Structural Chemistry

https://doi.org/10.1007/s11224-020-01602-z

ORIGINAL RESEARCH

Quinolone and isoquinolone alkaloids: the structural-electronic

effects and the antioxidant mechanisms
Nguyen Tien Dung 1 & Do Minh Thanh 2 & Nguyen Thi Huong 3 & Phan Thi Thuy 4 & Nguyen Thi Hoan 5 &
Dinh Thi Mai Thanh 6 & Nguyen Van Trang 2 & Ninh The Son 7

Received: 1 May 2020 / Accepted: 28 July 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Quinolone and isoquinolone alkaloids, which were found in the plant kingdom, are now potential antioxidants. In this case study,
a quantum calculated procedure utilizing the density functional theory (DFT)-B3LYP method coupled with basis set 6–311++
G(d,p) was used to investigate free-radical quenching activity of alkaloidal quinolone viridicatol (1) and alkaloidal isoquinolone
5-hydroxy-8-methoxy-4-phenylisoquinolin-1(2H)-one (2). On the basis of thermodynamic perspective and from the findings, the
powerful antioxidative potential of these two title compounds in the liquids water, methanol, and especially DMSO was mostly
driven by the proton affinity (PA), consistent with the SPLET (sequential proton loss electron transfer) mechanism. The
environmental effect has also been investigated, and the antioxidative action caused by O–H bond disruption is easier than that
of N–H bond in both the gaseous phase and liquids. In the gaseous phase, the combinations of two studied compounds and •OOH/
DPPH radicals are kinetic evidence, including two intermediates and one transition state. From thermodynamic and kinetic
viewpoints, compound 2 can be seen as a therapeutically useful agent in antioxidative treatment because of the role of a 5-
hydroxy group.

Keywords Quinolone . Isoquinolone . Density functional theory . Antioxidative

Introduction
Reactive oxygen species (ROS) has considerably shown as a
chemical species consisting of oxygen. The well-known rad-
ical agents, such as hydroxyls, peroxides, superoxide, singlet
oxygen, or alpha-oxygen, are now presenting in inside and
outside living organisms [1]. ROS is recognized to be caused
by brain injury after ischemic stroke or apoptosis after cerebral
ischemia [2]. ROS cellular overproduction may claim for ox-
idative stress occurrences and biomolecule damage of normal
cells and tissues [3]. Historic documents have contained nu-
merous notes indicating that the application of synthetic sub-
stances as traditional antibiotics was often associated with
high costs, long treatment durations, and drug failures [4].
Hence, searching for novel antioxidants from medicinal plants

Electronic supplementary material The online version of this article

(https://doi.org/10.1007/s11224-020-01602-z) contains supplementary
material, which is available to authorized users.

* Nguyen Van Trang 3

Faculty of Chemical Technology, Hanoi University of Industry, 298
nguyenvantrangsphn1909@gmail.com Cau Dien, North District Tu Liem, Hanoi, Vietnam
* Ninh The Son 4
School of Natural Sciences Education, Vinh University,
yamantson@gmail.com Vinh, Vietnam
5
1
Centre for Informatics and Computing, VAST, 18 Hoang Quoc Viet,
Faculty of Chemistry, Hanoi National University of Education, 136 Cau Giay, Hanoi, Vietnam
Xuanthuy, Cau Giay, Hanoi, Vietnam 6
University of Science and Technology of Hanoi, VAST, 18 Hoang
2 Quoc Viet, Cau Giay, Hanoi, Vietnam
Institute for Tropical Technology, Vietnam Academy of Science and
7
Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Institute of Chemistry, VAST, 18 Hoang Quoc Viet, Cau Giay,
Hanoi, Vietnam Hanoi, Vietnam

in the fight against a large number of free radicals is
warranted.
Viridicatol (1) has been successfully precipitated out of the
marine-derived fungal strain Penicillium sp. SF5295 or
Penicillium sclerotiorum, whereas a new alkaloid
isoquinolone, 5-hydroxy-8-methoxy-4-phenylisoquinolin-
1(2H)-one (2), was isolated from endophytic fungus
Penicillium sp. R22 in Nerium indicum (Fig. 1) [5–7].
Naturally occurring compounds 1–2, which were categorized
as alkaloids, were structurally formulated by 4-
phenylquinolone and 4-phenylisoquinolone backbones, re-
spectively. Quinolones and isoquinolones have been demon-
strating great roles in pharmacological uses, but mostly con-
cern about antioxidative examinations. For instance, a survey
conducted by Chung and Woo (2001) suggested that the pre-
viously undescribed compound 4-carbomethoxy-6-hydroxy-
2-quinolone possessed the moderate IC50 value of 36.4 μg/
mL compared with reference compound ascorbic acid (IC50
21.8 μg/mL) in DPPH free-radical scavenging assay [8].
Regarding two studied compounds 1–2, the recent publi-
cation recommended the employment of viridicatol (1) as ma-
trix metalloproteinase inhibitors MMP-2 and MMP-9 in
HT1080 cell line following by MAPK signaling mechanism.
Quinolone alkaloid 1 itself has also shown the biologically
useful role in anti-inflammatory treatment because it would
help to inhibit nitric oxide (NO) and cyclooxygenase (COX-2)
productions, as well as nitric oxide synthase (iNOS) expres-
sion when inflammatory processes in RAW264.7 and BV2
cell lines were caused by lipopolysaccharide [5, 9].
Meanwhile, new isoquinolone 2 possessed the unique MIC
value of 31.2 μg/mL against the pathogenic fungi Alternaria
brassicae, Alternaria alternata, and Botrytis cinerea and was
comparable with reference compound carbendazim (MIC
31.2 μg/mL) [7].
To date, the antioxidative experiments on secondary me-
tabolites 1–2 have not yet been performed, adding that the
theoretically computational documents using the classes of
4-phenylquinolones and 4-phenylisoquinolones were quietly
limited. Consequently, herein, we set up a computational DFT
Fig. 1 General structure of
quinolinone 1 and isoquinolone 2 5'
with atom numbering
5 5
4 OH
4a
6 6
B A
7 8a
8 1
Viridicatol (1)
Struct Chem
attempt to obtain in-depth knowledge of structural aspects,
conformational features, and electronic analyses, primarily
based upon B3LYP functional with 6-311++G(d,p) basis set
in the gaseous phase and liquids methanol, water, and DMSO.
The outcomes emphasized on elucidating their reactivity with
•
OOH/DPPH radicals.
Computational method
All the calculations were carried out by utilizing Gaussian 09
package [10]. To gain the ground state structures, the B3LYP
functional method with no constraints was applied, coupled
with basis set 6-311++G(d,p) in liquids methanol (ε = 32.61),
water (ε = 78.35), DMSO (ε = 47.24), and the gaseous phase
(ε = 1.00) [11–14]. Vibrational frequencies have been calcu-
lated to accurate for zero-point energy (ZPE), and also af-
firmed the appearances of optimized results without imaginary
frequencies. The IEF-PCM solvation model (integral equation
formalism polarizable continuum model) was employed to
determine solvent influences [15, 16].
From the publications, there were three renowned mecha-
nisms, HAT (H atom transfer), SET-PT (single electron
transfer-proton transfer), and SPLET (sequential proton loss
electron transfer), discussing the radical quenching actions of
the original molecule (Alkal-OH) [12–14].
1 The HAT pathway concerns with O–H bond disruption of
Alkal-OH (Eq. 1) and then transmits to radicals and has
been usually monitored by BDE (homolytic bond dissoci-
ation enthalpy) (Eq. 2):
Alkal−OH þ R1 −O• →Alkal−O• þ R1 OH ð1Þ
BDE ¼ ΔHðH• Þ þ ΔHðAlkal−O• Þ−ΔHðAlkal−OHÞ ð2Þ
OH
5'
3' 3'
C C
OH
1' 1'
4
4a
3
3 B
A
7 N
8a 2
N 2 O H
8 1
H OCH3 O
5-Hydroxy-8-methoxy-4-phenylisoquinolin-1(2H)-one (2)
Struct Chem

ΔH(H•), ΔH(Alkal-O•), and ΔH(Alkal-OH) were the en- descriptors can be written by Eqs. 9–13 [12–14]:
thalpies of H•, Alkal-O•, and Alkal-OH, respectively.
A≈−EL ð9Þ
2. The SET-PT mechanism has undergone two steps (Eq. 3), I o ≈−EH ð10Þ
in which the first stage is due to the loss of an electron to χ≈ðEL þ EH Þ=2≈ðI o þ AÞ=2 ð11Þ
yield the molecular radical cation Alkal-OH+•. Since then,
Alkal-OH+• is deprotonated. The first reaction is de- η≈ðEL −EH Þ=2≈ðI o −AÞ=2 ð12Þ
scribed by the sum of the ionization potential (IP), where- μ≈−ðEL þ EH Þ=2≈−ðI o þ AÞ=2 ð13Þ
as heterolytic bond dissociation enthalpy (PDE) is char-
acteristic of the deprotonated process (Eqs. 4–5): where EL and EH present the energies of the LUMO and
HOMO, respectively.
The global electrophilicity parameter ω revealed the stable
energy of a molecule since it was saturated by electrons from
Alkal−OH þ R1 • →Alkal−OH•þ þ R1 − →Alkal−O• outside. Consequently, the higher-value ω + (electron
accepting) resulted in remarkable electrophilicity, whereas
þ R1 OH ð3Þ
the lower-value ω− (electron donating) has apparently evi-
•þ –
IP ¼ ΔHðAlkal−OH Þ þ ΔHðe Þ−ΔHðAlkal−OHÞ ð4Þ denced better nucleophilicity of a substance. These descriptors
were proposed by the below equations (Eqs. 14–16) [12–14]:
PDE ¼ ΔHðAlkal−O• Þ þ ΔHðHþ Þ−ΔHðAlkal−OH•þ Þ ð5Þ

ΔH(Alkal-OH+•) is recognized as the enthalpy of the alkaloid ω ¼ μ2 =2η≈ðI o þ AÞ2 =½4ðI o −AÞ≈ðEL þ EH Þ2 =½4ðEL −EH Þ
radical cation Alkal-OH+• after electron removal of the parent ð14Þ
alkaloid molecule. The calculated gaseous-phase enthalpies of
ω− ¼ ð3I o þ AÞ =½16ðI o −AÞ
2
ð15Þ
H+ and e− are 1.48, and 0.75 kcal/mol, respectively, whereas
þ 2
the IEF-PCM model exerts values of − 20.54, and − ω ¼ ðI o þ 3AÞ =½16ðI o −AÞ ð16Þ
247.97 kcal/mol in methanol, − 25.08 kcal/mol and −
244.15 kcal/mol in water, and − 28.43 kcal/mol and − Generally, the Fukui descriptors contain useful information
255.61 kcal/mol in acetone, respectively [17–19]. relating to selective feature in a chemical reaction. The atom
accompanied by the high electronic settling is the most reac-
3. Regarding the SPLET pathway, alkaloid deprotonates to tive place and better than surrounding atoms in a system
produce an anion Alkal-O−, and subsequent electron [12–14]. Fukui indices, consisting of nucleophilic (fk+), elec-
transmission from this anion happens (Eq. 6). Two con- trophilic (fk–), and/or radical attacks (fk0), were conceivably
ceptual parameters proton affinity (PA) and electron expressed by the following equilibria (Eqs. 17–19) [12–14]:
transfer enthalpy (ETE) correspond to deprotonation and f k þ ¼ qt ðN þ 1Þ−qt ðN Þ ð17Þ
electron transfer, respectively (Eqs. 7–8):
–
f k ¼ qt ðN Þ−qt ðN −1Þ ð18Þ
f k ° ¼ ½qt ðN þ 1Þ−qt ðN −1Þ=2 ð19Þ
Alkal−OH→Alkal−O− þ Hþ ; Alkal−O− where qt(N): electronic population of atom t in a neutral
• • − − þ molecule.
þ R1 →Alkal−O þ R1 ; R1 þ H →R1 H ð6Þ
qt(N + 1): electronic population of atom t in an anionic
PA ¼ ΔHðAlkal−O− Þ þ ΔHðHþ Þ−ΔHðAlkal−OHÞ ð7Þ molecule.
• –
ETE ¼ ΔHðAlkal−O Þ þ ΔHðe Þ−ΔHðAlkal−O Þ −
ð8Þ qt(N − 1): electronic population of atom t in a cationic
molecule.
ΔH(Alkal-O−) presents the enthalpy of the Alkal-O− after In the studies of thermodynamics and kinetics, the B3LYP
proton removal of the parent molecule. functional is recognized as a significant method [20, 21]. In a
Antioxidative processes are also elucidated by DFT-based radical reaction, the constant rate K is exposed as below [22]:
reactive chemical parameters [12–14], comprising of the en-
T :kB −ΔG#
ergies of LUMO and HOMO, atomic net charges, electron k ðT Þ ¼ κ e RT ð20Þ
affinity A, ionization potential Io, electronegativity χ, global h
hardness η, chemical potential μ, global electrophilicity de- where T, kB, h, and κ are temperature, the Boltzmann constant,
scriptor ω, and chemical Fukui indices. Planck constants, and the Wigner coefficient, respectively.
It is depended on the DFT theoretical approach of the finite The ΔG# (Gibbs activation energy) has been calculated at
difference approximation and Janak’s theorem; these 298.15 K, and induced the different energy between reactant
 Struct Chem

and transition state.
The Wigner coefficient κ is formulated by the relationship
between the electronic barrier height ΔEB,0 and the imaginary
frequency of the transition state structure v (cm−1) of a con-
siderable reaction via Eq. 21 [22]:
    pounds are slightly enlarged by 0.001–0.002 Å, except
1 hcv 2 RT
κ¼1þ 1þ ð21Þ
24 T :kB ΔEB;0
Results and discussion
Conformational structure
Emerging evidence showed that the chemical structural
properties such as stereochemistry, length of bonds, and
especially the behavior of hydroxyl groups, have greatly
affected the results of radical scavenging reactions [23].
We now provide information on the computational geo-
metrical results of two alkaloids 1–2 at theoretical DFT-
B3LYP/6-311++G(d,p) level. As shown in all the stud-
ied media (Table 1 and Fig. S1), the most sophisticated
character could be viewed from the state forms 1–2, in
which π-electrons were delocalized over the whole mol-
ecule. However, the coplanar between the systematic
ring AB and ring C has lost. In each compound, the
local minimum energies from studied media have no
distinction (Table 2).
The bond lengths seem to have suffered by environ-
mental use. While converted gas into solvents, the bond
lengths of OH and NH groups in two studied com-
the hydroxy group at carbon C-3 of compound 1.
However, this phenomenon observed the difference be-
tween 1 (increased by 0.003 Å) and 2 (decreased by
0.001 Å) in C4-C1′ bond, deducing from 3-OH effect.
In agreement with this, the bond angle θ1 (C3-C4-C1′)
of 1 is found to be larger than that of 2 by 4°.
Again, the solvent factor and 3-OH group of 1 response
significantly changed in the dihedral angle (Table 1).
Regarding compound 1, θ2 (C3-C4-C1′-C2′) reached −
60.0° in the gaseous phase as compared with the values of
around − 72.0° in methanol, water, and DMSO. In the mean-
time, the θ2 of 2 apparently tends to change from gas (− 70.0°)
to liquids (− 63.4°).
The potential energy plot against the torsional angle θ2
in the gaseous state has been considered for the relative
position between the rings A and C. In the same condition
for both compounds 1–2, θ2 was scanned in the charac-
teristic 10° values from − 180° to 180° at B3LYP/6-
311++G(d,p) level (Table S1). To accurate, two com-
pounds 1–2 were so far optimized around each conforma-
tional minimum, and the outcomes are provided in Fig. 2.

Table 1 Optimized bond distances, bond angles (θ1) and dihedral angles (θ2) of studied compounds 1–2 in gas, methanol, water, and DMSO mediums
at B3LYP/6-311++G(d,p) level of theory

No. Bond lengths

N–H 3 (O–H) 5 (O–H) 3′ (O–H) C4-C1′
1 Gas 1.012 0.976 0.963 1.490
Methanol 1.013 0.975 0.965 1.493
Water 1.013 0.975 0.965 1.493
DMSO 1.013 0.975 0.965 1.493
2 Gas 1.011 0.963 1.496
Methanol1.012 0.965 1.495
Water 1.012 0.965 1.495
DMSO 1.012 0.965 1.495
No. Bond angles Dihedral angles
θ1 (H–N–C2) θ1 (H–N–C1) θ1 (C4–C3–OH) θ1 (C4a–C5–OH) θ1 (C3–C4–C1′) θ1 (C2′–C1′–C4) θ2 (C3–C4–C1′–C2′)
1 Gas 115.6 123.6 120.3 120.0 − 60.0
Methanol 116.2 123.2 120.3 119.9 − 71.3
Water 116.2 123.2 120.3 119.9 − 72.4
DMSO 116.2 123.2 120.3 119.9 − 71.9
2 Gas 114.0 118.6 116.4 120.6 − 70.0
Methanol 115.0 118.6 116.3 120.6 − 63.5
Water 115.0 118.6 116.3 120.6 − 63.3
DMSO 115.0 118.6 116.3 120.6 − 63.4
Struct Chem

Table 2 Chemical reactivity indices obtained using DFT method in gas, methanol, water, and DMSO mediums at B3LYP/6-311++G(d,p) level of
theory

No. Medium η χ μ (eV) Io A ɷ (eV) Dipole moment Polarizability Energy EHOMO ELUMO
(eV) (eV) (eV) (eV) (Debye) (au) (kcal/mol) (eV) (eV)
ω ω− ω+

1 Gas 2.180 3.975 − 3.975 6.155 1.794 3.622 5.882 1.908 3.352 201.014 − 858.682827 − 6.155 − 1.794
Methanol 2.225 4.016 − 4.016 6.241 1.791 3.624 5.910 1.894 5.022 278.022 − 858.698989 − 6.241 − 1.791
Water 2.229 4.018 − 4.018 6.247 1.789 3.622 5.910 1.892 5.101 280.958 − 858.699560 − 6.247 − 1.789
DMSO 2.227 4.017 − 4.017 6.244 1.790 3.622 5.909 1.892 5.059 279.517 − 858.699290 − 6.244 − 1.790
2 Gas 2.102 3.637 − 3.637 5.739 1.536 3.147 5.229 1.591 3.621 213.462 − 897.935729 − 5.739 − 1.536
Methanol 2.098 3.733 − 3.733 5.831 1.635 3.320 5.449 1.716 5.372 295.034 − 897.953351 − 5.831 − 1.635
Water 2.098 3.737 − 3.737 5.835 1.639 3.329 5.460 1.722 5.438 298.322 − 897.953975 − 5.835 − 1.639
DMSO 2.098 3.735 − 3.735 5.833 1.637 3.325 5.455 1.719 5.407 296.734 − 897.953668 − 5.833 − 1.637

In case of quinolone alkaloid viridicatol 1, the local
minimum conformer locates at ± 110° which was
destabilized by ΔE = 0.26 kcal/mol with reference to
the global minimum conformer at ± 60°. The flipping
ring C has been observed in both two minima.
Trouillas et al. (2004) pointed out that at room temper-
ature, the barrier energy of less than 2.0 kcal/mol will
facilitate conformational conversion for these minima
[24]. The conformational barriers peak at ± 180° and
10° with interconvertible energies of respective ΔE =
12.37 and 12.30 kcal/mol, relative to global conformer.
With the absence of 3-OH group, the potential energy
curve of isoquinolone (2) has shown a few differences,
in which the absolute minima lie at − 70.0° and 110°.
Only one interconversion barrier has been identified at
20° with its interchangeable energy ΔE = 13.05 kcal/
mol. Collectively, the structural properties can lead to
Fig. 2 Potential energy curves versus the dihedral angles θ2 (C3-C4-C1′-
C-2′) in the gaseous medium at B3LYP/6-311++G(d,p) level of theory
the differences in electronic and antioxidative results
between 1 and 2.
Orbital and spin density analyses
The π-electron delocalization is becoming more and more
concerned about the stabilization of the neutral and radicals
after proton removal [12–14]. The FMO (frontier molecular
orbital) approach is likely to be a useful method for elucidat-
ing the relationship between the neutral and radical forms,
particularly the delocalization of electrons. At the DFT-
B3LYP/6-311++G(d,p) theoretical level, there has not been
a difference in HOMO and LUMO neutral images of each
studied molecule when converting gas into liquids (Fig. 3).
HOMO neutral illustrations indicate that electrons delocalized
in the whole ring AB and little in ring C of molecules 1–2.
Regarding pictorial HOMO of NH and OH radicals, the elec-
trons extremely concentrate on the whole structures 1–2, ex-
cept HOMO plots of 1–3′-OH radical and 2–5-OH radical (the
low electron density in ring C). LUMO neutral image of 1
with the presence of 3′-OH has consisted of electron density
higher than that of 2. In the meantime, LUMO cases of 1–3′-
OH radical and 2–5-OH have slightly changed when com-
pared with their HOMO pictures. It is expected that
conjugative ring AB would help to promote antioxidative re-
actions better than ring C.
As shown in Eqs. 9 and 10, the higher EHOMO (the better
ability to donate electrons) and the lower ELUMO (the better
sensitivity to accept electrons) are equal to the lower Io and the
higher A, respectively. The antioxidative reactivity can be
assessed by Egap = ELUMO − EHOMO, thereby implying that
the lower Egap will support the electron transfer easily.
The application of solvents allows decreasing the
EHOMO values. In both two compounds 1–2, the equiva-
lence of the EHOMO outcomes rests on the evidence of
using polar protic solvents methanol and water or the
 Struct Chem

Compound 1 Compound 2

1-Neutral HOMO 1-Neutral LUMO 2-Neutral HOMO 2-Neutral LUMO

1-NH radical-HOMO 1-NH radical LUMO 2-NH radical-HOMO 2-NH radical LUMO

1-3-OH radical-HOMO 1-3-OH radical-LUMO 2-5-OH radical-HOMO 2-5-OH radical-LUMO

1-3'-OH radical-HOMO 1-3'-OH radical-LUMO

Fig. 3 HOMO and LUMO images of neutral and radical forms in all studied mediums at B3LYP/6-311++G(d,p) level of theory

aprotic polar liquid DMSO and smaller than that in the
gaseous phase (Table 1). As expected, it clearly reveals
the solvents could promote ionization so that SPLET anti-
oxidant action is able to happen easily [25]. In contrast to
1, the solvent mediums would also set up a better condition
for decreasing the ELUMO values in 2. Having a look at Egap
in all environments, the visible order of the Egap values of
quinolone alkaloid 1 are run as follows: water (4.458 eV) >
DMSO (4.455 eV) > methanol (4.450 eV) > gas
(4.361 eV), but the environment seems not to influence
this parameter in compound 2. However, it could be pri-
marily predictable the antioxidative capacity of 1–2 be-
cause the Egap values of isoquinolone 2 have always been
observed to be smaller than that of quinolone 1.
Struct Chem

0.348 0.418
OH OH O
0.169

0.303
0.463
0.158 0.207

0.139 137 520 0.320

0.248 OH O OH
0.247
0.162

0.187
N O 123 N O N O
0.216 0.316 0.102 H H

1 NH radical 1 3-OH radical 1 3'-OH radical

0.285
OH O

0.146 0.474
0.113 0.251
0.106 0.229 0.168

N 0.227 NH
0.172
0.106 0.106
0.272

OCH3 O 0.187 OCH3 O

2 NH radical 2 5-OH radical

Fig. 4 Spin density distribution of structural radicals in the gaseous medium at B3LYP/6-311++G(d,p) level of theory

The spin density is a helpfully reliable representation of
estimating the stability of a radical after H-removal. It notes
that the more spin density delocalizes in radicals, and the
radical is formulated easily, thereby the BDE values are lower
[26]. The calculation of this parameter of various radicals after
H-removal from two title alkaloids 1–2 is presented in Fig. 4.
Generally, the computed outcomes indicate that the strong
spin distributions in two molecules 1–2 happen at heteroatom
oxygens and nitrogens, and several aromatic carbons. H-
separation from 3′-OH of compound 1 is facilitated due to
the stabilization of ring C, in which carbons C-1′ and C-5′
bear negative spin density, and carbons C-2, C-4, and C-6
are central positions of positive ones. It resembles that with
the high spin concentration at some carbons, the ring AB
(isoquinolone nuclear) of compound 2 promotes H-
abstraction out of NH and 5-OH better than ring C.
Sadasivam and Kumaresan (2011) proposed that the lower
spin densities in gas might be tantamount to the lower BDE
enthalpies [27]. Of compound 1, the gaseous spin densities of
oxygen atom radical orderly generate as 1–3′-O• (0.418) >1–
3-O• (0.320) > 2–5-O• (0.285), whereas the remarkable order
of 2-2-N• (0.227) > 1-1-N• (0.216) is assignable to N-atom
radicals. Despite the fact that the spin densities of N-atom
radicals are lower than those of O-atom radicals, the strategy
for the antioxidative reactions is to disrupt OH bonds rather
than to do with NH bonds due to the stabilization of
conjugative amide bonds.
Natural bond orbital analysis
The natural bond orbital analysis (NBO) model is now avail-
able to provide useful information when considered the
delocalized electron from donor (occupied Lewis-type) to ac-
ceptor (unoccupied non-Lewis-type). The hypothetical NBO
was arisen from electron density transmission from filled do-
nor to empty acceptor NBO due to conjugative and
hyperconjugative interactions. The outcome demonstrates
the possible interaction E(2) energy utilizing the second-order
perturbation rule (Eq. 22) [28]:

2

Eð2Þ ¼ Eij ¼ −qi Fi j = E j –Ei ð22Þ
 Struct Chem

Table 3 Condensed Fukui indices of studied compounds in the gaseous medium at B3LYP/6–311++G(d,p) level of theory

Position 1 2

f+ f− fo Δfk f+ f− fo Δfk

NH − 0.022 − 0.022 − 0.022 0.000 − 0.006 − 0.045 − 0.026 0.039

CO − 0.038 − 0.007 − 0.023 − 0.031 0.053 0.004 0.029 0.049
CO − 0.113 − 0.110 − 0.112 − 0.003 − 0.083 − 0.101 − 0.092 0.018
C3 − 0.130 − 0.031 − 0.081 − 0.099 − 0.272 − 0.076 − 0.174 − 0.196
3-OH − 0.060 − 0.093 − 0.077 0.033
C4 0.033 − 0.052 − 0.010 0.085 0.231 0.020 0.126 0.211
C5 − 0.035 − 0.019 − 0.027 − 0.016 0.008 − 0.024 − 0.008 0.032
5-OH − 0.034 − 0.060 − 0.047 0.026
C4a 0.054 0.001 0.028 0.053 0.066 − 0.026 0.020 0.092
C6 − 0.028 − 0.048 − 0.038 0.020 − 0.032 − 0.021 − 0.027 − 0.011
C7 − 0.063 − 0.047 − 0.055 − 0.016 − 0.049 − 0.075 − 0.062 0.026
C8 − 0.036 − 0.016 − 0.026 − 0.020 − 0.007 0.010 0.001 − 0.017
8-OCH3 − 0.024 − 0.037 − 0.031 0.013
C8a − 0.023 0.016 − 0.004 − 0.039 − 0.176 − 0.023 − 0.100 − 0.153
C1′ − 0.038 − 0.060 − 0.049 0.022 − 0.044 − 0.044 − 0.044 0.000
C2′ 0.012 0.002 0.007 0.010 0.001 − 0.030 − 0.015 0.031
C3′ − 0.030 − 0.064 − 0.047 0.034
3′-OH − 0.020 − 0.023 − 0.022 0.003 0.104 − 0.023 − 0.041 0.127
C4′ 0.018 0.001 0.010 0.017 0.118 − 0.030 0.044 0.148
C5′ − 0.078 − 0.072 − 0.075 − 0.006 − 0.184 0.006 − 0.089 − 0.190
C6′ − 0.022 − 0.022 − 0.022 0.000 − 0.006 − 0.045 − 0.026 0.039

where Ei and Ej present for diagonal elements, and qi and Fi j
are orbital occupancy and off-diagonal NBO Fock matrix el-
ement, respectively.
As shown in Eq. 20, the higher the energy E(2) is, the more
the interaction takes place and the more electron transmission
from donors to acceptors is observed, therefore expanding
conjugative situation in the studied compound. In the NBO
assay of compound 1 at the same DFT-B3LYP/6-311++
G(d,p) level, the conjugative interaction LP(1)N → π*(C=O)
(energy achieves to highest value of 80.16 kcal/mol), together
with the π(C3-C4) → π*(C=O)/π*(C4a-C5) and LP(2)O
from CO → σ*(N-C2) response for the stable condition of
the conjugative ring A (Table S2). The intramolecular
conjugative interactions π(C4a-C5) → π*(C6-C7), π*(C8-
C8a), π(C6-C7) → π*(C4a-C5)/π*(C8-C8a) are caused for
stabilizing ring B. The stabilization of phenyl unit (ring C)
has been shown to be associated with many conjugative and
hyperconjugative interactions (Table S2). Among them,
conjugative interaction π(C5′-C6′) → π*(C1′-C2′) and
hyperconjugative interaction σ(O3′-H3′) → σ*(C1′-C2′) asso-
ciate with the high energies of 38.97 and 151.78 kcal/mol,
respectively.
The same manner was found in isoquinolone alkaloid 2, at
which the stabilization energies E(2) achieve the highest
maximal values of 3019.41 and 1627.93 kcal/mol due to in-
teractions LP(1)O5 → σ*(C8-8a)/σ*(C3-H3), and several
significant values, such as 1117.92 and 1009.83 kcal/mol,
which derived from LP(1)N → π*(C5′-C6′)/σ*(C4-C4a).
Furthermore, the typical interactions of σ → σ* are also found
to be prevalent in 2. From these mentions, it notes that the lone
pair electrons of heteroatoms, like oxygens and nitrogen, es-
tablish the key characters to alter the charge distributions,
thereby significantly influencing on radical reactions.
Electronic analysis
The global hardness η is applied to determine an attempt to
prevent transferable charge [29]. Quinolone alkaloid 1 has the
minimal chemical hardness η value of 2.180 eV in the gaseous
phase, but there has been an increase by using solvents
(Table 2). In contrast, isoquinolone alkaloid 2 yields the max-
imal η value of 2.102 eV in gas but affords the same value of
2.098 eV in three studied solvents.
The electronegativity χ is recognized as a tendency of an
atom to receive surrounding electrons unto it, whereas the
chemical potential μ shows the same value with this parameter
but has negative signal [29]. By means of Sanderson’s princi-
ple, a molecule, which is accompanied by the high
Struct Chem

Table 4 Studied phases reaction enthalpies at 298 K for radicals of studied compound 1 at B3LYP/6–311++G(d,p) level of theory (in kcal/mol)

Compounds BDE IP PDE

Gas Water Methanol DMSO Gas Water Methanol DMSO Gas Water Methanol DMSO
1
NH 93.88 92.67 94.84 94.84 173.43 112.52 117.77 117.77 236.26 27.47 23.17 5.02
3-OH 83.35 78.36 80.74 80.50 225.75 13.14 8.84 9.32
3′-OH 83.37 81.70 83.85 83.85 225.75 16.48 11.95 5.97
2
NH 88.87 85.76 87.91 87.91 162.21 102.96 107.98 107.98 242.23 30.34 26.04 7.88
5-OH 74.53 73.58 75.73 75.73 228.14 18.16 13.62 4.3
Compounds PA ETE
Gas Water Methanol DMSO Gas Water Methanol DMSO
1
NH 334.92 48.26 45.15 26.28 74.53 91.97 95.55 96.27
3-OH 335.88 46.58 43.96 24.84 63.07 79.07 82.66 83.61
3′-OH 340.90 48.26 45.62 26.51 58.29 80.74 84.33 85.04
2
NH 341.14 52.32 49.69 30.58 63.55 80.74 84.33 85.28
5-OH 333.49 46.58 43.72 24.84 56.86 74.29 78.11 78.83

electronegativity, may promptly reach equalization and sets
the low reactivity [30]. As a consequence, it is taken note that
the lower χ is always taken as good advance for the antioxi-
dative reactions. The χ parameters of both two studied com-
pounds increase when converted gas into solvents. However,
contrary to quinolone 1, isoquinolone alkaloid 2 achieves the
lowest electronegativity χ value of 3.637 eV in gas. The χ
values of 1 are higher than those of 2 in all the studied envi-
ronments (Table 2).
Polar solvents, like methanol, water, and DMSO, are the
reason why the polarizability of both two molecules 1–2 is
more than in the gaseous phase. By means of hard and soft
acids and bases (HSAB) theory, it is common to conclude that
environment is a key for a transferable tendency from “low
polarizability and high oxidation state” to “high polarizability
and low oxidation state” [30]. Regarding a molecule, the di-
pole moment is likely to be a good way to predict the isolation
of negative and positive charges. The dipole moment with
high magnitudes is accompanied by the high polarity and
the high charge densities of bonds [27]. Han et al. (2009)
suggested that molecules had lower dipole moment which
seems to have better biological examinations [31]. In this
study, liquids-type methanol, water, or DMSO drastically
scale up dipole moment of metabolites 1–2, as compared with
the use of the gaseous phase.
Taking the global electronegativity into account, the
change from gas to solvents will cause for increasing the glob-
al electrophilicity parameter ω− and decreasing of ω+ in com-
pound 1. The ω value of 1 seems not to change in both four
studied mediums, but all three parameters ω, ω−, and ω+ of 2
are found to increase when gas was replaced by liquids. The
ω− values of compounds 1–2 were about threefold higher than
those of ω+ in all mediums. It is similar to other classes of
isolated compounds such as flavonoids [12–14], in which

Table 5 Calculated ΔG# and K at

the at the B3LYP/6-311G//6- Reaction ΔG# (kcal/mol) K (L/mol s) Reaction ΔG# (kcal/mol) K (L/mol s)
311++G** level of theory at
298.15 K in the gas phase 1 + •OOH 2 + •OOH
1–1-NH 12.3 1.920 × 107 2–2-NH 6.1 9.922 × 109
1–3-OH 5.7 2.083 × 1010 2–5-OH 3.0 3.036 × 1011
1–3′-OH 7.2 4.110 × 109
1 + DPPH 2 + DPPH
1–1-NH 20.9 1.524 × 103 2–2-NH 16.2 3.057 × 105
1–3-OH 11.5 4.459 × 107 2–5-OH 10.3 1.613 × 108
1–3′-OH 15.4 6.287 × 105
 Struct Chem

Fig. 6 The optimized structures of intermediates (Ints) and transition b

states (TSs) of •OOH attack compounds 1–2 at B3LYP/6–311++G(d,p)
level of theory in gaseous phase

atoms of OH moieties. It was desirable that radical quenching

reactions that happen in OH moieties were easier.
Lastly, the electronic properties of alkaloids 1–2 were fur-
ther analyzed by MEP (molecular electrostatic potential) mod-
el. The electrostatic potential is demonstrated by correspond-
ing colors. The potential increases follow the visible order
blue > green > yellow > orange > red, in which blue is in
conjunction with the region of the most positive charge, red
and orange set up zones of the most negative potential, while
green shows the region with zero charge [35]. In both the two
considered compounds 1–2, oxygen is mostly represented by
Fig. 5 Energy diagram for the reaction of •OOH radicals attack at yellow and red, whereas blue and green can be assigned to
B3LYP/6-311++G(d,p) of theory hydrogens, nitrogens, and aromatic carbons (Fig. S2). This
finding confirms that the hydroxyl groups of alkaloids type
of quinolones and isoquinolones acted as nucleophiles [35].
alkaloid derivatives have a certain characteristic of donating
electrons rather than capturing.
The Mulliken population analysis (MPA) was used to
establish net charges of a system ring. MPA generates as
Antioxidative mechanisms
an advantageous method to estimate a chemical reaction.
HAT mechanism
The Mulliken charge values of each atoms applying DFT
model are provided in Table S4. Generally, the environ-
HAT mechanic action has taken place when a random H-atom
mental use has not affected on charges. Because of the
was removed out of OH and NH groups and gives a free
effective negative charges, oxygens and nitrogens in alka-
alkaloid radical since the result of bond dissociation was ho-
loids 1–2 show off donating their electrons. The charges of
molytic and mostly monitored by the BDE. From Table 4,
carbons C7, C8a, and C4′ in 1 are directly opposite with
quinolone alkaloid 1–3-OH radical consists of the smallest
those of 2 in both four mediums. Furthermore, the phenyl
BDE values of 78.36 kcal/mol in water, while the significant
group of 1 is stabilized by negative charges of carbons C2′-
other value of 81.70 kcal/mol belongs to the water BDE en-
C3′ and C5′-C6′ and high cumulative positive charges of
thalpy of 3′-OH radical. In both 1–3-OH and 1–3′-OH radical
C1′ and C4′. Collectively, the stable ring C of alkaloid 1
cases, the BDE results have been affected by mediums which
can be seen as an active center to possibly facilitate anti-
establish as follows: gas > methanol ≥ DMSO > water. The
oxidative procedures of 3′-OH [32].
gaseous BDE enthalpies of OH radicals of 1 seem to be of
Besides the FMO and electronic structural analyses, Fukui
equivalence, but 1–3-OH radical always induces BDE en-
descriptors were also among the best key parameters and a
thalpies lower than those of 1–3′-OH by ca 3.0 kcal/mol in
prompt way to analyze the actively reactive condition of each
three solvents water, methanol, and DMSO. In agreement
atom. Generally, electrophilicity is associated with Δfk = fk+ −
with the above spin density outcomes, NH radicals of 1 afford
fk– > 0. However, Δfk < 0 was characteristic of nucleophilicity
the BDE enthalpies higher than OH radicals of 1 by 10.0 kcal/
[33]. The Fukui indices given in Table 3 have been computed
mol in gas and by 11.0–14.0 kcal/mol in liquids.
in gas, based upon the HSAB theory. Aromatic carbons of
To bear a resemblance to alkaloid 1, in water, compound 2
alkaloids 1–2 have been playing as good places for either
5-OH radical has consisted of the lowest BDE value of
electrophilic or nucleophilic attacks, and OH moiety serves
73.58 kcal/mol as compared with that of NH radical
as marginal electrophiles [34]. Alkaloid-type quinolone 1
(85.76 kcal/mol). The BDE outcomes of both 2–5-OH and
and isoquinolone 2 can differ from amide group, in which Δf-
2-NH radicals keep remaining unchanged in methanol and
k ≤ 0 of this group in 1 is in contrast to that of 2. The most
DMSO. 5-OH radical always associates with the BDE en-
important is that the negative fko condensed Fukui values rep-
thalpies lower than those of NH radicals. It, once again, cor-
resented the production of radicals. With the exceptions of
responds to spin density, the BDE enthalpies of the radicals
carbons C4a, C2′, and C4′ in 1 and CO, C4, C4a, C8, and
also are found as follows 2–5-OH < 1–3-OH <1–3′-OH < 2-
C4′ in 2, the remaining atoms in two studied compounds 1–2
NH < 1-NH in each studied medium.
have been remarked by the negative values, especially O-
Struct Chem

1-NH (Int-1) 1-NH (TS) 1-NH (Int-2)

1-3-OH (Int-1) 1-3-OH (TS) 1-3-OH (Int-2)

1-3孪-OH (Int-1) 1-3孪-OH (TS) 1-3孪-OH (Int-2)

2-NH (Int-1) 2-NH (TS) 2-NH (Int-2)

2-5-OH (Int-1) 2-5-OH (TS) 2-5-OH (Int-2)


SET-PT and SPLET mechanisms
The SET-PT and SPLET pathways have been playing as main
actions in environmental solvents [36]. From Eqs. 3–8, these
two mechanisms have undergone two prevailing stages but
favorably depended on first reaction [12, 13, 36].
Consequently, the calculated IP enthalpies are knowledge of
the SET-PT pathway. Table 4 points out that this parameter of
both two compounds 1–2 did not change in methanol and
DMSO. In addition, the IP values of quinolone 1 in each
studied medium are always higher than those of isoquinolone
2, and a visible arrangement for this parameter has been ob-
served from both compounds 1–2: water < methanol = DMSO
<< gas. It affirms that the environmental polarity has quietly
influenced charged species. The second action of SET-PT is
the process of the deprotonation of radical cation, which is
determined by the lowest PDE. As can be seen, the gaseous
phase is not advanced to promote the deprotonated way, be-
cause of deducing from the largest PDE enthalpies for both
NH and OH radicals of two studied compounds. 1–3-OH rad-
ical yields the lowest PDE values of 13.14 and 8.84 kcal/mol
in polar solvents water and methanol, respectively.
Meanwhile, 1-NH and 1–3′-OH radicals reach the lowest
PDE numbers of 5.02 and 5.97 kcal/mol in DMSO,
respectively.
Of isoquinolone 2, the PDE tendency is the same way with
the BDE in each studied medium, including 5-OH radical <
NH radical. DMSO also seems to be the best way to decrease
the PDE, in which NH or 5-OH radicals afford the lowest ones
of 7.88 and 4.3 kcal/mol.
Considering the first stage of SPLET mechanism, the PA
value is very susceptive to the changes of the environment.
Both OH and NH radicals from two compounds 1–2 in
DMSO generate the PA enthalpies ca 1.5 times less than in
Fig. 7 Energy diagram for the reaction of DPPH radicals attack at
B3LYP/6-311++G(d,p) level of theory
Struct Chem
Fig. 8 The optimized structures of intermediates (Ints) and transition„b
states (TSs) of DPPH radicals attack compounds 1–2 at B3LYP/6-
311++G(d,p) level of theory in gaseous phase
water and methanol, and far less than in the gaseous phase. In
DMSO, the lowest value of 24.84 kcal/mol has occurred at 1–
3-OH and 2–5-OH radicals, while the PA enthalpy of 1–3′-
OH radical (26.51 kcal/mol) mostly equalizes with that of 1–
1-NH radical (26.28 kcal/mol) but is lower than that of 2–2-
NH radical (30.58 kcal/mol). Regarding the second step, the
electron transfer ETE enthalpies exert a similar trend with the
BDE values. From both the two compounds 1–2, this param-
eter of OH radicals is always lower than that of NH radicals in
each studied medium. Again, 2–5-OH radical establishes the
lower ETE value in comparison with 1–3-OH and 1–3-OH
radical cases, and 2–2-NH radical has always performed the
lower ETE enthalpy in reference to 1–1-NH radical case in
each medium. However, the ETE result assigned to each rad-
ical is based on this rule: gas < water < methanol < DMSO.
Preferential mechanisms
The advantageous radical scavenging pathways of alkaloids
1–2 are possibly discussed through the preferentially thermo-
dynamic BDE enthalpies of HAT, IP enthalpies of SET-PT,
and PA enthalpies of SPLET [36]. A minimum value of BDE,
IP, and PA revealed that the mechanism happens easily. As
resulted in Table 4, the BDE and IP values are found higher
than the PA values in all the three studied solvents, especially
in DMSO, and have been observed as PA < BDE < IP.
Therefore, the favorable mechanism SPLET is predominant
for alkaloids 1–2 in liquids. Regarding the application of me-
dium gas, it assumes that HAT mechanism happened, and 5-
OH radical production in isoquinolone 2 is easier than 3-OH
and 3′-OH radical cases in quinolone 1. A final conclusion is
that radicals formed by OH bond breakdown need lower en-
ergies than that of NH bonds.
The kinetic reactions induced by the attack of hydroperoxyl
and DPPH radicals
As we know, •OOH is a well-known agent to promote harmful
oxidative stress reactions in both inside and outside of living
organisms, whereas DPPH is now a famous experiment sub-
stance for radical scavenging assessments in laboratories
[37–42]. There are many computational approaches to predict
the action of these agents. For instance, Vo et al. (2019) used
•
OOH radical to compare the antioxidative capacity of OH and
CH groups of flavonoids [23]. In the current paper, to get rid
of the influence of solvent, we then moved on to determine
how •OOH and DPPH radicals attack two studied compounds
1–2 in the gaseous phase. To date, having no computational
Struct Chem

1-NH (Int-1) 1-NH (TS) 1-NH (Int-2)

1-3-OH (Int-1) 1-3-OH (TS) 1-3-OH (Int-2)

1-3'-OH (Int-1) 1-3'-OH (TS) 1-3'-OH (Int-2)

2-NH (Int-1) 2-NH (TS) 2-NH (Int-2)

2-5-OH (Int-1) 2-5-OH (TS) 2-5-OH (Int-2)


documents dealt with the application of alkaloid-type quino-
lone and isoquinolone to compare the kinetic reactions of OH
and NH groups. Generally, at theoretical B3LYP/6-311++
G(d,p) level, the reactions of •OOH and DPPH radicals to
alkaloids 1–2 have undergone two intermediates (Ints) and
one transition state (TS) (Table 5; Figs. 5, 6, 7, and 8).
The attacks of •OOH radicals on OH groups of two com-
pounds 1–2 lead to the TS energies ranging from − 10.4 to
1.0 kcal/mol, while the TS energies of − 4.1 and 5.0 kcal/mol
are caused by the interactions of •OOH radicals with 1–1-NH
and 2–2-NH groups, respectively. It can also be predicted the
low antioxidative capacity of 1–1-NH because the optimized
structures of TS and Int-2 of 1–1-NH + •OOH appear with the
stable cyclization (Fig. 6). As revealed in the literature, the
lower the ΔG# and the higher the K, the TS formation is easier
[43, 44]. Herein, these parameters show well agreement with
the gaseous BDE enthalpies; the 2–5-OH group captures
•
OOH radical with the lowest ΔG# value of 3.0 kcal/mol
and the highest K value of 3.036 × 1011 L/mol s and better
than those of 1–3-OH (ΔG# = 5.7 kcal/mol, K = 2.083 ×
10 10 L/mol s) and 1–3′-OH (ΔG # = 7.2 kcal/mol, K =
4.110 × 109 L/mol s). Also, the relative energy ΔETS − Int-1
of 2–5-OH reaches the lowest value of 3.0 kcal/mol (Fig. 5).
Likewise, 2–2-NH with ΔG# = 6.1 kcal/mol and K = 9.922 ×
109 L/mol s is capable of performing the stable TS with •OOH
radical better than 1–1-NH (ΔG# = 12.3 kcal/mol, K =
1.920 × 107 L/mol s).
As can be seen from Table 5 and Fig. 7, NH or OH groups
of two compounds 1–2 combining DPPH radical have always
resulted in the larger ΔG# and the lower K than the outcome
from •OOH radical attacks the corresponding groups. It is
similar to •OOH radical case; the bond length between OH
(or NH) of compounds 1–2 and nitrogen radical atom of
DPPH in each TS has been always observed shorter than in
each corresponding Int-1 (Fig. 8). 2–5-OH + DPPH radical
affords the lowest ΔETS−Int-1 and ΔG# values of 10.3 and
10.2 kcal/mol, respectively, but gets the highest K value of
1.613 × 108 L/mol s. As compared with this, DPPH radical
attacks hydroxyl groups of compound 1 with the higher
ΔG# values and the lower K values. To interact with DPPH
radical, the ΔG# necessary for the case 2–2-NH is less than
that of 1–1-NH by 4.7 kcal/mol, but K value induced by 2–2-
NH is 100 times higher. It can be concluded that the OH and
NH groups of isoquinolone 2 seem to conquer radical rather
than those of quinolone 1, respectively.
Conclusion
The antioxidative activity of alkaloidal constituent-type quin-
olone 1 and isoquinolone 2 has successfully been studied by
computational DFT approach. The prospective result con-
cludes that SPLET mechanism is favorably antioxidative
Struct Chem
action of two studied alkaloids 1–2 in the solvents, especially
in terms of DMSO. Chemical descriptors such as ionization
potential IP, spin density, and proton affinity PA provide use-
fully supportive evidence to affirm that the radical quenching
processes preferentially happen by O–H and N–H bonds dis-
ruption. 5-OH group of compound 2 not only gets the lowest
PA value of 24.84 kcal/mol in DMSO but also yields the
analogous BDE value of ca 75.0 kcal/mol in four studied
mediums. The results from the kinetic progress deduce a con-
clusion that the attacks of •OOH and DPPH radicals on 2–5-
OH have also been shown to be associated with the highest
rate constant K values of 3.036 × 1011 and 1.613 × 108 L/
mol s, respectively. The experiment studies using quinolone
and isoquinolone derivatives as antioxidant agents have not
yet been performed extensively. This current account will be a
guide for future researches.
Funding information This work was financed by Vietnam Academy of
Science and Technology-2020.
Compliance with ethical standards
Conflict of interest The authors declare that there are no conflicts of
interest.
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