Schiff base metal complexes of 4-methyl-1H-indol-3-carbaldehyde derivative as a series of potential antioxidants and antimicrobial: Synthesis, spectroscopic characterization and 3D molecular modeling

Article abstract of DOI:10.1016/j.molstruc.2019.05.101

Novel mononuclear Fe(III), Cu(II), Cd(II), Sn(IV) and binuclear Ni(II) and Hg(II) complexes with the Schiff base ligand: (E)-N'-((4-methyl-1H-indol-3-yl)methylene) nicotinohydrazide were synthesized. The elucidation of the structure of the prepared compounds were performed by elemental analyses, magnetic measurements, thermogravimetry, 3D molecular modeling, molar conductance techniques and by various spectroscopic (IR, ¹H NMR, UV–Visible, EPR) tools. Antioxidant activity in vitro by DPPH scanning of the ligand and its metal complexes was studied. The results indicated that all test compounds are excellent antioxidants and better than the standard (Ascorbic acid).[Sn(HL)Cl₂(OH)₂]_·2H₂O complex (5) showed the highest antioxidant activity. Moreover, the ligand and its metal complexes were screened against the sensitive organisms Staphylococcus aureus as Gram-positive bacteria, Escherichia coli as Gram-negative bacteria and two strains of fungi (Aspergillus flavus and Candida albicans). The results showed that all metal complexes have higher antimicrobial activity than the metal free ligand and the binuclear [Hg₂(HL)Cl₄]·EtOH complex (6) possessed excellent antibacterial activity better than the standard drug Ampicillin (antibacterial agent) and showed excellent antifungal activity against Aspergillus flavus, better than Amphotericin B (antifungal agent).

Full text of DOI:10.1016/j.molstruc.2019.05.101

Accepted Manuscript
Schiff base metal complexes of 4-methyl-1H-indol-3-carbaldehyde derivative
as a series of potential antioxidants and antimicrobial: Synthesis, spectroscopic
characterization and 3D molecular modeling
Ohyla A. EL-Gammal, Heba A. Alshater, Hanaa A. El-Boraey
PII:
S0022-2860(19)30673-8
DOI:
https://doi.org/10.1016/j.molstruc.2019.05.101
MOLSTR 26608
Reference:
To appear in: Journal of Molecular Structure
Received Date: 23 February 2019
Revised Date: 25 April 2019
Accepted Date: 23 May 2019
Please cite this article as: O.A. EL-Gammal, H.A. Alshater, H.A. El-Boraey, Schiff base metal complexes
of 4-methyl-1H-indol-3-carbaldehyde derivative as a series of potential antioxidants and antimicrobial:
Synthesis, spectroscopic characterization and 3D molecular modeling, Journal of Molecular Structure
(2019), doi: https://doi.org/10.1016/j.molstruc.2019.05.101.
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ACCEPTED MANUSCRIPT
Schiff base metal complexes of 4-methyl-1H-indol-3-carbaldehyde derivative as a
series of potential antioxidants and antimicrobial: Synthesis, Spectroscopic
Characterization and 3D molecular modeling
3
Ohyla A. EL-Gammal1, Heba A. Alshater2, Hanaa A. El-Boraey
1Department of Pathology, University Hospital, Menoufia University, Shebin El- Kom, Egypt
2Department of Forensic Medicine and Clinical Toxicology, University Hospital, Menoufia University,
Shebin El- Kom, Egypt
3Department of Chemistry, Faculty of Science, Menoufia University, Shebin El- Kom, Egypt
Abstract
Novel mononuclear Fe(III), Cu(II), Cd(II), Sn(IV) and binuclear Ni(II) and Hg(II)
complexes with the Schiff base ligand: (E)-N'-((4-methyl-1H-indol-3-yl)methylene)
nicotinohydrazide were synthesized. The elucidation of the structure of the prepared
compounds were performed by elemental analyses, magnetic measurements,
thermogravimetry, 3D molecular modeling, molar conductance techniques and by various
1
spectroscopic (IR, H NMR, UV–Visible, EPR) tools. Antioxidant activity in vitro by
DPPH scanning of the ligand and its metal complexes was studied. The results indicated
that all test compounds are excellent antioxidants and better than the standard (Ascorbic
acid).[Sn(HL)Cl2(OH)2].2H2O complex (5) showed the highest antioxidant activity.
Moreover, the ligand and its metal complexes were screened against the sensitive
organisms Staphylococcus aureus as Gram-positive bacteria, Escherichia coli as Gram-
negative bacteria and two strains of fungi (Aspergillus flavus and Candida albicans). The
results showed that all metal complexes have higher antimicrobial activity than the metal
free ligand and the binuclear [Hg2(HL)Cl4].EtOH complex (6) possessed excellent
antibacterial activity better than the standard drug Ampicillin (antibacterial agent) and
showed excellent antifungal activity against Aspergillus flavus, better than Amphotericin
B (antifungal agent)
Keywords: Mono and binuclear metal complexes, Spectroscopic studies, Modeling,
Antioxidants, Antimicrobial activity, IC50
1. Introduction
Corresponding author. Tel.: +2- 0111-7532777; Fax: +20 48 2235689.
E-mail address: helboraey@yahoomail.com (Hanaa A. El-Boraey).
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Indole is the parent substance of a large number of important compounds and it is one of
the most abundant and relevant heterocycles in natural products and pharmaceuticals [1].
On the other hand, the chemistry of indole compounds has received a great interest owing
to their several biological activities [2,3]. A considerable number of natural products and
currently available drugs carry an iodole moiety [4,5]. Indole derivatives are found to
contain several biological activities such as anti-inflammatory [5,6], anti-bacterial [7],
anti-viral[8], analgesic[5,9] and anti-tumor activities [10,11]. Therefore, indole plays an
important class in the synthesis of new pharmaceutical products [1,12,13]. The indole
core is well known as one of the most important scaffolds for drug discovery and it has
been a major focus of research for generations [14]. Indole-2,3dione (isatin) is an
endogenous indole with a variety of pharmacological actions, including anticonvulsant,
antimicrobial and antiviral activities, inhibition of monoamine oxidase and behavioral
effects [15]. Schiff bases have played an important role in the development of
coordination chemistry because they form stable complexes with most of transition, non-
transition, lanthanides and actinides metals [16]. Schiff bases are known to exhibit a
broad range of biological activities including antifungal, antibacterial, antimalarial, anti-
inflammatory, antiviral and antipyretic properties [17,18]. Schiff base complexes
involving oxygen and nitrogen donor ligands are well known and have excited wide
attention among chemists because of their applications in catalysis and their relevance to
bioinorganic systems [19]. The formation of the Schiff-base reactions are stabilized when
aldehydes and amino acids can form two five membered rings, chelated to the metal ion.
The metal ion plays a role in holding the amino acid in the plane of the aromatic ring
after chelation [20]. Hydrazones have attracted the attention of researchers due to their
well-known flexible characterization and the capability of hydrazine to form stable
complexes [21]. Hydrazides (R-CO-NH-NH2) and their derivatives play an important role
in the development of various biological activities, such as antimycobacterial, antifungal,
antibacterial, antitumor [22]. The chemistry of hydrazine is significant due to its ability to
form various mixed-ligand complexes with transition metals, whose stability and other
properties change dramatically depending upon the cations as well as the anions [23]. The
biological activity of hydrazones showed that they become more carcinostatic and
bacteriostatic upon chelation [2]. Many hydrazone derivatives are employed in the
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treatment of diseases like tumor, tuberculosis, leprosy and mental disorder [24]. In the
light of these findings, it is worth to synthesize Schiff base ligand containing both indole
and hydrazide moieties. We report herein the successful synthesis, spectral identification,
thermal, in vitro antioxidant, antimicrobial and molecular modeling studies of new metal
complexes with (E)-N'-((4-methyl-1H-indol-3-yl)methylene) nicotinohydrazide.
2. Experimental
2.1 Instrumentation
The ligand and its metal complexes were analyzed for C, H and N at the Microanalytical
Laboratory, Faculty of Science, Cairo University, Giza, Egypt using CHNS-932 (LECO)
Vario Elemental Analyzer. The presence of metal ion and halide in the complexes was
evaluated using standard methods [25]. FT-IR spectra of the ligand and its metal
complexes were measured using KBr discs with NenexeusNicolidite-640-MSA FT-IR,
Thermo-Electronics Co spectrophotometer within the range 400-4000 cm-1. Electronic
spectra of the ligand and its complexes were obtained in DMF solution using a Shimadzu
1
UV–240 UV–Vis recording spectrophotometer (200–800 nm region). The H NMR
spectra were recorded in DMSO-d6 using Varian Gemini 200 NMR spectrophotometer at
300 MHz. Magnetic susceptibilities were measured at 25oC by the Gouy method using
magnetic susceptibility Johnson Matthey Balance. Diamagnetic corrections were
estimated from Pascal’s constant [26]. The magnetic moments were calculated from the
equation: ꢀeff = 2.828 (χmT)1/2 B.M., where χm is the molar susceptibility corrected for
diamagnetism of all atoms in the compounds. Molar conductance was measured on a
Tacussel type CD6NG conductivity bridge using DMF solution (10-3M). Thermal
analysis (TG/DTG) was obtained out by using a Shimadzu DTA/TG-50 Thermal
o
Analyzer with heating rate of 10 C/min in nitrogen atmosphere with a flowing rate 20
mL/min in the range of ambient temperature up to 800 oC using platinum crucibles.
2.2. Materials and methods
All the reagents employed for the preparation of the ligand and its complexes were of the
best grade available, obtained from Sigma, Aldrich and Fluka. Metal salts (FeCl3.6H2O,
NiCl2.6H2O, CuCl2.2H2O, CdCl2.H2O, SnCl4.5H2O or HgCl2) were purchased
commercially from E. Merck and solvents used without further purification.
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2.3. Synthesis of the Schiff base ligand
The hot (70 oC) ethanolic solution (20 mL) of nicotinohydrazide (0.28 g, 2.04 mmol) was
o
added to a hot (70 C) ethanolic solution (20 mL) of 4-methyl-1H-indol-3-carbaldyhde
(0.3 g, 1.89 mmol), which was initially acidified with few drops of glacial acetic acid and
then reflux for 6 h. After cooling the solution, pour it in bath ice and leave it till the
precipitate is formed. The formed precipitate was filtered off, washed several times with
methanol and dried in a vacuum desiccator over P4O10 (Scheme 1).
Insert Scheme 1 and its caption near here:
2.4. Synthesis of Schiff base metal complexes
o
A hot (60 C) ethanolic solution (20 mL) of different metal salts {FeCl3.6H2O (0.86 g),
NiCl2.6H2O (0.76 g), CuCl2.2H2O (0.54 g), CdCl2.H2O (0.64 g), SnCl4.5H2O (0.83 g) or
o
HgCl2 (0.86 g) for complexes 1-6, respectively} was added dropwise to a hot (70 C)
solution (20 mL) of the ligand (0.97 g) in the same solvent in molar ratio 1L:1M. The
reaction mixture was refluxed with stirring for 3 h, cooled to room temperature; the solid
product was collected by filtration, washed with ethanol and dried in a vacuum desiccator
over P4O10.
2.5. Biological tests
2.5.1 Antioxidant Activity
DPPH free radical scavenging assays
The free radical scavenging activity can be measured by using 2,2′-diphenyl-1-picryl-
hydrazyl (DPPH) by the method of Blois [27]. The reaction mixture (3.0 mL) consists of
2.0 mL of DPPH in DMSO (0.002%) and various concentrations (µg/mL) of tested
compounds. It was incubated for 10 min in dark, then the absorbance was measured at
517 nm on a UV-Vis Shimadzu Spectrophotometer (UV-1601 PC), against methanol as a
blank and control was prepared by DPPH and methanol in place of sample. Ascorbic acid
was used as a positive control. The percentage of radical scavenging activity (RSA) can
be calculated by using the formula:
RSA (%) = [(A0 – Ai )/A0]× 100
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Where; A0 is the absorbance of DPPH in the absence of test compound (control)
and Ai is the absorbance of DPPH in the presence of test compounds. All analyses were
undertaken on three replicates and the results averaged. The IC50 values were calculated
by linear regression plots, where the abscissa represented the concentration of tested
compound solution and the ordinate represented the average percent of antioxidant
activity from three separate tests. IC50 was defined as the concentration of an antioxidant
extract which was required to quench 50% of the initial DPPH· under the experimental
conditions given.
2.5.2. In vitro antimicrobial activity
The antimicrobial activities were carried out at the Microanalytical Center, Cairo
University, Egypt. Antibacterial and antifungal activities of the ligand and its complexes
were tested in vitro against the bacteria species by the modified Kirby-Bauer disc
diffusion method [28] using Gram- positive bacteria as S. aureus (ATCC 12600), Gram-
negative bacteria as E.coli (ATCC 11775) and fungal species, A. flavus, C. albicans
(ATCC 7102). The test organisms were grown on Meuller-Hinton agar that is rigorously
tested for composition and pH in petri plates. The concentration 20 mg/mL of tested
compounds were prepared in DMSO as controlling solvent and soaked in paper disks
(Schleicher & Schuell, Spain) with a diameter of 8.0 mm, the disks were placed on
previously seeded plates. Plates were inoculated with filamentous fungi A. flavus at 25 oC
o
for 48 h; C. albicans were incubated at 30 C for 24-48 h. and Gram- positive bacteria
o
S. aureus and Gram- negative bacteria E. coli were incubated at 35-37 C for 24-48 h.
The diameter of “inhibition Zone” or" Clear zone" around each disc was measured in
mm. Control flask of the experiment was designed to perform under the same condition
described previously for each microorganism but with N,N‐dimethylformamide solution
only and by subtracting the diameter of inhibition zone resulting with DMF from that
obtained in each case, so antibacterial activity could be calculated. Standard discs of
Ampicillin (antibacterial agent) and Amphotericin B (antifungal agent) were served as
positive controls for antimicrobial activity. All experiments were performed as triplicate
and data plotted were the mean value.
3. Results and Discussion
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The analytical, physical and spectral data are compatible with the suggested
structures. The complexes are colored, stable in air at room temperature and insoluble in
water, ethanol and non-polar solvents as benzene. However, they dissolve in polar
solvents as DMF or DMSO. The molar conductance of the complexes carried out in 10-3
M DMF as solvent at room temperature indicates the non-electrolytic nature of the
complexes and indicates the coordination of anions to the metal ions [29]. The results of
elemental, spectral, magnetic and thermal analyses and molecular modeling data were
tabulated in Tables 1-6. The analytical data (Table 1) indicated that complexes (1,3-5) are
mononuclear, formed in 1M: 1L molar ratio, while complexes (2,6) are binuclear, formed
in 2M:1L molar ratio.
3.1. ¹H NMR spectral studies of the ligand
The 1H NMR spectrum of the ligand (Fig. 1S, Table 2) showed no signal observed
related to the free amino group of hydrazide which supports the formation of the ligand.
The 1H NMR spectrum of the ligand displayed singlet at δ 11.658 ppm (s,1H,- NH-CO)
due to the amide proton. This suggests that the free ligand exists in keto form even in
polar solvent as DMSO [1]. The indole ring -NH proton appears as a singlet at δ 11.59
ppm. The signal for azomethine proton (m, 1H,-CH=N-) in the ligand appears at 9.058,
signal observed at δ 8.72-8.74 ppm is due to (m,1H, CH–NH) indole [7], the multiplet
signals obtained in the δ 7.127–8.59 ppm range are due to the resonance of the aromatic
and pyridine ring protons. The signal for the indole ring carbon attached methyl proton
(3H,-CH3) appears as a singlet at δ 1.843 ppm. Thus, the 1H NMR spectral data confirm
the assigned structure.
Insert Table 1 and its caption near here
3.2. 1H NMR spectra of the diamagnetic complexes
1
The H NMR spectra of the diamagnetic complexes (4,5 and 6) were recorded in
DMSO-d6 and tabulated in Table 2 (Fig. 1S). The signal due to amide proton (NH-CO) is
present in the complexes at nearly the same ppm as in the free ligand, indicating the
presence of these complexes mainly in keto form [1]. Further, the indole ring -NH proton
doesn’t shift significantly in the spectra of the complexes compared with that of the
ligand which indicates that the indole nitrogen is not involved in the coordination. The
6

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azomethine proton in the complexes shows a peak at δ 9.02-9.07 ppm, the shielding
observed indicates the coordination of azomethine nitrogen atom to the metal ion [19].
[Sn(HL)Cl2(OH)2].2H2O (5) exhibited signals at 9.404,9.199 ppm may be due to two
terminal hydroxyl groups [30]. The spectrum of complex (5) also shows signals support
the neutral presence of tautomeric forms of the ligand molecule in the isolated complex
(Scheme 1S). The spectra of complexes (4-6) showed signal at 3.31-4.58 ppm are
assigned to coordinated and/or hydrated water/ solvent molecules.
Insert Table 2 and its caption near here
3.3. Infrared spectra
The IR spectral data and their possible assignments are given in the Table 3. The IR
spectrum of ligand exhibits strong band at 1600 cm–1 was assigned to ν(C=N) group
which is shifted to the lower or higher frequencies upon complexation. This shift shows
that azomethine nitrogen is involved in the coordination [31]. Further the Schiff base
ligand exhibits a band at 1628 cm-1 due to the amide ν(C=O). This band has been shifted
to 1630–1670 cm-1 in all complexes indicating the chelation of carbonyl oxygen atom
with the metal ions, and hence the ligand coordinates with metal ions in keto neutral form
[1,19]. The stretching absorption bands due to indole NH and amide NH in the metal
complexes were observed in the region 3245–3249 cm-1, appeared at about the same
region as in the ligand, thus confirming the non-involvement of either indole or amide
NH in coordination with the metal ions [1]. Further, the IR spectra of complexes (1,6)
showed a band at 3450-3355 cm–1 which is ascribed to hydrated water or solvent
molecules [32], that confirmed by the elemental and thermogravimetric analyses. In the
IR spectra of complexes (2-5), the bands at 3450-3400, 824–801 and 620–614 cm−1 are
present which are characteristic bands of ν(OH), ρr(H2O) and ρw(H2O).These bands are
assigned to the coordinated water molecule [32]. The IR spectra of all complexes
showed new bands in the 520–566 and 437–480 cm-1 regions, which may probably be
due to the formation of ν(M–O) [33] and ν(M–N) bonds, respectively [34,35]. Thus, the
ligand acts in all metal complexes as neutral bidentate one coordinating through the
azomethine nitrogen and the carbonyl oxygen atom.
Insert Table 3 and its caption near here
7

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3.4. Electronic spectra and magnetic moments
The electronic spectra of ligand and its metal complexes were measured in DMF
solution at room temperature. The data listed (λmax, nm) and effective magnetic moment
values (ꢀeff B.M.) are represented in Table 3. The electronic spectrum of free ligand is
characterized by two absorption bands at 270 and 360 nm which attributed to π→π*
transition and n→ π* transitions, respectively.
The electronic spectrum of Fe(III) complex (1) displays two bands at 600 and 455
nm. The former band could be assigned to d-d transition, and the later band can be
assigned to L→M charge-transfer transition. These bands are consistent with the range of
spectral bands reported for five coordinated square pyramidal geometry around Fe(III)
ion [36]. The value of ꢀeff per iron(III) atom is found to be 6.11 B.M., indicating the
presence of high-spin Fe(III) ion [36,37].
The UV-Vis spectrum of binuclear Ni(II) complex (2) exhibits bands at 425 and
410 nm, these bands probably arise from a ligand to metal charge transfer (LMCT)
transition [38]. The magnetic moment value for nickel(II) complex at RT is 4.2 B.M. (2.1
B.M./Ni+2 ion), is lower than the predicted values. This may arise from antiferromagnetic
interaction [39].
The electronic spectrum of the copper(II) complex (3) shows two broad bands in the
visible region at 410 and 385 nm were assigned to L→M charge-transfer transition of
tetragonally distorted octahedral Cu(II) ion [40,41]. It is worth to mention that the region
of charge-transfer transition obscured the metal d-d band transitions. The value of
magnetic moment (1.9 B.M.) is an evidence for distorted octahedral geometry around
Cu(II) ion [34].The UV–Vis spectra of all complexes displayed an intense band centered
in the range 326–365 nm which is attributed to n→π* transitions. There is another intense
band in the high-energy region at 235–272 nm which is related to the π→π* transitions
and this band is dramatically intensified as compared to the ligand.
No d-d transition bands were observed in the spectra of the Cd(II) (4), Sn(IV) (5) and
binuclear Hg(II) (6) complexes which were quite common with the d10 complexes. These
complexes are diamagnetic as expected. Based on elemental analyses, molar conductance
8

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and IR spectral data, an octahedral {Cd(II) (4), Sn(IV) (5)} and square planar Hg(II) (6)
structures were suggested for these complexes.
3.5. EPR spectroscopic studies
The room temperature solid state EPR spectrum of [Cu(HL)Cl2(H2O)2].H2O complex (3)
was recorded on the X-band frequency 9.719 GHz. The EPR spectrum of copper(II)
complex (Fig.1) exhibits axially behavior with tensor values; g// =2.195,
g
= 2.048
following the trend g// > g > 2.0023, which is consistent with the Cu(II) center has a
tetragonally distorted geometry with dx2 –y2 orbital as a ground state [33,42]. In the axial
spectrum the g-values are related by the expression [43],
G = ( g// -2.0023)/( g -2.0023),
the calculated =4.01 pronounces that there is no exchange interaction in the Cu(II)
G
complex in the solid state. The ‘ gav ’ value averaged to overall distortion was calculated
using the relation: gav = (2 g + g// )/3, the calculated gav (2.097) indicates considerable
covalent environment in the Cu–L bond [44]. Molecular orbital coefficients α2 (covalent
in plane σ bonding) β 2 (covalent in plane π bonding), and γ 2 (covalent out-of-plane π
bonds) have been calculated [34] using the following equations [44,45]:
A
3
α 2
=
+ (g// − 2.0023) + (g − 2.0023) + 0.04
//
0.036
7
β 2 = (g //− 2.0023)E /8λα 2 γ 2
= (g −
2.0023)E / 2λα 2
,
The parallel and perpendicular components of orbital reduction factor were estimated
using the expressions reported elsewhere [46]. If the value of
2 = 0.5, then it indicates
100% covalent character, while a value of
2 =1 suggests complete ionic bonding. The
α
α
observed values of α 2 is found to be 0.5357 supported the covalent nature of this
complex. The value of β 2 (1.323) is more than unity indicating the presence of in-plane
π
-bonding and γ 2 (1.272)
bonding. The lower value of α 2 (0.5357) compared to β 2 (1.323) indicates that the
˃ 1, indicates the covalent character of the out-of-plane π-
in
‐plane σ‐bonding has higher covalent character than the in‐plane π‐bonding. The
9

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parallel and perpendicular components of orbital reduction factor were estimated using
the expressions reported elsewhere [46].
The [Cu(HL)Cl2(H2O)2].H2O complex (
significant out of –plane -bonding [46]. Moreover, the lower value of
(0.8312) is indicative of its covalent nature [35]. The factor g// A =
//
3
) shows
K
// (0.842)
˃
K
(0.8257) indicating
than unity
215 further
π
K
f
=
confirms the distorted octahedral geometry around copper (II) ion [43].
Insert Fig.1 and its caption near here
3.6. Thermal studies
The complexes were characterized on the basis of thermogravimetric analysis (TG/DTG)
technique in the temperature range 28–800 °C. The TGA curves for complexes are shown
in Fig. 2, and the data are tabulated in Table 4.
The TG curve of iron(III) complex (1) shows mass loss in the temperature range ~30-
89 ºC (Calc./Found%: 8.02/8.02) accompanying with one endothermic DTG peak at 52
°C, that can be attributed to loss of two hydrated water molecules. The TG curve also
shows that the complex gradually decomposed at 190 °C in cumulative steps, the mass of
final residue corresponds to Fe metal (Calc/Found % 10.90/10.97).
The TG curve of binuclear nickel(II) complex (2) shows weight loss in the
temperature range 30–150 °C (Calc/ Found % 6.27/5.86) associated with one broad
endothermic DTG peak at 54 °C, that is related to release of two hydrated water
molecules. The TG curve also shows that the complex gradually decomposed in
cumulative steps at 240 °C, ended with the formation of air stable nickel oxide.
The TG curve of copper(II) complex (3) shows weight loss in the temperature range
30–130 °C (Calc/Found % 3.86/3.86) associated with one endothermic DTG peak at 44
°C, that is assigned to release of one hydrated water molecule. The TG curve also shows
that the complex gradually decomposed at 142 °C, remaining copper metal as a final
product.
The TG curve of cadmium(II) complex (4) shows mass loss in the temperature range
90-140 °C (Calc/ Found % 3.49/3.59) associated with one endothermic DTG peak at 128
°C, that is related to loss of one hydrated water molecule. The TG thermogram also
10

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shows that the complex is thermally stable up to 290°C, where it rapidly degrades in the
temperature range 290-700 °C, with the decomposition of organic part, leaving cadmium
metal as a residue.
The TG thermogram of tin(IV) complex (5) shows weight loss at the temperature
range 50–116 °C (Calc/Found % 6.69/6.18) associated with one endothermic DTG peak
at 81°C, corresponding to loss of two hydrated water molecules. The TG curve also
shows that the complex starts its decomposition at 160 °C with weight loss of
(Calc/Found % 6.32/6.74) corresponds to loss of 2OH groups within the temperature
range 160-270 °C. The TG thermogram also shows gradual decomposition till 532 °C,
ended with residue may be SnO2 contaminated with three carbon atoms.
The TG curve of binuclear [Hg2(HL)Cl4].EtOH complex (6) shows mass loss within
the temperature range 30-110 °C (Calc/Found% 5.30/5.30) corresponding to loss of one
ethanol molecule, that is correlated with an endothermic DTG peak at 64 °C. The
complex starts to decompose at nearly 170°C through loss of Cl2 molecule within the
temperature range 170-230 °C (Calc/Found% 8.18/8.70), this step is followed by gradual
departure of the organic ligand leaving no residue [47]. Thus, the results of thermal
analyses (Table 4, Fig. 2 ) are in agreement with elemental and spectral analyses
.
The differences in the thermal stability of the complexes may be attributed to difference
in the geometry; type as well as number of central metal ion, type of the formed chelate
rings these factors play an important role in their thermal stability. The thermal stability
of the complexes follows the order: Cd(II)>Ni(II)>Fe(III)>Hg(II)>Sn(IV)>Cu(II).
Insert Table 4 and its caption near here
Insert Fig. 2 and its caption near here
3.7. 3D-Melocular Modeling
The 3D molecular modeling of the ligand and its Fe(III) (1) and Sn(IV) (5) complexes
were carried out using Hyper Chem Sketch 15.0 version (Figs.3,4,5). The selected
physical parameters such as bond lengths and bond angles were calculated and are given
in Tables 5 and 6. The total internal energy of the ligand was found to be 21.78, 25.46
kcal/mol for keto/enol form, respectively. The priority of the keto form towards the
coordination is based on its lower internal energy in comparing with the enol form. The
actual bond lengths of N(9)-N(10) and C(7)-O(8) for the ligand are 1.354 and 1.208 Å,
11

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respectively. The bond length of these groups changed to 1.352 and 1.221 Å; 1.351 and
1.224 Å for Fe(III) and Sn(IV) complexes, respectively suggesting the bonding of the
ligand with these metal ions. The M-O bond length is shorter than M-N and M-Cl bond
length (Table 5) i.e. the bond length obeyed the order M-Cl > M-N > M-O [47]. The
bond angles C(7)-N(9)-N(10), N(9)-N(10)-C(11), O(8)-C(7)-N(9) and C(6)-C(7)-O(8) of
the ligand are changed upon coordination [48]. New bond angles were formed between
the ligand and metal ions as Cl(3)-Fe(1)-O(9), Cl(10)-Sn(6)-O(5), with values 169.63-
168.84o, Cl(3)-Fe(1)-Cl(4), Cl(9)-Sn(6)-Cl(10) with values 96.28-92.05o and N(8)-Fe(1)-
O(9), N(4)-Sn(6)-O(5) with different values ranges between 85.86-85.82o, respectively.
These bond angles indicated that Fe(III) and Sn(IV) complexes adopt a square pyramidal
and distorted octahedral geometry, respectively and are in agreement with results
obtained from other similar complexes described previously [36,47-49].
Insert Figs. 3,4,5 and their caption near here
Insert Tables 5,6 and their caption near here
Basis on the elemental analyses, molar conductance measurements, magnetic
susceptibilities, 3D molecular modeling studies, different spectral and thermal data the
suggested structures for the complexes are given in Fig.6.
Insert Fig.6 and its caption near here
3.8. Biological activity
3.8.1. Antioxidant activity
The DPPH assay gives an easy and rapid way to determine the antioxidant activity of the
ligand and its metal complexes (2,4,5,6) tested in this study at different concentration
(100,150 and 200 µg/mL). The data of the suppression ratio for DPPH are depicted in
Fig.7 and are listed in Table 1S. All the tested metal chelates as well as the metal free
ligand have excellent antioxidant activity [50]. The IC50 value obtained for the ligand was
3.82
IC50:12.41, 4.36, 3.42, 28.01
that of the standard ascorbic acid (IC50: 144.56
demonstrated the highest activity with IC50 = 3.42
ꢀ
g/mL. All the tested metal complexes showed high antioxidant activity with
g/mL for complexes 2,4,5 and 6, respectively higher than
g/mL). [Sn(HL)Cl2(OH)2].2H2O (
g/mL, whereas the binuclear
ꢀ
ꢀ
5)
ꢀ
12

ACCEPTED MANUSCRIPT
[Hg2(HL)Cl4].EtOH (
6
) has the lowest activity with IC50 =28.01 ꢀg/mL, but still better
than the standard ascorbic acid. From the obtained results, the DPPH scavenging activity
of ligand and its tested metal complexes is better than ascorbic acid, indicating that these
compounds have a strong free radical scavenger activity when compared to ascorbic acid
as standard. The order of scavenging activity is:
Sn(IV)(5) > HL > Cd(II)(4) >Ni(II)(2) > Hg(II)(6) > Ascorbic acid
Scavenging activities of synthesized ligand and its complexes may be due to the relative
ability for the H-N hydrogen atom abstraction from the compounds as depicted in
Scheme 2. Also the results showed that the ligand and its metal complexes containing
antioxidant parts which can donate a hydrogen atom and/or an electron.
Insert Scheme 2 and its caption near here
Insert Fig.7 and its caption near here
3.8.2. Antimicrobial activities
3.8.2.1. Antibacterial activity
The synthesized ligand and its metal complexes were also evaluated for their
antimicrobial activity against gram positive as S.aureus and gram negative as E.coli
bacterial strains using disc diffusion method [28]. The data are presented in Fig. 8 and are
listed in Table 2S. The compounds were tested at the concentration of 20 ꢀg/mL in
DMSO and compared with standard Ampicillin. The results indicated that the ligand is
active against both the bacterial strains S. aureus (11.00 mm mg-1) and E. coli (11.00 mm
mg-1) and all the tested metal compounds exhibited significant activity against both gram
positive and gram negative bacterial strains in the range of concentrations used, greater
than their metal free ligand. The binuclear [Hg2(HL)Cl4].EtOH complex (6) was the most
potent compound examined (34, 30 mm mg-1) against both bacterial strains better than
the marketed antibacterial drug ampicillin. Such enhanced activity of the metal
complexes can be explained on the basis of chelating theory [51]. The variation in the
activity of the tested metal complexes against the microorganisms depends on the
impermeability of the cell or differences in the ribosomes in the microbial cells. The lipid
membrane surrounding the cell favors the passage of any lipid- soluble materials and it is
known that liposolubility is an important factor controlling antimicrobial activity [52]
13

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The metal complexes provide favorable condition for the penetration into bacterial cell;
the process is apparently facilitated by increased lipophilicity of the indole and hydrazide
nucleus upon chelation [53]. The antibacterial activity of the compounds follows the
order:
Hg(II) > ampicillin > Sn(IV) > Cu(II) > Ni(II) > HL For S. aureus
Hg(II) > ampicillin > Cu(II) > Sn(IV)= Ni(II) > HL For E. coli
3.8.2.2. Antifungal activity
The antifungal activity of the ligand and its complexes was investigated against the
sensitive fungal strains as A. flavus and C. albicans, inspection of data (Fig.8) revealed
that, with regard to A. flavus, the results indicated that the ligand and its complexes (2,5
were inactive, complex ( ) exhibited moderate activity while complex (6) showed
excellent activity and it was the most potent compound examined against fungal strain
A. flavus) better than the marketed antifungal drug Amphotericin B. With C.albicans
the ligand also showed no activity, while Ni(II)( ), Cu(II) ( ) and Sn(IV) (5) complexes
exhibited moderate activity, again the binuclear [Hg2(HL)Cl4].EtOH ( ) was the most
)
3
(
,
2
3
6
potent compound examined. It is clear that the inhibition by metal chelates is higher than
that of the free ligand. The presence of chloride ion in the complexes may enhance
antimicrobial activity due to the formation of hypochlorous acid which decomposes to
HCl and O2. The oxygen oxidizes the cellular components and destroyed the microbes
[54]. The results are in good agreement with previous findings with respect to
comparative activity of free ligand and its complexes [55-56].
Insert Fig.8 and its caption near here
4. Conclusions
In conclusion, we have designed and synthesized a series of 4-methyl-1H-indol -3-
carbaldehyde derivative metal complexes with mononuclear Fe(III), Cu(II), Cd(II),
Sn(IV) and binuclear Ni(II) and Hg(II) complexes. The compounds were synthesized
and characterized by various physico-chemical methods. The different analyses
confirmed the composition and structures of the current compounds. FT-IR spectra
indicated that the ligation of the ligand to the metal atom is through the azomethine
nitrogen and the carbonyl oxygen atom, in keto form as a neutral bidentate one. The
14

ACCEPTED MANUSCRIPT
geometry of the complexes is assigned as square pyramidal or octahedral. EPR studies
indicated the covalent nature of the Cu(II) complex. All the tested compounds showed
excellent DPPH activity. [Sn(HL)Cl2(OH)2].2H2O showed excellent DPPH activity much
better than standard (Ascorbic acid). The binuclear [Hg2(HL)Cl4].EtOH complex
possessed the highest activity against the tested microbial species compared to that of
ligand and other complexes. Based on the obtained results, the prepared compounds have
promise for use as drugs.
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Table1: Analytical and physical data for the ligand and its metal complexes.
Elemental analysis Calc./F. %
(Λm)a
Yield
No
.
Compound
Color Empirical formula
D.T /0C
(%)
25
C
H
N
M
Cl
HL.1½H2O
C16H17N4O2
-
62.95/63.03 5.57/5.21 18.35/18.35 -
-
-
Buff
Dark
green
Pale
[Fe(HL)Cl3].2H2O
C16H18N4O3Cl3Fe
C16H24N4O3Cl2Ni2
65
190
240
40.31/40.80 3.78/3.81 11.76/12.42 11.73/11.97
22.36/21.93 10
1
2
[Ni2(HL)Cl2(OH)2(H2O)2].2H2O
60
33.378/33.78 4.22/4.19 9.85/9.84
20.65/20.35
12.49/12.67 12.7
green
Dark
green
[Cu(HL)Cl2(H2O)2].H2O
C16H20N4O4Cl2Cu
70
142
41.16/41.5
4.28/3.45 12.00/11.90 13.61/13.55
13.61/12.55 22
13.78/14.25 11
3
[Cd(HL)Cl2(H2O)2].H2O
[Sn(HL)Cl2(OH)2].2H2O
Yellow C16H20N4O4Cl2Cd
65
60
290
160
37.28/36.08 3.88/3.04 10.87/10.06 21.81/21.1
35.71/35.60 3.34/3.26 10.41/10.40 22.08/22.30
4
5
Pale
yellow
C16H20N4O5Cl2Sn
13.20/13. 80
8
Dark
[Hg2(HL)Cl4].EtOH
C18H26N4O2Cl4Hg2 60
170
25.61/24.67 2.49/3.21 6.64/6.10
23.78/23.90
19.42/19.44 4.4
6
yellow
a:ꢀ-1 cm2 mol-1DMF solutions (10-3M)
1

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Table 2 : 1H-NMR spectral data (δ, ppm) of the ligand and its diamagnetic complexes (4,5 and 6).
Compound
HL
Assignments
11.658 (s, 1H,CO NH), 11.596 (s, 1H, indole NH),9.058 (m,1H,–HC=N), 8.723-
8.74 (m,1H, CH–NH indole), 7.127-8.591 (m,7H, Ar,py H), 1.811 (s, 3H, indole-
CH3), 3.317 (s,3H, H2O).
11.669 (s, 1H, CO NH), 11.594 (s, 1H, indole NH),9.061 (m,1H,–HC=N), 8.73-
8.74 (m,1H, CH–NH indole), 7.126-8.59 (m, 7H,Ar and py H), 1.812 (s, 3H, indole
-CH3)
4
5
6
11.848 (s, 1H, CO NH), 11.590 (s, 1H, indole NH), 9.404,9.199 (m ,2H terminal
OH), 9.027(m,1H,–HC=N), 8.926-8.86 (m,1H, CH–NH indole),, 7.131-8.675
(m,7H, Ar and py H), 1.812 (s, 3H, indole - CH3)
11.657 (s, 1H, CO NH), 11.594 (s, 1H, indole NH),9.075 (m,1H,–
HC=N),8.726((m,1H, CH–NH) indole, 7.129-8523 (m, 7H, Ar and py H), 1.843 (s,
3H, indole - CH3)
2

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Table 3: Important IR spectral bands (cm-1)a, electronic absorption spectra λ max/nm and room temperature effective
magnetic moment values ꢁeff /B.M. of the compounds.
No
1
Compound
ν(OH/NH)
ν(C=O)
ν(C=N)
ν(N-N)
ν(M-O)
ν(M-N)
λmax(nm)
µeff (B.M.)
HL.1½H2O
3450(b)
3355(s)
1628(m)
1656(m)
1607(m)
1600(s)
1010
1024
-
-
360,290,270
600/455/330/270
-
[Fe(HL)Cl3].2H2O
550(m)
463(m)
6.11
[Ni2(HL)Cl2(OH)2(H2O)2].2H2O
[Cu(HL)Cl2(H2O)2].H2O
3450(vb)
3400(b)
1621(b)
1638(w)
1540(w)
1600(s)
1025
1015
535(w)
525(w)
437(m)
455(s)
425/410/365/270
2.11/Ni(II)
1.93
2
3
410/385/360/292/272
[Cd(HL)Cl2(H2O)2].H2O
[Sn(HL)Cl2(OH)2].2H2O
[Hg2(HL)Cl4].EtOH
3450(b)
3450(b)
3450(s)
1630(s)
1700(m)
1650(m)
1610(s)
1630(s)
1600(s)
1042
1122
1028
520(w)
540(w)
566(m)
455(s)
480(m)
470(m)
327/269
d10
d10
d10
4
5
6
400/380/330/272
400/326/271/235
a :vb, very broad; s, strong; m, medium; w, weak; b, broad; ν, stretching
3

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Table 4: Thermal data of the complexes.
Temperature range/ oC
Mass loss / %
No Compound
Leaving species
DTG
TG
Calc.
F.
52
30-89
190-700
at 700
8.02
81.08
10.90
8.02
1
[Fe(HL)Cl3].2H2O
-2H2O
decomp.
≡ Fe
209,258,362
81.47
10.97c
54
287,
358,436
30-150
240-477
at 477
6.27
70.70
26.06
5.86
2
[Ni2(HL)Cl2(OH)2(H2O)2].2H2O
[Cu(HL)Cl2(H2O)2].H2O
- 2H2O
decomp.
≡ 2NiO
- H2O
68.65
28.11c
44
30-130
3
4
5
3.86
3.86
205,263,302,641 142-690
at 690
82.2
13.87
83.59
12.55c
decomp.
≡ Cu
36
90-140
[Cd(HL)Cl2(H2O)2].H2O
[Sn(HL)Cl2(OH)2].2H2O
3.49
3.59
-H2O
128,308,358,629 290-700
at 700
74.81
21.7
84.91
21.5c
decomp.
≡Cd
81
50-116
160-270
270-530
6.69
6.18
6.74
52.84
34.24c
5.30
-2H2O
190,236
344
6.32
-2OH
51.73
34.72
≡Completation of decomp.
at 530
≡ SnO2+3C
-EtOH
6
64
208,250
30-110
170-230
230-400
5.30
8.18
86.52
[Hg2(HL)Cl4].EtOH
8.70
86.52
-Cl2
-
a:desolvation, :decomposition, final product percent
b
c:
4

ACCEPTED MANUSCRIPT
Table 5: Selected bond length (Å) of ligand (HL) and its Fe(III) and Sn(IV) complexes.
HL
bond
lengths
1.009
1.354
1.261
1.208
1.364
1.369
Fe(III)
bond
lengths
1.006
1.352
1.269
1.221
1.361
1.360
1.860
1.833
2.170
2.169
2.167
Sn(IV) complex
(5)
bond
lengths
1.007
1.351
1.269
1.224
1.364
1.369
2.092
2.050
2.051
2.403
2.402
complex (1)
N(7)-H(26)
N(7)-N(8)
N(8)-C(10)
C(6)-O(9)
C(5)-C(6)
C(6)-N(7)
N(8)-Fe(1)
O(9)-Fe(1)
Fe(1)-Cl(2)
Fe(1)-Cl(3)
Fe(1)-Cl(4)
N(9)-H(26)
N(9)-N(10)
N(10)-C(11)
C(7)-O(8)
C(6)-C(7)
N(3)-H(27)
N(3)-N(4)
N(4)-C(11)
C(2)-O(5)
C(1)-C(2)
C(2)-N(3)
N(4)-Sn(6)
Sn(6)-O(7)
Sn(6)-O(8)
Sn(6)-Cl(9)
Sn(6)-Cl(10)
C(7)-N(9)
5

ACCEPTED MANUSCRIPT
Table 6: Selected bond angles (o) of ligand (HL) and its Fe(III) and Sn(IV) complexes.
HL
bond
Fe(III)
bond angles
Sn(IV)
bond
angles
Complex (1)
Complex (5)
angles
N(10)-C(11)-H(27)
C(6)-C(7)-N(9)
C(7)-N(9)-N(10)
N(10)-N(9)-H(26)
C(7)-N(9)-H(26)
O(8)-C(7)-N(9)
C(6)-C(7)-O(8)
C(6)-C(7)-N(9)
113.448
119.704
123.276
116.152
112.185
116.389
123.843
119.704
N(8)-C(10)-H(27)
N(8)-C(10)-C(12)
N(7)-N(8)-C(10)
N(8)-N(7)-H(26)
C(6)-N(7)-H(26)
N(7)-C(6)-O(9)
C(5)-C(6)-O(9)
C(5)-C(6)-N(7)
Cl(2)-Fe(1)-Cl(3)
Cl(2)-Fe(1)-Cl(4)
Cl(2)-Fe(1)-N(8)
Cl(2)-Fe(1)-O(9)
Cl(3)-Fe(1)-Cl(4)
Cl(3)-Fe(1)-N(8)
Cl(3)-Fe(1)-O(9)
Cl(4)-Fe(1)-N(8)
106.370
139.867
111.912
122.460
121.788
116.674
125.807
117.494
88.607
102.367
158.648
85.533
96.287
96.724
N(4)-C(11)-H(30)
N(4)-C(11)-C(13)
N(3)-N(4)-C(11)
N(4)-N(3)-H(27)
C(2)-N(3)-H(27)
N(3)-C(2)-O(5)
C(1)-C(2)-O(5)
C(1)-C(2)-N(3)
Sn(6)-O(8)-H(29)
Sn(6)-O(7)-H(28)
N(3)-N(4)-Sn(6)
C(11)-N(4)-Sn(6)
O(7)-Sn(6)-O(8)
O(7)-Sn(6)-Cl(9)
O(7)-Sn(6)-Cl(10)
O(7)-Sn(6)-N(4)
105.232
145.498
130.605
74.896
75.418
109.933
106.690
127.416
106.645
106.259
88.797
110.004
156.534
79.423
169.636
97. 596
79.771
111.370
Cl(4)-Fe(1)-O(9)
N(8)-Fe(1)-O(9)
Fe(1)-N(8)-N(7)
Fe(1)-O(9)-C(6)
93.318
85.828
O(7)-Sn(6)-O(5)
O(8)-Sn(6)-Cl(9)
O(8)-Sn(6)-Cl(10)
O(8)-Sn(6)-N(4)
O(8)-Sn(6)-O(5)
Cl(9)-Sn(6)-Cl(10)
108.017
79.750
90.299
91.043
79.478
92.054
101.567
109.837
Cl(9)-Sn(6)-N(4)
Cl(9)-Sn(6)-O(5)
Cl(10)-Sn(6)-N(4)
Cl(10)-Sn(6)-O(5)
N(4)-Sn(6)-O(5)
165.767
81.818
98.879
168.846
85.865
6

ACCEPTED MANUSCRIPT
2.00E+04
1.00E+04
0.00E+00
-1.00E+04
-2.00E+04
-3.00E+04
-4.00E+04
(3)
1700
2700
3700
4700
G
Fig. 1: X-band EPR spectrum of [Cu(HL)Cl2(H2O)2].H2O(3)
1

ACCEPTED MANUSCRIPT
Fig. 2 TG/DTG curves of complexes (1,3,4 and 6).
Asterisk indicates mass of sample (mg).
2

ACCEPTED MANUSCRIPT
Fig.3: 3D molecular structure of ligand (HL)
3