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Synthesis and radical scavenging activity of new phenolic

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DOI: 10.1016/j.molstruc.2021.131546

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 Journal of Molecular Structure 1249 (2022) 131546

Contents lists available at ScienceDirect

Journal of Molecular Structure

journal homepage: www.elsevier.com/locate/molstr

Synthesis and radical scavenging activity of new phenolic

hydrazone/hydrazide derivatives: Experimental and theoretical studies
Houssem Boulebd a,∗, Yasmine Zine a, Imene Amine Khodja a, Arif Mermer b, Adem Demir c,
Abdelmadjid Debache a
a
Laboratory of Synthesis of Molecules with Biological Interest, University of Frères Mentouri Constantine 1, Constantine, Algeria
b
University of Health Sciences Turkey, Experimental Medicine Research and Application Center, Uskudar, 34662, Istanbul, Turkey
c
Recep Tayyip Erdogan University, Department of Chemistry, 53100, Rize, Turkey

a r t i c l e i n f o a b s t r a c t

Article history: Hydrazone and hydrazone-hydrazide-based compounds represent important classes of compounds that
Received 28 June 2021 continue to attract increasing interest due to their diverse pharmacological actions. In the present study,
Revised 27 August 2021
a series of new phenolic hydrazone/hydrazide derivatives (1–10) have been successfully synthesized and
Accepted 20 September 2021
evaluated for their antiradical activity using experimental and theoretical methods. The hydrazones 1–5
Available online 21 September 2021
were found to be significantly more reactive than their analogs hydrazone-hydrazide 6–10 via the main
Keywords: antiradical mechanism as well as toward DPPH and ABTS radicals. The NH group of the hydrazone is
Hydrazone more reactive than the NH group of the hydrazide and the phenolic OH groups. The carbonyl group of
Hydrazide the hydrazide plays a negative role in the antiradical activity of such molecules. Among the studied com-
Antioxidant activity pounds, compound 4 was found to be the best radical scavenger with SC50 values (concentration causing
DFT calculations 50% of DPPH or ABST scavenging) comparable to those of ascorbic acid and Trolox. These findings provide
Radical scavenger
insights on the structure-activity relationship of hydrazone and hydrazone-hydrazide type compounds, as
well as open up new perspectives for the development of novel potent antioxidants.
© 2021 Elsevier B.V. All rights reserved.

1. Introduction
Hydrazones belong to a class of organic compounds with a
structure of type R1 HC=NNH2 . These compounds contain two nu-
cleophilic nitrogen atoms (imine and amino) and a strongly po-
larized C = N double bond. The reaction of a hydrazine derivative
with a carbonyl molecule [1] is the most frequent method for ob-
taining the hydrazone group; however, it may also be obtained by
combining an aryl diazonium salt with β -keto ester or an acid (re-
action of Japp-Klingemann) [2]. Compounds bearing the hydrazone
functional group exert various biological properties such as anti-
cancer [3], antimicrobial [4], anticonvulsant [5], antitumor [6], an-
tidepressant [7], anti-inflammatory [8], and antiviral [9]. Further-
more, due to the lability of the NH proton of the hydrazone func-
tion and the capacity of the azomethine group as well as the phe-
nolic moiety to stabilize the generated radical through resonance,
molecules containing the hydrazone group are potent radical scav-
engers [10–14].
Hydrazides are distinguished from hydrazones by the presence
of a carbonyl group and the absence of the imine. They have the
∗
Corresponding author.
E-mail address: boulebd.houssem@umc.edu.dz (H. Boulebd).
general structure R1 (C = O)-NH–NH2 and are formed via the con-
densation of hydrazine with different acyl derivatives such as es-
ters [15], cyclic anhydrides [16], and acyl halides [17]. Anthelmintic
activity [18], analgesic activity [19], anti-inflammatory activity [20],
antiviral activity [21], antidiabetic activity [22], and antibacterial
activity[23] are among the biological actions of molecules derived
from hydrazide. Hydrazide-based compounds have been exten-
sively studied in terms of antioxidant activity, and numerous in-
vestigations have indicated that molecules containing this pharma-
cophore are potent antioxidants [24–27].
Condensation between the hydrazide and an aldehyde or a ke-
tone leads to the hybrid group hydrazone-hydrazide (R1 (C = O)-
NH–N=CHR2 ) which bearing both hydrazone and hydrazide func-
tions. The compounds carrying this scaffold have demonstrated in-
teresting biological activities, in particular antimicrobial [28], an-
ticancer [29], anti-inflammatory [30], antidiabetic [31], antidepres-
sant [7], and anti-tuberculosis activities [32]. Several studies have
also been conducted on the antioxidant activity of these com-
pounds, and the hydrazone-hydrazide group has been identified to
be a suitable scaffold for antiradical activity [33–35].
Despite the biological relevance of the scaffolds mentioned, par-
ticularly their antioxidant effects, few studies have focused on
their structure-activity relationship. Furthermore, no experimen-

https://doi.org/10.1016/j.molstruc.2021.131546
0022-2860/© 2021 Elsevier B.V. All rights reserved.
H. Boulebd, Y. Zine, I.A. Khodja et al.
Scheme 1. Synthetic route of compounds 1–10. Reagent and conditions: (a) EtOH, RT, 12 h, acetic acid.
tal or computational investigation comparing their radical scav-
enging capacities has been done. The purpose of this paper is to
explore the radical scavenging activity of a series of phenolic hy-
drazone and hydrazone-hydrazide derivatives in order to (1) de-
velop new potent antiradical compounds, (2) compare the anti-
radical activity of hydrazone and hydrazone-hydrazide derivatives,
and (3) get further insights on the structure-activity relationship
for this type of molecule. To achieve these goals, we have synthe-
sized two series of phenolic compounds derived from hydrazone
1–5 and hydrazone-hydrazide 6–10 bearing identical substituents
(Scheme 1). The antiradical activity of these compounds was then
examined using a computational approach by calculating the ther-
modynamic descriptors of the main antiradical mechanisms. To
support our results, antiradical activity was also carried out in vitro
by DPPH and ABTS assays and compared to the theoretical predic-
tions.
2. Experimental section
2.1. Materials and instrumentation
Phenolic aldehyde derivatives (4-hydroxybenzaldehyde,
5–chloro-2-hydroxybenzaldehyde, 4–hydroxy-3,5-dimethoxy
benzaldehyde, 2–hydroxy-1-naphthaldehyde, and 4–hydroxy-
3-methoxybenzaldehyde) and 4-chlorobenzohydrazide and 4-
chlorophenyl hydrazine were purchased from Alfa Aesar (Kandel,
Germany) and used without further purification. 1 H and 13 C NMR
spectra were recorded in CDCl3 or DMSO–d6 on a Bruker Avance
DPX250 spectrometer. Chemical shift (δ ) values are given in ppm
(parts per million). The peak patterns are indicated as follows: s,
singlet; d, doublet; m, multiplet. The coupling constants (J) are
reported in hertz (Hz). Melting points were determined on a Kofler
melting point apparatus and are uncorrected. Commercial grade
2
Journal of Molecular Structure 1249 (2022) 131546
reagents were used as supplied (Alfa Aesar). The mass spectra
were obtained on a Quattro EI-MS (70 eV) Instrument.
2.2. General procedure for the synthesis of compounds 1–10
In a 25-mL Erlenmeyer flask, 1 mmol of 4-chloroben
zohydrazide or 4-chlorophenyl hydrazine, 1 mmol of aldehyde
derivatives (4-hydroxybenzaldehyde, 5–chloro-2-hydroxyben
zaldehyde, 4–hydroxy-3,5-dimethoxybenzaldehyde, 2–hydroxy-
1-naphthaldehyde, or 4–hydroxy-3-methoxybenzaldehyde), and
3 drops of acetic acid were dissolved in 5 ml of ethanol. The
reaction mixture was stirred for 12 h at room temperature. After
completion of the reaction monitored using TLC, the residue
obtained was filtered, washed with ethanol, and dried on air, to
afford the pure product.
(E)−4-((2-(4-chlorophenyl)hydrazono)methyl)phenol (1). Yield
93%: (yellow powder). Mp = 158–160 °C. 1 H NMR (250 MHz,
DMSO–d6 ): δ 10.22 (s, 1H, NHHyd ), 7.79 (s, 1H, CHHyd ), 7.60 (d,
J = 8.46 Hz, 2H, HArm ), 7.22 (d, J = 8.73 Hz, 2H, HArm ), 7.02 (d,
J = 8.73 Hz, 2H, HArm ), 6.68 (d, J = 8.46 Hz, 2H, HArm ). 13 C NMR
(62.5 MHz, DMSO–d6) δ 157.9, 144.6, 138.0, 128.9, 127.4, 126.6,
121.3, 119.1, 115.6, 113.1. ESI MS m/z (%): Calcd. C13 H9 ClN2 O [M-2]+
244.69, found 244.85 (100%).
(E)−4–chloro-2-((2-(4-chlorophenyl)hydrazono)methyl)phenol (2).
Yield 73%: (yellow powder). Mp = 182–184 °C. 1 H NMR (250 MHz,
DMSO–d6 ): δ 10.65 (s, 1H, NHHyd ), 10.42 (s, 1H, OH), 8.10 (s,
1H, CHHyd ), 7.68 (s, 1H, HArm ), 7.29–7.25 (m, 2H, HArm ), 7.22–
7.16 (m, 1H, HArm ), 7.04–7.00 (m, 2H, HArm ), 6.93–6.87 (m, 1H,
HArm ). 13 C NMR (62.5 MHz, DMSO–d6) δ 154.1, 143.8, 134.0, 129.1,
128.7, 124.9, 123.2, 123.0, 122.3, 117.7, 113.4. ESI MS m/z (%): Calcd.
C13 H10 Cl2 N2 O [M-2]+ 278.02, found 278.80 (100%).
(E)−4-((2-(4-chlorophenyl)hydrazono)methyl)−2,6-
dimethoxyphenol (3). Yield 62%: (yellow powder). Mp = 170–
172 °C. 1 H NMR (250 MHz, DMSO–d6 ): δ 10.31 (s, 1H, NHHyd ), 8.69
H. Boulebd, Y. Zine, I.A. Khodja et al.
(s, 1H, OH), 7.77 (s, 1H, CHHyd ), 7.23 (d, J = 8.81 Hz, 2H, HArm ),
7.05 (d, J = 8.81 Hz, 2H, HArm ), 6.92 (s, 2H, HArm ), 3.81 (s, 6H,
OMe). 13 C NMR (62.5 MHz, DMSO–d6 ) δ 148.2, 144.5, 138.2, 136.3,
128.9, 126.0, 121.4, 118.9, 113.2, 103.3, 56.0. ESI MS m/z (%): Calcd.
C15 H15 ClN2 O3 [M-2]+ 304.74, found 304.91 (100%).
(E)−2-((2-(4-chlorophenyl)hydrazono)methyl)naphthalen-1-ol (4).
Yield 95%: (yellow powder). Mp = 226–228 °C 1 H NMR (250 MHz,
DMSO–d6 /CDCl3 ): δ 12.11 (s, 1H, NHHyd ), 10.31 (s, 1H, OH), 8.92
(s, 1H, CHHyd ), 8.03 (d, J = 8.60 Hz, 1H, HArm ), 7.83–7.65 (m, 2H,
HArm ), 7.49–7.43 (m, 1H, HArm ), 7.30–7.26 (m, 1H, HArm ), 7.19–7.11
(m, 3H, HArm ), 6.90 (d, J = 8.80 Hz, 2H, HArm ). 13 C NMR (62.5 MHz,
DMSO–d6 /CDCl3 ) δ 155.9, 142.4, 137.7, 130.8, 130.1, 128.6, 128.4,
127.6, 126.5, 123.1, 122.7, 119.7, 118.2, 112.6, 108.9. ESI MS m/z (%):
Calcd. C17 H13 ClN2 O [M-2]+ 294.75, found 294.83 (100%).
(E)−4-((2-(4-chlorophenyl)hydrazono)methyl)−2-methoxyphenol
(5). Yield 71%: (white powder). Mp = 130–132 °C. 1 H NMR
(250 MHz, DMSO–d6 ): δ 10.25 (s, 1H, NHHyd ), 9.30 (s, 1H, OH),
7.78 (s, 1H, CHHyd ), 7.22–7.17 (m, 3H, HArm ), 7.09–7.00 (m, 3H,
HArm ), 6.76 (d, J = 9.47 Hz, 1H, HArm ), 3.84 (s, 3H, OMe). 13 C
NMR (62.5 MHz, DMSO–d6 ) δ 148.0, 147.4, 144.6, 138.1, 128.9,
127.1, 121.3, 120.0, 115.5, 113.2, 108.5, 55.6. ESI MS m/z (%): Calcd.
C14 H13 ClN2 O2 [M-2]+ 274.05, found 274.88 (100%).
(E)−4–chloro-N’-(4-hydroxybenzylidene)benzohydrazide (6). Yield
61%: (white powder). Mp > 260 °C. 1 H NMR (250 MHz, DMSO–
d6 ): δ 11.68 (s, 1H, NHHyd ), 8.33 (s, 1H, CHHyd ), 7.90 (d, J = 8.52 Hz,
2H, HArm ), 7.56 (d, J = 8.39 Hz, 2H, HArm ), 6.82 (d, J = 8.52 Hz, 2H,
HArm ), 6.78 (d, J = 8.39 Hz, 2H, HArm ). 13 C NMR (62.5 MHz, DMSO–
d6) δ 162.2, 159.7, 148.7, 136.6, 132.4, 129.7, 129.2, 128.7, 125.3,
119.3, 115.9. ESI MS m/z (%): Calcd. C14 H11 ClN2 O2 [M-2]+ 272.03,
found 272.92 (100%).
(E)−4–chloro-N’-(5–chloro-2-hydroxybenzylidene)benzohydrazide
(7). Yield 86%: (white powder). Yield 73%: (yellow powder). Mp
> 260 °C. 1 H NMR (250 MHz, DMSO–d6 ): δ 12.33 (s, 1H, NHHyd ),
11.32 (s, 1H, OH), 8.96 (s, 1H, CHHyd ), 7.95 (d, J = 8.39 Hz, 2H,
HArm ), 7.69 (s, 1H, HArm ), 7.65 (d, J = 8.39 Hz, 2H, HArm ), 7.39–7.26
(m, 1H, HArm ), 6.98–6.94 (m, 1H, HArm ). 13 C NMR (62.5 MHz,
DMSO–d6) δ 161.9, 156.0, 145.9, 136.9, 131.5, 130.9, 129.6, 128.7,
127.5, 123.0, 120.7, 118.3. ESI MS m/z (%): Calcd. C14 H10 Cl2 N2 O
[M-2]+ 306.01, found 306.66 (100%).
(E)−4–chloro-N’-(4–hydroxy-3,5-dimethoxybenzylidene)benzohy
drazide (8). Yield 83%: (white powder). Mp = 158–160 °C. 1 H NMR
(250 MHz, DMSO–d6/CDCl3 ): δ 11.31 (s, 1H, NHHyd ), 10.96 (s, 1H,
OH), 8.16 (s, 1H, CHHyd ), 7.78 (d, J = 8.35 Hz, 2H, HArm ), 7.28 (d,
J = 8.27 Hz, 2H, HArm ), 6.87 (s, 2H, HArm ), 2.77 (s, 6H, OMe). 13 C
NMR (62.5 MHz, DMSO–d6/CDCl3 ) δ 163.2, 149.3, 147.3, 137.4,
131.8, 129.1, 128.3, 124.7, 119.0, 104.5, 56.1. ESI MS m/z (%): Calcd.
C16 H15 ClN2 O4 [M-2]+ 332.07, found 332.77 (100%).
(E)−4–chloro-N’-((1-hydroxynaphthalen-2-
yl)methylene)benzohydrazide (9). Yield 84%: (yellow powder).
Mp > 260 °C. 1 H NMR (250 MHz, DMSO–d6): δ 12.74 (s, 1H,
NHHyd ), 12.29 (s, 1H, OH), 9.79 (s, 1H, CHHyd ), 8.56–8.40 (m, 1H,
HArm ), 8.00–7.93 (m, 4H, HArm ), 7.70–7.64 (m, 3H, HArm ), 7.41–7.38
(m, 2H, HArm ). 13 C NMR (62.5 MHz, DMSO–d6) δ 161.5, 158.1,
147.2, 137.0, 132.9, 131.7, 131.4, 129.6, 128.8, 127.9, 123.6, 120.7,
118.9, 108.6. ESI MS m/z (%): Calcd. C18 H13 ClN2 O2 [M-2]+ 322.06,
found 322.90 (100%).
(E)−4–chloro-N’-(4–hydroxy-3-methoxybenzylidene)benzohydrazide
(10). Yield 80%: (white powder). Mp > 260 °C. 1 H NMR (250 MHz,
DMSO–d6 ): δ 11.79 (s, 1H, NHHyd ), 9.65 (s, 1H, OH), 8.33 (s, 1H,
CHHyd ), 7.93 (d, J = 8.36 Hz, 2H, HArm ), 7.61 (d, J = 8.27 Hz,
2H, HArm ), 7.33 (s, 1H, HArm ), 7.10 (d, J = 7.97 Hz, 1H, HArm ),
6.85 (d, J = 8.03 Hz, 1H, HArm ), 3.79 (s, 3H, OMe). 13 C NMR
(62.5 MHz, DMSO–d6 ) δ 161.9, 149.1, 148.7, 148.1, 136.5, 132.3,
129.5, 128.6, 125.6, 122.4, 115.4, 108.8, 55.5. ESI MS m/z (%): Calcd.
C15 H13 ClN2 O3 [M-2]+ 302.06, found 302.81 (100%).
3
Journal of Molecular Structure 1249 (2022) 131546
2.3. Computational details
The antiradical action can occur via several different mecha-
nisms, including hydrogen atom transfer (HAT), sequential electron
transfer proton transfer (SETPT), and sequential proton loss elec-
tron transfer (SPLET) [14,36–39]. All these mechanisms involve the
reaction of OH/NH bond of antioxidant with free-radical according
to the following reactions:
HAT mechanism
AntioxH + R. → Antiox. + RH
SETPT mechanism
AntioxH + R. → AntioxH+. + R− → Antiox. + RH
SPLET mechanism
AntioxH → Antiox− + H+ ; Antiox− + R. → Antiox. + RH
These mechanisms could be characterized by the following
thermodynamic descriptors: bond dissociation enthalpy (BDE), ion-
ization potential (IP), proton dissociation enthalpy (PDE), proton
affinity (PA), and electron transfer enthalpy (ETE), which could be
calculated as reported in our previous work [40–43].
DFT (density functional theory) calculations were performed to
determine the geometry and frequencies of all the species involved
in the mentioned mechanisms using Gaussian 09 software [44].
M06–2X functional [45] and the 6–311++G(d,p) basis set were em-
ployed for all calculations. Several studies have confirmed the reli-
ability of the DFT/M06–2X method for thermodynamic calculations
[46,47]. The solvation effects of polar and non-polar environments
(mimicked by water and pentyl ethanoate, respectively) were ap-
proximated using solvation model density (SMD) [48].
2.4. In vitro antioxidant evaluation
2.4.1. DPPH free radical scavenging assay
DPPH (1,1-diphenyl-2-picrylhydrazyl) free radical scavenging as-
say was performed under the following protocol [49]. 0.15 mL sam-
ple of different concentrations was mixed with 0.15 mL of freshly
prepared DPPH (0.1 mM) in methanol and incubated for 30 min
in the dark. The violet color of DPPH solution disappeared when
it was reduced by test samples. The decrease in absorbance was
recorded by multiplate reader (Spectra max-384, USA) at 517 nm.
Results were shown in terms of SC50 values means the minimum
concentration of compounds required to scavenge 50% of DPPH
radicals. All test reactions were done in triplicate.
2.4.2. ABTS radical scavenging assay
The (ABTS+ ) 2,2 -azino-bis(3-ethylbenzothiazoline-6-sulphonic
acid) free radical cation scavenging ability protocol of the com-
pounds was performed by the standard method [49]. ABTS solution
and potassium persulfate solution were mixed in equal quantities
and allowing to the oxidation reaction of ABTS by K2 S2 O8 at room
temperature in the dark to form the ABTS•+ radical. This solution
was then diluted with methanol to obtain an ABTS•+ radical solu-
tion which has an optical density of 0.700 ± 0.01 at 734 nm using
a spectrophotometer. 100 microliters of sample were allowed to re-
act with 300 μL of the ABTS•+ radical solution and the absorbance
was measured at 734 nm after 30 min using a spectrophotome-
ter. The ABTS•+ scavenging capacity of the samples was compared
with that of Trolox and ascorbic acid and reported with SC50 val-
ues (μg sample/ mL).
3. Results and discussion
3.1. Synthesis
The synthesis of the target hydrazone/hydrazide deriva-
tives (1–10) was carried out as outlined in Scheme 1. The
H. Boulebd, Y. Zine, I.A. Khodja et al.
Fig. 1. Optimized molecular geometries of compounds 1–10 computed in the gas phase.
reaction of an equimolar quantity of 4-chlorophenylhydrazine
or 4-chlorobenzohydrazide and benzaldehyde derivatives
(4-hydroxybenzaldehyde, 5–chloro-2-hydroxybenzaldehyde,
4–hydroxy-3,5-dimethoxybenzaldehyde, 2–hydroxy-1-naphthal
dehyde, and 4–hydroxy-3-methoxybenzaldehyde) in the pres-
ence of acetic acid as catalyst gives the corresponding hydra-
zone/hydrazide compounds in good to excellent yields (61–95%).
The molecular structure of the synthesized compounds was
confirmed by spectroscopic methods including 1 H and 13 C NMR
and mass spectrometry. For example, the 1 H NMR spectrum of
compound 1 shows, among others, a broad singlet assigned to the
proton NH of the hydrazone group at 10.22 ppm and a singlet at
7.79 ppm assigned to the proton of CH of the hydrazone group. It
can be observed from the 1 H NMR of compound 6, in particular
the presence of a broad singlet assigned to the proton NH of the
hydrazide group at 11.68 ppm and a singlet at 8.33 ppm assigned
to the proton of CH of the hydrazide group. These data confirm
the formation of hydrazone and hydrazone-hydrazide groups.
3.2. In silico study of the antiradical activity
3.2.1. Geometry optimization
Since the reactivity of the OH/NH bonds is significantly in-
fluenced by the surrounding environment, molecular geometry is
critical for investigating the antiradical activity of the synthesized
hydrazone/hydrazide derivatives. Thus, geometry optimization and
conformation analysis were carried out for all the studied com-
pounds. Based on prior research, only the E configuration of the
hydrazone function was taken into account, whereas all potential
conformers for the hydrazide group were investigated [14,50–52].
Fig. 1 shows the most stable geometry of compounds 1–10 deter-
mined at the M06–2X/6–311++G(d,p) level in the gas phase. As
can be seen, all the hydrazone derivatives are nearly planar, except
for compound 4 which slightly deviates from planarity by 19.74°
On the other hand, all hydrazone-hydrazide derivatives (6–10) are
non-planar molecules with torsion angles ranging from 28.15° to
29.95° These results indicate that the hydrazone derivatives may
4
Journal of Molecular Structure 1249 (2022) 131546
exhibit higher antiradical activity than their hydrazone-hydrazide
analogs [53]. The optimized molecular geometry of compound 6
is in good agreement with that derived from the single crystal
diffraction analysis reported in previous work [54].
3.2.2. Highest occupied molecular orbitals analysis
The highest occupied molecular orbital (HOMO) is the most
easily donated electron orbital. This orbital characterizes the
electron-donating ability of a molecule and also indicates the most
favored sites for free radical attack [40,42,55]. The distribution and
energy of the HOMOs of compounds 1–10 computed at M06–
2X/6–311++G(d,p) level in the gas phase are depicted in Fig. 2.
As shown, the HOMOs of all the investigated hydrazones (1–5)
are almost distributed over the whole molecular structure, which
explains the overall planarity of these molecules. On the other
hand, the HOMOs of hydrazone-hydrazide derivatives (6–10) are
mainly localized on the hydrazone-hydrazide and phenolic moi-
eties without any contribution from the chlorobenzene ring. This
indicates that the presence of carbonyl prevents electron delocal-
ization, which explains the non-planarity of these compounds.
Analysis of HOMO energies reveals that the hydrazones 1–
5 present significantly higher HOMO energy (–6.74 to –6.46 eV)
than the hydrazone-hydrazide analogs 6–10 (–7.76 to –7.23 eV).
This suggests that the electron-donating ability of compounds 1–
5 should be higher than that of compounds 6–10.
3.2.3. Investigation of the antiradical mechanisms
The main antiradical mechanisms i.e. HAT, SETPT, and SPLET
have been investigated for compounds 1–10 by computing their re-
lated thermodynamic descriptors (BDE, IP, PDE, PA, and ETE). The
obtained data are reported in Fig. 3 and Table 1. In terms of the
HAT mechanism, the estimated BDE values of all the NH bonds of
the hydrazones (1–5) are substantially lower than those of the OH
bonds (Fig. 3). For example, the BDE of the NH of compound 1
is approximately 5 kcal/mol lower than that of the OH. These re-
sults suggest that the NH group is more reactive via HAT mech-
anism than the phenolic OH group. On the other hand, reverse
H. Boulebd, Y. Zine, I.A. Khodja et al. Journal of Molecular Structure 1249 (2022) 131546

Fig. 2. Highest occupied molecular orbitals (HOMOs) of compounds 1–10 in the gas phase.

that of the OH bond. Thus, the presence of the carbonyl group

negatively influences the radical scavenging activity of the stud-
ied compound via the HAT mechanism. By comparison, the OH
bonds of hydrazones 1–5 have slightly lower BDE values (approx-
imately 1 to 3 kcal/mol) than their analogs hydrazone-hydrazides
6–10. This implies that the carbonyl group decreases also the an-
tiradical activity of the phenolic moiety. Based on BDE values, the
most potent antiradical agents are compound 4 for the hydrazones
and compound 8 for the hydrazone-hydrazides. It should be noted
that the BDEs of the hydrazones 1–5 are comparable to those of
some reported natural antioxidants such as thymol [56], umbellif-
erone [56], α -tocopherol [57], resveratrol [58], and ascorbic acid
[59], suggesting that these compounds are promising radical scav-
engers.
To explain the discrepancies in BDE values, the spin density dis-
tributions of the radical forms of compounds 1 and 6, as represen-
tative molecules, were computed. The spin density distribution of
the radicals 1-N• and 1-O• extends throughout the whole struc-
Fig. 3. BDE values of the NH/OH bonds of compounds 1–10.
ture of the molecule, as seen in Fig. 4, explaining their stability.
The radicals of compound 6 have a spin density distribution that
is restricted to the hydrazone-hydrazide and phenol moieties. This
Table 1
Thermodynamic indicators in kcal/mol of compounds 1–10 in the gas phase. indicates that the carbonyl group blocks the delocalization of spin
density and thus weakens the stability of the radicals. These find-
Compound Bond SETPT SPLET
ings are consistent with the calculated BDE values.
IP PDE PA ETE Concerning the SETPT mechanism, the IP values of hydrazones
1 NH 163.3 228.3 339.0 52.7 1–5 are also lower than those of hydrazone-hydrazide analogs 6–
OH 163.3 233.4 333.4 63.2 10 (Table 1). This can be observed, for example, with compound 1
2 NH 167.1 226.0 336.2 56.9 which has an IP value lower by 16.2 kcal/mol than that of com-
OH 167.1 230.0 330.2 66.9
pound 6. The sequence of the IPs for the hydrazones is 3 < 4 ≈ 5
3 NH 159.3 232.3 338.6 53.1
OH 159.3 235.2 340.0 54.4 < 1 < 2, and for the hydrazone-hydrazides is 8 < 9 ≈ 10 < 6 < 7.
4 NH 160.0 226.7 345.6 41.1 As observed with BDEs, the PDEs of the NH are lower than those of
OH 160.0 231.7 319.6 72.0 the OH for hydrazones 1–5, while the reverse was observed for the
5 NH 160.6 230.5 338.6 52.5 hydrazone-hydrazide derivatives 6–10. These findings further sug-
OH 160.6 236.5 338.7 58.4
6 NH 179.5 227.4 338.1 68.8
gest that the presence of the carbonyl group has a negative impact
OH 179.5 219.7 329.2 70.0 on the antiradical activity of the investigated compounds via the
7 NH 185.7 223.0 336.2 72.5 SETPT mechanism.
OH 185.7 212.6 321.9 76.4 As for the SPLET mechanism, PAs of the OH bonds of all
8 NH 173.0 233.3 337.6 68.7
the studied compounds are lower than those of the NH bonds
OH 173.0 222.0 331.9 63.1
9 NH 175.7 228.0 329.9 73.8 (Table 1). The PA of the OH bond of compound 4 is, for exam-
OH 175.7 228.3 330.9 73.1 ple, approximately 26 kcal/mol lower than the NH bond. This can
10 NH 174.2 231.9 337.9 68.2 be understood by the higher electronegativity of oxygen than that
OH 174.2 224.8 334.6 64.4 of nitrogen, which allows the oxygen atom to stabilize negative
charges better than the nitrogen atom. For the ETE values, the ob-
tained results are in line with BDEs and IPs. ETEs of the hydrazones
results were obtained for the hydrazone-hydrazide derivatives 6– 1–5 are lower than those of the hydrazone-hydrazides 6–10. This
10. For these compounds, the BDE of the NH bond is significantly indicates that, for the SPLET mechanism, the carbonyl group plays
higher than that of the OH bond. For example, the BDE of the also a negative role in the antiradical activity of the studied com-
NH bond of compound 6 is approximately 7 kcal/mol higher than pounds.

5
H. Boulebd, Y. Zine, I.A. Khodja et al. Journal of Molecular Structure 1249 (2022) 131546

Fig. 4. Spin density distribution of compounds 1 and 6.

Fig. 5. DPPH and ABTS radical scavenging activities of compounds 1–10.

Since the antiradical activity takes place in solution, the envi- reactive than their analogs hydrazone-hydrazide 6–10 in all the
ronment is a key element that might impact the radical scaveng- studied mechanisms and environments. The NH group decides the
ing processes. Thus, the effects of water and pentyl ethanoate (to antiradical activity of compounds 1–5 while the OH group seems
mimic polar and non-polar environments, respectively [60,61]) on to be more reactive for compounds 6–10. Compound 4 is the most
the antiradical mechanisms were also considered using the SMD promising molecule among all the studied compounds.
model [48]. The computed thermodynamic indicators in the stud-
ied environments for compounds 1–10 are presented in Table S1
3.3. In vitro study of the antiradical activity
and S2 in SI. As shown, the studied solvents did not significantly
influence the BDE values. In water and pentyl ethanoate, for exam-
In order to confirm the theoretical predictions, all of the pre-
ple, the BDE of the NH bond of compound 1 was only enhanced by
pared compounds were assayed for their DPPH and ABTS scaveng-
around 3 and 4 kcal/mol, respectively. This indicates that the stud-
ing activities (see Table S3 in SI and Fig. 5). As shown, all of the
ied environments do not affect the HAT mechanism, which is in
compounds exhibited good to moderate DPPH and ABTS radical
line with previous studies [42,62]. For IP, PA, and PDE, the obtained
scavenging abilities with SC50 values ranging from 13.32 ± 0.74
data for the gas phase were reduced dramatically in solution in the
to 234.92 ± 10.47 μg/mL. Among the compounds, compound 4
order water > pentyl ethanoate. For example, the IP of compound
including naphthalen-2-ol core linked to imine bond showed the
1 was decreased by about 66 and 43 kcal/mol in water and pentyl
highest activity for both DPPH and ABST radical scavenging. This
ethanoate, respectively. These findings suggest that polar solvents
molecule had radical scavenging activity as high as the well-
facilitate the SETPT and SPLET mechanisms, which is also in good
known antioxidant standards Trolox and ascorbic acid. Further,
agreement with previous studies [55,63]. It should be noted that
compound 3 having a trisubstituted phenyl ring linked to the
the solvent did not affect the reactivity of the compounds exam-
imine bond showed the second-highest activity with an SC50 value
ined, except for compounds 3 and 5, which had lower BDE values
of 17.08 ± 1.14 μg/mL for DPPH. When compared to the synthe-
for the OH bond in solution than the NH bond.
sized compounds, hydrazones 1–5 displayed better potency than
As may be established from the prior discussions, all of the in-
the hydrazone-hydrazides 6–10 (Fig. 5). For instance, compound
vestigated compounds are effective radical scavengers via the pri-
1 showed DPPH (SC50 =20.82 ± 1.04 μg/mL) and ABTS scavenging
mary antiradical pathways. Hydrazones 1–5 are significantly more
activities (SC50 =43.06 ± 2.14 μg/mL), respectively, whereas com-

6
H. Boulebd, Y. Zine, I.A. Khodja et al.
pound 6, which differs by the presence of a carbonyl group into
the structure, exhibited 7-fold less activity than the corresponding
compound (SC50 = 43.06 ± 2.14 for DPPH and 234.92 ± 10.47 for
ABTS). These results are in line with the theoretical predictions.
4. Conclusion
The antiradical activity of newly synthesized hydrazone and
hydrazone-hydrazide derivatives has been investigated using the-
oretical and experimental methods. The hydrazone derivatives
(1–5) were found to be better radical scavengers than their
analogs hydrazone-hydrazide (6–10). The structure-activity rela-
tionship analysis reveals that the NH group of the hydrazone is
more reactive than the NH group of the hydrazide as well as the
phenolic OH groups. The carbonyl group of the hydrazide plays a
negative role in the antiradical activity of this type of molecule.
Compound 4 was identified as the best radical scavenger among
the examined compounds, with activity comparable to that of
ascorbic acid and Trolox. These findings suggest that the hydra-
zone function is good support for the development of potent an-
tioxidants.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
CRediT authorship contribution statement
Houssem Boulebd: Conceptualization, Formal analysis, Visu-
alization, Software, Methodology, Writing – review & editing.
Yasmine Zine: Investigation. Imene Amine Khodja: Investigation.
Arif Mermer: Investigation, Formal analysis. Adem Demir: Investi-
gation, Formal analysis. Abdelmadjid Debache: Resources.
Acknowledgments
We gratefully acknowledge the MESRS (Ministère de
l’Enseignement Supérieur et de la Recherche Scientifique, Algeria),
the DGRSDT (Direction Générale de la Recherche Scientifique et
du Développement Technologique, Algeria), and the HPC resources
of UCI-UFMC (Unité de Calcul Intesif of the university Fréres
Mentouri Constantine 1).
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.131546.
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