Transition-metal complexes of N,N′-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide: synthesis, characterization, biological activities, ADMET and drug-likeness analysis

Article abstract of DOI:10.1016/j.inoche.2021.108509

Coordination compounds of N,N’-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide (L1) were synthesized via the reaction of Cu (II), Co (II) and Zn (II) salts in molar ratio 1 : 1 in the presence of ammoniac as basic media. The Ligands and the complexes formed were characterized using FT-IR, UV–visible and fluorescence spectrophotometric analyses, mass spectrometry, elemental analyses and NMR spectroscopy. It was concluded that N,N’-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide (L1) coordinated as a mono ligand for all the complexes; it also coordinated via the –OH and –NH groups. The electrochemical behaviour of these compounds was determined by cyclic voltammetry. The synthesized compounds were screened for their antimicrobial and antioxidant activities. All the complexes except that of copper show good activities against the S. aureus and those of cobalt and zinc have very interesting diameters of inhibition but lower antioxidant activity than the ligand L1. Parameters drug-likeness and ADMET (Absorption, Distribution, Metabolism, and Excretion) properties have been calculated.

Full text of DOI:10.1016/j.inoche.2021.108509

Inorganic Chemistry Communications 127 (2021) 108509
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Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Short communication
Transition-metal complexes of N,N′-di
(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide: synthesis,
characterization, biological activities, ADMET and drug-likeness analysis
,
,c
Drifa Belkhir-Talbia b, Naima Ghemmit-Doulacheb, Souhila Terrachet-Bouazizb
,
Malika Makhloufi-Cheblia *, Amal Rabahid, Lhassane Ismailie, Artur M.S. Silvaf
,
a LPCM Laboratory, Department of Chemistry, Faculty of Sciences, University Mouloud Mammeri, 15000 TiziOuzou, Algeria
b Department of Chemistry, Faculty of Sciences, University M’hamed Bouguerra, Boumerdes, Algeria
c Laboratory of Applied Organic Chemistry, Faculty of Chemistry, University of Sciences and Technology Houari Boumediene, BP32, El-Alia 16111 Bab-Ezzouar, Alger,
Algeria
d
´
´
Laboratoire de Physico-Chimie Theorique et de Chimie Informatique, Faculte de Chimie, USTHB, BP 32, El Alia 16111 Bab-Ezzouar, Alger, Algeria
e
´
´
´
´
Laboratoire de Chimie Organique et Therapeutique, Neurosciences integratives et cliniques, EA 481, Univ. Bourgogne Franche-Comte, UFR Sante, 19, rue Ambroise
´
Pare, F-25000 Besançon, France
f QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
A R T I C L E I N F O
A B S T R A C T
Keywords:
Coordination compounds of N,N’-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide (L1) were syn-
thesized via the reaction of Cu (II), Co (II) and Zn (II) salts in molar ratio 1 : 1 in the presence of ammoniac as
basic media. The Ligands and the complexes formed were characterized using FT-IR, UV–visible and fluorescence
spectrophotometric analyses, mass spectrometry, elemental analyses and NMR spectroscopy. It was concluded
that N,N’-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide (L1) coordinated as a mono ligand for all
the complexes; it also coordinated via the –OH and –NH groups. The electrochemical behaviour of these com-
pounds was determined by cyclic voltammetry. The synthesized compounds were screened for their antimi-
crobial and antioxidant activities. All the complexes except that of copper show good activities against the S.
aureus and those of cobalt and zinc have very interesting diameters of inhibition but lower antioxidant activity
than the ligand L1. Parameters drug-likeness and ADMET (Absorption, Distribution, Metabolism, and Excretion)
properties have been calculated.
Coumarin-carboximidamide
Metal complexes
Antioxidant capacity
Antibacterial activity
Theoretical studies
ADMET drug-likeness
1. Introduction
important potential applications have led to the development of syn-
thetic procedures, either by conventional approaches or by transition
Metal complexes have been used for a considerable time as phar-
maceutical agents, especially in the chemotherapy against cancer [1,2].
More recently, large interest has grown in the use of transition metal
complexes [3–6].
metal-catalysis [10–21]. The complexation of coumarins with transition
metal ions has been extensively studied [22–29], as they are known to
have good complexing ability [30]. The formation of metal complexes
with coumarin plays an important role in their reported biological ac-
tivity. Recently, it has been reported that 4-methyl-7-hydroxycoumarin
complexes with several metals show anticoagulants and spasmolytic
properties [31,32]. Ferroquine, a metal complex, can produce reactive
oxygen species (ROS), which kill the parasites resistant to chloroquine
[33]. Considerable effort has now been given to the functionalization of
coumarin so that metal-coumarin complexes could be synthesized to-
wards the development of artificial photosynthetic systems, chemical
sensors, and molecular level devices [34]. As a result of resistance to
On the other hand, Coumarins are an important class of heterocyclic
natural products displaying significant biological and pharmacological
activities, presenting among others, antibacterial, or antibiotic power
(Novobiocin, Clorobiocin). A number of their synthetic analogues have
been also reported to be good antifungal and antibacterial agents [7–9].
Preliminary structure–activity relationship studies have shown that the
presence of hydroxyl or carboxylic acid derivatives in the coumarin
nucleus is necessary to account for the antimicrobial activity [9]. These
* Corresponding author.
E-mail address: makhloufi_malika@yahoo.fr (M. Makhloufi-Chebli).
https://doi.org/10.1016/j.inoche.2021.108509
Received 23 December 2020; Received in revised form 24 January 2021; Accepted 6 February 2021
Available online 5 March 2021
1387-7003/© 2021 Elsevier B.V. All rights reserved.

D. Belkhir-Talbi et al.
Inorganic Chemistry Communications 127 (2021) 108509
current drugs and emerging new diseases there is constant need of
obtaining antimicrobial and anticancer agents with minimal side effects.
The reported widespread applications of the coumarin moiety and their
coordination compounds, therefore, informed our interest in the syn-
theses of novel ligand complexes containing coumarin with the aim of
obtaining more potent antimicrobial and cytotoxic agents with possible
minimal side effects. Hence, following our studies on the synthesis of
coumarins and their transition metal complexes [35], in this work we
report the synthesis of a new series of Cu (II), Co (II) and Zn (II) metal
complexes derived from compound N,N’-di(4-bromophenyl)-4-hydrox-
ycoumarin-3-carboximidamide (L1) as well as their antimicrobial and
antioxidant activities.
Scheme 1. Synthesis of p-bromophenyl isothiocyanate.
2. Experimental
after all the NH4OH has been added, and then the reaction mixture was
allowed to stand for another thirty minutes at ambient temperature. The
milky suspension becomes clear and a heavy precipitate of ammonium
4-bromophenyldithiocarbamate crystallizes. The salt was allowed to
stand overnight, then filtered and washed with diethyl ether.
2.1. Materials and instrumentation
All the chemical reagents and solvents (Fluka products) used were of
analytical grade and without further purification. Melting points were
determined on a Stuart scientific SPM3 apparatus fitted with a micro-
scope and are uncorrected. The infrared spectra were recorded in the
region 4000–400 cmꢀ 1 on a BRUKER TENSOR 27 IR spectrophotometer.
UV–visible spectra were measured on a JENWAY 6800 UV–visible
spectrophotometer; measurements were made from 200 to 800 nm.
Fluorescence was measured on a JASCO - FP ꢀ 8200 spectrofluorometer.
The fluorescence quantum yields were determined using fluorescein
disodium salt (Φ = 0.90) as standard and calculated using the classical
formula:
The salt was dissolved in 800 mL of distilled water and transferred to
a 2-liter round bottom flask. Aqueous solution of 43.50 g (0.13 mol)
of Pb(NO3)2 dissolved in 87.50 mL of distilled water was added with
constant stirring. Lead (II) sulfide separates as a heavy brown precipi-
tate, which soon turned black. The mixture was then distilled with steam
(steam distillation), the 4-bromophenyl isothiocyanate 2 was recovered
in a flask containing 2.50 mL of 0.5 M sulfuric acid. The latter was
separated as white–grey solid and washed with cold water to eliminate
traces of sulfuric acid. The yield of 4-bromophenyl isothiocyanate was
39% (12.42 g) and melting point 61 ◦C (reported 50%, 61 ◦C [37]).
ΦX = (ΦS.AS.FX.nX2)/(AX.FS.n
S2)
2.2.2. Syntheses of ligands N,N’-di(4-bromophenyl)-4-hydroxycoumarin-
3-carboximidamide (L1) and of N-4-bromophenyl-4-hydroxycoumarin-3-
carbothioamides (L2)
where “A” is absorbance at the excitation wavelength, “F” the area under
the fluorescence curve and “n” is the refractive index of the solvents
used. Subscripts “s” and “x” refer to the standard and to the sample of
unknown quantum yield, respectively. Proton and Carbon NMR spectra
were recorded on a Bruker AC 300 spectrometer (Bruker Biospin). The
chemical shifts are expressed in parts per million (ppm) using TMS as
internal reference. Mass spectra are obtained with ESI (+) and GC–MS.
The elemental microanalysis (C, H, N) was carried out on Truspec
630–200 ꢀ 200 Elementary Analysis-Equipment, Service of Microanal-
ysis, Department of Chemistry-University of Aveiro, Portugal. The
conductimetric analysis was performed using a Consort C3030 con-
ductivity meter. The compounds were synthesized using method re-
ported by Makhloufi and all [36] with some modifications. Cyclic
voltammetry study was carried out in an organic medium DMSO at
25 ◦C, in the presence of the electrolyte support sodium perchlorate
(NaOClO4)⋅10ꢀ 1 M on a Pt disk electrode as a working electrode, the
reference electrode was with calomel saturated (ECS) and electrode
counters it’s a platinum wire (Pt). A scan rate of 100 mVsꢀ 1 was fixed for
all the voltammograms. All solutions were deoxygenated by passing a
stream of pre-purified N2 into the solution for at least 15 min prior to
recording the voltammograms.
A mixture of 0.81 g (5 mmol) of 4-hydroxycoumarin 1 and 0.8 mL (5
mmol) of triethylamine dissolved in 10.0 mL of DMSO was stirred during
15 mn and then 15.00 mmol of 4-bromophenyl isothiocyanate was
added. The reaction mixture was stirred at room temperature for 15 h,
50.0 mL of cold water was added followed by treatment with a mixture
of diethyl ether-light petroleum (1:1). The solid precipitate formed was
recrystallized from isopropyl alcohol giving N,N’-di(4-bromophenyl)-4-
hydroxycoumarin-3-carboximidamide L1 (1.15 g, 45%).
The aqueous layer was acidified with HCl 1 N (pH = 4–5) and the
precipitate thus formed was collected by filtration and washed several
times with cold water. The solid was recrystallized from isopropyl
alcohol giving N-4-bromophenyl-4-hydroxycoumarin-3-carbothioamide
L2 (659.80 mg, 35%).
2.2.2.1. N,N’-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide
(L1). White Powder, mp 235–236 ◦C; 1H NMR (CDCl3): δ 6.74 (d, 2H, J
= 9.6 Hz, ArH), 7.17 (d, 2H, J = 8.7 Hz, ArH), 7.28 (d, 1H, J = 9.3 Hz,
ArH), 7.31 (d, 2H, J = 8.7 Hz, ArH), 7.37 (t, 1H, J = 9.3 Hz, ArH), 7.55
(d, 2H, J = 9.6 Hz, ArH), 7.69 (t, 1H, J = 9.3 Hz, ArH), 8.12 (d, 1H, J =
9.3 Hz, ArH), 13.35 (s, 1H, NH), 17.46 (s, 1H, OH); 13C NMR (CDCl3): δ
89.4, 97.4, 116.1, 122.2, 123.8, 124.5, 124.7, 126.9, 131.3, 135.7,
149.2, 151.6, 158.7, 162.7, 166.0, 174.3, 180.2, 189.5; ms (EI): m/z 512
(40), 449 (9), 447 (10), 359 (18), 357 (20), 216 (15), 215 (100), 214
(15), 213 (99), 183 (3.9), 181 (4), 158 (2.5), 156 (3), 155 (25), 143 (2),
134 (50), 117 (2), 107 (9), 76 (8). Anal. Calcd. for C22H14Br2N2O3
(514.17): C, 51.39; H, 2.74; N, 5.45. Found: C, 51.54; H, 2.850; N, 5.81.
2.2. Synthesis of ligands and complexes
2.2.1. Synthesis of 4-bromophenyl isothiocyanate
The compound 4-bromophenyl isothiocyanate 2 was synthesized as
reported in the literature [37] (scheme 1): To a 250 mL round-bottomed
flask, fitted to a magnetic stirrer and a dropping funnel leaving the third
neck open and surrounded by an ice-salt cooling bath (10 – 15 ◦C), the
amount of 25.80 g of 4-bromoaniline (0.15 mol) was introduced. To this
flsk, 12.37 mL (0.20 mol) of carbon disulfide and 20.00 mL of ethanol
were added. The stirrer was started, and 22.50 mL (0.56 mol) of NH4OH
(d = 0.88) was added drop-wise into the mixture from a separatory
funnel in about twenty minutes. The temperature of the mixture should
be between 10 and 15 ◦C. The stirring was continued for thirty minutes
2.2.2.2. N-(4-bromophenyl)-4-hydroxycoumarin-3-carbothioamide (L2).
Yellow powder, mp 270–271 ◦C; 1H NMR (CDCl3): δ 6.75 (d, 2H, J = 9.8
Hz, ArH), 7.17 (d, 2H, J = 9.8 Hz, ArH), 7.31 (t, 1H, J = 9.0 Hz, ArH),
7.37 (d, 1H, J = 9.0 Hz, ArH), 7.69 (t, 1H, J = 9.0 Hz, ArH), 8.12 (d, 1H,
J = 9.0 Hz, ArH), 13.34 (s, 1H, NH), 17.45 (s, 1H, OH); 13C NMR
(CDCl3): δ 97.3, 116.0, 123.7, 125.3, 126.8, 131.2, 131.7, 134.7, 135.7,
2

D. Belkhir-Talbi et al.
Inorganic Chemistry Communications 127 (2021) 108509
136.0, 151.5, 162.7, 179.4 (C-OH), 188.4 (C = S); ms (ESI+): m/z 400
[26, (M + Na)+, 81Br], 398 [29, (M + Na)+, 79Br], 378 [96, (M + H)+,
81Br], 376 [100, (M + H)+, 79Br]. Anal. Calcd. for C16H10 BrNO3S
(376.23): C, 51.08; H, 2.68; N, 3.72. Found: C, 51.29; H, 2.84; N, 3.65.
2.5. Theoretical study
In order to establish theoretically the coordination sites and make a
comparison with the experimental observations, quantum chemical
calculations of Mulliken atomic charges have been carried out. For this,
the 2D structures of synthesized ligands and metallic complexes were
drawn with Marvin Sketch [41]. The geometries optimization and fre-
quencies calculation were calculated using ORCA, an electronic struc-
ture program package [42,43] at density functional theory (DFT) using
standard Becke’s three-parameter hybrid model, Lee–Yang–Parr
(B3LYP) functional and 6-31G** [44,45] and LANL2DZ basis sets, for
ligand L1 and synthesized metallic complexes, respectively. Since the
density functional theory (DFT) was not able to describe long-range
London dispersion interactions, we corrected the local density with
the original D3 damping function [46]. In order to perform a compar-
ative study of the stability of the synthesized metallic complexes, we
calculated the Binding Energy (BE), which is given by:
2.2.3. Syntheses of Cu (II), Zn (II) and Co (II) complexes of ligand L1
The complexes of ligand L1 were prepared from metal chloride salts
of copper, cobalt and zinc as follows:
To an ethanolic solution containing 0.50 mmol of MCl2⋅xH2O (M =
Cu (II), Co (II) and Zn (II)) dissolved in 5.00 mL was added 0.50 mmol
(0.257 g) of L1 dissolved in a mixture ethanol- chloroform (10.00 mL/
20.00 mL). NH4OH was then added while adjusting the pH to 7–8 and
the mixture was refluxed for 6 h until formation of precipitate. The solid
precipitate formed was collected by filtration, washed with hot ethanol
and hot chloroform and dried.
2.3. Screening for antibacterial activity by the agar diffusion method for
L1 and its transition metal complexes
Ebinding = Ecom plex – (Em etal + Eligand
)
(2)
The antimicrobial activities of ligand L1 and its Cu (II), Co (II), and
Zn (II) complexes were evaluated for their antibacterial activities against
Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853)
and Staphylococcus aureus (ATCC 25923) by the agar diffusion method
[38]. A sterile physiological water solution contained bacterial colonies,
was prepared at room temperature, with an optical density of 0.08–0.10
corresponding to a concentration of 106 cells/mL. The bacterial solution
was inoculated in the Muller-Hinton agar medium by swabbing using
Petri dishes at room temperature. The tested compounds were dissolved
in dimethylsulfoxide (DMSO) with a concentration of 5.00 mg/mL.
Twenty-five microlliters of tested sample were poured onto filter paper
discs 6 mm in diameter, which were then delicately placed on the sur-
face of the agar plates. These were later maintained at 37 ◦C for 24 h.
Activities were determined by measuring the diameter of the inhibition
zone (mm).
where, Ecomplex is the energy of the optimized complex and ELigand is the
single point energy of ligand in the optimized one. The highest BE cor-
responds to the most stable complex. UV–visible, IR spectra and defor-
mation electron density were generated using Gabedit 2.5.0 [47] and
Multiwfn [48].
2.6. ADMET and drug-likeness analysis
The ADMET (absorption, distribution, metabolism, excretion, and
toxicity) properties of molecules describe their disposition within an
organism [49]. Therefore, it was necessary to use the computational
tools to predict ADMET properties which used only the molecular
structure [50]. Several studies using in silico ADMET properties analysis
were reported in the literature [35].
In this context, admetSAR [51] and SwissADME [52] servers were
used to predict AMES toxicity (AMEST) [53], Carcinogenicity [54],
Human Ether-a-go-go-Related Gene (hERG), P-glycoprotein inhibition
(PG Inhibitors) [55], inhibition of four cytochrome P450 isoforms
(CYP2C19, CYP2D6, CYP3A4 and CYP450 2C9) [56], Blood-brain bar-
rier (BBB) permeability [57], and human intestinal absorption (HIA)
[58], CaCo-2 permeability (PCaco-2) [59]. Some physicochemical
properties were also evaluated such as Log P and TPSA.
2.4. Antioxidant activity
The antioxidant activity of the synthesized L1 and its complexes was
evaluated using the 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH.)
scavenging assay [39,40]. DPPH. solution was prepared by dissolving
DPPH. in ethanol to give a concentration of 4.00 mg/100 mL. Com-
pounds L1, [Zn(L1)(NH3)2Cl2]H2O, [Cu(L1)(NH3)2Cl2]H2O and [Co(L1)
(NH3)2Cl2]H2O were dissolved in DMSO to obtain solutions of 1.00 ×
10ꢀ 1 M. The concentration of test compounds was diluted with DMSO to
get final concentrations 5.00 × 10ꢀ 2, 25.00 × 10ꢀ 3 and 12.50 × 10ꢀ 3
mol/L for all the compounds. The standard was further diluted to give
concentration solutions of 1.00 × 10ꢀ 1, 5.00 × 10ꢀ 2, 25.00 × 10ꢀ 3
12.50 × 10ꢀ 3, 6.25 × 10ꢀ 3, 31.25 × 10ꢀ 4 and 15.63 × 10ꢀ 4 mol/L. To
3. Results and discussion
The condensation of 4-hydroxycoumarin 1 with 4-bromophenyliso-
thiocyanate 2 in the presence of triethylamine as basic catalyst in
DMSO as solvent at room temperature for 15 h, led to the formation of
two compounds L1 and L2 (see scheme 2) [36].
40 μL of each concentration of tested compounds was added 2.00 mL of
The IR spectrum of L1 showed strong peaks at 1670 and 1609 cmꢀ 1
,
DPPH solution. The mixtures were incubated in the dark at room tem-
perature for 1 h and then the absorbances were measured at 517 nm.
Ascorbic acid (AA) was used as standard for the antioxidant activity
screening and a blank containing only ethanol with DMSO was used as
the control. DPPH scavenging effect was calculated as percentage of
DPPH discoloration using the equation:
corresponding respectively to the carbonyl C = O and imine C = N
groups of the coumarin ring. The –OH and –NH groups displayed ab-
sorptions around 3126 and 3066 cmꢀ 1 respectively [36].
The mass spectra of compounds L1 indicated that the coumarin ring
was conserved, confirmed by the observed peaks at m/z 134, 143 and
117 corresponding to the fragmentation of the coumarin ring [60,61].
The elemental analysis and the mass spectra of L1 indicated the absence
of sulfur in the structure and that two molecules of 4-bromophenyl
isothiocyanate 2 reacted with 1.
RSA (%) = [(Ac - As)/Ac] × 100
(1)
where Ac was the absorbance of the control (absorbance of DPPH
ethanol solution without sample), and As was the absorbance of the
tested compound after 60 min incubation.
The 1H NMR spectra showed the presence of signals corresponding to
the resonances of two exchangeable protons at δ 13.35 and 17.46 ppm,
assigned to the –NH and –OH groups respectively. The 13C NMR spectra
showed that compound L1 exist as a mixture of two tautomers (Scheme 2
and Fig. 11). In fact L1 displayed two signals for the resonance of car-
bons 3 (δ 97.4 and 116.1 ppm), C-4 (δ 179.6 ppm assigned to C-OH; δ
188.5 ppm assigned to C = O) and C-9 (δ 166.0 ppm assigned to = C
All the tests were made in duplicate and at least two different assays
were performed for each sample.
3

D. Belkhir-Talbi et al.
Inorganic Chemistry Communications 127 (2021) 108509
Scheme 2. Synthesis of the ligands L1 and L2.
(NHAr)2; δ 179.6 ppm assigned to -C(NHAr) = NAr and the signals of the
aromatic carbon]: C-3 (δ 97.4 and 116.1 ppm) and C-4 (δ 179.6 ppm
assigned to C-OH; δ 188.5 ppm assigned to C = O) (see experimental
section).
effect on the wavelength band at 337 nm is observed (Fig. 3, see sup-
plementary information).
3.1.2. Effect of the nature of metal
The 1H NMR spectra of L2 showed two singlets at δ 13.34 and 17.45
ppm corresponding to the resonance of –NH and –OH groups, whereas
the 13C NMR spectra show a characteristic carbothiamoyl signal at δ
188.40 ppm (C = S) (see experimental section and ref [36]).
The effect of the nature of metal has also been studied (see supple-
mentary information). The results showed that the absorbance and the
wavelength were much affected by the presence of the metal. The
various metal ions (Mn2+, Co2+, Ni2+ and Zn2+) caused absorption
spectra changes of L1 and L2.
The zinc, nickel, manganese and the cobalt ions shift the wavelength
towards the red whereas the copper towards the blue (Fig. 4-A and B, see
supplementary information). In this regard, L1 and L2 exhibit satisfying
selectivity for transition metal ions M2+. The absorption characteristics
are collected in Table 1 ans Beer-Lambert’s law was satisfied in the range
of concentration studied (6x10ꢀ 5 M). The molar extinction coefficient
was measured at the CT band maximum. For compound L1 and L2, it
was found to be equal to 23,953 and 23428 Mꢀ 1 cmꢀ 1 respectively
(Table 1). In contrast, addition of metal cations, induced a hypochromic
and hypsochromic (only Cu2+)/batochromic (other cations) shift on the
CT band (Fig.4, see supplementary information). The molar extinction
coefficient decreases upon addition of metal cation M2+ indicating in
this case, that the CT bands also decreased.
3.1. UV–Visible spectroscopic study
3.1.1. Absorption spectrum titrations of L1 and L2 with Cu2+
To optimize the complexation, a study was carried out to determine
the molar ratio M/L required for the synthesis of the complexes. Thus,
the solutions of the ligands and metal were prepared in DMSO at con-
centrations of 6x10ꢀ 5 M.
The absorption spectrum of the free ligands L1 and L2 was studied. In
the case of L1, the weak wavelength at 268 nm was attributed to the n-π*
transition of the imine group and the intense long-wavelength band
situated around 337 nm was attributed to the * transition of the
π–π
coumarins’ carbonyl group. Addition of CuCl2 to a solution of L1
(6x10ꢀ 5 M) in DMSO induced drastic changes in the absorption spec-
trum. A strong hypochromic effect on the short-wavelength band at 268
nm (Fig. 1-A, curves a to i) was observed. The band around 337 nm
underwent a hypochromic effect, lost its plateau shape and shifted to the
red. The same effect was observed for the three investigated cations.
For L2, the intense long-wavelength band situated around 358 nm
3.2. Effect of pH on the absorption spectra of the ligands L1 and L2
A UV–visible spectrophotometry study of the effect of pH on the
displacement of the ligands L1 and L2 wavelengths was carried out in
order to optimize the pH value affecting the absorption wavelength of
the coumarin nucleus. The pH change was made by the addition of
ammoniac to solutions of L1 and L2 ligands dissolved in DMSO at con-
centrations of 6.00 × 10ꢀ 5 M. As shown in Fig. 5 (see supplementary
information) the pH showed an effect on the absorption spectra of L1
and L2. In fact initially, the pH value recorded for 6.00 × 10ꢀ 5 M ligands
solutions is of the order of 6–7 units and the addition of the ammoniac
drops gave rise to a pH variation. A slight Hyperchromic displacement of
the absorption wavelength at 337 nm attributed to coumarin was
observed for L1. Concerning L2 hypochromic and batochromic dis-
placements at 268 and 358 nm was observed. From pH 8 no variation
was observed on the spectrums, involving that the base did not affect the
ligands and that there was no interaction between the L1 and L2 ligands
and the ammonia as well as no deprotonation of the hydroxyl groups.
The effect of the addition of ammonia on the equimolar mixture L1/
CuCl2 was also studied by UV–visible analysis (Fig. 6, see supplementary
was attributed to the
π–π* transition of the carbonyl group and the weak
one at 268 nm which appears as a shape was attributed to the n-
π
*
transition of the carbothionyl group. The addition of CuCl2 to a solution
of L2 (6x10ꢀ 5 M) in DMSO induced drastic changes in the absorption
spectrum. A strong hypochromic effect on the wavelength band at 358
nm and on the shape at 268 nm (Fig. 1-B, curves a to i) was observed.
Then, the absorbance as a function of cation concentration was
analysed (Figs. 2A and 2B). As the shape of the absorption spectrum
varied strongly in the presence of cations, the absorbance was recorded
at two different wavelengths chosen in order to obtain maximum in-
formation. For each salt, the calculation was performed simultaneously
on the two bands obtained by absorption spectroscopy there by giving
good fits, as displayed in Fig. 2.
The results of Fig. 2 showed that from an equimolar ratio metal/
ligand, the absorbance becomes constant. The time factor on metal-
–ligand coordination (1:1) of L1/Cu2+ is also studied. Hypochromic
4

D. Belkhir-Talbi et al.
Inorganic Chemistry Communications 127 (2021) 108509
(A)
1,6
1,4
1,2
1,0
0,8
0,6
0,4
337
(A)
2+
a
L (0 eq Cu
1
)
1,4
337 nm
267 nm
b
c
d
e
f
0,25 eq
0,5 eq
075 eq
1 eq
1,25 eq
1,5 eq
1,75 eq
2 eq
1,2
1,0
268
g
h
i
0,8
0,6
0,4
0,2
0,0
0,0
0,5
1,0
1,5
2,0
300
400
500
600
700
2+
[Cu
]
λ (nm)
Fig. 2A. Fitted spectrophotometric data for compound L1 in DMSO vs. cation
concentration. Variation of absorbance: λ = 267 and 337 nm.
(B)
1,4
358
2+
)
a
b
c
d
e
f
g
h
i
L2 (0eq Cu
0,25eq
0,5eq
0,75eq
1eq
1,25eq
1,5eq
1,75eq
2eq
(B)
358 nm
268 nm
1,2
1,0
0,8
0,6
0,4
0,2
0,0
268
1,4
1,2
1,0
0,8
0,6
0,4
300
400
500
600
λ (nm)
0,0
0,5
1,0
1,5
2,0
2+
Fig. 1. (A) Absorption spectrum of L1 (6x10ꢀ 5 M) in DMSO in the absence
(curve a) and presence of increasing amounts of CuCl2: Curves b to i: effect of
CuCl2 addition. From top to bottom at 268 nm and 337 nm: CuCl2 (6x10ꢀ 5 M):
0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75 and 2.00 equivalents (B) Ab-
sorption spectrum of L2 (6x10ꢀ 5 M) in DMSO in the absence (curve a) and
presence of CuCl2. Curves b to i: effect of CuCl2 addition. From top to bottom at
268 nm and 358 nm: CuCl2 (6x10ꢀ 5 M): 0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50;
1.75 and 2.00 equivalents.
[Cu
]
Fig. 2B. Fitted spectrophotometric data for compound L2 in DMSO vs. cation
concentration. Variation of absorbance: λ = 268 and 358 nm.
Table 1
Spectroscopic characteristics of L1 and L2 in the absence and in the presence of
different transition metal ions: Maximum absorption wavelength of the CT Band
(λabs max) and apparent molar extinction coefficient at the absorption maximum
information). The results showed a variation on the absorption wave-
length after addition of ammonia and remain unchangeable after pH
7–8.
(
ε
).
Ligand
L1
Ion
λ
abs max (nm)
ε
(M¡1 cm¡1
)
/
337
343
321
343
358
354
322
354
354
358
23,953
12,913
11,672
11,672
23,428
09,906
08,073
09,822
09,913
10,090
Co2+
Cu2+
Ni2+
/
3.3. Fluorescence spectra study
3.3.1. Effect of the stoichiometric amount of the metal on the ligands
On the other hand, the fluorescence spectra of L1 and L1 + Cu2+
were also recorded in the optimized experimental condition. In the
absence of CuCl2, the emission spectra of L1 (6x10ꢀ 5 M, λex = 337 nm) in
DMSO showed only one band with maxima situated at around 423 nm
Stokes shift equal to 6033 cmꢀ 1. In the presence of CuCl2, and with the
same excitation wavelength (Fig. 7-A), the results showed that the in-
tensity emission peaks at 423 nm increases with the addition of Cu2+ and
the fluorescence intensity becomes constant at an equimolar ratio
metal/ligand, indicating the formation of L1-Cu2+ complex.
L2
Co2+
Cu2+
Ni2+
Zn2+
Mn2+
wavelength (Fig. 7-B), the results showed that the intensity emission
peaks at 408 nm decreases with the addition of Cu2+ and the variation of
the fluorescence intensity becomes very weak from an equimolar ratio
metal/ligand, indicating the formation of L1-Cu2+ complex.
In the case of L2, the emission spectra (6x10ꢀ 5 M, λex = 358 nm) in
DMSO showed one band with maxima situated at around 408 nm
wavelength. In the presence of CuCl2, and with the same excitation
Ligands L1 and L2 exhibited quantum yields of 0.031 and 0.078
5

D. Belkhir-Talbi et al.
Inorganic Chemistry Communications 127 (2021) 108509
3.4. Characterization of the complexes
(A) 800
2+
0 eq Cu
a
b
c
d
e
f
3.4.1. Elemental analyses
2+
0,25 eq Cu
The elemental analyses data agreed well with the proposed formula
for the metal (II) complexes. The results showed a 1:1 (metal : ligand)
stoichiometry and the appearance of a high percentage of nitrogen
indicating its presence in the complex. The analytical results are in good
agreement with those required mole ratio for the general formula [ML
(NH3)2Cl2].H2O. Table 2 summarized the results obtained for the
elemental analyses.
2 eq
2+
0,5 eq Cu
2+
600
400
200
0
1 eq Cu
1,25 eq Cu
2+
0
2+
1,5 eq Cu
2+
g
h
1,75 eq Cu
2+
3.4.2. NMR study of the complexes
2 eq Cu
The proton NMR spectra of the free ligand L1 (Fig. 11, see supple-
mentary information) and the complexes (Fig. 12, see supplementary
information) were recorded in CDCl3 and DMSO‑d6 respectively. Com-
parison of the spectra of the complex with the ligand L1 revealed that
the resonances were considerably broadened and also shifted on
complexation. The 1H NMR spectrum of the zinc complex proton
(Fig. 12) showed that the peak of the –NH and –OH groups were
conserved, which implied the conservation of the latter. The spectro-
scopic variations suggested that definite interactions took place between
ligand and metal cation. The peak of –OH group is more shifted than the
–NH group which implied its participation in the complexation. The 1H
NMR spectrum of L1 complexes at saturation in DMSO showed very
weak shifts on the peaks corresponding to the aromatic protons. Addi-
tional techniques were used to provide more information about the
structure of the complexes.
350
400
450
500
550
600
650
λ (nm)
(B)
1000
2+
a
b
c
d
e
f
0eq Cu
0
2+
0,25eqCu
2+
0,5eqCu
2 eq
2+
0,75eqCu
2+
1eqCu
500
2+
3.4.3. Infrared
1,25eqCu
Infrared spectra are the most suitable technique to determine the
coordinating atoms of the ligands by comparing the free ligand spectra
with those of the complex. The Table 3 summarized the results obtained
by IR analysis (see Supplementary material section).
2+
g
h
i
1,5eqCu
2+
1,75eqCu
2+
2eqCu
A careful study of IR spectra of Cu (II), Co (II) and Zn (II) complexes,
and a comparison with the ligand L1, showed that the band corre-
sponding to –OH stretch was affected by complexation and shifted to
higher frequencies in both complexes. In addition, the stretching vi-
bration band of the –NH of the carboximidamide ring was weakened and
shifted to 3052 cmꢀ 1, 3100 cmꢀ 1 and 3050 cmꢀ 1 for the Cu (II), Co (II)
and Zn (II) complexes respectively. The stretching vibration band of the
carbonyl bond of the pyronic ring was weakened and shifted to
1652–1659 cmꢀ 1 for all the complexes and less affected by the nature of
the metal. This later band was observed as an intense band, suggesting
that the carbonyl-group was not coordinated with the metal. These
variations were also found for the imine vibration band C = N of car-
boximidamide. The results are in favor of metal–ligand interactions
through the oxygen atom of pyronyl hydroxyl –OH and –NH of car-
boximidamide. New broad bands appear at 3500 cmꢀ 1, 3550 cmꢀ 1 and
at 3400 cmꢀ 1 for the copper, cobalt and zinc complexes respectively,
probably due to water [62] indicating the presence of the latter in the
chelates.
0
400
450
500
λ (nm)
550
600
Fig. 7. (A): Fluorescence emission spectra of L1 (6x10ꢀ 5 M, in DMSO) in the
absence (curve a) and presence of increasing amounts of CuCl2: Curves b to h:
effect of CuCl2 addition. From bottom to top at 423 nm: CuCl2 (6.10ꢀ 5M): 0.00;
0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75 and 2.00 equivalent. Excitation wave-
length 337 nm. (B): Fluorescence emission spectra of L2 (6x10ꢀ 5 M, in DMSO)
in the absence (curve a) and presence of increasing amounts of CuCl2: Curves b
to i: effect of CuCl2 addition. From top to bottom at 408 nm: CuCl2 (6x10ꢀ 5M):
0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75 and 2.00 equivalent. Excitation
wavelength 358 nm.
respectively. The presence of Cu2+ ion increase the quantum yield of L1
and decrease the one of L2. Fitted spectrofluorimetric data for com-
pounds L1 and L2 in DMSO vs. cation concentration (Fig. 8, A-B, see
supplementary information) showed that from an equimolar ratio
metal/ligand, the intensity becomes constant.
The spectrum of the complexes also exhibited a broad band at 2942
cmꢀ 1 (CuL1), 2962 cmꢀ 1 (CoL1) and 2992 cmꢀ 1 (ZnL1), related to –NH3
bonded [63] suggesting that ammoniac had not deprotonated the –OH
group but it participated in the coordination. Apparition of new peaks
due to the Mꢀ O and Mꢀ N bonds of the complexes [64,65] signify the
coordination of L1 with Cu (II), Co (II) and Zn (II) cations. The charac-
teristics of the FTIR spectra of all complexes were in agreement with the
suggested structural formula.
3.3.2. Effect of the nature of metal
The effect of the nature of metal on the emission spectra has also
been studied. The results showed that the presence of the metal affects
the intensity more than the emission wavelength, except for the copper
where the emission wavelength was displaced and a bathochromic effect
was observed (Fig. 9-A and B, see supplementary information).
The effect of the addition of ammonia on the equimolar mixtures L1-
MCl2 and L2-MCl2 at pH 7–8 was also studied (see Fig. 10-A and B,
supplementary information). The results showed a variation on the
emission spectrum and the intensity becomes more important.
3.4.4. Electronic spectra
The UV–visible absorption spectra of the three complexes are shown
in Fig. 13A-C and Table 4 below summarizes the results obtained for the
electronic absorption bands of complexes.
The UV–visible absorption spectrum of the complex [Cu(L1)
(NH3)2Cl2]H2O (Fig. 13-A, see supplementary information) showed in
6

D. Belkhir-Talbi et al.
Inorganic Chemistry Communications 127 (2021) 108509
Table 2
Elemental analyses data of the investigated compounds.
Complex
C%
H%
N%
Cl %
Calcd.
Found
Calcd.
Found
Calcd.
Found
Calcd.
Found
[Zn(L1)(NH3)2Cl2]H2O
[Co(L1)(NH3)2Cl2]H2O
[Cu(L1)(NH3)2Cl2]H2O
38.50
38.85
38.60
38.33
38.96
38.49
3.51
3.54
3.52
3.44
3.72
3.75
7.81
7.88
7.83
7.61
7.68
7.95
9.88
9.97
9.91
10.12
9.83
10.09
Table 3
Relevant infrared spectra bands for the ligand and complexes (cmꢀ 1).
̶
̶
̶
̶
̶
̶
̶
Comp.
v(OH)
ν(H2O)
ν
(NH3)as
ν
(C = O)
ν
(C = N)
ν
(NH)
ν
(Mꢀ O)
ν
(Mꢀ N)
L1
3132
3152
3256
3220
–
–
1670
1652
1657
1656
1609
1602
1602
1602
3088
3050
3052
3100
–
–
[Zn(L1)(NH3)2Cl2]H2O
[Cu(L1)(NH3)2Cl2]H2O
[Co(L1)(NH3)2Cl2]H2O
3400
3500
3550
2992
2942
2962
522
559
494
495
442
446
charges have been carried out in order to determine theoretically the
coordination sites and make a comparison with the experimental
observations.
Table 4
Electronic spectral data of the complexes recorded in DMSO.
Samples
λ (nm)
ν
(cmꢀ 1
)
Transitions
Fig. 14 represents the optimized geometries of the ligand L1 as well
as the charge density values calculated. It has been found that the
highest negative values were those of the oxygen hydroxyl group
(ꢀ 324) and the nitrogen of –NH group (ꢀ 457), suggesting that the
latter favor more the coordination with the transition metals.
Time-Dependent Density Functional Theory (TD-DFT) calculations
and B3LYP method which is the hybrid functional Becke, three-
parameter, Lee-Yang-Parr [44,45] with an effective core potential
basis set LANL2DZ [69–72] of the calculated UV–visible absorption, was
in agreement with the experimental results. It is worth noting that
previous studies were demonstrated the capability of chosen method
and basis set to predict the electronic properties of metallic complexes
quite reasonably [73–76]. For example, the calculated absorption
spectrum of the complex ZnL1 (Fig. 15) showed in the ultraviolet
[Zn(L1)(NH3)2Cl2]H2O
274
342
415
268
338
411
530
590
267
346
436
551
645
36,496
29,240
24,096
37,313
29,586
24,331
18,868
16,949
37,453
28,902
22,936
18,179
15,505
n → π*
π
→
π
*
MLTC
n →
[Cu(L1)(NH3)2Cl2]H2O
[Co(L1)(NH3)2Cl2]H2O
π
*
π
→
π
*
MLTC
2B1g → 2Eg
2B1g → 4A1g
n → π*
π
→ π*
MLTC
4T1g → 4T1g(P)
4T1g → 4T2g(F)
the ultraviolet domain two bands located at 37313 cmꢀ 1 and at 29586
cmꢀ 1 respectively. The latter were due to the intra ligand transitions n
domain two bands due to the intra-ligand transitions
π → π*. Another
band located at 400 nm corresponded to the metal–ligand charge
transfer.
→
π
* and
π
→
π
* respectively. Another band located at 24331 cmꢀ 1 as a
shoulder corresponded to the metal–ligand charge transfer. Two bands
appear in the visible at 16949 cmꢀ 1 and at 18868 cmꢀ 1 corresponding to
transitions 2B1g → 2A1g and 2B1g → 2Eg. These electronic transitions were
characteristic of an octahedral geometry [66].
The ligand coordination sites that were involved in bonding with the
metal ions have been determined by careful comparison of the infrared
absorption spectra of the complexes with that of the parent ligand. The
vibrational assignments were carried out with support DFT calculations
using the Minnesota M06 global hybrid meta-GGA functional [77] with
LANL2DZ basis set [78,79]. The experimental and theoretical FT-IR
spectra of CuL1 were given in Fig. 16 (see supplementary informa-
tion). The IR spectra indicate that the ligand was coordinated through
the O (of –OH) and N (of –NH) atoms of L1 and the N-atoms from the
The electronic absorption spectra of the complex [Co(L1)(NH3)2Cl2]
H2O (Fig. 13-B, see supplementary information) showed two bands
located at 37453 cmꢀ 1 and 28902 cmꢀ 1 due to the transitions n →
π* and
π
→
π
* respectively. A shoulder appears at 22936 cmꢀ 1 corresponded to
the metal–ligand charge transfer (CT). Two new bands appear in the
visible at 18149 cmꢀ 1 and at 15504 cmꢀ 1 were attributed to the 4T1g →
4T1g(P) and 4T1g → 4T2g(F) transitions respectively. These correspond to
an octahedral geometry [67].
The spectra of [Zn(L1)(NH3)2Cl2]H2O (Fig. 13-C, see supplementary
information) have been shifted towards the high wavelengths at 36496
cmꢀ 1 and 29240 cmꢀ 1, which showed ligand engagement in complex
formation. A new wavelength at 24096 cmꢀ 1 was attributed to the
charge transfer of the metal–ligand. The absorption spectrum exhibited
no band in the visible region of the spectrum. No d-d absorption band
was observed in the visible region. This is partly due to the fully filled 3d
of Zn (II) ion. An octahedral geometry is proposed for this complex [68].
3.5. Complex structures and theoretical studies
All geometries of synthesized ligand L1 (A and B) were optimized
with density functional theory (DFT) using Becke’s three-parameter
hybrid model, Lee–Yang–Parr (B3LYP) [44,45] with 6-311G** using
ORCA program [42,43]. Frequency analysis was performed at the same
level of theory. Quantum chemical calculations of Mulliken atomic
Fig. 14. Optimized Geometry, the Mulliken atomic charges distribution and
calculated thermodynamics parameters: Enthalpy = ꢀ 3968.99.103 Kcal/mol of
the ligand L1.
7

D. Belkhir-Talbi et al.
Inorganic Chemistry Communications 127 (2021) 108509
Table 5
Calculated binding energies of synthesized metallic complexes at the DFT level
of theory.
CoL1
CuL1
ZnL1
|EB| (eV)
11,70
10,34
11,16
Table 6
Analytical and physical data of the investigated compounds.
Comp.
Yield
Color and aspect
Pf
Λ Ωꢀ 1.cm2.
(◦C)
molꢀ 1
In DMSO
[Cu(L1)(NH3)2Cl2]
H2O
61
58
67
Green powder
˃260
˃260
˃260
10.51
5.43
9.32
Fig. 15. Theoretical absorption spectra of ZnL1.
[Co(L1)(NH3)2Cl2]
H2O
Dark red powder
ammoniac moiety, resulting in neutral species.
[Zn(L1)(NH3)2Cl2]
H2O
White yellowish
powder
On basis of the elemental analysis, NMR, electronic spectra and
theoretical studies, the complexes were formulated as [ML1(NH3)2Cl2]
H2O (Fig. 17).
(III) corresponding to the potential values Epa equal to ꢀ 449 mV/SCE,
ꢀ 1479 mV/SCE and 167 mV/SCE respectively. In the cathodic direc-
tion, it showed tow peaks of reduction pc (I) and pc (II) corresponding to
the potential values Epc equal to ꢀ 559 mV/SCE and ꢀ 1289 mV/SCE.
The anodic process corresponding to peak pa (I) and peak pa (III) can
only be the result of a redox process of ligand L1. The other peak (peak
2) observed in Fig. 19 was supposed to be the result of an oxidation and
reduction occurring at the level of the Cu (II) ion [80]. In the negative
potential range and on the cathode scan, the peak attributed to the metal
shown by the cyclic voltammogram of the complex was intense. How-
ever, when scanning in the opposite direction, the anode peak related to
the cathode wave was not intense. This indicated that during cathodic
reduction, the electrode process was complicated by a chemical
reaction.
In order to study the stability of the synthesized complexes, their
binding energy have been calculated (Table 5). The lowest value of the
binding energy corresponded to the most stable complex. Analysis of
these results shows that the CoL1 complex had the highest binding en-
ergy value, which indicated that this complex was the least stable. On
the other hand, CuL1 and ZnL1 complexes have the lowest binding en-
ergies indicating that these complexes were the most stable.
3.6. Conductivity
The conductimetric measurements of the complexes were performed
in DMSO at a concentration of 1 × 10ꢀ 3 M. The results showed that the
complexes are non-electrolytes. The analytical data and physical prop-
erties of the complexes were summarized in Table 6.
During a scan ranging from + 1500 mV to ꢀ 2000 mV, the Co (II)
complex has two shallow cathodic responses in the form of a shoulder at
about ꢀ 585 mV and ꢀ 1408 mV and three localized anodic peaks at
ꢀ 351 mV, ꢀ 1501 mV and 210 mV. On the cathodic scan, the reduction
peak located at ꢀ 1408 mV and the oxidation peak displayed at ꢀ 1501
mV were attributed to the redox pair Co (II)/Co (I) [81]. The rest of the
peaks correspond to oxidation and reduction at the ligand center (see
Fig. 20, supplementary information).
3.7. Electrochemical: Cyclic voltammetry study
The electrochemical properties of free ligand L1 and its complexes of
copper, zinc and cobalt were investigated. The redox potentials, ΔEp
(difference between the anodic peak potential and the cathodic peak
potential) and the Ipa/Ipc ratios (Ipa = anodic peak current, Ipc = peak
current cathode) obtained are classified in Table 7.
The electrochemical response of the Zn (II) complex shown on the
cyclic voltammogram (Fig. 21, see supplementary information) showed
on the cathodic scan two oxidation–reduction processes and on the
anodic scan an oxidation peak without a cathodic response. A reduction
wave was observed within the range of the studied potential attributed
to the reduction of the Zn (II) metal ion to Zn (I). The Ipa/Ipc ratio of
0.46 far from unity indicated irreversible behavior.
The voltammogram of the free ligand L1 (Fig. 18) was registered on a
tension field going of ꢀ 2000 and +1500 mV/SCE at a scanning rate v =
100 mV/s. The ligand L1 present one peak of reduction at ꢀ 551 mV/SCE
and tow oxidation peaks at ꢀ 495 mV/SCE and 93 mV/SCE. The cathodic
peak corresponds to the reduction of imine group and the low peaks
anodic were attributed to the oxidation of the imine and phenolic
groups.
The voltammogram obtained for the CuL1 complex (Fig. 19), in the
anodic direction, displayed three oxidation peaks pa (I), (pa (II) and pa
Fig. 17. Proposed structures for L1 complexes.
8

D. Belkhir-Talbi et al.
Inorganic Chemistry Communications 127 (2021) 108509
Table 7
Cyclic voltametry data for Ligand L1 complexes.
Compound
Epc [V]
Ipc (mA)
Epa [V]
Ipa (mA)
ΔEP[V]
E1/2(V)
ipa/ipc
L1
ꢀ 0.551
ꢀ 0.044
ꢀ 0.495
0.093
0.059
0.037
0.041
0.032
0.012
0.060
0.039
0.025
0.092
0.053
0.066
0.056
ꢀ 0.523
1.34
CuL1
CoL1
ZnL1
0.167
ꢀ 0.559
ꢀ 1.289
ꢀ 0.024
ꢀ 0.175
ꢀ 0.449
ꢀ 1.479
0.210
0.110
ꢀ 0.504
ꢀ 1.384
1.33
0.07
ꢀ 0.190
ꢀ 0.585
ꢀ 1.408
ꢀ 0.025
ꢀ 0.086
ꢀ 0.376
ꢀ 1.501
0.604
0.209
ꢀ 0.480
ꢀ 1.454
1.56
0.29
ꢀ 0.093
ꢀ 0.640
ꢀ 1.169
ꢀ 0.033
ꢀ 0.145
ꢀ 0.430
ꢀ 1.057
0.210
0.112
ꢀ 0.535
ꢀ 1.113
1.60
0.46
Table 8
Range of diameters inhibition zones (mm) for the ligand L1, the complexes and
the reference antibiotic (Gentamicin 10 g).
L
1
1,0
0,8
μ
Bacterial
Diameters of inhibition zones (in mm)
L1
CuL1
CoL1
ZnL1
ATB
0,6
S. Aureus
E. Coli
13
þþ
11
þ
6
17
17
þþ
11
þ
20
0,4
-
þþ
22
6
6
þ
9
-
0,2
-
þþþ
18
p (I)
p (II)
a
P. Aeruginosa
10
þ
10
þ
9
a
þ
þþ
0,0
p (I)
c
The sensitivity of microorganisms, toward tested compounds, was identified in
the following manner: no activity (ꢀ ≤ 8 mm), slightly active (8 < + < 16 mm),
moderately active (16 ≤ ++ ≤ 20 mm) and highly active (+++ > 20 mm). ATB:
antibiotic
-0,2
-0,4
-0,6
-2,0
-1,5
-1,0
-0,5
E(V)
0,0
0,5
1,0
1,5
indicated a moderate activity of L1 with respect to the three bacteria.
This activity varied in the case of complexes according to the nature of
the metal. All the complexes except that of copper showed good activ-
ities against the S. Aureus and those of cobalt and zinc had very inter-
esting diameters of inhibition. Copper and cobalt complexes were
inactive against E.Coli, but in the case of zinc, the activity was the same
as the ligand L1. The activity of the copper, cobalt and zinc complexes
against P. Aerugenosa remains the same as that of the ligand L1. The
results also showed that the complexes had an enhanced activity
compared to the ligand itself. This is especially shown against S.Aureus.
Finally the metal activity decreases in the order Zn > Co > Cu.
Fig. 18. Cyclic voltamogramm of L1 (10ꢀ 3 M) in DMSO (100 mV sꢀ 1 scan rate).
The arrows show the peak positions.
0,2
CuL
1
0,1
p (III)
p (I)
a
a
p (II)
3.9. Antioxidant activity
a
0,0
-0,1
-0,2
-0,3
The antioxidant activity of the ligand L1 and its complexes was
measured in terms of their hydrogen donating or radical scavenging
ability by UV–visible spectrophotometer using the stable 2,2-diphenyl-
1-picrylhydrazyl radical (DPPH.). Fig. 23 shows the variation of absor-
bance versus concentration of the ligand L1 and the different complexes
(Fig. 23a, see supplementary information) and of the standard ascorbic
acid (Fig. 23b, see supplementary information). The lower the absor-
bance of the reaction mixture indicates the higher free radical scav-
enging activity (RSA). The capability to scavenge the DPPH (as % of
inhibition) was calculated using Eq. (1).
p (I)
c
p (II)
c
-2,0
-1,5
-1,0
-0,5
E(V)
0,0
0,5
1,0
1,5
The ligand L1 exhibited higher scavenging activity than its corre-
sponding complexes. It is very interesting to note that RSA of the syn-
thesized compound L1 is greater than the one of ascorbic acid
(standard). This high activity was probably due to the presence of the
OH group. The decrease of the antioxidant activity of the complexes is
due to the low oxidation potential of the metal ions, which can easily
release an electron to participate in the reduction of DPPH. Minimum
inhibitory concentrations IC50 of the tested compounds are illustrated in
Fig. 24.
Fig. 19. Cyclic voltamogramm of CuL1 (10ꢀ 3 M) in DMSO (100 mV sꢀ 1 scan
rate). The arrows show the peak positions.
3.8. Antimicrobial activity
A comparative evaluation of the antimicrobial activity of L1 and the
synthesized complexes was carried out against one Gram-positive
(S. Aureus) bacteria and two Gram-negative bacteria (E. Coli and
P. Aeruginosa). The results obtained were presented in Table 8 and
illustrated in Fig. 22 (see supplementary information). The result
9

D. Belkhir-Talbi et al.
Inorganic Chemistry Communications 127 (2021) 108509
Table 9
ADMET properties of synthesized ligands (L1a, L1b, L2) and metallic complexes
(CuL1, CoL1 and ZnL1) predicted by admetSAR and SwissADME web servers.
Property
L1a
L1b
L2
CuL1
CoL1
ZnL1
AMEST
Non
Non
Weak
Non
Non
Yes
Non
Non
Weak
Yes
Non
Non
Weak
Non
Non
Non
Yes
Non
Non
Weak
Non
Non
Non
Non
Non
+
Non
Non
Weak
Non
Non
Non
Non
Non
+
Non
Non
Weak
Non
Non
Non
Non
Non
+
Carcinogenic
hERG
PG Inhibitor
CYP2C19
CYP2D6
CYP3A4
CYP2C9
BBB
Yes
Non
Non
Yes
Non
Non
+
Yes
–
+
–
+
HIA
+
+
+
+
Caco-2
poor
5.19
78.83
Yes
poor
4.76
67.43
Yes
poor
3.55
94.56
Yes
poor
3.83
81.31
Yes
poor
3.52
81.31
Yes
poor
3.52
81.31
Yes
Log P
TPSA (Å2)
Verber rule
salts. This result was established using complementary techniques: ab-
sorption and emission spectrophotometry, as well as semi-empirical
calculations.
Fig. 24. IC50 (mg/mL) values of the antioxidant compounds tested.
In view of the high affinity of the ligand for d-metal cations, this
work could lead to the design of new photoactive sensors potentially
useful for chemical or biomedical analysis.
4. ADMET and drug-likeness analysis
In silico ADMET analysis was performed to verify if the synthesized
complexes and ligands present any toxicity through the human body.
Table 9 reports predicted pharmacological and ADMET properties of
synthesized ligands and metallic complexes. Analysis of results showed
that studied compounds were predicted as non-AMES-toxic (AMEST),
and non-carcinogenic. It is worth noting that’s AMES toxicity represents
an excellent measure of bacterial mutagenicity. In addition, all com-
plexes were predicted as weak Human Ether-a-go-go-Related Gene
(hERG) blockers. It is important to remember that hERG potassium
channel plays a central role in regulating cardiac excitability and
maintenance of normal cardiac rhythm. Thus, hERG channel blockade
can cause cardiac arrythmia. Additionally, most synthesized compounds
are a non-Permeability-glycoprotein (PG) and non-Cytochrome P450
inhibitors for most isoforms such as CYP2C19, CYP2D6, CYP3A4 and
CYP2C9. The cytochrome P450 proteins play a vital role in metabolism
and an inhibition of its isoforms would lead to drug interactions, accu-
mulation and toxicity [82]. Interestingly, most of the synthesized com-
pounds showed positive values of Blood-brain barrier penetration (BBB)
[83].
We have prepared a series of three metal complexes of N,N’-di(4-
bromophenyl)-4-hydroxycoumarin-3-carboximidamide L1. These com-
plexes were characterized using instrumental techniques and confirmed
the complexation and the presence of metals. Furthermore, they were
evaluated as antioxidant and antimicrobial agents showing, for the
complexes, a reduced antioxidant power and an improved antimicrobial
activity compared to L1. It worth of note that among of the three com-
plexes, those with cobalt and zinc showed the best antimicrobial
activity.
These results were supported by theoretical studies. ADMET and
drug likeness analyses showed that most compounds have satisfactory
pharmacokinetics and drug like parameters values.
Author agreement
All authors have seen the final version of the manuscript and
approved the same before submission.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Additionally, all compounds demonstrated good pharmacokinetic
profile in human intestinal absorption (HIA), which could allow them to
reach the site of action. All synthesized compounds showed poor
penetration to colorectal carcinoma permeability (Caco-2). The octa-
nol–water partition coefficient (Log p = -0,4 – 5,6), which usually
quantified molecular lipophilicity, and Total Polar Surface Area (TPSA
≤ 160), a good indicator of the bioavailability of the drug molecule,
were in the acceptable ranges. Therefore, all synthesized compounds
pass the verber rule defined as TPSA and number of rotatable bond less
than 140 Å and 10, respectively [84].
Acknowledgments
Thanks are due to University of Aveiro and FCT/MEC for the finan-
cial support of the QOPNA research unit (FCTUID/QUI/00062/2013)
through national founds and, where applicable, co-financed by the
FEDER, within the PT2020 Partnership Agreement, and to the Portu-
guese NMR Network. We would like to thank the Ministry of Higher
Education and Scientific Research of Algeria for awarding an exchange
scholarship.
5. Conclusion
In this work, N,N’-di(4-bromophenyl)-4-hydroxycoumarin-3-car-
boximidamide L1 and N-(4-Bromophenyl)-4-hydroxycoumarin-3-car-
bothioamide L2 were synthesized and structurally characterized by FT-
IR, mass spectrometry, elemental analyses and NMR spectroscopy. It
was shown that the probes N, N’-di(4-bromophenyl)-4-hydrox-
ycoumarin-3-carboximidamide L1 and N-(4-Bromophenyl)-4-hydrox-
ycoumarin-3-carbothioamide L2 are sensitive to the presence of metal
cations. The pectroscopic properties of these dyes allowed us to show
that strong interactions take place between L1 (and L2) and d-metal
cations in DMSO solutions, at very low concentrations of product and
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.inoche.2021.108509.
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