ctDNA could refer to the
hydrodynamic reactivity of different concentrations from HLZNa, VOLZNa or MoO2LZNa in
DMSO (0.0 - 5.0 μM) with ctDNA solution in DMSO at 25 °C. The time consumption for the
ctDNA solution fluidity with or without the current compound (in seconds) under inert media
(N2 gas bubbling into the studied solution), could be used to evaluate the viscosity.[20] The free
ctDNA viscosity is ηo and the mixed ctDNA with different concentrations of HLZNa, VOLZNa
or MoO2LZNa viscosity is η. Both ηo and η is obtained by Eq. 7:[38]
𝑡−𝑡 𝑜
𝜂= (7)
𝑡𝑜
From Eq. 7, t represents the consumed time for the different concentrations fluidity for each
tested compound after mixing with ctDNA solution. In addition, to represents the taken time
for the fluidity of the different concentrations from each compound in absence of ctDNA
solution. Within the plotting of the ctDNA viscosity versus the reciprocal of R (1/R), which
obtained by Eq. 8, the viscosity ratios (η/η°) could be deduced.
[𝐷𝑁𝐴]
𝑅 = [𝐶𝑜𝑚𝑝𝑜𝑢𝑛𝑑] (8)
[DNA] represents the concentration of ctDNA in DMSO, and [compound] is referring to the
diluted concentrations of HLZNa, VOLZNa or MoO2LZNa solution in DMSO.
2.4.7 | Conformational analyses

2.4.7.1 | The structural optimization
Gaussian 09[41] was used to construct optimal geometries of the molecular structure of HLZNa,
VOLZNa or MoO2LZNa using the DFT/B3LYP procedure. Such analyzes were carried out
using the valence double-zeta with polarization feature (6-31G*), as the basis set. 6-d-functions
must be added to the 6-31G set for polarization via the polarizable model of Integral Equation
Formalism Variant to explore the ground and excited levels (IEF-PCM). Two computing files
(Log and chk) were generated, but a third (fchk) was acquired after the chk file, which created
using Gauss-prog.[42] To determine essential physical indices, all three files were examined
using Gauss-View and Gauss-Sum 2.2[42] according to the numbering schemes. Owing to the
increased reliability of computational data, chemistry professionals were very interested in

such computational study, especially giving many challenges, they had in isolating single
crystals of HLZNa, VOLZNa and MoO2LZNa.
2.4.7.2 | Silico assays

(a) Swiss ADME link
This method was used to utilize molecular structure, pharmacokinetics and physicochemical
factors to anticipate ADME (absorption, distribution, metabolism and excretion) attributes.[43]
The therapeutic effects of HLZNa ligand were easily checked, but owing to their high
molecular weights, which were difficult to control in this approach, we have been unable to
test these complexes. We looked examined physicochemical characteristics, pharmacokinetic
qualities and drug-likeness.
(b) Pharmacophore search

Employing grid-based and ligand-based kinds, a pharmit link was created to examine the
possible therapeutic efficacy of VOLZNa and MoO2LZNa complexes.[44] Staphylococcus
aureus (1bdd), Candida albicans (1nmt), Serratia marcescence (3zfi) and the receptor tyrosine
kinase (2a91), as well as, the human oestrogen receptor (2iok) of breast cancer cells, were the
proteins chosen for the current investigation (Fig. S3). This choice was done mainly according
to in vitro studies showing that these complexes had a high level of activity against known
pathogens, as well, as a breast cancer cell line. Such study allowed them to create a simulated
behavior inside infected cells. The PDB protein designations were determined from the
database bank of proteins. Each protein was entered into the application, the interaction
characteristics were entered, and the procedure began after each complex was saved as a mol2
file. When the stable interaction profile was reached, the analysis was completed. The patterns
were then acquired, and we used a pharmacophore inquiry to look for drug-like isoforms in the
MolPort and Zn drug banks, which totaled 112,939,594 and 123,399,574 conformers,
respectively. Also, the content of banks was upgraded at 01:19:34 in Jul-2021 and 58:08 in
Jun-2019,[45] respectively, and comprise 7,875,286 and 13,190,317 molecules. H-bonding
between the chemical and the protein-receptors was quantified and characterized.
(c) MOE- module of molecular docking

The silico method was used to enhance the biological inquiry and to confirm the right proof for
the simulated behavior of VOLZNa and MoO2LZNa complexes within changeable pathogenic
cells using the Molecular Operating Environmental (2018 Edition) software.[46] The analytical

data were appeared to be within excellent accuracy, allowing for a reasonable estimate of the
biological efficacy of the given compounds. This silico screening was recommended for usage
before or after an in vitro study to evaluate the results and monitor the inhibitor-pathogenic
protein interaction. For this estimation, each of VOLZNa or MoO2LZNa interacted with 1bdd,
1nmt, 5uw2, 3zfi, 2iok, and 2a91 as the PDB proteins chosen for this study and also previously
characterized (the above part). To start the docking operation, several orientations must be done
over each complex and the target proteins. The complex must be modified until energy
minimization is achieved, at which point the atomic charges must be rendered and the potential
energy values must be managed. After that, a database could be achieved just to save the
compound as an MDB file, which is now ready for docking. Every protein was also upload into
the software as a PDB file. Additionally, using the MMFF-force field[46] could remove the
solvent molecules after detecting the receptors, and then insert the hydrogen atoms over the
receptors.[46] As a result, the unwanted helix was excluded, the receptor types were linked,
potential energy was fixed, and then the receptors and dummies were explored. The generated
pose was the steadiest of the 30 poses, which generated by the docking approach demonstrating
a wide range of allosteric interactions with protein pockets. The London dG-scoring method
was used to change these poses, which enhanced two times with the help of the triangle-
matcher. The correct docking routes were found and undesirable collisions that caused false
removed poses. The inhibitory rank was determined by the length of interaction bonds (H-
bonding), which could not exceed 3.5 Å thus according to Van der Waals, as well as, the
scoring values were calculated using a traditional relationship.
3 | Results and discussion

3.1 | Synthesis and characterization
New water-soluble ligand, as a green chelating reagent (HLZNa), was synthesized in good
yield (81%) by the equimolar condensation of 2,4-dinitrophenylhydrazine with 5-sodium
sulfonate-3-formyl-4-hydroxybenzene in aqueous methanol (water : methanol, 1 : 1) (Scheme
1), as reported for the non-polar substituted aroylhydrazones.[47]
The attached 5-sodium sulfonate group to the new eco-friendly ligand enhanced its solubility
in H2O during the complexation with VO2+and MoO22+ ions. HLZNa ligand acted as a green
chelating reagent with mono-basic N,O-bidentate towards VO2+ and MoO22+ ions (Scheme 2).
Therefore, the complexation was carried out in 2 : 1 molar ratios of HLZNa ligand to the metal

ion with good yields (69 and 74%), respectively. The structural confirmation of HLZNa,
VOLZNa and MoO2LZNa was accomplished by different spectroscopic methods, i.e. NMR,
UV-Visible and IR spectra, as well as, the analytical methods i.e. EA and conductivity
measurements (Table 1).
The most required analyses, CHN micro-analyses, of HLZNa ligand and its VO- and MoO2-
complexes were compatible with the calculated values for their structural confirmation with
less difference (˂ 4%) between the obtained and the calculated percentages, which refer to their
purity. The measured melting points for the crystalline solids, HLZNa (289 °C), VOLZNa (>
300 °C) and MoO2LZNa (> 300 °C), demonstrated remarkable stability, due to the attached 5-
sodium sulfonate group.[38] The salting nature of the current compounds could be realized by
studying their molar conductivity in water, DMSO and DMF, which revealed high conducting
characteristics. The conductivity nature of the free ligand (HLZNa) gave low values compared
to their M-complexes, due to the lower number of the released counter ions in the solution.
HLZNa ligand gave two ions per molecule, whereas each complex gave three ions per molecule
in their solutions (two sodium cations and the whole anionic molecule) (Table 1). The
stoichiometry of the molar solutions of the reacted HLZNa ligand with VO2+ and MoO22+ ions
in the aqueous medium was probed by using of continuous variation method (Fig. S4). Hence,
each oxy-metal ion chelated with two hydrazone ligand molecules (i.e. in 1 : 2 molar ratios,
respectively). Based on the various pH values, the VO(II) and MoO2(II) complexes stability
was tested in standard universal buffers.[39] The aqueous solutions of both M-chelates are stable
in pH range (= 3.2 to 10.5, as given in Fig. S5). Due to the ionic nature of the compounds, they
are quite soluble in H2O and all other coordinating solvents, i.e. DMSO and DMF, but slightly
soluble in polar organic solvents, i.e. acetonitrile, methanol and ethanol. VOLZNa complex
showed a paramagnetic nature according to 3d1 configuration in VO2+ ion (2.11 B.M.). The
MoO2LZNa complex showed diamagnetic properties, therefore, it was studied by NMR
technique.
As documented, in protic solvents, Schiff base complexes were known to be decomposed, such
as water, and with strong coordinating solvents they can easily react, such as DMF and DMSO,
to give place to different coordination species.[48] So that, the stability experiments were
progressed in water, DMSO and acetonitrile spectroscopically before further applications take
place. The results signify no observable decomposition for the free ligand and its complexes
over four days at room temperature.

3.1.1 | NMR spectra
The 1H and 13
C nuclear magnetic resonance spectra of the bidentate sodium sulfonate
aroylhydrazone ligand (HLZNa) are presented (Figs. S1a,b). The high significant 1HNMR
spectral signals were positioned at δ = 9.37 and 10.53 ppm for the ―CH=N― (Schiff base)
proton and the amino proton (―NH), respectively. Those signals were highly influenced by
the complexation with MoO22+ ion, which shifted to δ = 11.61 ppm, as a broad singlet signal,
for the —NH group and at 12.32 ppm, as a sharp singlet signal, for the azomethine group (Figs.
S1a and S2a). The (―CH=N―) proton displayed strong downfield shift, which could indicate
the reduction of electron density over nitrogen atom due to its coordination with MoO22+ ion
(Scheme 2).[18,20]
The 13C NMR spectral scan assigned the most distinguished signals, which were located at
173.22 ppm referring to the azomethine (―CH=N―) carbon nuclei for the free ligand,
HLZNa, (Fig. S1b). The characteristic signal was also notably shifted after complexation with
MoO22+ ion to 192.52 ppm. This could denote a successful complexation towards MoO22+ ion
through the azomethine group (Figs. S2b). The other characteristic signals were also influenced
by the coordination of HLZNa to MoO22+ ion. The high purity of HLZNa and MoO2LZNa
could be clarified by the results of 1H and 13CNMR spectra.
3.1.2 | Electronic spectra

In aqueous solutions of HLZNa, VOLZNa and MoO2LZNa, the significant molecular
electronic transitions were determined from Fig. 1 and tabulated in Table 1. The recorded data
were distinguished for the maximum absorption wavelength (λmax) for each detected electronic
transition and the molar absorptivity (ε), which listed in Table 1. In the UV-area, the diluted
solution of HLZNa showed a sharp band at 247 nm, which corresponds to π→π* transition. In
the Vis.-area, a very broad band was appeared at 400 nm, assigned to L→CT transitions. For
the chelating complexes, in the Vis.-area, they gave two spectral bands for the aqueous solution
of VOLZNa at 249 and 275 nm, while at 251 and 271 nm for MoO2LZNa, referring to the
π→π* and n→π* transitions, respectively (Fig. 1). Both complexes gave two absorption bands
for the aqueous solution of VOLZNa at 347 and 422 nm, while at 345 and 424 nm for
MoO2LZNa, which belong to n→π* and M→LCT (ligand to metal charge transfer) transitions,
respectively.[40] Additionally, a very broad band was likely observed at 741 nm in the VOLZNa
complex spectrum, which attribute to 2B1g (dz2)→2Eg (dxz, dyz) and 2T2g→2Eg transitions in a
distorted square pyramidal geometry of VOLZNa.[12,26]

3.1.3 | IR spectra
The most important FT-IR vibrational bands of the free ligand HLZNa and its respected M-
complexes are listed in Table 1 (Fig. S6). A broad band of hydroxyl group vibration in the free
HLZNa ligand spectrum was located at 3297 cm-1 with a complete disappearance in the
complexs' spectra. This could be interpreted by its deprotonation and covalence attachment
with the metal ions.[20] In particular, the 𝜈 (CH=N) band of azomethine group in HLZNa ligand at
1723 cm-1, was shifted obviously due to the complexation with VO2+ and MoO22+ ions to
appear at 1642 and 1631 cm-1 for VOLZNa and MoO2LZNa, respectively. The above observed
shift could interpret the participation of the azomethine nitrogen with VO2+ and MoO22+ ions
in their coordination, respectively (Scheme 2). The two nitro groups showed two characteristic
bands at 1572 and 1295 cm-1for N=O and N-O bonds.[38] Both stretching bands were little
shifted in presence of the central metal ion after complexation to 1575 and 1311 cm-1 (for
VOLZNa) and at 1571 and 1255 cm-1 (for MoO2LZNa), respectively. The slight shift of the
vibrational bands of the moiety of SO3-, i.e. S―O- and S=O bonds in HLZNa, which positioned
at 1257 and 1488 cm-1, respectively, was remarked after complexation for VOLZNa at 1462
and 1275 cm-1 and for MoO2LZNa at 1509 and 1255 cm-1, respectively. Significantly, the bands
at 819 and 610 cm-1, which distinguished as new additional weak bands (for VOLZNa) for the
complexation with the V―O and V―N bond formation. Similarly, the new Mo―O and
Mo―N bonds in MoO2LZNa were assigned based on significant bands at 822 and 816 cm-1,
respectively. Also, two additional weak stretching bands (at 977 and 971 cm-1) are attributed
for the cis-O=Mo=O and V=O double bonds, respectively, as reported elsewhere.[20]
3.1.4 | Mass spectra

The MS for the methanolic-aqueous solution of HLZNa, VOLZNa and MoO2LZNa were
scanned and shown in Figs. S7a,b,c. The base peaks of MS for HLZNa were analyzed to
display significant positive peaks for the ionized species of [HL + Na+] at 427.3 m/z and of
[HL + 1] at 405.3 m/z. Moreover, an additional strong base negative peak was detected for the
ionized form [HL – Na+] at 381.8 m/z. Also, the spectrum of HLZNa ligand showed an
additional high intense peak at 301.5 m/z, which explored the mass of the molecule without
the salting substituent [HL – SO3-Na+]. VOLZNa and MoO2LZNa complexes displayed
characteristic spectral positive peaks at 896.5 m/z (for VLOZNa) and 958.1 and 957.3 m/z
referring to [ML + Na+]. In addition, other base peaks at 874.5 and 935.2 m/z of [ML + 1] for
VOLZNa and MoO2LZNa complexes, respectively. Moreover, other observable weak negative
peaks at 827.4 and 888.0 m/z were considered for [ML – 2Na+] for VOLZNa and MoO2LZNa

complexes, respectively. Finally, two significant base peaks were located at 667.0 and 728.5
m/z for VOLZNa and MoO2LZNa complexes, respectively, which correspond to the complex
mass in absence of the two salting groups [ML – 2SO3-Na+].
3.2 | Catalysis
3.2.1 | Catalytic epoxidation reactions
The catalytic reactivity of VOLZNa and MoO2LZNa complexes was studied in 1,2-cyclooctene
oxygenation under aerobic conditions using H2O2, as the oxidant, at the temperature range of
50-100 ºC, homogeneously. The percentages of the conversion, the chemoselectivity and the
yield of epoxy-product were estimated by GC/MS and presented in Tables 2a,b for VOLZNa
and MoO2LZNa, respectively. Blank experiments, which were likely achieved in the
oxygenation processes, i.e. in the absence of the catalysts, didn’t give the target product. The
optimized reactivity of VOLZNa and MoO2LZNa catalysts was accomplished under a
controlled time and temperature, as shown elsewhere.[49]
3.2.2 | Effect of temperature and time

In the system at 50 °C, both VOLZNa and MoO2LZNa catalysts represented low potential even
with a long reaction time up to 6 h, with detection of the percentages of both obtained data of
conversion and selectivity, see entries 1-4 in Tables 2a,b. In addition, the reaction was not
promoted notably at 60 °C, since the epoxy-product yield % were not improved up to 6 h with
either VOLZNa or MoO2LZNa catalyst. The oxygenated product amount percentages were
increased gradually within the time from 1 to 6 h (28, 48, 53 and 61% using VOLZNa, and 24,
46, 51 and 56% using MoO2LZNa catalyst) (entries 5-8, Tables 2a,b). It was noted that the
yield of the side unwelcomed products was increased during passing the time at 50 and 60 °C
but with low percentages.
At higher temperature (70 °C), the percentages of conversion, selectivity and product amount
were grown notably, as recorded in entries 11 and 12 for both VOLZNa and MoO2LZNa
catalysts, respectively. After 1 h, the yielding of epoxy-1,2-cyclooctane was almost low with
both catalysts, in which the yield was recorded as 43 and 38% with VOLZNa and MoO2LZNa,
respectively, (entry 9) in both Tables 2a,b. After 6 h, the amount of epoxy-1,2-cyclooctane
obtained to be 77% (for VOLZNa) and 73% (for MoO2LZNa) as the highest percentages with
an obvious increase of the conversion and selectivity with both VOLZNa and MoO 2LZNa
catalysts.

The catalytic reactions at 80 °C were remarkably enhanced of the chemoselective product with
yielding data 66, 74, 81, and 84 with VOLZNa and 66, 70, 73, and 79% with MoO2LZNa after
1, 2, 4 and 6 consumed hours, respectively, as noted in entries 13-16 (Tables 2a,b). However,
after 1 h, the selectivity percentage was optimized (100% with both catalysts), while decreasing
by time with improving the yield percentages of side products. At 90°C, both values of TONs
and TOFs, as well as, the percentages of the conversion were observably raised after 1, 2, 4
and 6 h with both catalysts. Also, the amount of epoxy-1,2-cyclooctane was increased by time
from 1 to 2 h giving 87 to 92% using VOLZNa and from 1, 2 to 4 giving 83, 87 and 91% using
MoO2LZNa (entries 17, 18, and 19). It was shown that the highest yield percentages with high
selectivity were given at 90 °C, but with various times with VOLZNa and MoO2LZNa, since
the reaction afforded the optimized yields of oxygenated product after 2 h with VOLZNa (92%,
entry 18, Table 2a) and 4 h MoO2LZNa (91%, entry 19, Table 2b). When the time was run
furthermore, the selectivity percentages were reduced and the yield percentages were recorded
as 81 and 89% after 6 h with VOLZNa and MoO2LZNa, respectively.
Within reaction temperature 100 °C, a strong increase in the amount of unwanted side-products
was awarded by GC, as given in entries 21-24, with a dramatic diminish of epoxy-selective
product amount catalyzed by either VOLZNa or MoO2LZNa. Furthermore, at 100 °C, an
excellent conversion was remarked (100%), whereas the reduced selectivity percentages were
obtained within running times. Considerably, within evaporation of the catalytic contents at
100 °C, less selectivity has probably documented. Moreover, the excess amount of H2O2 could
strongly motivate further oxygenation of epoxy-1,2-cyclooctane at 100 °C to other
unwelcomed oxy-products (see TONs and TOFs values in Tables 2a,b).[3]
Conclusively, both VOLZNa and MoO2LZNa catalysts exhibited excellent catalytic potential
toward epoxidation of 1,2-cyclooctene. The optimized time and temperature were assigned by
the percentages of epoxy-product and its selectivity, as reported elsewhere.[49] In particular,
VOLZNa catalyst demonstrated an optimal conditions at 90 °C (2 h) awarding 92% of the
product amount and 96% of the selectivity (entry 18, Table 2a). On the other hand, MoO2LZNa
demonstrated the optimized conditions of yielding 91% and selectivity 92% at 90 °C (4 h)
(entry 19, Table 2b). Due to the interchangeable behavior with a strong character of Lewis
acidity due to the attached double bond oxygen of both metal ion in the catalysts could explain
their distinguished catalytic potential,[41] whereas Mo-catalyst consumed a longer time than
that of VO-catalyst with little less yield percentage of the target product (only oxygen transfer
aspects).[20] Specifically, the strong reversible electrochemical feature between V4+/V5+ ions in
VOLZNa, as called redox couple, could give an additional feature for VOLZNa over that of

MoO2LZNa catalyst. This feature could strongly improve the catalytic reactivity of VOLZNa
compared to that of MoO2LZNa via electron and oxygen transfer aspects.[47]
3.2.3 | Solvent Effect

Interestingly, beside acetonitrile, other solvents, such as chloroform, water and free solvent
environment were probed in oxygenation processes at the optimized conditions. According to
derived results in Table 3, the catalytic reaction in acetonitrile gave the optimized reactivity
with both catalysts (92 and 91% for VOLZNa and MoO2LZNa, respectively). The high polarity
nature of AN (with strong dipole moment) could enhance reactivity of the catalytic system
towards 1,2-cyclooctene oxygenation with the high polar oxidant, i.e. H2O2, with the
mechanistic aspects of electron and oxygen transfer cycles.[50] Additionally, acetonitrile
couldn't easily be oxidized in such a catalytic system specifically at 90 and 100 °C, as high
reaction temperatures, but could promise for further oxygenation of the redox reactions. In
chloroform, the selectivity and yield % of epoxy-1,2-cyclooctane were good with almost 100%
conversion (86 and 85% VOLZNa, and 88 and 88% for MoO2LZNa, respectively) with high
performance of their catalytic potential, Table 3. Additionally, the less polarity nature of
CHCl3 could not improve remarkably the electron and/or oxygen transfer processes between
reaction components compared to that in AN.[51]
In the best solvent (water, the ecofriendly solvent), the conversion was acceptable with good
percentages (88 % for VOLZNa and 90% MoO2LZNa), however, the percentages of both the
amount and selectivity were moderate with both catalysts (Table 3), 58 and 67% with VOLZNa
and 61 and 68% with MoO2LZNa, respectively. Significantly, there was no solubility of the
precursor in water, but the complex catalyst and the oxidant (H2O2) were highly soluble. So,
the miscibility between the reaction components was poor enough to reduce the reactivity of
the catalytic reactions.[18] But at high temperatures (90 and 100 °C), both the precursor and the
epoxy-selective product could enter further oxidation reaction but promotion of an aqueous
hydrolysis processes awarding high yielding of unwelcomed side products, mainly the
cyclooctane-1,2-diol (Scheme 3).[5]
1,2-Cyclooctene is considered as a nonpolar-molecule, which is not completely miscible with

H2O2 (inorganic oxidant) and the catalyst complex (the high polar species) under solvent-free
conditions. This could explain the less reactivity of homogeneous catalysts in the 1,2-
cyclooctene oxygenation processes.[18] It was recorded that the practical amount and selectivity

% of the catalytic reaction by VOLZNa (75 and 82%, respectively) and MoO2LZNa (69 and
78%, respectively) (Table 3), referring to the low potential of both M-complex catalysts under
solvent-free environment compared to that systems in CH3Cl or AN.
3.2.4 | Kinetics of epoxidation protocols

For the epoxidation process under a temperature of 50, 60, 70, 80, 90 and 100 °C, the kinetic
parameters could be determined for VOLZNa and MoO2LZNa catalysts. Under pseudo-first-
order kinetics, the reactions were monitored with a high concentration of H2O2 compared to
that of the reactant one. Applying Eq. 9, plots of ln (C/Co) against t (time) in Fig. 2 (for
VOLZNa) and in Fig. S8 (for MoO2LZNa), the rate constant was estimated of each catalytic
reaction at the given temperature.
𝐶
−𝑙𝑛 (𝐶 ) = 𝑘𝑡 (9)
𝑜
where, t is the time, k is the catalytic rate constant, Co is the initial 1,2-cyclooctene
concentration and C is the residual 1,2-cyclooctene concentration. Also, k values were
determined from the slope in Figs. 2a and S8a. With the Arrhenius equation (Eq. 10), the
activation energy for the epoxidation reactions Ea was derived from plots ln k against 1/T, T is
the temperature in kelvin (Figs. 2b and S8b).
𝐸𝑎
𝑙𝑛𝑘 = 𝑙𝑛 𝐴 − (10)
𝑅𝑇
since, R is represented as the gas constant and A is represented as the pre-exponential factor.[52]
The derived values of Ea and A for 1,2-cyclooctene epoxidation using VOLZNa and
MoO2LZNa catalysts from the slope and intercept are documented at the given temperature
from 50 to 100 °C in Table 4.
𝑘𝐵 𝑇 −∆𝐺 #⁄
𝑘= 𝑒 𝑅𝑇 (11)
ℎ
since, Planck's constant is given by h and Boltzmann’s constant is given as kB. From Eq. 11,
∆𝐺 # is represented as the average Gibb’s free energy for epoxidation processes with both
VOLZNa and MoO2LZNa catalysts, which could be calculated and listed in Table 4. The

activation energy for epoxidation catalyzed by VOLZNa has a higher magnitude than that
reaction catalyzed by MoO2LZNa. Consequently, according to Ea values, VOLZNa catalyst
assigned more enhanced catalytic behavior towards 1,2-cyclooctene oxygenation than that of
MoO2LZNa. As mentioned above, a strong reversible electrochemical feature of VOLZNa
supported the higher reactivity of VOLZNa catalyst.
3.2.5 | Epoxidation of various alkenes

Screening of the catalytic epoxidation for alternative alkenes of aliphatic and cyclic backbone
was tested at the optimized atmosphere of both catalysts, in which the conversion and
selectivity were listed in Table 5. Both VOLZNa and MoO2LZNa showed respectable
efficiency towards the epoxidation of the listed alkenes in Table 5 to their corresponded
selective epoxide by using H2O2. Noteworthy, 1,2-cyclopentene, styrene and 1,2-cyclohexene,
as well as, 1,2-cyclooctene, as cyclic alkenes behave as strong electron-donor via C=C double
bond, which could promote the chemoselective epoxidation potential with both catalysts more
than that of the aliphatic and acyclic alkenes.[18] This could be interpreted by the inner double
bonding feature of the C=C bond in the cyclic precursors with respect to that terminal C=C
double bonding in acyclic and aliphatic alkenes. The reactivity for such epoxidation reactions
could be influenced by the type of the alkene C=C double bond. This could enhance the
coordination of C=C in the alkene to the metal ion in its complex catalyst as appeared in the
catalytic mechanistic cycles, which will be discussed below.[52]
3.2.6 | Mechanistic aspects

Firstly, the catalytic system was not operated via a simple free radical mechanism within the
formation of hydroxyl radicals of H2O2, due to the applying of a radical trap (e.g. Ph2NH). Such
study assigned that there was no concerted or free radical mechanism could take place in the
current catalytic systems.[50]
Based on the literature survey of the electronic spectral changes of the characteristic bands for
the homogenous catalyst (MoO2LZNa) in the redox systems, the mechanistic pathway could
be predicated. From Fig. 3, the characteristic absorption bands for MoO2LZNa was notably
shifted after mixing with the reactant and oxidant in the reaction media from 424 nm to 402
nm (for M→LCT), which could be due to the obvious transformation in the coordination
atmosphere of the surroundings to MoO22+ ion in its chelating-catalyst.[52] Hence, the
probability for the oxygenation (i.e. an oxygen transfer process) from the oxidant accompanied
with the alkene approach or binding to the metal ion could be the reason for such spectral shift.

The proposed mechanism could clarify that the formation of an active intermediate catalyst (B)
with the oxygen transfer process[53] and the binding of the alkene molecule to Mo6+ ion in the
intermediate active catalyst (C), as shown in Scheme 4.[51]
3.3 | The biological activities

3.3.1 | The antimicrobial properties
For estimation of the antimicrobial potential of the newly synthesized compounds, the growth
of different organisms was inhibited with the current compound and the results were recorded
in Table 6. The standard antibacterial and antifungal antibiotics were Gentamicin and
Fluconazole, respectively, which well-known as high effective drugs.[38] Generally, the tested
compounds exhibited higher antibacterial activity against the Gram-positive bacteria (S.
aureus) more than that of the Gram-negative ones (E. coli and S. marcescens). This might be
due to the higher permeability of the Gram +ve bacteria cell wall compared to that of the Gram
-ve ones.[54]
Both M-complexes reduced all the microbial growth to a higher extent than that of HLZNa, the
free ligand, and this was in good agreement with our previous reports.[54] Since, the transition
metal pincer chelates exhibited higher antimicrobial action compared to their respective free
organic ligands.
Depending upon the Overtone's and Tweedy's theory, the anti-microorganism potentials were
enhanced remarkably within the double-bonded oxygen atoms, which attached to the central
metal ions, i.e. V4+=O and cis-O=Mo6+=O species.[18,40] This in turn facilitates the diffusion
through the microbial lipid membrane due to the enhanced lipophilicity. Ultimately, the high
oxidation states of the Mo 6+ and V4+ ions and their corresponding strong electrophilic character
interpret the similar VOLZNa and MoO2LZNa complexes' antimicrobial reactivity. [38] The
polarity of the central metal ion is significantly diminished after bonding with the hydrazone
ligand donor atoms, which promoted its lipophilic character.[55] Accordingly, the presence of
the central metal ion enhances the complex overall penetrating ability through the microbes’
cell wall membranes compared to the free ligand. Subsequently, M-chelates could therefore
inhibit microbial growth by disturbing and blocking the respiration process.[51]
The antimicrobial potential of the compounds was deduced from the activity index percentage
(A, %) according to Eq. 1 and presented in Fig. 4a,b (see also Tables S1 and S2). Furthermore,
the lowest effective microbial growth inhibition concentration of HLZNa, VOLZNa, or

MoO2LZNa was determined from the MIC assay and values are presented in Table S3. Within
this regard, the MIC of the HLZNa ligand was 6.00-7.50 μM against the bacterial strains and
6.25-7.25 μM against the fungal strains, respectively. On the other hand, VOLZNa displayed
MIC in the range 2.75-3.25 μM against the bacterial strains and 2.50-3.10 μM against the fungal
strains. Finally, the MIC of MoO2LZNa was 2.75-3.50 μM against the bacterial strains and
2.50-3.00 μM for the fungal strains (Table S3). These results further confirmed the close
antimicrobial similarity between the VOLZNa and MoO2LZNa.[21,22]
3.3.2 | The antioxidant potential

3.3.2.1 | DPPH assay
For both VOLZNa and MoO2LZNa complexes, their antioxidant behavour was examined by
the DPPH assay employing ascorbic acid (as a positive control). The obtained results were
listed in Table 7. Within the intense absorption in the visible region of the 1,1-Diphenyl-2-
picryl-hydrazine radical, which gave deep violet (at 517 nm), could be evaluated. The fading
of the violet color of DPPH to pale yellow, displayed for the free radical scavenging ability.[56]
Furthermore, the violet color decolorization is stoichiometrically determined within respect to
the number of scavenged electrons. After that, the percentages of scavenging activity of the
studied M-complexes were calculated using Eq. 2 and shown in Table 7. VOLZNa and
MoO2LZNa complexes manifested good radical scavenging activities, i.e. 51% and 54%,
respectively. Furthermore, MoO2LZNa complex reduced slightly the DPPH radical to a higher
extent compared to that of VOLZNa chelate. This could be interpreted by the electrophilic
nature of the central metal ion. Mo6+ ion in MoO2LZNa chelate has higher electrophilic
character compared to that of the V4+ ion in VOLZNa within its high positive charge.
3.3.2.2 | SOD screening

The neutralized oxygen reactive species were pivotal for the chemoprevention of several
diseases.[40] Such process could be controlled within some redox enzymatic substances, e.g.
superoxide dismutase (SOD), glutathione peroxidase and catalase. SOD is considered as a
metalloprotein, which stimulates the transformation of superoxide radicals into hydrogen
peroxide and oxygen. Inherently, the SOD-like activity of VOLZNa and MoO2LZNa
complexes could be estimated via evaluation of their O2.- scavenging potential employing SOD
kit and the superoxide inhibition %, which shown in Table 7.[27]

Both VO- and MoO2-complexes exhibited an interesting SOD-like action. Depending on the
DPPH and antimicrobial obtains, MoO2LZNa complex displayed a higher inhibiting action
(82.6%) than that of VOLZNa complex (79.2%). To this point, VOLZNa and MoO2LZNa
complexes manifested a respective potential antioxidant activity as represented in the SOD and
DPPH assays. Such behavior could be accorded to the coordinated central metal ion in its
complexes, which in turn could progress their compounds redox behaviour.
3.3.4 | Anticancer potential

The cytotoxicity potential of the HLZNa, VOLZNa and MoO2LZNa was evaluated using the
SRB assay against HepG-2, MCF-7, and HCT-116 tumor cell lines. Vinblastine was used as
the positive control and IC50 concentrations were listed in Table 8, by applying of Eq. 3.
VOLZNa and MoO2LZNa complexes were generally more obvious cytotoxic action than that
of their free ligand HLZNa. Both M-complexes exhibited good antitumor activity against the
HCT-116 cells (IC50 = 20.43 and 17.08 μM respectively), MCF-7 cells (10.92 and 10.11 μM,
respectively), and Hep-G2 cells (14.25 and 12.85 μM, respectively). Indeed, both VOLZNa
and MoO2LZNa complexes displayed comparable cytotoxicity against all the tested tumor
cells, which again might be due to attached central metal ion (V4+or M6+ ion) according to
Tweedy's theory.[20,38] Moreover, the VO and MoO2 chelates high Lewis acidic character might
also inhibit the cancer cells' growth.
3.3.5 | ctDNA interaction

3.3.5.1 | UV-Vis. study
The ctDNA interaction with HLZNa, VOLZNa and MoO2LZNa was investigated
spectrophotometrically.[54] Their binding mode with ctDNA could be estimated by studying the
changes and shifts of the characteristic absorption bands at λmax in DMSO with various ctDNA
concentrations within pH control, as shown in Fig. 5a for various VOLZNa solutions.
The binding interaction of HLZNa and its complexes with the nitrogenous base pairs of ctDNA
through π-aromaticity and their characteristic functional groups as —NH, —NO2, and —
CH=N— through electrostatic mode. The electronic transition changes for π→π* (from 242 to
288 nm) and L-CT (from 389 to 408 nm), were monitored. Such type of interaction could be
observed due to the decay of the absorption bands for the π→π* and or n→π* transitions in
HLZNa, VOLZNa and MoO2LZNa complexes with Δn = 46, 17 and 12, respectively (Table

7).[54] Furthermore, the shift and decay of the characteristic broad bands of M→LCT and d→d
transitions assigned the role of V4+ and Mo6+ ions on the interaction potential of their complexes
(VOLZNa and MoO2LZNa, respectively) with ctDNA through intercalative mode.[38] The
distinguished shift and decay of the characteristic M→LCT bands was detected with Δn = 39
and 19, from 420 to 459 nm and from 422 to 441 nm, for VOLZNa and MoO2LZNa,
respectively (Fig. 5a). Additionally, the observed shift and increase of the low energetic band
of the d→d transition for VOLZNa (Δn = 9) was observed also by shifting from 738 to 729
nm. Notably, for the M-chelate structures, the interaction mode could be also supported with
the substitution mode of VOLZNa and MoO2LZNa complexes, but less favored choice, due to
the absence of labile coordinating molecules (solvent), as studied previously.[57]
From Eq. 4, the binding constant, Kb, as a detectable for the strength of interaction between
ctDNA and HLZNa, VOLZNa or MoO2LZNa, could be derived. From Fig. 5b, the obtained
Kb values are recorded in Table 7, giving 2.88, 4.45 and 5.01 × 108 mol-1 dm3 for HLZNa,
VOLZNa and MoO2LZNa, respectively. Moreover, using Eq. 5, beside the binding strength
measurements, the Gibbs’ free energy, which referred to the interacting HLZNa, VOLZNa or
MoO2LZNa with ctDNA, were derived as negative values (∆𝐺𝑏≠ ) and listed in Table 7. The
values of ∆𝐺𝑏≠ were found as -31.14, -32.22 and -32.52 kJ mol-1 for HLZNa, VOLZNa and
MoO2LZNa, respectively. Both derived parameters displayed that VOLZNa and MoO2LZNa
complexes showed higher interaction towards ctDNA more than that of their free ligand,
HLZNa, elucidating the importance of the metal ions for enhancing their complexes’ reactivity
towards ctDNA. The mode of chromism could be also deduced using the spectroscopic changes
for all studied reagents with their increasing or decreasing red shift (Fig. 5a). HLZNa,
VOLZNa and MoO2LZNa represented a hypochromic effect for their interaction with the
double helix structure of ctDNA (Table 7). Hypochromism could be due to the ctDNA
interaction with HLZNa, VOLZNa and MoO2LZNa via electrostatic, intercalative and
replacement modes (Scheme 5), whereas, the hyperchromism could be due to the distortion of
ctDNA double helix structure, as reported previously.[57] Particularly, both MoO22+ and VO2+
ions in their M-chelates displayed more effective interaction with ctDNA than that of their
uncoordinated ligand (HLZNa) with more promotion of the intercalative interaction with
ctDNA, due to the more lipophilic character.[54]

3.3.5.2 | Viscosity measurements
The distinguished discrimination in the particular free ctDNA viscosity and with HLZNa,
VOLZNa or MoO2LZNa could aim to understand the degree of the binding strength using Eqs.
6 and 7.[55] Additionally, EB (ethidium bromide) was applied as a standard interacting agent
(positive control) with ctDNA to compare its reactivity with the studying compounds (HLZNa,
VOLZNa and MoO2LZNa) depending on the measured improvement in the viscosity of ctDNA
solution. The more progressed interaction of HLZNa, VOLZNa or MoO2LZNa with ctDNA
could refer to the more enhancement of the ctDNA viscosity, which followed particularly with
the increase of the studied compound concentrations, as shown in Fig. 6.[56]
From Fig. 6, both VOLZNa and MoO2LZNa complexes represented similar reactivity with
ctDNA, while their free ligand showed observable less potential. But, both M-complexes
displayed a slightly lower enhancement in the viscosity scales compared to that observed for
EB. MoO2LZNa ≈ VOLZNa > HLZNa, this order is referring to the more developed viscosity
of ctDNA with different concentrations of the current compounds. Accordingly, M2+ ions could
be highlighted here as the most effective issue for the studying compounds referring to their
ability to promote the binding with ctDNA with increase of the ctDNA viscosity, via both types
of interaction with ctDNA (intercalation and replacement modes), as reported previously[20]
(Scheme 5). Also, the electrostatic mode could be also taken into the consideration due to the
presence of polar functional groups in the interacting current compounds (Na+SO3-— group).
A further explanation for such interaction for the M-chelates with more effective rigid planar
structural geometry could be considered, which progressed for the intercalation mode with
ctDNA. Thoroughly, the neutralization of the negative charged ligand (HLZNa) with the
positively charged VO2+ or MoO22+ ion through the complexation, affording more diminish in
the electrostatic repulse between the ctDNA and the interacting MO-complexes, as observed
elsewhere.[56,57] The results of this study are agreed with the above obtains from spectroscopic
studies.
3.4 | Conformational analyses

3.4.1 | Structural optimization
DFT/B3LYP approach was applied to deduce the structure confirmation of HLZNa, VOLZNa
and MoO2LZNa within the valence double-zeta involving the polarization property (6-
31G*).[58] The presence of C(17)-O(22) and C(15)=N(14) groups in the optimized form of
HLZNa ligand indicated that they were more easily coordinated with metal ions (Fig. S9).

While the ruling out of N(13)H from the coordination may be due to its existence on the 2,4-
dinitrophenyl ring, which was directly affected by a strong inductive effect excreted by the two
nitro-groups. Such groups have the highest electron-withdrawing characteristic.
3.4.1.1 | Physical features

To determine or analyze the mechanism of binding, Mulliken charges over electron pairs were
recovered from Logfile using a numbering technique (Fig. S10).[58] The charges upon this
O(22) and N(14) atoms (A) of HLZNa ligand were -0.206786 and -0.234994, respectively,
which appear to have adequate nucleophilicity for coordination. The -0.138717 charge upon
this N(13)H atom display less affectivity of this nucleophile. The electron-withdrawing
property of two nitro-groups substituted in the benzene ring influenced this charge
minimization. After coordination with VO(II) and MoO(II) ions, the negative charges of
coordinating atoms (A, 14 and 22) were generally improved (Fig. S10). Due to the participation
of two ligands in the same molecule, the coordinating atoms were renumbered (A, 3, 11, 17
and 25). Considering their cooperation, which must lower atom negativity, M→LCT action
may be responsible for the improvement in charges.
The functional groups N(14)=C(15), O(22)-C(17), and N(14)-N(13) in the ligand have bond
lengths of 1.35848, 1.36556, and 1.23212 Å, respectively. The hybridization of their central
atoms, which differed between sp2 and sp3 types, corresponded to such lengths. The bond
lengths of such groups in the two M-complexes, on the other hand, were elongated after their
coordination (Table 9). In addition, the functional groups in the M-complexes were renamed
C(6)-O(11), C(4)=N(3), C(18)=N(17) and C(20)-O(25). The coordinating groups' stretching
was minimal when compared to the lengths in free HLZNa ligand, indicating that there was no
undesired strain in the bonds.[59]
The bond angles and dihedral angles surrounding the metal atoms were calculated (Table 5).
The angles in the free ligand for selected functional groups looked to be close to 120o, which
corresponded to the already existing sp2 hybridization type. The bond angles around the metal
atoms of square-pyramidal VOLZNa and octahedral MoO2LZNa were measured and found to
be quite similar to the known (90o and 180o), with a little variation indicating a partial
distortion.[60] This distortion could be owing to the Jahn-Teller effect in the VOLZNa, while it
could be due to distinct coordinating sites in the MoO2LZNa (NO). The border orbitals' values
(HOMO and LUMO) were computed and typed (Table 9). The energy differences between the
two orbitals (ELUMO-EHOMO) in the complexes were lower than in the free ligand. This showed,
how metal coordination affected the electronic transitions inside chemical systems. To

establish the degree of solubility of the M-compounds, the dipole moment values (Debye) were
calculated. The ligand has the greatest value (31.7433), followed by the MoO 2LZNa complex
with a value of 24.727 and the VOLZNa complex with a value of 9.506. The results assigned
that VOLZNa complex has a lower polarity, which favored the penetration through the living
cell walls, as well as miscibility with its lipids and hence direct contact with biological systems.
Consequently, VOLZNa complex could have therapeutic potential. Furthermore, the formation
energy values reveal the complexes' high stability (a. u.) over the free ligand.
3.4.1.2 | Frontiers orbitals and Electrostatic potential Maps

3D-maps were displayed on the surface of the free ligand HLZNa or its corresponded M-
chelates (VOLZNa and MoO2LZNa) to differentiate some physical characteristics. From Fig.
7, both HOMO and LUMO patterns for the free ligand were created to illustrate and
differentiate between the two orbitals. These orbitals in the ligand focused on the sodium
sulfonate group, which was far from the targeted groups of coordination. This feature was
strongly expected due to the presence of ionic moiety inside the molecule attracting the highest
electron density compared to the other covalence groups. On the other hand, the feature of these
orbitals was completely changed in the two complexes. They appeared perfectly distributed
mostly over the molecules. This reflected the impact of metal ions on the distribution of
electron cloud at all.
The molecular electrostatic map, MEP, was designed on the molecular surface in particular to
the highlight crucial aspects, see Fig. S11. The electrophilic, nucleophilic and neutral zones of
the free ligand (HLZNa) were marked on this map. For assigning the binding mode inside the
complexes, the nucleophilic character of the heteroatomic functional groups towards M2+ ions
could be evaluated. The electrophilic, nucleophilic and neutral zones were given on the maps
with various colors of red, blue and green, respectively. Because of its high electron density,
the red zone was frequently focused on the ionic moiety (sodium sulfonate). This property was
slightly reduced in MoO2LZNa complex but was completely absent in VOLZNa complex. The
predominant green color in VO2+-complex map reflected the relative neutrality in the
distribution of electron density of complexation.[61]

3.4.1.3 | Supporting the catalytic mechanism of MoO2LZNa complex
The proposed mechanism for MoO2LZNa catalysis was established using the Hartree-Fock
technique (HF) and a correlation-consistent (LanL2DZ) basis set in a molecular modeling
program as Gaussian 09 under the correlation-consistent (LanL2DZ) basis set, due to no
defined analytical solutions could be applied for many-electron systems. Such approximation
method solved the equation numerically. A self-consistent field method was a nonlinear
approach. When it applied to big molecules, this approach (HF) produced results that were the
closest to an X-ray single crystal. Both B and C complex intermediates were treated to reduce
energy content and assess intermediate stability in order to track the mechanism step by step.[55]
The spectroscopic scan changes of MoO2LZNa with 1,2-cyclooctene in presence and absence
of H2O2 in the reaction media of acetonitrile at 50 °C (15 min of the time interval for 6 h), were
recorded and used for practical elucidation of the mechanism (Scheme 4). Here we estimated
the theoretical aspects that facilitated the catalysis success of MoO2LZNa complex in the
alkene epoxidation process with H2O2 as follow;
1) The big size of Mo(VI) ion (as 4d-element) according to its ionic radii recorded (73 pm),
compared to that of the radii of V(IV) ion (72pm), as 3d-element, promoted its associative
mechanism of the reaction. Then, the binding of Mo(VI) ion with the oxygen atom of H2O2
logically happened easily, which followed by oxygen transfer to alkene (i.e. 1,2-cyclopentene).
2) The intermediate B was optimized via energy minimization till to the formation energy E =
-7685.78 a. u., while the second intermediate (C) exhibited a lower formation energy value (-
7162.51 a. u.). These values reflected the relative stability of the two intermediates, which was
less than that of the original complex catalyst (A). This could be due to the activation energy
consumed to accomplish the catalytic reaction. After the completion of the epoxidation
reaction, the original complex was produced without loss and may be reused in different times
by the same efficiency (A*).
3) The diagram of the catalytic cycle was drawn (Scheme 6) to expect the thermodynamic
feature of MoO2LZNa catalysis by using H2O2 in the 1,2-cyclopentene epoxidation reaction.
3.4.2 | In silico assays aspects

3.4.2.1 | Swiss ADME results
For small compounds, the Swiss ADME online software[62] assisted in predicting the most
appropriate pharmacokinetics and drug-analog characteristics. We could analyze HLZNa
ligand alone, however, due to their huge sizes of the M-complexes, they were not handled. The
ligand's response to the blood-brain barrier (BBB) and human intestinal absorption (HIA) was

negative, indicating that they have a lower drug-like characteristic. P-glycoprotein (P-gp)
played a vital role in protecting the central nervous system (CNS) from hazardous chemicals,
and HLZNa had a beneficial effect on P-gp.[62] P-gp was also highly expressed in some tumor
cells, leading to multidrug-resistant cancers. It was suggested that the cytochromes P450 (CYP)
and P-gp enzymes could collaborate to protect organs and organisms by efficiently processing
small compounds. This suggested that HLZNa ligand had carcinogenic properties and could
not protect against drug absorption and permeability. Table 6 shows the physicochemical and
drug-like properties, which calculated and displayed to predict the bioactivity of the modified
ligand. The degree of miscibility with cell-lipids was measured using the lipophilicity
(XLOGP3), polarity (TPDS) and partition coefficient for n-octanol/water (log Po/w) indices.
The more solubility of a substance in lipid assigned a great bioactivity and ability to permeate
the hydrophobic wall of cells. In addition, the degree of interaction with the five major iso-
enzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4 could measure some
pharmacokinetic aspects.
Lipophilicity (XLOGP3 = 2.14), polarity (TPSA = 201.84), size (MW = 404.29 g/mol),
solubility (Log S = -6.01), molar reactivity (91.59), flexibility (number of rotatable bonds = 6)
and saturation (Fraction Csp3 = 0.01) were evaluated. The following pharmacokinetic
characteristics (BOILED-Egg, Table 10) were also determined: inhibition of
CYP1A2/CYP2D6/CYP2C9/CYP3A4 = No, whilst inhibition of CYP2C19 = Yes,
bioavailability score = 0.55, Log Kp (skin permeation) = -7.25 cm/s, drug-likeness = No and
medicinal chemistry: PAINS = 0, Partition coefficient (Log po/w = -1.95). The ligand had a
higher solubility (Log S) in water, indicating that it had lower lipophilicity as initially assumed.
HLZNa ligand, on the other hand, inhibited four important isoenzymes
(CYP1A2/CYP2D6/CYP2C9/CYP3A4). The ligand blocked these iso-enzymes, which
influenced important pharmacokinetic properties. Inhibition of these iso-enzymes was one of
the most common causes of pharmacokinetics in drug interactions.[63] Despite its lower
lipophilicity, the ligand had an efficient therapeutic function.
Interestingly, this software could be used to estimate the HLZNa targets in biological systems
inside the infected cells. The interaction directions of HLZNa ligand inside the cell were drawn
and displayed (Fig. 8). HLZNa ligand may be directed to carbonic anhydrase II (CA2) as lyase
target by 40%, to squalene synthetase (FDFT1), as enzyme target by 20%, to phosphodiesterase
3 (PDE3A) as a phosphodiesterase target by 20% and to neprilysin (MME) as a protease target
by 13.3%. The selectivity of HLZNa ligand became higher towards Lyase targets and enzymes.

3.4.2.2 | Pharmacophore assay
The patterns of such interaction were yielded from VOLZNa and MoO2LZNa complexes with
the proteins of Staphylococcus aureus (1bdd), Candida albicans (1nmt), Serratia marcescence
(3zfi) and the receptor tyrosine kinase (2a91), as well as, the human oestrogen receptor (2iok)
of breast cancer cells (Fig. S3). The excluding of the ligand from this silico assay due to its
physical characteristics, which has been estimated, confirmed its biological ineffectiveness.
While, both complexes have the opportunity for a successful role, particularly VOLZNa, as
reported in part 3.4.1, which agreed with in vitro results. This web tool aided in the creation
and modification of quires for filtering medication databases.[64] The pharmacophore was a
spatial structure of the reaction's fundamental characteristics, and the shape of the molecule
defined inquiries. Energy reduction could be used to rank and filter search results. Researchers
can test their possible medications in one of several pre-built databases that contain common
chemicals. Pharmit screens millions of chemicals using sub-linear algorithms.
For comparison, this assay aimed to imitate the activity of M-complexes inside distinct
pathogens, which have a substantial impact on in vitro treatment. The interaction profiles were
gathered and shown on the screen (Figs. 9 and S12). The profiles belong to Staphylococcus
aureus (1bdd) and Serratia marcescence (3zfi) proteins definitively, which they showed an
effective interaction between the complexes and the reported proteins (1bdd, 3zfi and 1nmt)
only. While the other profiles (Fig. S12) revealed absent interaction for the M-complexes with
2iok and 2a91 proteins. So that, the effective inhibition of such complexes for a receptor
tyrosine kinase (2a91) and for the human oestrogen receptor (2iok) of breast cancer cells is
unexpected.[65] Furthermore, pharmacophore searches in the MolPort and Zn databases turned
up no hits. The number of H-bonding, which produced towards 1bdd and 3zfi proteins, were
calculated as follows: three for H-acceptor, six for H-acidic and five for H-donor types with
VOLZNa complex. There were also four H-acceptor, six H-acidic and six H-donor kinds in
MoO2LZNa complex (Fig. 9).
This approach was insufficient to produce a comprehensive report on biological forecasting for
these complex systems. The final view on its pharmacologic role would be made by the
subsequent Molecular Operating Environmental Docking (MOE). Breast cancer cells, in
particular, have a noteworthy variation in the in vitro results, particularly in terms of outcomes.
This discrepancy would be addressed in the following test (part C), which establish one of
them's veracity.[66]

3.4.2.3 | MOE module for docking
The MOE module was utilized in this silico experiment to imitate the action of the two
complexes towards the chosen proteins from bacteria and fungi (1bdd, 3zfi and 1nmt), as
previously described.[67] This silico technique gave the most precise picture of bioavailability
inside infected cells, which was generally correct in practice. The allosteric binding affinity of
MoO2LZNa and VOLZNa complexes with protein base pairs within the pockets was predicted
using docking complexes (Figs. 10 and S13), which illustrated in Table S4. The two
complexes had distinct interactions with the three pathogens, which corresponded to the
findings provided in the computational and practical discussion sections. As a result, the
inhibitory activity of the two complexes against Staphylococcus aureus (1bdd), Candida
albicans (1nmt) and Serratia marcescence (3zfi) proteins was influenced by the following
remarks:
I) VOLZNa complex docking scored values (S) ranged from -8.4882 to -7.9696, whereas the
MoO2LZNa complex docking values ranged from -8.4081 to -7.9987. These results indicated
that the complexes were effectively inhibiting these microorganisms.[67]
II) According to Van der Waals, all bond lengths between donor sites in interacting molecules
with receptors or dummies were typical to ≤ 3.5 Å. (Table S4).
III) In terms of VOLZNa docking, the binding sites with LYS5 (A), ASN4 (A), HOH587 (B),
LYS301 (B), HOH590 (B), ASN40 (A) and ARG107 (A) residues were O13, O14, O28, O29,
and O56. Apart from only one H-ionic bond, the allosteric binding created inside the pockets
was the H-acceptor kind. The interacting residues were a polar residue (pink circle) via a side
chain acceptor link, a basic residue (blue circle) via a backbone acceptor bond, and solvent
residues interacted as well.[65] In the three docking patterns, a smaller ligand exposure surface
indicates that the entire interaction was achieved from the molecule and there is no further
bonding could be formed. The proximity contour perfectly encompassed all docking sites,
indicating that bonding saturation had been reached.[64]
IV) The binding locations for ASN29 (A), ARG28 (A), MET252 (A), ESR241 (A), LYS407
(A), LYS75 (A), and ARG107 (A) residues in the MoO2LZNa complex docking were O13,
O28, O30, O41, and O53. The allosteric binding created inside the pockets was of the H-
acceptor and H-donor types, with only one H-ionic bond. The interacting residues were a polar
residue (pink circle) via side-chain acceptor bond, a basic residue (blue circle) via backbone
acceptor bond, and a greasy residue (green circle) via backbone donor type.[65] The three
docking patterns have a smaller ligand exposure surface, indicating that the entire interaction
was gained from the molecule and no additional bonding could be created. But the surface is

wider than the VOLZNa patterns, indicating fewer features of MoO2LZNa than the VOLZNa
interaction. The proximity contour perfectly covered all docking sites, indicating that bonding
saturation had been reached.[68]
With all docking complexes, modest formation energy values were observed, the values were
from -0.3 to -5.4 Kcal/mol.[68] This indicates the moderate stability of interacting profiles with
targeted proteins. Finally, the two complexes may be promising as antibiotics for definite
microbes.
4 | Conclusions
A new polar aroylhydrazone ligand (HLZNa) behaves as a mono-basic bidentate chelating
ligand with vanadyl and molybdenyl ions to give new M-complexes (VOLZNa and
MoO2LZNa, respectively) under sustainable environments. HLZNa, VOLZNa and
MoO2LZNa were characterized by the most possible spectroscopic tools. IR spectra displayed
high shift of the CH=N band with disappearance of O-H band of HLZNa after its coordination
to V4+ and Mo6+ in VOLZNa and MoO2LZNa, respectively. 1HNMR spectra supported the
above observation for HLZNa compared to that of MoO2LZNa for the spectral signal of CH=N
and O-H groups. In UV-Vis. spectra, VOLZNa showed an additional spectral band at 741 nm
for the d→d transition, which assigned such complexation. The catalytic potential of the
complexes was tested in an epoxidation reaction of unsaturated alkene (1,2-cyclooctene to the
selective epoxy-1,2-cyclooctane) by an aqueous H2O2, in which VO2+-complex catalyst
exhibited little more distinguished catalytic performance over that of MoO22+-complex catalyst.
The optimum reaction atmosphere for both catalysts was found at 90 °C after 2 h with VO(II)-
catalyst (92% amount of epoxy-selective product) and 4 h for MoO2-catalyst (91% yielding of
the selective product) in acetonitrile. The reactivity of the VOLZNa catalyst was a little better
than that of the MoO2LZNa catalyst for the optimization of the 1,2-cyclooctene epoxidation.
The high electrochemical reversible character (i.e. V4+/V5+ redox couple) for the VOLZNa
catalyst could interpreter such behavior.
The biological properties of the two new complexes (VOLZNa and MoO2LZNa) exhibited an
effective antibacterial and antifungal potential versus some titled pathogens over their free
ligand HLZNa. Furthermore, the anticancer reactivity of VOLZNa and MoO2LZNa complexes
assigned observable more action than that of their uncoordinated ligand HLZNa. Additionally,
both complexes were studied as antioxidants through DPPH and SOD methods and also gave
high efficiency. Furthermore, their interaction with ctDNA was tested by spectral analysis and
viscosity measurements and they showed high binding action towards ctDNA.

Spectroscopically, the degree of interaction between VOLZNa and MoO 2LZNa with ctDNA
was measured by the derived binding constant (4.45 and 5.01 × 108 mol-1 dm3, respectively)
assigning more interaction than that of the free ligand with ctDNA (HLZNa, 2.88 × 108 mol-1
dm3). Moreover, the Gibbs’ free energy values (∆𝐺𝑏≠ ) for such interaction supported their high
potential against ctNDA over their ligand (-31.14, -32.22 and -32.52 kJ mol-1, for HLZNa,
VOLZNa and MoO2LZNa, respectively). The geometry of each studied compound was
oriented via the Gaussian 09 program to estimate essential aspects that were used to confirm
the mode of bonding and to evaluate their ability towards biological or catalytic applications.
The mechanism suggested for the catalysis of MoO2LZNa towards epoxidation, was confirmed
via Hartree-Fock method under LanL2DZ basis set. Three silico approaches were implemented
to evaluate the biological feature of the current compounds and the outcomes point to the
ineffectiveness of HLZNa ligand compared to its complexes. Also, the inhibition activity of
the complexes was shinned against definite microorganisms in agreement with antimicrobial
results.
Acknowledgments
This work was supported through the Annual Funding track by the Deanship of Scientific
Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal
University, Saudi Arabia [Project No. AN00036].

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Scheme 1. Synthesis of 3-((2-(2,4-dinitrophenyl)hydrazineylidene)methyl)-4-hydroxybenzene
sodium sulfonate (HLZNa) ligand.

VOLZNa cis-MoO2LZNa
Scheme 2. The synthesis of VO(II) and cis-MoO2(II)-complexes from bis-HLZNa ligand under
sustainable conditions.

3.5 0.20
MoO2LZNa
3.0 VOLZNa
HLZNa
0.15
Abs
2.5
0.10
2.0
Abs
1.5 0.05
500 600 700 800
 , nm
1.0
0.5
0.0
200 300 400 500 600 700 800
, nm
Figure 1. UV-Vis. spectra of the aqueous solutions (1.0 × 10-5 and 1.0 × 10-2 mol dm-3) for
HLZNa, VOLZNa and MoO2LZNa at room temperature.

Scheme 3. Further oxidation and hydrolysis processes of epoxy-1,2-cyclooctane by H2O2 in
H2O in presence of VOLZNa and MoO2LZNa at the optimal atmosphere.

0 (a)
Y = -0.1426X + 0.0434
2
R = 0.9951
-1
Y = -0.1887X + 0.1239
2
R = 0.9721
-2 Y = -0.5975X + 0.2173
2
ln C/Co
R = 0.9856 Y = -0.3323X + 0.1718

2
R = 0.9852
-3
Y = -1.0944X + 0.5708
2
R = 0.9612
-4
Y = -1.2628X + 0.2114
2 o o
R = 0.9604 50 C 60 C
-5 o
70 C
o
80 C
o o
90 C 100 C
-6
0 1 2 3 4 5 6 7 8
Time, h
0.5 (b) VOLZNa
0.0
-0.5
ln k
-1.0
-1.5
-2.0
-2.5
0.0026 0.0027 0.0028 0.0029 0.0030 0.0031
1/T
Figure 2. (a) Kinetic plots of ln (C/Co) versus t time (in hours) for the 1,2-cyclooctene
epoxidation by H2O2 catalyzed with VOLZNa at temperature range from 50 to 100 °C; (b) the
Arrhenius plot for the temperature range from 50 to 100 °C for the kinetics of the 1,2-
cyclooctene epoxidation by H2O2 catalyzed with VOLZNa.

1.2
1.0
0.8
Abs
0.6
0.4
0.2
0.0
200 250 300 350 400 450 500 550
, nm
Figure 3. The UV-Vis. spectroscopic scans for MoO2LZNa in presence of 1,2-cyclooctene

before and after mixing with an aqueous H2O2 in acetonitrile at 50 °C with the time interval 15
min for 6 h for the epoxidation system.

Scheme 4. The proposed mechanistic steps for the alkene epoxidation process with H2O2
catalyzed by MoO2LZNa.

Figure 4. A (the activity index, %) for 20 μM concentration of HLZNa, VOLZNa and
MoO2LZNa at 25 °C for (a) antibacterial and (b) antifungal assay.

2.5
(a)
2.5
2.0
2.0 1.5
Abs
1.0
1.5
Abs
0.5
1.0 0.0
300 350 400 450 500
, nm
0.5
0.0
200 300 400 500 600 700 800
, nm
60 (b)
50
10 [DNA] / (a-f)
40
30
20
10
10
-10
0 20 40 60 80 100 120
6
10 [DNA]
Figure 5a,b. (a) UV-Vis. spectral studies of ctDNA different concentrations, μM, with DMSO
solution of VOLZNa at ambient temperature; (b) the [DNA]/(εa - εb) plot versus alternative
concentrations of ctDNA in DMSO for VOLZNa at room temperature.

1.6
MoO2LZNa
VOLZNa
1.5
HLZNa
EB
1.4
1/3
1.3

1.2
1.1
1.0
0.0 0.1 0.2 0.3 0.4 0.5
[Compound]/[DNA]
Figure 6. The effect of HLZNa, VOLZNa and MoO2LZNa concentrations on the ctDNA
relative viscosity for [ctDNA] = 0.5 mM at 25 °C.

Scheme 5. The interaction mode between ctDNA and VOLZNa or MoO2LZNa via
intercalative and/or replacing modes.

Figure 7. HOMO and LUMO levels of HLZNa, VOLZNa and MoO2LZNa compounds.

Scheme 6. The diagram of the thermodynamic path for the catalytic cycle of MoO2LZNa
complex.

Figure 8. The predicted targets for HLZNa ligand inside pathogen cells.

MoO2LZNa -1bdd
MoO2LZNa-3zfi

VOLZNa-1bdd
VOLZNa-3zfi
Figure 9. The interaction profiles for MoO2LZNa and VOLZNa complexes towards different
pathogens.

Figure 10. The inhibition validity of MoO2LZNa and VOLZNa towards Staphylococcus
Aureus protein (1bdd).

Table 1. The molecular electronic spectra for compounds at [conc.] ≈ 1.0 × 10 -5 mol dm-3 in
water and at 25 °C, infrared spectrum (𝜈, cm-1) and Molar conductivities, Λm at [conc.] ≈ 1.0 ×
10−3 mol dm-3 in DMSO, DMF and water at 25 °C.
Λm
UV-Vis. spectra
(Ω−1·cm2·mol−1) IR spectra
Comp.
λmax ε
Assign. DMSO DMF H2O 𝜈, cm-1
(nm) (mol-1 cm-1)
HLZNa 247 5749 π→π* 134 147 220 3297 (O-H); 3165 (N-H); 3088 (C-
400 br 2324 L-CT Har), 1723 (CH=N); 1572 (N=O);
1488 (S=O); 1393 (C-O); 1295
(N-O); 1257 (S-O); 1211 (C-N).
VOLZNa 249 10149 π→π* 228 235 318 3241 (N-H); 3047 (C-Har), 1642
275 8006 n→π* (CH=N); 1575 (N=O); 1462
347 6588 n→π* (S=O); 1390 (C-O); 1311 (N-O);
422 4056 M→LCT 1275 (S-O); 1167 (C-N); 971
741 1176 d-d (V=O); 819 (V-O); 610 (V-N).
MoO2LZN 251 7847 π→π* 221 214 309 3215 (N-H); 3031 (C-Har), 1631
a 271 6027 π→π* (CH=N); 1571 (N=O); 1509
345 4484 n→π* (S=O); 1395 (C-O); 1312 (N-O);
424 br 3284 M→LCT 1255 (S-O); 1171 (C-N); 977
(Mo=O); 822 (Mo-O); 618 (Mo-
N).
* br = broad band

Table 2a. VOLZNa catalyzed the 1,2-cyclooctene epoxidation by an aqueous H2O2.
Entrya Temp. Time Amount (%)b Conversion Selectivity TONe TOFd
(oC) (h) 1,2- Epoxy-1,2- Side (%) (%)
Cyclooctene cyclooctane products
1 50 1 81 19 0 19 100 9.5 9.50
2 2 69 31 0 31 100 15.5 7.75
3 4 55 42 3 45 93 21.0 5.25
4 6 41 51 8 59 86 25.5 4.25
5 60 1 72 28 0 28 100 14.0 14.00
6 2 51 48 1 49 98 24.0 12.00
7 4 42 53 5 58 91 26.5 6.63
8 6 30 61 9 70 87 30.5 5.08
9 70 1 57 43 0 43 100 21.5 21.50
10 2 38 60 2 62 97 30.0 15.00
11 4 20 73 7 80 91 36.5 9.13
12 6 13 77 10 87 89 38.5 6.42
13 80 1 34 66 0 66 100 33.0 33.00
14 2 21 74 5 79 94 37.0 18.50
15 4 10 81 9 90 90 40.5 10.13
16 6 2 84 14 98 86 42.0 7.00
17 90 1 12 87 1 88 99 43.5 43.50
18 2 4 92 4 96 96 46.0 23.00
19 4 1 90 9 99 91 45.0 11.25
20 6 0 81 19 100 81 40.5 6.75
21 100 1 15 71 14 85 84 35.5 35.50
22 2 8 67 25 92 73 33.5 16.75
23 4 0 56 44 100 56 28.0 7.00
24 6 0 47 53 100 47 23.5 3.92
a 1,2-cyclooctene (1.0 mmol) + aqueous H O (3.00 mmol) + VOLZNa (0.02 mmol) in 10 mL acetonitrile for 6 h, at 50, 60, 70, 80, 90 or 100
2 2
°C.
b The yielding percentages of epoxy-1,2-cyclooctane + other side products derived from GC-MS.
c Turnover number (TON) = ratios of mmoles of benzaldehyde to mmoles of VOLZNa catalyst.
d Turnover frequency (TOF) = turnover number/time (TON/h) in mmol catalyst -1 h-1.
Table 2b. MoO2LZNa catalyzed the 1,2-cyclooctene epoxidation by an aqueous H2O2.

Entrya Temp. Time Amount (%)b Conversion Selectivity TONc TOFd
(oC) (h) 1,2- Epoxy-1,2- Side (%) (%)
Cyclooctene cyclooctane products
1 50 1 84 16 0 16 100 8.0 8.00
2 2 71 29 0 29 100 14.5 7.25
3 4 59 38 3 41 93 19.0 4.75
4 6 46 46 8 54 85 23.0 3.83
5 60 1 76 24 0 24 100 12.0 12.00
6 2 54 46 0 46 100 23.0 11.50
7 4 45 51 4 55 93 25.5 6.375
8 6 37 56 7 63 89 28.0 4.67
9 70 1 62 38 0 38 100 19.0 19.00
10 2 41 57 2 59 97 28.5 14.25
11 4 26 69 5 74 93 34.5 8.63
12 6 18 73 9 82 89 36.5 6.08
13 80 1 38 66 0 66 100 33.0 33.00
14 2 26 70 4 74 95 35.0 17.50
15 4 17 73 10 83 88 36.5 9.13
16 6 8 79 13 92 86 39.5 6.58
17 90 1 17 83 0 83 100 41.5 41.50
18 2 10 87 3 90 97 43.5 21.75
19 4 1 91 8 99 92 45.5 11.38
20 6 0 89 11 100 89 44.5 7.42
21 100 1 18 72 10 82 88 36.0 36.00
22 2 10 69 21 90 77 34.5 17.25
23 4 0 59 41 100 59 29.5 7.38
24 6 0 51 49 100 51 25.5 4.25
a 1,2-cyclooctene (1.0 mmol) + aqueous H O (3.00 mmol) + MoO LZNa (0.02 mmol) in 10 mL acetonitrile for 6 h, at 50, 60, 70, 80, 90 or
2 2 2
100 °C.
b The yielding percentages of epoxy-1,2-cyclooctane + other side products derived from GC-MS.
c Turnover number (TON) = ratios of mmoles of benzaldehyde to mmoles of VOLZNa catalyst.
d Turnover frequency (TOF) = turnover number/time (TON/h) in mmol catalyst -1 h-1.

Table 3. Epoxidation of 1,2-cyclooctene by an aqueous H2O2 catalyzed by VO(II) or MoO2(II)
complex (VOLZNa and MoO2LZNa) under the effect of various solvent atmosphere.
Solventa Catalyst Amount (%) Conversion (%) Selectivity (%)
1,2- Epoxy-1,2- Side products
Cyclooctene cyclooctane
Acetonitrile VOLZNa 4 92 4 96 96
Chloroform 1 85 14 99 86
H2 O 12 58 30 88 67
Solvent free 9 75 16 91 82
Acetonitrile MoO2LZNa 1 91 8 99 92
Chloroform 0 88 12 100 88
H2 O 10 61 29 90 68
Solvent free 12 69 17 88 78
a 1,2-cyclooctene (1.0 mmol) + H O (3.00 mmol) + (0.02 mmol) catalyst in 10 mL solvent (or without solvent in solvent free conditions) at
2 2
the optimized temperature and time for VOLZNa and MoO2LZNa catalysts.
Table 4. Derivation of the kinetic data for 1,2-cyclooctene epoxidation by H2O2 catalyzed by
VOLZNa or MoO2LZNa complex at optimized reaction environments.
Catalyst A × 107 Ea, kJ mol-1 ΔG#, kJmol-1
VOLZNa 7.34 49.09 62.3
MoO2LZNa 9.05 47.99 58.7
Table 5. Catalytic epoxidation of alternative cyclic and aliphatic alkenes by an aqueous H2O2
catalyzed by VOLZNa or MoO2LZNa.
Entrya Alkene Product Conversion, %
(Selectivity, %)
VOLZNa MoO2LZNa
83 81
1
(76) (77)
95 90
2
(91) (87)
87 83
3
(79) (72)
69 60
4
(56) (53)
62 57
5
(45) (44)
66 60
6 HO (41) (43)
aEpoxidation
of alkene (1.0 mmol) by an aqueous H2O2 (3.0 mmol) catalyzed by 0.02 mmol of catalyst at the optimized atmosphere of
VOLZNa and MoO2LZNa.

Table 6. The antimicrobial activities of the HLZNa, VOLZNa, and MoO2LZNa.
Inhibition zone (bacterial strains, mm) Inhibition zone (fungal strains, mm)
Serratia Escherichia Staphylococcus Candida Aspergillus Trichophyton
Comp. Marcescence coli aureus albicans flavus rubrum
HLZNa 12±0.45 10±0.12 14±0.95 11±0.65 8±0.90 9±0.80
VOLZNa 33±0.12 31±0.85 40±0.50 31±0.40 19±0.58 22±0.20
MoO2LZNa 33±0.55 32±0.38 41±0.15 31±0.12 18±0.15 21±0.85
Gentamicin 40±0.33 37±0.72 46±0.11
Fluconazole 37±0.62 25±0.90 31±0.88
Table 7. The spectral parameters for the interaction of HLZNa, VOLZNa or MoO2LZNa with
ctDNA. The antioxidant action of VOLZNa and MoO2LZNa chelates via DPPH and SOD
studies.
λmax λmax ∆n Chromism Kb × 108 ∆𝐺𝑏≠
free bound % Type mol-1 KJ mol-1 DPPH screening SOD screening
Comp. (nm) (nm) dm3
Inhibition
Radial scavenging (%) ∆OD560 (5 min)
(%)
HLZNa 242 288 46 28.55
Hypo 2.88 -31.14 -- -- --
389 408 19 12.28
VOLZNa 345 362 17 14.78
420 459 39 27.07 Hypo 4.45 -32.22 51 0.47 79.2
738 729 9 8.11
MoO2LZ 254 266 12 11.26
Na 341 359 18 15.41 Hypo 5.01 -32.52 54 0.51 82.6
422 441 19 20.60
Vitamin C 89.6 --a --a
Control --a 0.516 --a
HR SOD --a 0.163 68.42
a Absorbance was not recorded.
Table 8. The cytotoxic activity of HLZNa, VOLZNa and MoO2LZNa.

IC50 (µM)
Compound HCT-116 MCF-7 HepG-2
HLZNa 88.08±0.15 66.05±0.10 76.40±0.44
VOLZNa 19.15±0.55 10.82±0.35 14.79±0.65
MoO2LZNa 17.33±0.12 11.10±0.75 12.90±0.25
Vinblastine 13.30±0.11 4.12±0.14 7.50±0.10

Table 9. Some physical features calculated for the optimized structures
The compound, parameters Bond Lengths (Å) Dihedral angles (o)
HLZNa N(14)=C(15) 1.35848 N(13)-N(14)-C(15) 118.7899
HOMO =-0.18736 eV O(22)-C(17) 1.36556 N(14)-C(15)-C(16) 121.09121
LUMO = -0.16219 eV N(14)-N(13) 1.23212 O(22)-C(17)-C(16) 120.83966
Dipole moment = 31.7433 Debye
Formation energy = -1880.84 a. u.
VOLZNa C(6)-O(11) 1.36142 O(11)-V(54)-O(55) 89.8361
HOMO = -0.17940 eV C(4)=N(3) 1.48410 N(17)-V(54)-O(25) 94.93559
LUMO = -0.16665 eV C(18)=N(17) 1.36831 O(11)-V(54)-N(3) 103.6482
Dipole moment = 9.5063Debye C(20)-O(25) 1.40941 N(3)-V(54)-O(25) 100.4098
Formation energy = -4754.09 a. u.
MoO2LZNa C(16)-O(11) 1.45621 O(11)-Mo(54)-N(3) 94.04194
HOMO = -0.17880 eV C(4)=N(3) 1.44914 O(25)-Mo(54)-N(17) 93.33008
LUMO = -0.16250 eV O(25)-C(20) 1.36746 O(55)-Mo(54)-O(25) 81.6287
Dipole moment = 24.727 Debye N(17)=C(18) 1.37897 O(56)-Mo(54)-N(3) 73.06272
Formation energy =-7844.75 a.u.

Table 10. Essential pharmacokinetic estimation for HLZNa.
HLZNa Physicochemical properties
-lipophilicity: XLOGP3 = 2.14.
-Size: MW = 404.29 g/mol.
-Molar reactivity = 91.59.
-Polarity: TPSA = 201.84 Å².
-Solubility: logS = -6.01.
-Saturation: Fraction Csp3 = 0.01.
-Flexibility: number of rotatable bonds = 6.
-BBB permeant, No.
-Log Kp (skin permeation) = -7.25 cm/s.
-P-gp substrate, Yes.
-Log Po/w = -1.95.
-bioavailability score = 0.55.
-CYP1A2(No), CYP2C19(Yes), CYP2C9(No),
CYP2D6(No) and CYP3A4(No).
Properties diagram

BOILED-Egg

Two ionic oxo-vanadate and dioxo-molybdate complexes of dinitro-aroylhydazone
derivative, as effective catalysts in the epoxidation reactions and antimicrobial,
antioxidant and anticancer reagents. ctDNA binding studies.
Mohamed Shaker S. Adam1,2*, Saad Shaaban1,3, Nashwa M. El-Metwaly3,4

1
Chemistry Department, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa 31982, Saudi Arabia.
2
Chemistry Department, Faculty of Science, Sohag University, Sohag-82534, Egypt.
3
Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt.
4
Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah 24230, Saudi Arabia
**Corresponding author: madam@kfu.edu.sa; mohamed.shaker@science.sohag.edu.eg (M.S.S. Adam);

n_elmetwaly00@yahoo.com; nmmohamed@uqu.edu.sa (N.M. El-Metwaly).
Highlights
 Two ionic complexes VOLZNa and MoO2LZNa were synthesized and characterized.
 Catalytically, VOLZNa exhibited little more catalytic potential more than that of
MoO2LZNa catalyst in the epoxidation of 1,2-cyclooctene.
 All compounds were examined through binding to ctDNA via spectroscopy and
viscosity changes.
 VOLZNa and MoO2LZNa enhanced their screening for the antioxidant, antimicrobial
and antitumor activities over their ligand.
 The molecular docking studies support the nature of ctDNA interactions.

2022 Applied Organometallic Chemistry

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2022 Applied Organometallic Chemistry

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Adam Mohamed (Orcid ID: 0000-0002-1757-0689)

Shaaban Saad (Orcid ID: 0000-0002-7835-6926)

Two ionic oxo-vanadate and dioxo-molybdate complexes of dinitro-aroylhydazone

Mohamed Shaker S. Adam1,2* | Saad Shaaban1,3 | Nashwa M. El-Metwaly3,4

Tel. +966505669287, Fax. +966920002366

*Corresponding authors: madam@kfu.edu.sa; mohamed.shaker@science.sohag.edu.eg (M.S.S. Adam)

This article is protected by copyright. All rights reserved.

Keywords: dinitro-aroylhydazone, complexes, epoxidation, ctDNA interaction, in vitro, silico

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2.2.2 | Synthesis of VO2+- and MoO22+-aroylhydrazone complexes

2.3 | Catalytic epoxidation of alkenes

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2.4 | Antimicrobial studies

2.4.2 | The antifungal potential

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2.4.3 | Minimal Inhibitory Concentration (MIC) and activity index (A)

𝐼𝑛ℎ𝑖𝑏𝑖𝑡𝑖𝑜𝑛 𝑧𝑜𝑛𝑒 (𝑚𝑚)

2.4.4 | Antioxidant potential

where, Ao is the control absorption and As is the sample absorption.

2.4.4.2 | SOD screening

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2.4.5 | Anticancer potential

2.4.6 | ctDNA interaction nature

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∆𝐺𝑏≠ = −𝑅𝑇𝑙𝑛𝐾𝑏 (5)

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2.4.7 | Conformational analyses

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2.4.7.2 | Silico assays

(b) Pharmacophore search

(c) MOE- module of molecular docking

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3 | Results and discussion

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3.1.2 | Electronic spectra

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3.1.4 | Mass spectra

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3.2.2 | Effect of temperature and time

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3.2.3 | Solvent Effect

1,2-Cyclooctene is considered as a nonpolar-molecule, which is not completely miscible with

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3.2.4 | Kinetics of epoxidation protocols

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3.2.5 | Epoxidation of various alkenes

3.2.6 | Mechanistic aspects

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3.3 | The biological activities

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3.3.2 | The antioxidant potential

3.3.2.2 | SOD screening

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3.3.4 | Anticancer potential

3.3.5 | ctDNA interaction

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3.4 | Conformational analyses

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