Bis-dioxomolybdenum (VI) oxalyldihydrazone complexes: Synthesis, characterization, DFT studies, catalytic epoxidation potential, molecular modeling and biological evaluations

Received: 18 November 2019

DOI: 10.1002/aoc.5573

Revised: 12 January 2020

Accepted: 15 January 2020

F U L L P A P E R

Bis-dioxomolybdenum (VI) oxalyldihydrazone complexes:

Synthesis, characterization, DFT studies, catalytic

epoxidation potential, molecular modeling and biological

evaluations

Mohamed Shaker S. Adam^1,2

| Mohamed S. Mohamed Ahmed^1,3

|

Omar M. El-Hady²| Saad Shaaban^1,4

¹Department of Chemistry, College of

Two cis-bis-dioxomolybdenum oxalylsalicylidenedihydrazone complexes

(MoO₂L1 and MoO₂L2) were synthesized via the complexation of

dioxomolybdenum (VI) acetylacetonate with oxalylsalicylidenedihydrazone

(H₂L1) and p-sodium sulfonate oxalylsalicylidenedihydrazone (H₂L2) bis-

Schiff base chelating ligands, respectively. The structures of the newly

Science, King Faisal University, P.O. Box

380 Al-Hofuf, Al-Ahsa, 31982, Saudi

Arabia

²Chemistry Department, Faculty of

Science, Sohag University, Sohag, 82534,

Egypt

³Chemistry Department, Faculty of

Science, Cairo University, Giza, Egypt

synthesized complexes were confirmed by H- and ¹³C-NMR, IR, ultraviolet–

1

visible and mass spectra, as well as elemental analyses (EA) and conductivity

measurements. The spectrophotometric continuous variation method rev-

ealed the formation of 2: 1 (metal: ligand molar ratios). DFT studies were

applied for the ligands and their Mo-chelates. Interestingly, the bis-MoO₂(VI)

oxalyldihydrazone complexes showed remarkable catalytic sufficiency

towards the selective (ep)oxidation of 1,2-cyclooctene, benzyl alcohol and

⁴Chemistry Department, Faculty of

Science, Mansoura University, Mansoura,

Egypt

Correspondence

Mohamed Shaker S. Adam and Saad

Shaaban, Department of Chemistry,

College of Science, King Faisal University,

P.O. Box 380 Al-Hofuf, Al-Ahsa 31982,

Saudi Arabia.

ꢀ

thiophene using H₂O₂or tert-butyl hydroperoxide (tBuOOH) at 85 C. Under

aqueous conditions, the MoO₂L2 (with p-sodium sulfonate substituent)

exhibited superior that of the MoO₂L1 (without p-NaSO₃―group), highlight-

ing the role of sodium sulfonate substituent in the catalytic progress of the

Mo-chelate. The ligands (H₂L1 and H₂L2) and their corresponding Mo-

complexes (MoO₂L1 and MoO₂L2) were assessed for their antitumor and

antimicrobial activities. Furthermore, the antioxidant activity was also evalu-

ated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide dis-

mutase (SOD) assays. The binding nature between the Mo-complexes and

calf thymus DNA (ctDNA) was also studied within spectroscopic and hydro-

dynamic techniques.

Email: madam@kfu.edu.sa;

shakeradam61@yahoo.com; sibrahim@

kfu.edu.sa; dr_saad_chem@mans.edu.eg

Funding information

Deanship of Scientific Research, King

Faisal University, Grant/Award Number:

110143

K E Y W O R D S

anticancer, antimicrobial, Bis-dioxomolybdenum, catalysis

Appl Organometal Chem. 2020;e5573.

wileyonlinelibrary.com/journal/aoc

1 of 25

https://doi.org/10.1002/aoc.5573

2 of 25

ADAM ET AL.

1 | INTRODUCTION

aldehydes or ketones in this context are important syn-

thetic intermediates, which employed for the prepara-

tion of different industrial materials and petrochemicals,

such as paints, epoxy resins and surfactants.^[26]Industri-

ally, transition metal-based catalytic (ep)oxidation of

alkenes under mild conditions has recently gained great

interest.^[27,28](Ep)oxidation of alkenes and alcohols cata-

lyzed by Mo (VI)-complexes was intensively studied in

recent years.^[4,29]Mo^VIO₂-complexes are routinely used

in the production of industrial propylene oxide and in

the efficient chemoselective oxidation of linear and

branched alkenes.^[29–33]Recently, the molybdenum

(VI) complex of picolinic acid-based metallomicellar cat-

alyst was used in the controlled and chemoselective oxi-

dation of the activated alcohols in the aqueous medium,

which afforded high sufficiency.^[34]Supported dioxo-

molybdenum (VI) complex of Schiff base on Merrifield

resin assigned high selectivity in the oxidation of pri-

mary and secondary alcohols by H₂O₂.^[35]An interesting

metathetic oxidation of 2-butene to acetaldehyde by O₂

gas catalyzed by the immobilized MoO₂-hydrazone com-

plexes on SiO₂, heterogeneously, afforded high yields.^[36]

The heterogeneous molybdenum-salicylidene 2-picoloyl

hydrazone complex, which supported on Fe₃O₄

nano-particles, showed high catalytic potential in the

(ep)oxidation of various olefins.^[37]Molybdenum ace-

tylacetonate complexes, which supported on func-

tionalized boehmite nano-particles, investigated as

catalysts in the (ep)oxidation of unsaturated hydrocar-

bons presenting high potential.^[38]Dioxido-molybdenum

(VI) complexes as robust and highly efficient pre-

catalysts for alkene (ep)oxidation, were investigated

recently by Mösch-Zanetti et al.^[39]The catalytic activity

of chiral molybdenum (VI) complexes with tridentate

Schiff bases derives was evaluated in the oxidation of

prochiral sulfides and olefins.^[40]Homogeneously, the

homobinuclear molybdenum bis-oxazoline complex dis-

played high activity in the oxidation of alkenes and sul-

fides.^[41]Under the organic solvent-free condition, as

one of the most favored for the eco-friendly condition in

the oxidation protocols, recent efficient and selective

oxidation of alcohols with tBuOOH catalyzed by a

(MoO₂)²⁺-Schiff base complex was examined by Hatefi-

Ardakani et al.^[42]Such condition attacked also the cata-

lytic oxidation of olefins by tBuOOH and catalyzed by

dinuclear oxomolybdic complexes of salicylidene-

aminophenolate and -aminoethanolato ligands with

alternative catalytic sufficiency of the Mo-catalysts.^[43]

The high efficient catalytic and chemoselective prop-

erties of cis-(MoO₂)-complexes have therefore attracted

our attention to design novel class of MoO₂(VI)-

complexes based on the use of readily available yet cheap

ligands, e.g. oxalyldihydrazone ligands.

Molybdenum (Mo) is an essential trace element found in

several plant enzymes (e.g. nitrogenases and oxidases).^[1]

The indispensable role of Mo in biological processes was

intensively examined in the last decades owing to its

interesting redox-catalytic features. The coordination

nature around the molybdenum center could not only

stabilize various oxidation states of Mo ion in its com-

plexes but also could control its redox properties.^[2]

On the other hand, Schiff bases or imines exhibit

diverse pharmacological activities, e.g. anticancer, anti-

parasitic and anti-inflammatory activities.^[3]Interest-

ingly, the biological properties of Schiff bases are

usually improved after coordination with various transi-

tion metal ions.^[4]Indeed, Mo-Schiff base complexes

would not be of potential interest only in medicinal

chemistry but also in homogeneous and heterogeneous

catalysis.^[5,6]For example, the high affinity of the transi-

tion metal-imine pincer chelates to bind ctDNA was

used for nucleic acid footprinting.^[7]Accumulatly,

Abdel-Rahman et al.^[8,9]reported that the Pd (II), Ag (I),

and Cu (II) chlorobenzylidene Schiff base complexes

and the Ni (II), Mg (II), Cr (III), and V (II) imine com-

plexes exhibited good anticancer activity.^[8,9]Further-

more, oxide- and/or dioxide-vanadium imine complexes

were reported as protein-tyrosine phosphatase 1B inhibi-

tors^[10,11]and represented as ctDNA cleaving

reagents.^[12]Additionally, several imine-based complexes

of Cr²⁺, Fe²⁺, Mn²⁺, Cu²⁺, Cd²⁺, Co^2+,and Ni²⁺ions

manifested high interesting antimicrobial and anticancer

activities.^[13–16]

The chemistry and biology of aroyl hydrazones of

alternative aldehydes or ketones as metal-complexes

continue to accept much attention in research due to

their structural attractive features.^[17]Aroyl hydrazine

complexes were incorporated in zeolite as heteroge-

neous catalysts for the degradation of industrial

wastewater.^[18]

Dihydrazones are the most common chelating ligands

for the coordination with transition metal ions of differ-

ent oxidation states. In this context, aroyldihydrazones,

specifically oxalyldihydrazones, are stereochemically and

geometrically reactive,^[19]providing highly stable metal

complexes of wide applications in different scientific

areas (e.g. biological chemosensors^[20,21]and organic pho-

tovoltaic materials^[22,23]). Alternative metal-dihydrazones

pincer chelates reported good anticancer and antimicro-

bial activities owing to their ctDNA binding capability

and cleavage imperatively.^[24]

On the other hand, catalytic (ep)oxidation of olefins,

alcohols or thiophenes is still challenging in the synthe-

sis of pharmaceuticals and fine chemicals.^[25]Epoxides,

ADAM ET AL.

3 of 25

Herein we report the preparation, characterization

min heating rate from 30 to 400 ^ꢀC. Mass spectra

(in m/z) were determined on waters Q-tof Micro YA263

mass spectrometer for the current compounds. pH was

determined by a Metrohm 695 pH/ion meter to 0.005

units with control of temperature by a HAAKE model

F3-k as an ultrathermostat bath. The temperature of the

melting point, in Celsius, was evaluated by a Thermo

Scientific 9100 apparatus.

and molecular modeling of two cis-bis-dioxomolybdenum

(II) oxalyldihydrazone complexes. Different physic-

chemical and spectroscopic techniques are applied for

the characterization of the newly synthesized complexes.

Their catalytic potentials are examined in different (ep)

oxidation substrates, e.g. 1,2- cyclooctene, benzyl alcohol

and thiophene. Furthermore, the anticancer and micro-

bial activities of the ligands (H₂L1 and H₂L2) and their

corresponding Mo-complexes (MoO₂L1 and MoO₂L2) are

evaluated against different cancer cell lines and patho-

genic microbial strains. Moreover, their antioxidant prop-

erties are also assessed using DPPH and SOD assays.

Their characteristics binding to ctDNA are investigated

within different methods (spectrophotometry and viscos-

ity measurements) considering their combination with

ctDNA.

2.2 | Synthesis and characterization

2.2.1 | Synthesis of

1,2-bis[2-(2-Hydroxyphenyl)methylene]

hydrazide (H₂L1) and 1,2-bis[2-(5-sodium

sulfonate-2-hydroxyphenyl)methylene]

hydrazide (H₂L2)

H₂L1 and H₂L2 were prepared according to the previ-

ously published method with little modifications.^[2,29]

Briefly, an aqueous solution of oxalyldihydrazide (5.0

mmol, 0.59 g dissolved in 20 ml water) was mixed with

an aqueous solution of appropriate salicylaldehyde (10.0

mmol, 1.2 ml in 30 ml methanol) or salicylaldehyde

derivative (e.g. 5-sodium sulfonate, 10.0 mmol, 2.2 g in 30

ml water). The resulted mixture was heated under reflux

2 | EXPERIMENTAL

2.1 | Reagents and methodology

All starting materials, which are necessary for all chemi-

cal reactions and biological studies, ordered from

Across, Fluka and Sigma-Aldrich. They have been

assigned in all chemical processing systems without any

treatment. Percentages of main elements, C, H and N in

their compounds were evaluated by GMBH VarioEl

model V2.3 CHNS apparatus. The nuclear paramagnetic

resonance spectrum for H and C-atoms was determined

using Bruker ARX400 multinuclear NMR spectrometer

ꢀ

at 100 C for 2 hr and the completion of the dihydrazone

formation was detected by TLC. Methanol–water mixture

was slowly removed under reduced pressure and the

remaining slurry was washed by ethanol and purified by

recrystallization from ethanol/water (1: 1) ratios.

1

for H-nuclei at 400.1 Hz and for ¹³C-nucleus at 100.6

1,2-bis[2-(2-Hydroxyphenyl)methylene]hydrazide (H₂L1)

1

3

MHz at ambient temperature. Chemical shifts, δ, of H-

¹H NMR (DMSO-d₆, 400.1 MHz) δ 6.93 (t, J = 8.0 Hz,

nuclei and ¹³C-nucleus were accomplished in ppm. Cou-

4 H), 7.43 (t, ³J = 8.1 Hz, 2 H), 7.56 (d, ³J = 8.0 Hz, 1 H),

8.82 (s, 2 H), 11.00 (s, NH, 2 H) and 12.61 ppm (s br, 1 H,

CH=N). ¹³C NMR (DMSO-d₆, 100.6 MHz, dept-135): δ

116.69 (CH), 119.83 (CH), 126.86 (CH), 129.74 (CH),

131.53 (C_q), 47.07 (C_q), 156.72 (C_q) and 163.41 ppm

(CH=N) (Figures S1 and S2).

1

pling constant data (J) of neighbors H-nuclei in were

given by Hz, hertz, as J_HH. Ultraviolet and visible spec-

trophotometry for the studied compounds was estimated

using Jasco Ultra violet-Visible spectrophotometric appa-

ratus (model V-570) within a 10 mm silica cell at room

temperature by using a thermostatted cell holder. IR-

stretching spectral scans were measured from 4000 to

400 wavenumbers (cm⁻¹), as KBr discs, by using

Shimadzu FTIR-8101 Fourier Transform Infrared Spec-

trophotometer. Determination of conductivity measure-

ments of the studied complexes was achieved by Jenway

conductometer of model 4320, contacted with an epoxy

IR spectra (KBr tablets); ꢀν = 3347 (O―H_phenolic), 3272

(N―H), 1719 (C=O), 1611 (C=N), 1584 (NH―CO), 1329

(C―O), and 1039 cm⁻¹(C―N).

1,2-bis[2-(5-sodium sulfonate-2-hydroxyphenyl)

methylene]hydrazide (H₂L2)

3

¹H NMR (DMSO-d₆, 400.1 MHz): δ 6.87 (d, J = 8.0 Hz,

3

ꢀ

bodied conductivity cell, as two electrodes. At 25 C, cal-

2 H), 7.54 (dd, J = 7.2 and 8.1 Hz, 2 H), 7.83 (d, J = 2.2

Hz, 2 H), 8.82 (s br, 2 H, CH=N) and 11.00 ppm (s br,

2 H, ―NH). ¹³C NMR (DMSO-d₆, 100.6 MHz, dept-135):

δ 116.01 (CH), 118.09 (C_q), 126.64 (CH), 129.92 (CH),

140.53 (C_q), 150.76 (C_q), 156.36 (C_q) and 157.95 ppm

(CH=N) (Figures S3 and S4).

ibration of the cell constant was taken place from 0.01

to 19.99 of the conductometer. Under inert atmosphere

(nitrogen, as carrier gas) with flow of 20 cm³min⁻¹

,

thermogravimetric analysis was accomplished using

Shimadzu TGA-50H thermal analyzer with 10 ^ꢀCelsius/

4 of 25

ADAM ET AL.

IR spectra (KBr tablets); ꢀν = 3328 (O―H_phenolic), 3186

1231 (C―O), 1011 (C―N), 1339 (S=O), 1124 (S―O),

901 (Mo―O) and 558 cm⁻¹(Mo―N).

(N―H), 3061 (C―H_aromatic), 1674 (C=O), 1611 (C=N),

1564 (NH―CO), 1012 (C―N), 1415 (S=O) and 1142

cm⁻¹(S―O). The yield was 4.83 g (91%).

2.3 | Molecular structural modeling

(DFT)

2.2.2 | Synthesis of cis-bis-

dioxomolybdenum (bis[2-(2-oxyphenyl)

methylene]hydrazone) complex (MoO₂L1)

Density Functional Theory (DFT) calculations were prog-

ressed in order to investigate the equilibrium geometry of

the free ligands (H₂L1 and H₂L2) and their di-Schiff base

complexes (MoO₂L1 and MoO₂L2) using Gaussian 09 pro-

gram at the B3LYP/LANL2DZ level.^[44]Their molecular

geometrical structures were optimized within B3LYP and

6-31 g(d,p) for C, H, O, Mo, N, Na and S atoms in the gas

phase.

A solution of cis-MoO₂(acac)₂(10.0 mmol, 3.26 g in 50

ml of water) and H₂L1 (5.0 mmol, 1.63 g in 50 ml

methanol) were mixed together in a two-neck round

bottom flask. The obtained mixture was heated under

reflux for 4 hr. The solvent was slowly removed by

evacuation. The remaining residue was washed by eth-

anol and purified by recrystallization from ethanol. The

yield was 71%.

¹H NMR (DMSO-d₆, 400.1 MHz): δ 3.59 (s, 6 H,

2.4 | Catalytic procedures

3

―CH₃, methanol), 6.95–7.01 (m, 4 H), 7.41 (dd, J = 7.0

and 8.0 Hz, 2 H), 7.71 (d, ³J = 7.0 Hz, 2 H) and 9.01 ppm

(s br, 2 H, CH=N). ¹³C NMR (DMSO-d₆, 100.6 MHz,

dept-135): δ 57.71 (CH, ―CH₃, methanol), 115.17 (CH),

118.95 (C_q), 125.95 (CH), 126.59 (CH), 141.92 (CH),

149.57 (C_q), 156.97 (C_q) and 166.12 ppm (CH) (Figures S5

and S6).

IR spectra (KBr tablets); ꢀν = 3496 (O―H_methanol),

3029 (C―H_aromatic), 1643 and 1558 (C=N), 1273 (C―O),

1032 (C―N), 910 (Mo―O) and 531 cm⁻¹(Mo―N).

Catalytic (ep)oxidation of 1,2-cyclooctene, benzyl alcohol

and thiophene (1.0 mmol) was preceded by adding either

3.0 mmol of H₂O₂(30% in water) or 1.7 mmol of tert-

butyl hydroperoxides (tBuOOH, 70% in water), as an

external oxidizing agent. The catalytic protocol was cata-

lyzed by involving catalytic amounts of cis-MoO₂-chelates

(0.02 mmol) in 10 mL of H₂O at 85 ^ꢀC in an oil bath with

magnetic stirring for the optimized time in under air

atmosphere. The catalytic protocols were followed and

controlled to assign the best required time for the highest

percentage amount of the chemoselective product by tak-

ing ~ 1.0 ml samples of the catalytic reaction mixture at

the exact interval time. The taking samples were treated

with ~ 0.02 g of sodium persulfate to destroy the excess

unreacted oxidant, i.e. H₂O₂or tBuOOH. The obtained

slurry was filtered. The chemoselective products were

extracted from water by adding diethyl ether (2 ml). The

organic layer containing the chemoselective products was

submitted for measuring the amount percentages by

injection of a 1 μL to the GC.

2.2.3 | Synthesis of cis-bis-

dioxomolybdenum bis[{2-(5-sodium

sulfonate-2-oxyphenyl)methylene}

hydrazone] complex (MoO₂L2)

A solution of cis-MoO₂(acac)₂(10.0 mmol, 3.26 g in 60

ml of water) and H₂L1 (5.0 mmol, 2.56 g in 40 ml

water) were mixed together in a two-neck round bottom

flask. The mixture solution was heated under reflux for

4 hr. After that, the reaction mixture was cooled down

and then the solvent was slowly evacuated. The

remaining residue was washed by water and purified by

recrystallization from ethanol/water (1:1) ratios. The

yield was 68%.

Shimadzu Gas Chromatography-mass spectrometer of

QP2010 SE model equipped by Rxi-5 Sil MS capillary col-

umn (30 m length × 0.25 mm ID × 025 um film thick-

ness) was used to analyze the injected product sample

solutions. Detection of the product samples was carried

¹H NMR (D₂O, 400.1 MHz): δ 3.71 (s, 4 H, H₂O), 7.04

out_ꢀin GC at 250 C of the injection temperature and at

ꢀ

3

4

(dd, ³J = 8.1 Hz, 2 H), 7.88 (dd, J = 8.7 and J = 2.2 Hz,

40 C of the initial oven temperature, which held at the

given temperature for 1 min. Then the oven temperature

4

2 H), 8.07 (d, J = 2.2 Hz, 2 H) and 9.92 ppm (s br, 2 H,

CH=N). ¹³C NMR (D₂O, 100.6 MHz, dept-135): δ 117.99

(CH), 120.39 (C_q), 130.93 (CH), 133.90 (CH), 135.75 (C_q),

150.30 (C_q), 162.80 (C_q) and 186.88 ppm (―CH=N―)

(Figures S7 and S8).

was enhanced gradually with a rate of 10 C min⁻¹up to

ꢀ

200 ^ꢀC. The operated inlet was in the mode of the

spitless. The mass spectra transfer line was held at 200

^ꢀC. Helium gas, as an inert GC-carrier gas, which pure

with 99.999%, was applied with 1 mL min⁻¹of flow rate.

Applying LabSolution software was necessary to deduce

IR spectra (KBr tablets); ꢀν = 3400 and 1600_overlaped

(O―H_water), 3047 (C―H_aromatic), 1600_overlaped(C=N),

ADAM ET AL.

5 of 25

the yield percentages of the chemoselective product.

Define of resulted chromatogram peaks was realized by

comparing to those resulted MS of the reported com-

pounds with NIST mass spectra stored library.

2.6 | DNA binding studies

2.6.1 | ctDNA interaction (UV–visible

spectroscopy)

Electronic absorption measurements were performed at

pH = 7.23 using tris-(hydroxymethyl)aminomethane-HCl

buffer_ꢀsolution at the wavelength range 200–800 nm and

at 25 C. A UV-absorbance ratio of ctDNA was recorded

at 260 and 280 nm, A260/A280, which in turn was higher

than 1.8, indicating that there is no contaminated protein

in the tested ctDNA. The background absorbance of

ctDNA was eliminated by adding equal amounts of

ctDNA to the MoO₂-complexes and the reference solu-

tions.^[8,9]Concentrated stock solution (1.0 × 10⁻³M) of

the free ligands (H₂L1 and H₂L2) and the MoO₂-

complexes (MoO₂L1 and MoO₂L2) were also prepared in

Tris–HCl and NaCl solution (10: 1). Titration experi-

ments were performed by varying ctDNA concentration

with maintaining the cis-MoO₂-complexes concentra-

tions' constant. The binding constant, expressed as K_bfor

the interaction of the complex with ctDNA [DNA], could

be derived from absorption spectral titration data by plot-

ting [DNA]/(ε_a− ε_b) versus the various concentrations of

2.5 | Molecular docking

Dell Precision™ T3600 Workstation equipped with Intel

Xeon E5–1660 3.3GHz, 16GB 1600MHz DDR3, ECC

RDIMM 1 TB (7200RPM), 1GB NVIDIA Quadro 2000,

Windows 7 Professional (64 Bit), was machined to study

the molecular docking of H₂L1, H₂L2, MoO₂L1 and

MoO₂L2 using software MOE (Molecular Operating Envi-

ronment) package version 2019.0101.

X-ray analysis of a 1BNA dodecameric d (CGCG

AATTCGCG)2 crystal structure within 3⁰-5'direction

(ctDNA code: 1BNA) was used for the examination the

docking with 1.9 Å resolution. The introducing of the

molecular structure of ctDNA with its hydrogen atoms

could be calculated into MOE of the optimization of

energy and the resulted geometrical model of the struc-

ture was proposed for the systematic confirmation

research within a gradient of RMS of 0.01 kcal mol⁻¹with

overlooking of parameters in the involved Site Finder

device in MOE. Using ChemBioDraw Ultra 12.0, all stud-

ied current compounds were drawn for applying in the

MOE. Then, the draw structure of H₂L1, H₂L2, MoO₂L1,

and MoO₂L2 were concerned for the theoretical calcula-

tion of the molecular docking following three items:

(1) involving of hydrogen atoms in the drawing of the

molecular structure of all current compounds; (2) using

the conformational search for them; (3) within the

MMFF94 force field, the energy decreases with the opti-

mal conformers.^[45]Reducing of the energy along with

the steepest algorithm was examined, with the trial of the

conjugate gradient method till an RMS gradient reach to

be 0.00001 kcal mol⁻¹Å⁻¹. Moreover, a database of H₂L1,

H₂L2, MoO₂L1 or MoO₂L2 was obtained for more molec-

ular docking studies. Moreover, in MOE 2016.08, the

standard molecular docking was tested. The γ triangle

position, which could derive poses by random superposi-

tion of H₂L1 and H₂L2 atoms triplets γ sphere dummies

in the target site was used to determine the poses. The

London dG scoring function exposed the ligand-free bind-

ing energy from the specified pose. The optimal docked

molecules poses were assigned by more than 50 cycles of

theoretical calculations. The achieved molecular dock file

was produced with H₂L1, H₂L2, MoO₂L1 and MoO₂L2

different poses with a reconsideration of the final score

function (S). The final score, S, was not set as any. Inves-

tigation of the various poses, the browser of the resulted

database was selected for the optimization.

ctDNA, as [DNA], using Equation (1)^[8,9,23,24]

:

½DNAꢁ ½DNAꢁ

1

Â

À

ÁÃ

=

+

ð1Þ

ε_a−ε_f

ε_b−ε_f

K_bε_b−ε_f

where, [DNA] in mmoles is the ctDNA concentrations in

the nitrogenous base pairs. All values of ε_f, ε_aand ε_bare

presented as the extinction coefficients of free ctDNA

with the MoO₂-complexes (MoO₂L1 or MoO₂L2), respec-

tively. The calibration curves for the free MoO₂L1 and

MoO₂L2 complexes, A_abs/[complex] could be calculated,

as well as, the calibration curve for the free ctDNA, was

also determined by A_abs/[DNA]. The values ε_fand ε_awere

derived for both studied Mo-complexes and ctDNA,

respectively. K_bwas derived from the plot slope and the

plot intercept ratio of the above plotting. The standard

¼

Gibb's free energy, ΔG_b, for the interacted ctDNA with

MoO₂L1 or MoO₂L2, was obtained from Equation (2)^[8]

:

¼

ΔG_b= −RTlnK_b

ð2Þ

The category and magnitude of the chromism for

each Mo-complex were appreciated according to Equa-

tion (3):

A_free−A_bonding

Chromism,% =

ð3Þ

A_free

6 of 25

ADAM ET AL.

where A_freeand A_bondingare the significant absorbance

values of the MoO₂L1 and MoO₂L2 solution without and

with various concentrations of ctDNA at their character-

istic maximum absorption wavelength.

air. The medium used was Dulbecco's modified Eagle's

supplemented with 100 mg ml⁻¹streptomycin sulfate, 60

mg ml⁻¹penicillin G and 10% (v/v) calf serum.

3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium

bromide (MTT) was employed to estimate the cell viabil-

ity of the living cells, which formed purple-colored

formazan crystals.^[46,47]Stock solutions of the tested com-

pounds (10 and 5 mM) were prepared in sterilized

DMSO. Briefly, in 96-well microplates, 50,000 cells mL⁻¹

(120 μL cell suspension) were seeded and cultured for 48

hr at 37 ^ꢀC and 10% CO₂for optimal adherence. Then the

medium was removed and 200 μL of diluted concentra-

tion series of the tested cis-MoO₂-compounds in a fresh

medium were added with further incubation of the cells

for more 48 hr. MTT solution (75.0 μL) in phosphate-

buffered saline (PBS) was added and kept for two hr at 37

^ꢀC. The formed formazan crystals (precipitate) were cen-

trifuged and the supernatant was removed. The purple

formazan crystals were carefully washed three times with

100 μL of PBS and then solubilized in 100 μL DMSO.

ELISA plate reader was used to estimate the intensity of

the produced color at 590 nm. Experiments were

repeated twice and the IC₅₀values are defined when the

various concentrations of current compounds produce

50% of the absorbance of untreated cells. 5-Fluorouracil

was used as a positive control.

2.6.2 | Hydrodynamic measurements

Hydrodynamic viscosity measurements were performed

in order to give more evidence about the binding mode

between the reacted ctDNA and the current bis-

dioxomolybdenum complexes.^[4,9]The hydrodynamic

measurements were performed using Oswald micro-

viscometer at 25 ^ꢀC. Briefly, different concentrations

(5.0–50.0 μM) of MoO₂-complexes (MoO₂L1 or MoO₂L2)

were added to a defined concentration of ctDNA (250

mM). The resultant mixture was kept at 37 ^ꢀC for 10 min

with detection of the flow time rate by a digital stop-

watch. Each run was repeated three times and the calcu-

lated average flow time was subsequently determined.

From Equation (4), the particular viscosities η^ꢀand η

were determined in the absence and presences of differ-

ent concentrations of MoO₂L1 or MoO₂L2 to ctDNA,

respectively^[8,9,23,24]

:

t−t^o

t^o

η =

ð4Þ

The sulfo-Rhodamine-B stain assay was used to evalu-

ate the cytotoxicity of the prepared agents employing the

known reported method Ayuso, et al.^[48]This experiment

was also performed at the National Cancer Institute,

Cairo University. Briefly, cells were cultured in

96-multiwell microtiter plate (10⁴cells/well) for twenty-

four hours for optimal adherence. Test compounds were

solubilized in DMSO and diluted with saline buffer to the

desired concentration. Cells were then treated with serial

concentrations of the test compounds and incubated for

where, t is the fluid time of the reacted MoO₂L1 or

MoO₂L2 with ctDNA and t^ꢀis the buffer fluid time in the

absence of the reacted MoO₂-complexes (seconds). The

ratios of the measured viscosities, η/η^ꢀ, were plagiaristic

from the plot of the viscosity with the reciprocal of R.

Hence, R could be defined from Equation (5):

½DNAꢁ

R =

ð5Þ

½Compoundꢁ

ꢀ

48 hr at 37 C and in an atmosphere of 5% CO₂. After

The [DNA] refers to the concentration of ctDNA (250

mM), whereas, [compound] refers to the various concen-

trations (5.0–50.0 μM) of MoO₂L1 or MoO₂L2.

routine fixation and washing, cells were stained with

0.4% (wt vol⁻¹) SRB for a half-hour. Cells were then

washed 4X with 1% acetic acid to get rid of excess dye

and recovered again via Tris-EDTA buffer. ELISA reader

was accomplished to adjust the intensity values of color

an enzyme-linked immunosorbent assay. This experi-

ment was performed at least three times. The survival

curve of tumor cells was estimated by plotting drug con-

centration versus the surviving fraction.

2.7 | Anticancer potential

The anticancer activities of the cis-MoO₂-complexes

(MoO₂L1 and MoO₂L2) and their free bis-Schiff base

ligands (H₂L1 and H₂L2) were tested using MTT and

Sulfo-Rhodamine-B stain (SRB) assays against colon car-

cinoma (HCT-116), breast adenocarcinoma (MCF-7) and

human liver carcinoma (HepG2) cell lines purchased

from the National Institute of Cancer in Cairo (Egypt)

and in the Department of Cancer Biology, Pharmacology

Department, Cairo University (Egypt). Cells were grown

in a humidified atmosphere containing 15% (v/v) CO₂in

2.8 | Antioxidant activity

2.8.1 | DPPH assay

Free radical scavenging potential of MoO₂L1 and

MoO₂L2 was studied by the DPPH radical scavenging

ADAM ET AL.

7 of 25

assay by following the disappearance of the DPPH solu-

tion purple color in methanol to pale yellow color.

Briefly, 2.40 ml of DPPH in methanol (0.1 mM) was

poured into a 100 μM methanolic solution of MoO₂L1

and to an aqueous solution of MoO₂L2. The obtained

mixture was vortexed in a dark place at room tempera-

ture for 0.5 hr. The molar absorptivity of the final

obtained mixed solution was determined at 517 nm calo-

rimetrically. Vitamin C (ascorbic acid) was involved as a

positive control.^[49]The negative control (only methanol)

and a blank sample (no DPPH) were also performed for

comparison. The DPPH % of radical scavenging capacity

was estimated by applying Equation (6):

the antifungal fluconazole drug positive controls. The %

activity index was computed following Equation (7):

%activity index =

ðinhibition zone of the test compounds

ð7Þ

× 100

inhibition zone of the standard drug

Moreover, the minimum inhibitory concentrations

(MIC) in mM of the tested compounds were determined

by the microdilution method following the reported

method.^[51]The MIC was calculated after 18–20 hr and

defined as the lowest concentration of compound giving

complete inhibition of growth.

ꢀ

ꢁ

A_o−A_s

A_o

Radical scavenging% =

× 100

ð6Þ

3 | RESULTS AND DISCUSSION

where, A_ois the control activity and A_sis the sample

activity.

3.1 | Synthesis and structure evaluations

Salicylaldehyde is commonly used for the preparation of

a wide range of Schiff bases for various proposes.^[52]The

use of salicylidene hydrazone bis-analogs is however less

common in coordination chemistry.^[53]It was therefore

aimed to base our design criteria of cis-bis-

dioxomolybdenum complexes on the use of bis-

salicylidenedihydrazone ligands. Two bidentate bis-Schiff

base ligands (H₂L1 and H₂L2) derived from

salicylaldehyde and oxalyldihydrazide^[25]were synthe-

sized following the reported literature methods.^[54]It is

worth noting that, H₂L2 ligand bearing the hydrophilic

sodium sulfonate groups was used here as a water-soluble

analog. The synthesis of H₂L1 and H₂L2 ligands and their

related MoO₂-complexes is outlined in Scheme 1. The

structures of H₂L1 and H₂L2 ligands were elucidated by

¹H- and ¹³C-NMR, IR, mass and ultraviolet–visible spec-

tra, as well as elemental analyses (EA) and conductivity

measurements.

2.8.2 | SOD assay

The activity of superoxide dismutase (SOD) was explored

in the absence and presence of MoO₂L1 and MoO₂L2,

spectrophotometrically with SOD kit.^[50]The ability of

the enzyme to inhibit the reactivity of phenazine

methosulphate-mediated reduction was investigated by

nitro blue tetrazolium dye.^[51]The remarkable shift in the

maximum absorption bands (560 nm) for more than 5

min and then the intimating percentages were evaluated.

2.9 | Antimicrobial activity

The antibacterial potential of the studied ligands (H₂L1

and H₂L2) and their corresponding Mo-chelates

(MoO₂L1 and MoO₂L2) were examined using two Gram-

negative (Serratia Marcescence and Escherichia coli) and

one Gram-positive (Staphylococcus aureus) bacterial

strains. The fungal strains Candida albicans, Aspergillus

flavus, and Trichophyton rubrum were also used to assess

the compounds' antifungal activity.

3.2 | The cis-bis-dioxomolybdenum

complexes features

The antimicrobial potential was predestined using the

known agar well diffusion method employing 100 μL of

fungal/bacterial suspension (1.0 × 10⁴pores ml⁻¹of fungi

and 1.0 × 10⁸CFU ml⁻¹of the bacterial strains) spread

on potato dextrose agar, and nutrient agar medium,

respectively.^[51]6 mm diameter paper discs soaked with

20 μM of the compounds were put on the agar plates and

hold at 30 C for 24 hr, the antimicrobial activities were

estimated by measuring the inhibition zone and com-

pared with the standard antibacterial drug ofloxacin and

The bis-dioxomolybdenum complexes MoO₂L2 and

MoO₂L2 were obtained via the reaction of cis-

MoO₂(acac)₂with H₂L1 and H₂L2 ligands in 2: 1 ratio

with good yield percentages (74 and 69%), respectively.

The solid phase of Mo-complexes is stable, which decom-

ꢀ

pose at higher than 300 C without melting (Table 1).

Bis-dioxomolybdenum (II) ion coordinated to H₂L1 and

H₂L2 to form homo-bis-dinuclear pincer chelates within

2: 1 equivalent of cis-(MoO₂)²⁺: ligand, respectively. The

tentative molecular structure of the cis-MoO₂-complexes

ꢀ

8 of 25

ADAM ET AL.

SCHEME 1 The preparation of H₂L1, H₂L2 and their

cis-MoO₂-complexes (MoO₂L1 and MoO₂L2)

was in good agreement with other reported cis-MoO₂-

complexes in the literature.^[55]The stoichiometric molar

ratios of (MoO₂)²⁺-ions and H₂L1 or H₂L2 solutions were

estimated by the common spectrophotometric continuous

variation method (Figure S9).

The obtained continuous variation plots established

that all MoO₂-complexes formed in one equivalent of

ligand and two equivalents of cis-(MoO₂)²⁺ion. Alterna-

tive physico-chemical tools were applied to characterize

and elucidate the molecular structures of MoO₂L1, and

MoO₂L2 (Table 1). The resulted data of the elemental

analyses of the cis-MoO₂-chelates, as listed in Table 1,

were in good harmony with those theoretical data for the

suggested molecular formulae. The standard universal

buffers, which controlled the pH range of the ligands and

their MoO₂-complexes stability, assigned from 2.3 to 10.1

(Figure 1).^[25]

H₂L1 and MoO₂L1 are soluble in chloroform, dic-

hloromethane and also in strong coordinating solvents

such as dimethylsulfoxide (DMSO) and N,N⁰-

dimethylformamide (DMF). On the other hand, H₂L2

and MoO₂L2 are completely soluble in water as well as

DMSO and DMF. H₂L1, H₂L2, MoO₂L1, and MoO₂L2

showed spring solubility in most of the common organic

high polar solvents, e.g. acetonitrile and methanol. The p-

sodium sulfonate substituent in H₂L2 and MoO₂L2 is

responsible for its solubility in water and this facilitated

their conductivity features investigation in water. Three

counter ions were included in the solution for each mole-

cule of H₂L2 or MoO₂L2 since two of them are Na⁺ions

and the third ion is the complex anion as disulfonate

anion.^[29]

materials (Figures S1-S8). The characteristic singlet reso-

nating signals of NH— protons at 11.00 and 8.82 ppm for

both H₂L1 and H₂L2 were completely disappeared after

complexation to cis-(MoO₂)²⁺ions. Cis-(MoO₂)²⁺ions

forced the enolized form of H₂L1 or H₂L2 to coordinate

with cis-(MoO₂)²⁺ions. The high remarkable shift of the

boarded singlet signals of —CH=N—, Schiff base group,

were assigned from 12.61 and 11.00 ppm H₂L1 and H₂L2

to 9.01 and 9.92 ppm in MoO₂L1 and MoO₂L2, respec-

tively. The coordinating ability of the nitrogen lone pair

of the Schiff base moiety to cis-(MoO₂)²⁺ions could be

responsible for that strong shift. In ¹³C-NMR spectra, the

downfield shift of the significant Schiff base group form

163.41 and 157.95 ppm in H₂L1 and H₂L2, respectively,

to 166.12 and 186.88 ppm in MoO₂L1 and MoO₂L2,

respectively, could be due to the coordination of the

nitrogen lone pair of the Schiff base group to cis-

(MoO₂)²⁺ions. Moreover, the appearance of strong

downfield shift signals at 156.97 and 162.80 ppm after

complexation in MoO₂L1 and MoO₂L2, respectively,

could be resulted from the presence of dienolized tauto-

mer. Cis-(MoO₂)²⁺ion coordinated to the dienolized tau-

tomer of H₂L1 or H₂L2 (Scheme 1).^[29]

3.2.2 | Ultraviolet–visible spectroscopy

The characteristic electronic transitions of H₂L1, H₂L2,

MoO₂L1 and MoO₂L2 were assigned at the maximum

absorption wavelength (λ_max) and shown in Table 1 and

in Figure 2. In the UV-area, H₂L1 and H₂L2 exhibited

two characteristic high-energy bands of π ! π* transition

at 248 and 249 nm and n ! π* transition at 326 and 291

nm, respectively. Moreover, an observable absorption

band at 393 and 353 nm for H₂L1 and H₂L2, respectively,

due to the electronic transition of the ligand charge trans-

fer.^[5,19]The binding of the coordinated ligands to cis-

(MoO₂)²⁺ions caused an observable shift of the above

3.2.1 | NMR spectra

1

Further details on the spectrum data and copies of H-

and ¹³C-NMR spectra are assigned in the supplementary

ADAM ET AL.

9 of 25

FIGURE 1 pH effect on the stability of a methanolic solution

of MoO₂L1 and an aqueous solution of MoO₂L2

characteristic bands. Both π ! π* and of n ! π* elec-

tronic transitions were little shifted to lower energy

values (246, 300 and 315 nm, respectively for MoO₂L1

and 245 and 318 nm for MoO₂L2, respectively). Particu-

larly, the ligand-CT band was also shifted but with a

remarkable value to the lower energy area at 359 and 346

nm, for MoO₂L1 and MoO₂L1, respectively. The most

detected characteristic broad-band at 500 and 475 nm for

MoO₂L1 and MoO₂L1, respectively, was resulted from

the complexation and from the d ! d electronic transi-

tion of cis-(MoO₂)²⁺ion in its complexes.

3.2.3 | IR spectra

IR spectra of H₂L1, H₂L2, MoO₂L1 and MoO₂L2 are

documented in the supplementary materials (Figures

S10-S13). From the displayed absorption signals of IR

spectra, the diagnostic characteristic absorption signals of

the phenolic OH-dihydroxyl group (3347 and 3328 cm⁻¹

)

and NH-diimino group (3272 and 3186 cm⁻¹) in H₂L1

and H₂L2, respectively, were completely disappeared due

to the bonding of the deprotonated phenolic-hydroxy

group and the dienolized form of H₂L1 and H₂L2 in their

MoO₂-complexes. The stretching vibrational bands of

>C=O bonds were also disappeared in H₂L1 and H₂L2

(1719 and 1674 cm⁻¹, respectively) after complexation

with appearing of new vibrational bands of —C=N—

group at 1643 and 1600 cm⁻¹, respectively, this could

prove that the dienolized tautomer was the coordinated

form to cis-(MoO₂)²⁺ions, as reported previously.^[29]Fur-

thermore, the classified azo-methine group band (1611

cm⁻¹for H₂L1 and H₂L2) was remarkable shifted to 1558

cm⁻¹, respectively. This behavior could result from the

10 of 25

ADAM ET AL.

FIGURE 2 The electronic

spectral scans of H₂L1 and

MoO2L1 in methanol (a), H₂L2;

and MoO₂L2 in water (b)

bonding of nitrogen lone pair of —C=N— group to cis-

(MoO₂)²⁺ion.^[4,5]The labile coordinated solvent mole-

cules, i.e. methanol in MoO₂L1 and water in MoO₂L2,

could be also confirmed by the presence of new

stretching rotational bands at ꢀν = 3496 and 1599 cm⁻¹for

the methanol molecules in MoO₂L1 and 3400 and 1600

cm⁻¹for the water molecules in MoO₂L2.^[54]The p-

sodium sulfonate group in H₂L2 had two distinguished

stretching vibrational bands at 1142 and 1415 cm⁻¹cor-

responded to the S―O⁻and S=O bonds, respectively,

which have been little shifted to 1124 and 1339 cm⁻¹in

MoO₂L2, respectively, due probably to the complexation

to cis-MoO²⁺ions.^[54]Additionally, new characteristic

absorption bands were detected at 910 and 901 cm⁻¹in

MoO₂L1 and MoO₂L2, respectively, resulted from the

formed M―O bonds. Also, other weak bands at 531 and

558 cm⁻¹were referred to the M―N bonding in MoO₂L1

and MoO₂L2, as reported elsewhere for Mo―O and

Mo―N bonding.^[25,29]

whether the methanol and water molecules are inside or

outside the inner coordination sphere of the metal, ther-

mal analysis was carried out.^[56,57]The number of the

labile coordinated solvent molecules, i.e. methanol in

MoO₂L1 and MoO₂L2, respectively, were investigated by

thermogravimetric analyses (TGA). TGA results are

shown in supplementary materials Figure S18. The ther-

mogram presents a notable decomposed sequential step

ꢀ

in the range of 200 to 260 C. The mass percentage loss

was found to be Δm_exp.= 10.5 and 5.0%, which approxi-

mately convenient with the predictable mass loss (Δm_cal.

= 9.9 and 4.4% for MoO₂L1 and MoO₂L2, respectively).

The mass loses percentage referred to the two coordi-

nated methanol molecules in MoO₂L1. Similarly, the loss

percentage of the coordinated water molecules in

MoO₂L2 referred to the two water molecules' loss in that

temperature range.^[29]

3.3 | DFT results

3.2.4 | Mass spectra

The optimized geometrical structure of H₂L1, H₂L2,

MoO₂L1 and MoO₂L2 is presented in Figure 3 with the

lowest energy configurations resulted from DFT studies.

The natural charges of the current compounds were

obtained from Natural Bond Orbital Analysis (NBO). For

H₂L1, NBO showed that the more negative active sites

were on O1 (−0.554), O2 (−0.633), O3 (−0.729), O4

(−0.732), N1 (−0.479), N2 (−0.462), N3 (−0.255) and N4

(−0.238). From NBO analyses of MoO₂L1, Mo atom had

six-coordinated bonds in an octahedral geometry. Mo1

atom coordinated to O2, N4, O3 and O7 of H₂L1, which

were almost in one plane with little deviation by 3.243^ꢀ.

Mo2 atom was coordinated to N3, O4, O6 and O10,

which were, similarly, in one plane and deviated by

5.568^ꢀ. The bond angles in the octahedral around Mo1

atom were ranging from 72.94^ꢀto 103.7^ꢀand the bond

angles in the octahedral around Mo2 atom were ranging

from 70.05^ꢀto 107.7^ꢀ, as listed in Table S1 (Figure S19 in

the supplementary materials). The distances between

Mass spectroscopic results for H₂L1, H₂L2, MoO₂L1 and

MoO₂L2 are recorded in supplementary materials

(Figures S14-S17). The mass peaks that appeared at 327

m/z belong to H₂L1 and at 643, 648 and 649 m/z for [M

+ 1] for MoO₂L1, respectively. H₂L1 and MoO₂L1

showed peaks of [M + 1] at 531 m/z for H₂L1 and at

819, 820, 822, 824, 826 and 828 m/z for MoO₂L1. Other

base peaks of [M - Na⁺] exhibited at 485 m/z for H₂L2

and at 772 m/z for MoO₂L2. Moreover, base peaks of

[M - SO₃Na⁺] assigned at 362 m/z for H₂L2 and at 612

m/z for MoO₂L2.

3.2.5 | Thermogravimetric analyses

In order to obtain useful information about the thermal

stability of the prepared metal chelates and to decide

ADAM ET AL.

11 of 25

FIGURE 3 The optimized structure, the vector of the dipole moment, and the natural charges on active centers of H₂L1, H₂L2,

MoO₂L1, MoO₂L2 using B3LYP/LANL2DZ

donor atoms in H₂L1 were longer than those in MoO₂L1,

due to their coordination to cis-(MoO₂)²⁺ion, Table 2.

Furthermore, the natural charges, which derived from

NBO-analyses, were found on Mo1 (+1.244) and Mo2

(+1.180), as positive charges, and also found on O1

(−0.585), O2 (−0.600), O3 (−0.700), O4 (−0.620), O5

(−0.439), O6 (−0.376), O7 (−0.445), O8 (−0.494), O9

(−0.725), O10 (−0.708), N3 (−0.378) and N4 (−0.391), as

12 of 25

ADAM ET AL.

TABLE 2 Comparison between distances of coordinated atoms in H₂L1, H₂L2, MoO₂L1 and MoO₂L1

Bond length (Å)

Type of bond

N4^…..…O2

N4^…..…O3

H₂L1

3.556

4.027

6.754

H₂L2

3.550

4.045

6. 889

MoO₂L1

2.545

Type of bond

N3^…..…O1

N3^…..…O4

H₂L1

2.824

3.944

6.683

H₂L2

2.819

3.945

6.745

MoO₂L1

2.64

2.666

2.766

O2^…..…O3

3.884

O1^…..…O4

2.906

MoO₂L2

2.536

MoO₂L2

2.645

N4^…..…O2

N4^…..…O3

O2^…..…O3

N3^…..…O1

N3^…..…O4

O1^…..…O4

2.814

2.876

3.256

2.897

negative charges, Figure 3. For H₂L2, the most negative

active sites were found on O1 (−0.542), O2 (−0.574), O3

(−0.733), O4 (−0.710), N1 (−0.468), N2 (−0.473), N3

(−0.220) and N4 (−0.289).

In MoO₂L2 within an octahedral geometry, Mo1 atom

had O2, N4, O9 and O7, which was almost in one plane

with deviation by 6.003^ꢀ. Atoms of O1, N3, O5 and O6

coordinated to Mo2 atom in MoO₂L2, which deviated

from one plane by 0.583^ꢀ. The bond angles in the octahe-

dral around Mo1 atom were in the range from 75.14^ꢀto

116.5^ꢀand the bond angles in the octahedral around Mo2

atom were in the range from 80.93^ꢀto 94.28^ꢀ(Table S2

and Figure S19 in the supplementary materials). The dis-

tances between donor atoms in H₂L2 were longer than

those in MoO₂L2, which due to its coordination to

(MoO₂)²⁺ions (Table 2). The natural distributed charges,

which computed by NBO-analyses on the coordinated

atoms, were recorded as Mo1 (+1.072), Mo2 (+0.914), O1

(−0.459), O2 (−0.423), O3 (−0.516), O4 (−0.480), O5

(−0.436), O6 (−0.394), O7 (−0.344), O8 (−0.389), O9

FIGURE 4 Molecular electrostatic potential (MEP) surface of H₂L1, H₂L2 and their complexes (MoO₂L1 and MoO₂L2) using

B3LYP/LANL2DZ

ADAM ET AL.

13 of 25

(−0.713), O10 (−0.655), N3 (−0.209) and N4 (−0.230),

Figure 3.

catalyzed by MoO₂L1 or MoO₂L2 are 1,2-epoxy-

cyclooctane, benzaldehyde and thiophene oxide.^[28,61,62]

The chemoselective yield percentages were detected by

GC–MS. There are reported well-known side products of

benzyl alcohol and thiophene oxidation which are

benzoic acid and thiophene dioxide.^[28,29]The catalytic

potential of the less polar catalyst (MoO₂L1) and the high

polar one (MoO₂L2) was investigated and measured by

the yield amounts of the chemoselective product percent-

ages, which determined and list in Tables 4 and 5. TONs

and TOFs values were calculated also and recorded in

Tables 4 and 5.

The MEP surface, which presented in Figure 4, shows

the location of the positive (blue color) and negative (red

color, i.e. bound loosely or excess electrons) charged elec-

trostatic potential in the molecule. The total computa-

tional energy, the highest occupied molecular orbital

(HOMO) energies, the lowest unoccupied molecular

orbital (LUMO) energies and the dipole moment of

H₂L1, H₂L2, MoO₂L1 and MoO₂L2 were calculated and

listed in Table 3. The high stability of MoO₂L1 and

MoO₂L2 compared to that of the coordinated ligands

(H₂L1 and H₂L2) could be estimated by their more nega-

tive magnitudes of total energy than those of free ligands.

Also, the energy gap (ΔE_g), which assigned by the differ-

ence in values between E_LUMOand E_HOMO, was smaller

values for MoO₂L1 and MoO₂L2 than those for the free

H₂L1 and H₂L2, respectively, due to chelation effect of

ligand to metal ions, Table 3.^[9]The low magnitude of

ΔE_gfor MoO₂L1 and MoO₂L2 compared to that of l H₂L1

and H₂L2 was probably due to the charge transfer inter-

actions within the complex formation. Finally, all the

theoretical results agreed with the experimental obtains

for the Mo-complexes formation.

Both Mo (VI)-catalysts exhibited excellent catalytic

reactivity for all oxidation processes with excellent con-

version percentages (94–100%) using an aqueous H₂O₂in

water (Table 4), but unfortunately, only at high tempera-

ꢀ

ture (85 C). The chemoselective amounts were alterna-

tively in between excellent for 1,2-epoxy-cyclooctane

percentages, good for benzaldehyde percentages and

moderate for thiophene oxide percentages. The yields

were 84, 78 and 40% at the optimized times (3, 1.5 and 2

hr) of 1,2-epoxy-cyclooctane, benzaldehyde and thio-

phene oxide, respectively, catalyzed by MoO₂L1 and oxi-

dized by H₂O₂. The yield percentages with MoO₂L2 were

remarkably more assigned in the same reaction condi-

tions, which afforded 90, 88 and 47% at the optimal times

(2, 1.5 and 2 hr) of 1,2-epoxy-cyclooctane, benzaldehyde

and thiophene oxide, respectively, as observed in Figures

S20-S22 in the supplementary materials (Table 4). As a

consequence, MoO₂L2 seems to be more effective catalyst

for all subjected catalytic processes than that MoO₂L1

with H₂O₂(the most eco-friendly oxidant) in the aqueous

media. Both catalysts took almost similar reaction time to

reach the optimized amounts of the chemoselective prod-

uct percentages due to their similar chemical structures.

It is important to mention here that MoO₂L1 was very

sparingly soluble in the reaction media, but after adding

the oxidant, it was completely soluble.

3.4 | Catalytic (ep)oxidation studies

A comparative catalytic study was performed between

the less and high polar homo-dinuclear complex catalysts

(MoO₂L1 and MoO₂L2), respectively, in the (ep)oxidation

of 1,2-cyclooctene, benzyl alcohol and thiophene in water

under sustainable reaction conditions. Due to the most

applicability in the literature of the dioxo- and

peroxomolybdenum Schiff base chelates as appreciated

homogenous catalysts for (ep)oxidation protocols under

alternative conditions,^[32,58–60]both MoO₂L1 and

MoO₂L2 were involved in various (ep)oxidation systems.

The chemoselective products of 1,2-cyclooctene, benzyl

alcohol and thiophene (ep)oxidation by H₂O₂or tBuOOH

The solubility and miscibility of the catalyst in the

reaction media have observable influences on the

TABLE 3 Calculated energies of H₂L1, H₂L2 and their complexes (MoO₂L1 and MoO₂L2) at B3LYP/LANL2DZ

HOMO^b

−6.3825

−4.5677

−7.2108

−0.5606

LUMO^c

−2.2684

−4.0238

−3.5718

−0.1298

E_gap

Dipole moment^e

4.114

a

d

Compound

H₂L1

ΔE_g

−1137.78

−1804.14

−1608.89

−2193.50

4.1141

0.5439

3.6390

0.4308

MoO₂L1

H₂L2

6.301

15.020

MoO₂L2

16.921

^aE, the total energy (KCal mol⁻¹).

^bHOMO, highest occupied molecular orbital (eV).

^cLUMO, lowest unoccupied molecular orbital (eV).

^dE_g= E_LUMO- E_HOMO(eV).

^eDipole moment (Debye).

14 of 25

ADAM ET AL.

TABLE 4 Percentages of products yield of the catalytic (ep)oxidation of 1,2-cyclooctene, benzyl alcohol and thiophene using an

aqueous H₂O₂catalyzed by cis-MoO₂-complexes

Time

Complex^a(hrs)

Reactant

(%)

Product^b

(%)

Side product

(%)

Conversion

(%)

Selectivity

(%)

TON^cTOF^d

MoO₂L1

4

(10)^e

94

89

22.3

(6%)

(84)

(78)

2.5

98

79

31.6

(14) + (6)^e

(2%)

3.5

90

44

12.6

(10%)

(40)

(90)

(88)

(35) + (15)^e

(9)^e

MoO₂L2

2

99

91

88

91

88

45.5

58.7

(1%)

1.5

100

(8) + (4)^e

(0%)

(4%)

2

96

49

24.5

(47)

(41) + (8)^e

^aThe (ep)oxidation reaction of the substrate (1.0 mmol) with H₂O₂(3.00 mmol) catalyzed by MoO₂-complexes (0.01 mmol) in 10 mL water at 85 ^ꢀC.

^bThe yield percentages derived from GC–MS results (%).

^cTON (turnover number) = ratio of mmoles of the product (here oxide) to the mmoles of catalyst.

^dTOF (turnover frequency) (TON/h) are shown in parentheses (mmoles (mmoles catalyst)⁻¹h⁻¹).

^eOther unknown side products are (%).

catalytic processes and could enhance the catalyst activity

towards the (ep)oxidation reaction.^[28,29]MoO₂L2 is

highly soluble in water compared to MoO₂L1, which

probably improved its catalytic potential in the (ep)oxida-

tion of 1,2-cyclooctene, benzyl alcohol and thiophene

more than that MoO₂L1, especially with the more polar

oxidant, e.g. H₂O₂in the aqueous media.^[62]

Similarly, for the catalytic protocols with tBuOOH,

the conversion percentages were little improved

(94–100%), however, the chemoselectivity percentages

were little reduced catalyzed with MoO₂L1 and MoO₂L2

in water (Table 5). With MoO₂L1, the yield percentages

of 1,2-epoxy-cyclooctane, benzaldehyde and thiophene

oxide were 88, 81 and 46% with the consumed ideal times

(4, 2 and 2.5 hr), respectively, with little increase of the

target product amount using tBuOOH compare to the

above processes using aqueous H₂O₂.^[63]Within MoO₂L2

as a homogeneous catalyst for all catalytic processes, both

conversion and chemoselectivity were notably dropped

and also the amount of the target products was lowered

to be 85, 83 and 40% (4.5, 2 and 3 hr) of 1,2-epoxy-

cyclooctane, benzaldehyde and thiophene oxide, respec-

tively. The strong organic nature of the oxidant,

i.e. tBuOOH, might be performed the catalytic potential

ADAM ET AL.

15 of 25

TABLE 5 Percentages of products yield of the catalytic (ep)oxidation of 1,2-cyclooctene, benzyl alcohol or thiophene using tBuOOH

catalyzed by cis-MoO₂-complexes

Time

Complex^a(hrs)

Reactant

(%)

Product^b

(%)

Side product

(%)

Conversion

(%)

Selectivity

(%)

TON^cTOF^d

MoO₂L1

4

(12)^e

100

88

22.0

(0%)

(88)

(81)

2

100

81

40.5

(12) + (7)^e

(0%)

(3%)

2.5

97

47

18.8

(46)

(85)

(83)

(39) + (12)^e

(13)^e

MoO₂L2

4.5

98

87

83

87

83

19.3

41.5

(2%)

2

100

(11) + (6)^e

(0%)

(6%)

3

94

42

14.0

(40)

(36) + (18)^e

^aThe (ep)oxidation reaction of the substrate (1.0 mmol) with tBuOOH (1.70 mmol) catalyzed by MoO₂-complexes (0.01 mmol) in 10 mL water at 85 ^ꢀC.

^bThe yield percentages derived from GC–MS results (%).

^cTON (turnover number) = ratio of mmoles of the product (here oxide) to the mmoles of catalyst.

^dTOF (turnover frequency) (TON/h) are shown in parentheses (mmoles (mmoles catalyst)⁻¹h⁻¹).

^eOther unknown side products are (%).

of the less polar catalyst, MoO₂L1 with more organic

nature,^[64]compared to that MoO₂L2 with an aqueous

H₂O₂. Particularly, the catalytic reactivity of MoO₂L2 in

the (ep)oxidation reactions was little inhibited with

tBuOOH. The miscibility of the high polar catalyst with

tBuOOH could diminish its reactivity towards the forma-

tion of oxo−/peroxomolybdenum complex intermediate

catalyst.^[65]

ligand.^[66]So, from the catalytic results, it was clear that

the side substituent group as a polar group (Na⁺

SO₃―)^[64,67]of the coordinated ligands played the most

−

important role in the variation of the catalytic behavior

of MoO₂L1 and MoO₂L2 in the (ep)oxidation of

1,2-cyclooctene, benzyl alcohol and thiophene in water,

as reported from TONs and TOFs values in Table 4 using

the most eco-friendly oxidant (H₂O₂) and in Table 5

within tBuOOH oxidant. Moreover, the high observable

catalytic reactivity of the current homo-binuclear cis-

MoO₂-complexes could be related to the synergic effect of

Generally, most of the catalytic (ep)oxidation systems

are mainly sensitive and substantial to the catalyst type

and its nature, i.e. the type of metal ion and the attached

16 of 25

ADAM ET AL.

two central metal ions in their complex catalysts.^[29]The

synergic effect of two central metal ions could promote

the oxygen transfer process in the mechanistic pathway

of the (ep)oxidation reactions form the oxidant molecule

to the central metal ion (Scheme 2).^[68]Free radical (ep)

oxidation processes could not be taken into account here

due to the indicating test of diphenylamine performed

that the catalytic reactions could be carried with the radi-

cal mechanistic pathway.^[69]Based on the literature, the

oxygen transfer process could be progressed in the pres-

ence of a coordinated solvent molecule in the catalyst,^[37]

in which the oxidant molecule may replace the solvent

molecule (water or methanol, ROH) and then bond to

the central metal ion (A) in order to generate an active

oxo−/peroxomolybdenum complex intermediates,^[70]as

shown in Schemes 2 and 3. Both mechanistic pathways

could help to understand the difference in the catalytic

efficiency between H₂O₂and tBuOOH for the same cata-

lytic (ep)oxidation reaction. Bonding of the oxidant

(H₂O₂or tBuOOH) to the Mo-catalyst could be observed

experimentally due to the little change in the color of the

catalyst in the reaction media after mixing with the oxi-

dant^[29]awarding the first active intermediate (B in

Schemes 2 and 3). The μ-oxo−/peroxomolybdenum inter-

mediate (C in Scheme 2) could be formed with the attack

of H₂O₂only.^[60]On the other hand, the reaction of

tBuOOH with MoO₂-catalyst could afford peroxo-

molybdenum intermediate (B, Scheme 3) through the

bonding to the β-oxygen of tBuOOH to the central metal

ion,^[58]as tBuOO⁻anion to the Lewis acidic Mo^VI

ion.^[42,71]The bonded tBuOO⁻to Mo^VIion caused migra-

tion of H⁺of the oxidant to the cis-terminal oxygen

SCHEME 3 The proposed mechanistic pathway of the (ep)

oxidation of 1,2-cyclooctene, benzyl alcohol and thiophene

catalyzed by MoO₂L1 or MoO₂L2 using tBuOOH

cyclopentadienyl molybdenum imidazo[1,5-a]pyridine-

3-ylidene complexes in the olefin epoxidation using

tBuOOH.^[72]It was followed by the approach of the sub-

strate, as an electron-rich or as

a

nucleophile

(1,2-cyclooctene, benzyl alcohol and thiophene) to the

intermediate C to generate intermediate D.^[73]The inter-

mediate D caused oxidation of the substrate with the oxy-

gen transfer process to liberate the chemoselective oxy-

product and the regenerated catalyst (A) with the forma-

tion of H₂O in the case of using H₂O₂and tBuOH in the

case of using tBuOOH.

The differences in the formed intermediate using

H₂O₂or tBuOOH with Mo-catalyst, as μ-oxo−/

peroxomolybdenum intermediate or peroxointermediate,

respectively, aimed to illustrate the variation in the yield

percentages of the chemoselectives and in the efficiency

of the applied Mo-catalysts.

of Mo

= O species giving peroxointermediate C

(in Scheme 3). This was studied previously with new

SCHEME 2 The proposed mechanistic

pathway of the (ep)oxidation of 1,2-cyclooctene,

benzyl alcohol and thiophene catalyzed by

MoO₂L1 or MoO₂L2 using H₂O₂

ADAM ET AL.

17 of 25

3.5 | Molecular docking studies

NH―groups of H₂L2 with bond distances 2.99 and 3.17

Å, respectively. The docking results assigned the forma-

tion of one hydrogen bond between MoO₂L1 and

MoO₂L2 with the guanine (DG14) and the adenine

(DA18) bases of the ctDNA with bond distances of 3.33

and 2.91 Å, respectively. Moreover, there was a π–

hydrogen interaction in MoO₂L2 with a bond distance

of 4.66 Å.

Interestingly, the molecular docking obtains showed

that the polar p-sodium sulfonate group substituent in

MoO₂L2 had an obvious role in binding with ctDNA

(Figure 5), besides the hydrogen bonding of the labile

coordinated H₂O molecules. The molecular docking stud-

ies illustrated that the hydrogen bond(s) and the hydro-

phobic interaction of MoO₂L1 and MoO₂L2 played an

essential role in the binding interaction. Accordingly, the

interaction of the MoO₂-complexes with ctDNA was

probably grooved binding. These interesting results need

more studies and further investigations such as DNA

binding studies employing spectroscopic and viscosity

experiments, as shown below.

Molecular docking is a valuable tool used to explore and

explain the possible anticancer and antimicrobial mode

of action(s) of different bioactive molecules. In this con-

text, the molecular docking of H₂L1, H₂L2, MoO₂L1 and

MoO₂L2 was performed using MOE package version

2019.0101 in order to investigate their binding mode to

ctDNA with respect to their energy. The binding energy

(E_conf.) of H₂L1, H₂L2, MoO₂L1 and MoO₂L2 with ctDNA

and their final score function (S) were calculated and dis-

played in Table 6. The total hydrophobic surface area and

the number of hydrogen bonding of H₂L1-, H₂L2-,

MoO₂L1- and MoO₂L2-ctDNA of the docked structures

are shown in Figure 5. The docked structures, as shown

in Figure 5, suggested the possible formation of different

types of hydrogen bonding between H₂L1, H₂L2, MoO₂L1

and MoO₂L2 with B-DNA, providing the binding energy

and binding score magnitudes with hydrophobic interac-

tion character.

Indeed, the negative magnitudes of the binding

energy were found in the range of −603.3815 and −

932.8271 kcal mol⁻¹and the binding score was in the

range of −6.0514 and − 4.9293. The hydrophobic high

surface area was in the range of 3651.593 and 474.8554.

The former suggested a strong binding ability of the

current reagents with ctDNA, via non-covalent stacking

interactions. Accordingly, the docking studies referred

to the possible different types of the formed hydrogen

bonding between the current reagents and ctDNA.

Hence, a hydrogen bond could be formed between

H₂L1 (phenolic hydroxyl group) and the ctDNA (DG16)

with a bond distance of 3.18 Å. Additionally, two other

hydrogen bonds could also be formed between the

water molecule and the two hydrazone NH-groups of

H₂L1 with bond distances 3.02 and 3.06 Å, respectively.

For H₂L2, two hydrogen bonds could be formed

between the labile water molecule and the hydrazone

3.6 | DNA binding studies

3.6.1 | Absorption spectral studies

The most prominent spectral characteristics of the ctDNA

double-helix after reaction with other molecules is

hyperchromism and hypochromism.^[9]The later could be

formed from the stabilization of the ctDNA duplex either

via the electrostatic effect or the intercalative binding

mode. On the other hand, hyperchromism could be

formed from the splitting of the ctDNA duplex.^[74]There-

fore, the binding capacity of the ctDNA with the MoO₂-

complexes (MoO₂L1 and MoO₂L2) was estimated via the

evaluation of their electronic spectral changes after their

interaction with ctDNA. The absorption spectrum of

TABLE 6 The molecular docking calculated values for H₂L1 and H₂L2, and their cis-MoO₂-complexes

No. of Hydrogen

bonds

Interacting

nucleotide

Distances

()

E

Total hydrophobic

surface area

Comp.

(Kcal/mol)

k_b

S

E_conf.

H₂L1

1

DG16

H₂O

3.02

3.06

3.18

2.99

3.17

3.33

2.91

4.66

−2.6

−0.5

−0.9

−2.7

−0.5

−2.4

−2.5

−0.6

365.1593

5.51

−6.0514

−976.9422

2

3

H₂O

H₂L2

1

H₂O

251.6536

5.10

−5.8617

−932.8271

2

H₂O

MoO₂L1

MoO₂L2

1

DG14

DA18

DC11

474.8554

262.7468

4.56

5.27

−4.9293

−5.9698

−603.3815

−944.2164

1

π-H

18 of 25

ADAM ET AL.

FIGURE 5 Molecular docking interaction mode of H₂L1, H₂L2, MoO₂L1 and MoO₂L2 with ctDNA

MoO₂L1 and MoO₂L2 in the absence and presence of

ctDNA is presented in Figures 6 and 7.

suggested a stacking interaction binding mode between

the ctDNA base pairs and the aromatic chromophore of

the MoO₂-complexes. The small red-shift in the bands of

the MoO₂-complexes proposed a hypochromism. This

also beholds an intercalative binding mode of the

MoO₂-complexes through their interaction with ctDNA.

The intrinsic binding constant (K_b), as deduced in the

After the gradual addition of ctDNA, the band of

MoO₂L1 complex at 500 nm and MoO₂L2 complex at

246 exhibited a weak hypochromic effect of 7.71%

(bathochromism of 11 nm) and 2.46% (bathochromism

of 8 nm), respectively. The obtained spectral data

ADAM ET AL.

19 of 25

compared to those previously studied hydrazone reagents

towards similar cell lines.^[4,51]

3.6.2 | Hydrodynamic measurements &

viscosity measurements

Emission and absorption experiments provide additional

helpful information about the expected intercalative

binding mode with ctDNA.^[75]Viscosity measurements

were therefore performed to further explain the interac-

tive nature between the cis-MoO₂-complexes (MoO₂L1

and MoO₂L2) and ctDNA. The ctDNA viscosity is

expected to be increased after intercalation. On the other

hand, ctDNA viscosity could be reduced in non-classical,

partial or intercalation due to bending of the ctDNA

helix.^[76]Ethidium bromide was applied as a reference in

such experimental work. As shown in Figure 8, the rela-

tive viscosity of ctDNA was significantly enhanced in the

case of ethidium bromide. Similarly, the viscosity of

ctDNA improved steadily within increasing the amounts

of MoO₂-complexes, however; the viscosity increase

extent with EB was significantly more. The increased

degree of viscosity of ctDNA within MoO₂L2 was greater

than that with MoO₂L1. Conclusively, the UV-absorption

and viscosity measurement results suggested that the

binding mode of cis-bis-dioxomolybdenum complexes

involves base-pair intercalation which was in agreement

with the molecular docking studies.

FIGURE 6 The UV–Vis. spectral scans of MoO₂L1 in the

buffer solution in the absence and presence of ctDNA with interval

time 15 min (a); the visible zoom of the electronic spectra of

MoO₂L1 in absence and presence of ctDNA (b)

3.7 | Biological evaluation

3.7.1 | Anticancer activity evaluation

The antiproliferative potential of H₂L1, H₂L2, MoO₂L1

and MoO₂L2 was examined using HCT-116, MCF-7 and

HepG2 cell lines and the IC₅₀values were determined

and recorded in Table 8. Bis-dioxomolybdenum com-

plexes (MoO₂L1 and MoO₂L2) exhibited superior cytotox-

icity against all the three applicable cell lines comparing

to their corresponded free bis-Schiff base ligands (H₂L1

and H₂L2) (Figure S23). The enhancement of their anti-

cancer potential, for the reacting free ligands, could be

related to their various structural features and would be

attributable to redox-active molybdenum (VI) ions.^[77,78]

In general, the viability of HCT-116, MCF-7 and

HepG2 cells, which treated with the test current reagents,

decreased in a concentration-dependent manner, how-

ever, the anticancer activity of those studied reagents

(MoO₂-complexes and their free ligands) was less than

the standard drug, vinblastine (Table S3). All the probed

reagents were more cytotoxic against the MCF-7 cell line

FIGURE 7 The UV–Vis. spectral scans of MoO₂L2 in the

buffer solution in the absence and presence of ctDNA with interval

time 15 min (a); the visible zoom of the electronic spectra of

MoO₂L2 in absence and presence of ctDNA (b)

experimental section, was used for comparing the quan-

titative affinity of ctDNA binding to the studied MoO₂-

agents. The intrinsic binding constants K_bwere also

involved to determine quantitatively the extent of the

binding strength of the MoO₂-complexes. As depicted in

Table 7, the K_bvalues for MoO₂L1 and MoO₂L2 are 4.83

× 10⁵and 7.28 × 10⁵M⁻¹.

The obtained results of DNA-binding and K_bvalues of

the current MoO₂-complexes, as dihydrazone reagents,

afforded more distinguished reactivity towards DNA

20 of 25

ADAM ET AL.

TABLE 7 Spectral parameters for the interaction of cis-MoO₂-complexes with ctDNA

λ

_maxfree

λ

_maxbound

Type of

Chromism

Binding

Complex

(nm)

248

300

321

359

500

246

318

475

(nm)

240

300

321

358

511

254

318

469

Δn

0

Chromism (%)

constant^a× 10⁵

ΔG KJ mol⁻¹

−33.31

MoO₂L1

4.99

5.27

5.52

6.75

7.71

2.46

12.05

6.38

Hyper

4.83

0

−1

11

8

MoO₂L2

Hypo

7.26

−36.45

0

−6

TABLE 8 Influence of H₂L1, H₂L2, MoO₂L1, and MoO₂L2 on

the viability of HCT-116, HepG2, and MCF-7 cells

IC₅₀(μM)^b

Comp.^a

H₂L1

HCT-116

98.40

MCF-7

78.20

84.30

8.90

HepG-2

87.50

95.70

14.50

17.90

7.50

H₂L2

113.50

17.50

MoO₂L1

MoO₂L2

Vinblastine

25.60

13.20

4.12

13.3

The metabolic activity of the cells was estimated after 48 hr of incubation

with different concentrations of the investigated compounds by means of an

MTT assay.

^aThe IC₅₀value was determined from the dose–response curves as the mean

of two parallel experiments.

^bFluorouracil (5-Fu) was used as a positive control; Selectivity index (SI) is

the ratio of the IC₅₀value for normal cells (WI-38) to the IC₅₀values for

HepG2 and MCF-7 cells; No growth inhibition was recorded.

FIGURE 8 Effect of the increased amounts of MoO₂-

complexes on the relative viscosities of ctDNA at [DNA] = 0.5 mM

and 25 ^ꢀC

reaction of antioxidants with DPPH. The former had a

strong absorption band at 517 nm.^[46,47]The assay relied

on the absorption disappearance and decolorization due

to electron pairing in the presence of free radical scaven-

gers. In particular, the reaction was stoichiometric to the

number of electrons taken up. Methanol was used as a

blank, whereas, DPPH solution was applied as the nega-

tive control without the tested reacting compounds. The

scavenging activity percentages (%), which referred to the

free radical DPPH activity, was determined by that equa-

tion: inhibition % = [(Absorbance of control – Absor-

bance of the test sample)/Absorbance control] × 100.

Consequently, the cis-MoO₂-complexes, MoO₂L1 and

MoO₂L2, demonstrated moderate free radical-scavenging

activity compared to vitamin C, as reported in Table 9.

and MoO₂L1 presented the lowest IC₅₀values. Therefore,

MoO₂L1 considered to be the most potent among all the

tested compounds. Noteworthy, MoO₂L2 and H₂L2 bear-

ing the hydrophilic sodium sulfonate group displayed

lower anticancer activities compared to their analogs

MoO₂L1 and H₂L1, respectively. This may be due to its

poor lipophilic nature, as observed elsewhere.^[4]

3.7.2 | Antioxidant

DPPH assay

Since the bis-dioxomolybdenum complexes (MoO₂L1 and

MoO₂L2) displayed promising anticancer potential and

good ctDNA binding capability, the reducing abilities of

these current compounds were further estimated via the

DPPH assay (Table 9). The deep violet radical

1,1-diphenyl-2-picryl-hydrazine was formed by the

SOD assay

The formation of most ROS (e.g. singlet oxygen, hydrogen

.-

peroxide and hydroxyl radical) could rely on the O₂

ADAM ET AL.

21 of 25

TABLE 9 Evaluation of the antioxidant activity of

cis-MoO₂-complexes (MoO₂L1 and MoO₂L2) using the DPPH and

SOD assays

complexes (MoO₂L1 and MoO₂L2) and their

corresponding bis-dihydrazone ligands (H₂L1 and H₂L2)

encouraged us to examine their corresponding antimicro-

bial potentials. Several transition metal complexes,^[79]

specifically bis-dioxomolybdenum complexes,^[4,80]were

reported as selective suppressors of different microbial

action. Therefore, the antimicrobial activity of the MoO₂-

complexes and their free ligands under considerations

was examined using the disc diffusion and microdilution

methods against Staphylococcus aureus Gram-positive

bacteria and two Gram-negative bacteria namely,

Escherichia coli and Serratia Marcescence as well as Can-

dida albicans, Aspergillus flavus and Trichophyton rubrum

fungal strains. The results are depicted in Table 10. The

antimicrobial data were compared using the standard

antibiotics, ofloxacin (for bacteria) and fluconazole (for

fungi) and their corresponding % activity index have been

also listed in Table 10. The inhibition zones were the

clear zones around the discs, which were measured

in mm.

Intriguingly, it was observed that all the cis-bis-

dioxomolybdenum complexes revealed more obvious

antimicrobial activities than their corresponding free

ligands under identical experimental conditions against

the same organisms.^[4,8,9]For the four examined com-

pounds, MoO₂L1 strongly hampered the growth of the

bacterial and fungal strains. It was also worthwhile to

mention that MoO₂L2 and H₂L2 bearing the hydrophilic

sulfonate group displayed lower antimicrobial activity

compared to their analogs MoO₂L1 and H₂L1, respec-

tively. This could be attributable to their poor

lipophilicity. Furthermore, the current compounds were

thereafter selected for MIC studies (Table 11) and results

were in good agreement with the disc diffusion method

assay. The MIC of MoO₂-complexes and their free ligands

DPPH assay

SOD assay

Radial

scavenging (%)

ΔOD₅₆₀

(5 min)

Inhibition

(%)

Complex

MoO₂L1

MoO₂L2

Vitamin C

Control

56

0.52

0.59

--^a

89

61

97

--^a

89.6

--^a

0.516

0.163

HR SOD

68.42

^aAbsorbance was not recorded.

formation for antioxidant studies.^[77]Antioxidants could

.-

diminish the production of O₂, and in this way, it is pos-

sible to evaluate the superoxide anion scavenging effect

of different examined ligands and their corresponding

metal complexes. The activity of superoxide dismutase

(SOD) was explored in the absence and presence of

MoO₂L1 and MoO₂L2, spectrophotometrically with SOD

kit.^[61]The O₂scavenging capabilities of the agents in

.-

terms of inhibition % efficiency could be obtained in

Table 9. The obtained results showed that the MoO₂L2

complex had a higher inhibition effect (97%) than that of

MoO₂L1 (89%). Both MoO2-complexes illustrated respect-

able superoxide anion scavenging activity compared to

the reported MoO₂-hydrazone complexes.^[4]

3.7.3 | Antimicrobial activity assessment

The promising catalytic, anticancer and antioxidant fea-

tures of the newly synthesized bis-dioxomolybdenum

TABLE 10 Antimicrobial agar diffusion assay of H₂L1, H₂L2, and their corresponding cis-MoO₂-complexes: diameters (mm) of

inhibition zones (% of standard) after one day

Diameter inhibition zone in mm (% activity index)

Bacteria^a

Fungi^a

Serratia

Marcescence

Escherichia

coli

Microccus

Luteus

Aspergillus

flavus

Getrichm

candidum

Fusarium

oxysporum

Comp.

H₂L1

11(39)

9(32)

26(93)

24(86)

28(100)

b

9(41)

7(32)

21(96)

19(86)

22(100)

b

14(36)

11(28)

38(97)

35(90)

39(100)

b

9(41)

7(32)

21(95)

17(77)

b

16(41)

14(36)

37(95)

34(87)

b

11(42)

9(35)

25(96)

22(85)

b

H₂L2

MoO₂L1

MoO₂L2

Ofloxacin

Fluconazole

22(100)

39(100)

26(100)

^aDiameters (mm) of zones of inhibition (agar diffusion assay) are provided. In each case, 6 mm disks with 20 μM of the test compounds were incubated.

Ofloxacin and fluconazole were used as positive control.

^bValues refer either to not detected or inactive.

22 of 25

ADAM ET AL.

TABLE 11 Minimum inhibitory concentration (MIC/μM) for the antimicrobial assay of H₂L1, H₂L2, and their

cis-bis-dioxomolybdenum complexes

Minimum Inhibition concentration (MIC) μM

Serratia

Marcescence

Escherichia

coli

Microccus

Luteus

Aspergillus

flavus

Getrichm

candidum

Fusarium

oxysporum

Comp.

H₂L1

5.50

6.50

3.50

4.25

7.50

8.00

5.00

6.00

6.25

7.00

4.25

4.75

6.00

7.25

4.25

5.00

8.00

8.50

5.50

6.75

H₂L2

7.50

MoO₂L1

MoO₂L2

4.75

5.75

varied from 8.5 to 3.5 μM (Figure S24 in the supplemen-

tary materials).

alcohol and thiophene using an aque_ꢀous H₂O₂or tert-

butyl hydroperoxide (tBuOOH) at 85 C. The p-sodium

sulfonate group shows an appreciable influence by

improving the catalytic efficiency of MoO₂L2 compared

to MoO₂L1 (in absence of p-NaSO₃-group).

Both MoO₂L1 and MoO₂L2 interacted with ctDNA by

intercalative binding mode, which have been proven

using molecular modeling and DNA binding studies.

Both studies proposed that the binding mode of cis-

MoO₂-complexes involves base-pair intercalation.

The antiproliferative activity of H₂L1, H₂L2, MoO₂L1

and MoO₂L2 was evaluated using different cancer cell

lines including HCT-116, MCF-7, and HepG2 cells.

MoO₂L1 and MoO₂L2 showed improved cytotoxic poten-

tials in tested three cell lines compared to their

corresponding free bis-Schiff base ligands (H₂L1 and

H₂L2). Furthermore, the free radical scavenging abilities

of the current compounds were further estimated by their

strong interaction with the free stable radical DPPH.

MoO₂L1 and MoO₂L2 showed moderate free radical-

scavenging activity compared to ascorbic acid and good

superoxide anion scavenging activity. The bis-

dioxomolybdenum complexes manifested higher antimi-

crobial activities than that of the free ligands (bis-Schiff

bases) under identical experimental conditions against

the same organisms.

The superior biological activity of the MoO₂-

complexes compared to their corresponding dihydrazone

free ligands could be explained using the Tweedy's chela-

tion theory and Overtone's concept.^[78]After chelation,

the molybdenum atom lipophilicity was enhanced due to

the increase of π-electrons delocalization over the com-

plex sphere. Such behavior could favor the diffusion

through the cell membrane. On the other hand, the polar-

ity of molybdenum ion is extremely decreased due to the

partial sharing of its positive charge and overlapping of

the dihydrazone ligand orbital with donor groups.^[81]

There are many other factors for the superior bioac-

tivity of metal complexes compared to their free ligands

and these include pharmacokinetics, dipole moment,

conductivity, solubility and steric factors. However, more

intensive studies need to be made in order to identify

their biological pathways. Furthermore, the week biologi-

cal activity of MoO₂L2 and H₂L2 is due to the presence of

the polar sulfonate group, which in turn decreases their

corresponding lipophilicity and hence hampers their dif-

fusion through the cell membrane. The obtained assigned

more antimicrobial potential of the current compounds

more than those previously studied hydrazone reagents

of the similar cell membrane.^[4,8,9]

ACKNOWLEDGEMENTS

4 | CONCLUSIONS

This study was received funding from the Deanship of

Scientific Research, King Faisal University, Al-Ahsa

under the grant number 110143.

Two bis-tridentate oxalylsalicylidenedihydrazone Schiff-

bases, H₂L1 and H₂L2, were prepared by the reaction of

oxalyldihydrazide with suitable salicylaldehyde deriva-

tives. The reaction of cis-MoO₂(acac)₂with H₂L1 and

H₂L2 afforded the corresponding bis-dioxomolybdenum

complexes MoO₂L2 and MoO₂L2. The structures of

MoO₂L2 and MoO₂L2 were confirmed by EA,

ultraviolet–visible, mass spectra and FT-IR, as well as,

¹H- and ¹³C-NMR spectra. MoO₂L1 and MoO₂L2 con-

cerned as considerable active homogeneous catalysts in

the selective (ep)oxidation of 1,2-cyclooctene, benzyl

ORCID

Mohamed Shaker S. Adam https://orcid.org/0000-0001-

8826-3558

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SUPPORTING INFORMATION

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article.

How to cite this article: Adam MSS,

Ahmed MSM, El-Hady OM, Shaaban S. Bis-

dioxomolybdenum (VI) oxalyldihydrazone

complexes: Synthesis, characterization, DFT

studies, catalytic epoxidation potential, molecular

modeling and biological evaluations. Appl

Organometal Chem. 2020;e5573. https://doi.org/10.

1002/aoc.5573

[70] M. Zare, Z. Moradi-Shoeili, Appl. Organomet. Chem. 2017, 31,

e3611.

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Bis-dioxomolybdenum (VI) oxalyldihydrazone complexes: Synthesis, characterization, DFT studies, catalytic epoxidation potential, molecular modeling and biological evaluations

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