Computational and Theoretical Chemistry 1210 (2022) 113658

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Computational and Theoretical Chemistry

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

A DFT study of the chemical reactivity properties, spectroscopy and

bioactivity scores of bioactive flavonols
Eric O. Akintemi a, Krishna K. Govender b, c, Thishana Singh a, *
a
School of Chemistry and Physics, University of KwaZulu-Natal, P.M.B. X54001, Durban 4000, South Africa
b
Department of Chemical Sciences, University of Johannesburg, P.O. Box. 17011, Doornfontein Campus, 2028 Johannesburg, South Africa
c
Council for Scientific and Industrial Research, National Integrated Cyber Infrastructure, Centre for High Performance Computing, 15 Lower Hope Road, Rosebank, Cape
Town 7700, South Africa

A R T I C L E I N F O A B S T R A C T

Keywords: Density function theory calculations was used to determine the molecular parameters, electronic and chemical
DFT reactivity descriptors, spectroscopy, and non-linear optical properties, electronic dipole moment, polarizability
Flavonols and hyperpolarizability of fifteen (15) flavonol aglycones (no sugar moiety) from plant sources to investigate
Chemical reactivity properties
their possible application as drug candidates. Geometry optimisations was carried out using the hybrid functional
Spectroscopy
Bioactivity scores
and basis set: M06-2X/6-31+G(d,p). Our calculations show that all the flavonols investigated are chemically
reactive. Their reactivity is greatest in water hence making them suitable drug candidates since this is the ideal
medium for drug delivery. The highest negative charge on the oxygen atom of the hydroxyl and high positive
charge on the H atom of C5-OH are vital for antioxidant activity. The most reactive species, from reactivity
descriptor calculations, is Gossypetin. All the flavonols are active as enzyme inhibitors and moderately active as
G-protein-coupled receptors, ion channel modulators and protease inhibitors. The physicochemical properties
show the flavonols have good bioavailability. All the compounds agree with Lipinski’s rule of 5, signifying
potential use as oral active drugs.

1. Introduction
Flavonoids are a class of multi-phenolic secondary metabolites found
in fruits and edible vegetables [1]. Over 9000 flavonoids have been
isolated from different plant sources [2]. The health benefits and dietary
importance of polyphenols has drawn the attention of researchers [3,4]
due to their high anti-oxidant, anti-inflammatory, anti-bacterial, anti-
viral and anti-tumor properties [1,5,6]. Research reports confirm that
these properties arise from their ability to quench free radicals [7,8]. As
a result, there is an emerging study in the area of food, chemical and
pharmaceuticals towards unraveling sources of anti-oxidants to inhibit
radical induced ailments. Furthermore, the clarification of polyphenol
anti-oxidant activities is of vital importance in gaining knowledge about
other biological features [9].
The flavonoid family comprises of organic compounds characterised
by phenol structural units. Based on structural differences, the poly­
phenols are classified as flavones, flavonols, chalcones, lignans and
hydroxycoumarins. Flavonols have diverse chemical structure and
characteristics [10]. Flavonol glycosides are found primarily in the
leaves, flowers and outer part of the plant namely the skin and peel, with
reduction in concentration towards the core. Only minute quantities of
flavonols are present in parts of the plant below the soil surface, with the
significant exception of onions [11–14].
Theoretically calculated parameters to depict and explain the radical
scavenging activity of antioxidant phenols were first proposed, dis­
cussed and tested in computational studies performed in the 1990s
[15–17]. The correlation of experimentally determined phenolic O–H
bond dissociation enthalpies (BDE) and half-peak oxidation potentials
(Ep/2) [18,19] with the rate constants for reactions of phenols with
different free radicals prompted extensive studies of theoretical pa­
rameters associated with physicochemical properties, which are actually
the computed BDE and ionization potentials, IP.
Mendes et al., [20] carried out a computational investigation on the
antioxidant potential of myrcetin 3,4-di-O-α-L-rhamnopyranoside, a
double glycosylated derivative of Myricetin. The bond dissociation en­
ergy obtained suggests that the derivative has an antioxidant potential
that is as good as the parent molecule. The bond dissociation enthalpy of
the O–H group was computationally determined by Wright and co-

* Corresponding author.
E-mail address: singht1@ukzn.ac.za (T. Singh).

https://doi.org/10.1016/j.comptc.2022.113658
Received 8 January 2022; Received in revised form 21 February 2022; Accepted 26 February 2022
Available online 1 March 2022
2210-271X/© 2022 Elsevier B.V. All rights reserved.
E.O. Akintemi et al.
workers [7] and was the theoretical parameter successfully used to
measure the H-atom donor ability of flavonoids. An attempt was made
by Woldu and Mai [21] to investigate the thermodynamics and kinetics
of hydrogen atom withdrawal from flavonoids and related phenolic
compounds using theoretical computations. This study shed light on the
fact that some common elements such as hydrogen, influence the ther­
modynamics and kinetics of the chain breaking ability of flavonoids.
From their theoretical findings they further predicted that for flavonoids
and related polyphenols to serve as radical scavengers, they must donate
a pair of hydrogen atoms where the total enthalpy of reaction does not
exceed the enthalpy of the homolytic dissociation of the hydrogen
molecule (H2), 104.206 kcal mol− 1.
Weber and co-workers [22] assembled a dataset of flavonoid com­
pounds with pre-determined Trolox Equivalent Antioxidant Capacity
(TEAC) in 2,2′ -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical
scavenging assay and developed different classifications and analytical
models using calculated descriptors, including bond lengths, bond or­
ders, dipole moment, enthalpy of formation, polarizability, atom and
substituent charges, electronic and total energies, and frontier molecular
orbital energies of the flavonoid compounds. The extrapolated Partial
Least Square (PLS) model listed the molecular polarizability and the
total charge of the substituent at position 5 in A-ring (Fig. 1) as the most
important descriptors for TEAC. Similarly, Principal Component Anal­
ysis (PCA), hierarchical cluster analysis and k-nearest neighbours’
techniques by Werner and his team38 listed molecular polarizability,
charge on the carbon at the position 3, and total charge at positions 5
and 3′ as the chief descriptors for classifying flavonoids as having low
and high radical capacities.
Over the past few years, there has been increased interest in the use
of bioactive organic molecules in the area of solid state research
[23–26]. The reason for this interest is their potential as nonlinear optics
in electro-optics and conductors. Organic compounds have a high degree
of delocalization since they are formed by weak van der Waal’s and
hydrogen bonds. The result is that they are optically more nonlinear
than inorganic materials.
In this study, density function theory (DFT), will be used to present
detailed chemical reactivities for fifteen (15) flavonol aglycones (no
sugar moiety) of plant sources to investigate their possible application as
drug candidates (Fig. 2). Quantum mechanical calculations were used to
determine the molecular parameters, electronic and chemical reactivity
descriptors, spectroscopy, and non-linear optical properties. Electronic
dipole moment, polarizability and hyperpolarizability, which are non-
linear optical properties (NLO), were also calculated to demonstrate
the application of bioactive compounds in materials science.
2. Computational methodology
All the structures were obtained from PubChem [27]. With the aid of
the GaussView 6.0.16 [28], we verified that all the functional groups
and substituents at the various positions were correct. All the calcula­
tions were done using the Gaussian 16 Rev. B.01 [29] program.
Fig. 1. Flavonol substituents at positions 5 and 3 .
′
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Computational and Theoretical Chemistry 1210 (2022) 113658
Geometry optimisations was carried out at 298.15 K in vacuum using the
hybrid functional and basis set: M06-2X/6-31+G(d,p) [30]. This was
chosen since it showed good results in published reports [20,21]. Using
the gas-phase optimized structures, a single-point frequency calculation
in water (ε = 78.3553) and n-octanol (ε = 9.8629) was done to obtain
the free energy for evaluating the octanol–water partition co-efficient.
All frequency calculations in solvent was performed using the SCRF
keyword together with the SMD [31] solvent model. A single-point gas-
phase optimisation was carried out using the time-dependent density
functional theory (TD-DFT) [32] keyword and solving for 20 excited
states. The resulting molecules were submitted for optimisation in water
and ethanol (ε = 24.852) which were the experimental solvents for UV.
Drug-likeness scores and bioactivity prediction was carried out using the
online program Molinspiration cheminformatics [33]. Also, provided in
the Supporting Information is a list of keywords used for the different
calculations described above as well as the XYZ coordinates of all the gas
phase optimized structures.
3. Results and discussion
3.1. Chemical reactivity descriptors
In this study, DFT was used to give a concise structure-chemical
reactivity report of the flavonols to provide an understanding of the
chemical reactivity properties. All the chemical reactivity descriptors
are presented in Table 1. Energies from the frontier molecular orbitals
(FMOs) were used to calculate chemical reactivity descriptors arising
from conceptual DFT (the contour surfaces of the FMOs are in the
Supporting Information). The energy gap, Egap (Eq. (1)) is defined as the
energy difference between EL (the lowest unoccupied molecular orbital,
LUMO) and EH (energy of the highest occupied molecular orbital,
HOMO). This determines the chemical reactivity and kinetic stability of
a molecule. The lower the energy gap, the more reactive a molecule is,
which indicates that, it is more susceptible to react with other molecular
species, such as for example proteins or enzymes.
Egap = EL − EH (1)
It can be seen (Fig. 3) that the energy gap is slightly lower in water
than in ethanol. Since the preferred medium for drug delivery is water,
this means that all the flavonols are reactive, with Gossypetin having the
lowest Egap. The lower energy gap corresponds to a higher concentration
of the molecules, and hence greater the activity of the polyphenol in that
medium. Although Gossypetin and Myricetin have the same molecular
formula (Table S2), their energy gaps are not the same (Table 1). This
difference can be attributed to the position of the hydroxyl substituent.
In Myricetin, the sixth hydroxyl substituent is situated at C5′ on the
phenyl chain while in Gossypetin, it is attached at C8 in the main
chromone skeleton. The lower energy gap for Gossypetin may be
attributed to the more nucleophilic benzyl group in the chromone
backbone, and allows electronic interactions which are pivotal to the
flavonols’ reactivity. Thus, more hydroxyl groups on the chromone
structure is favourable for the radical scavenging activity of flavonols.
Although 3-hydroxyflavone and Natsudaidain have high inhibitory
activity, their energy gaps indicate no reactivity in the aqueous layer,
but imply probable reactivity in the lipid layers.
The electronic chemical potential, µ [34], which characterizes the
escaping tendency of electrons, is expressed by Eq. (2). There was no
significant difference in the chemical potential for the 15 flavonols.
Chemical potential values in water range from − 4.50 eV (3-hydroxy­
flavone) to − 4.15 eV (Gossypetin) and in ethanol from − 4.47 eV (3-
hydroxyflavone) to − 4.12 eV (Gossypetin). The low chemical potential
of Gossypetin in water further supports this flavonols’ good chemical
reactivity.
EL + EH
μ= (2)
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E.O. Akintemi et al. Computational and Theoretical Chemistry 1210 (2022) 113658

Fig. 2. 2D Structures of the 15 flavonols investigated.

Global hardness, η [35], is the resistance to charge transfer and has Electronegativity, χ (Eq. (5)), is a measure of electron distribution in
been successful in the validation of chemical processes [36], is calcu­ the molecule [37]. The high electronegativity obtained for these mole­
lated using Eq. (3). Global softness, s (Eq. (4)), is the inverse of global cules indicate they are good electron acceptors. In water, 3-hydroxyfla­
hardness, η and demonstrates the molecule’s susceptibility to charge vone had the highest χ value (4.50 eV) while Gossypetin had the lowest
transfer. Gossypetin has the smallest η value (2.862 eV) and invariably (4.15 eV). A possible explanation for high electronegativity for 3-
the highest s value of 0.349 eV in water. On the other hand, Natsudai­ hydroxyflavone is the lack of the –OH group on the phenyl moiety
dain has η value of 3.107 eV and s value of 0.321 eV. Hence, Gossypetin which leads to the molecule having a partially positive side. Gossypetin,
is the softest molecule, most susceptible to charge transfer and the most on the other hand is almost surrounded by –OH groups, hence an even
chemically reactive. Natsudaidain is the hardest molecule of all the electron distribution which accounts for the reduced electronegativity.
flavonols, most resistant to charge transfer and the least reactive.
χ= − μ (5)
E − EH
η= L (3) The electrophilicity index (ω), describes the stabilization energy of
2
the molecule when saturated by electrons approaching from the sur­
1 roundings; and is expressed by Eq. (6) [37]. The electron donating
s= (4)
η power and the electron accepting power are denoted as ω− and ω+, (Eqs.

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E.O. Akintemi et al. Computational and Theoretical Chemistry 1210 (2022) 113658

Table 1
Chemical reactivity descriptors for the 15 flavonols.a
EL EH Egap η S μ χ ω ω− ω+ Δω± μD I

3Hf(g) − 1.36 − 7.56 6.200 3.100 0.322 − 4.46 4.46 3.222 10.443 2.749 13.193 5.236 7.962
(w) − 1.42 − 7.58 6.161 3.080 0.324 − 4.50 4.50 3.291 11.856 2.849 14.706 8.012 6.153
(eth) − 1.39 − 7.56 6.168 3.084 0.324 − 4.47 4.47 3.249 11.747 2.793 14.540 7.714 6.184

Aza(g) − 0.98 − 7.33 6.346 3.173 0.315 − 4.15 4.15 2.725 9.561 2.085 11.646 4.899 7.626
(w) − 1.08 − 7.28 6.196 3.098 0.322 − 4.18 4.18 2.827 10.615 2.244 12.859 7.907 5.916
(eth) − 1.04 − 7.26 6.218 3.109 0.321 − 4.15 4.15 2.778 10.490 2.177 12.667 7.583 5.944

Fis(g) − 1.14 − 7.30 6.155 3.077 0.324 − 4.22 4.22 2.899 9.782 2.343 12.125 6.663 7.649
(w) − 1.25 − 7.23 5.979 2.989 0.334 − 4.24 4.24 3.017 11.029 2.534 13.564 10.188 5.880
(eth) − 1.22 − 7.22 5.999 2.999 0.333 − 4.22 4.22 2.968 10.907 2.466 13.374 9.830 5.894

Gal(g) − 1.42 − 7.47 6.049 3.024 0.330 − 4.44 4.44 3.271 10.434 2.850 13.284 4.617 7.925
(w) − 1.36 − 7.39 6.035 3.017 0.331 − 4.37 4.37 3.177 11.488 2.729 14.218 6.566 6.102
(eth) − 1.34 − 7.38 6.041 3.020 0.331 − 4.36 4.36 3.151 11.421 2.694 14.116 6.387 6.130

Gos(g) − 1.28 − 7.08 5.796 2.898 0.345 − 4.18 4.18 3.018 9.775 2.578 12.354 5.654 7.481
(w) − 1.28 − 7.01 5.724 2.862 0.349 − 4.15 4.15 3.009 10.886 2.584 13.470 8.201 5.687
(eth) − 1.26 − 6.99 5.732 2.866 0.348 − 4.12 4.12 2.975 10.796 2.536 13.333 7.974 5.707

Kfd(g) − 1.07 − 7.34 6.262 3.131 0.319 − 4.20 4.20 2.829 9.715 2.232 11.947 5.236 7.706
(w) − 1.12 − 7.30 6.179 3.089 0.323 − 4.21 4.21 2.874 10.737 2.307 13.044 6.726 5.979
(eth) − 1.09 − 7.28 6.189 3.094 0.323 − 4.19 4.19 2.841 10.651 2.263 12.914 6.622 6.007

Kfr(g) − 1.27 − 7.33 6.063 3.031 0.329 − 4.30 4.30 3.058 10.033 2.568 12.602 5.675 7.731
(w) − 1.25 − 7.22 5.969 2.984 0.335 − 4.23 4.23 3.005 10.993 2.521 13.514 8.272 5.899
(eth) − 1.22 − 7.20 5.980 2.990 0.334 − 4.21 4.21 2.973 10.910 2.476 13.387 8.040 5.922

Iso(g) − 1.11 − 7.32 6.210 3.105 0.322 − 4.21 4.21 2.864 9.749 2.287 12.036 6.086 7.681
(w) − 1.13 − 7.23 6.091 3.045 0.328 − 4.18 4.18 2.875 10.697 2.326 13.024 8.368 5.901
(eth) − 1.11 − 7.21 6.104 3.052 0.327 − 4.16 4.16 2.845 10.620 2.286 12.906 8.184 5.950

Mor(g) − 1.35 − 7.34 5.991 2.995 0.333 − 4.35 4.35 3.162 10.185 2.721 12.907 3.921 7.688
(w) − 1.25 − 7.15 5.893 2.946 0.339 − 4.20 4.20 3.000 10.943 2.532 13.476 6.106 5.812
(eth) − 1.24 − 7.14 5.902 2.951 0.338 − 4.19 4.19 2.978 10.886 2.501 13.388 5.875 5.834

Myr(g) − 1.32 − 7.34 6.014 3.007 0.332 − 4.33 4.33 3.122 10.123 2.663 12.786 6.476 7.717
(w) − 1.29 − 7.18 5.888 2.944 0.339 − 4.23 4.23 3.047 11.067 2.595 13.662 9.548 5.880
(eth) − 1.27 − 7.17 5.902 2.951 0.338 − 4.22 4.22 3.019 10.997 2.554 13.552 9.265 7.151

Nat(g) − 0.99 − 7.30 6.305 3.152 0.317 − 4.14 4.14 2.729 9.542 2.097 11.640 4.852 7.420
(w) − 1.20 − 7.41 6.215 3.107 0.321 − 4.31 4.31 2.990 11.068 2.446 13.514 7.127 5.892
(eth) − 1.15 − 7.38 6.230 3.115 0.320 − 4.26 4.26 2.925 10.899 2.360 13.259 6.888 5.905

Pac(g) − 1.14 − 7.22 6.084 3.042 0.328 − 4.18 4.18 2.880 9.699 2.335 12.034 3.342 7.386
(w) − 1.24 − 7.26 6.016 3.008 0.332 − 4.25 4.25 3.005 11.015 2.510 13.526 5.179 5.932
(eth) − 1.21 − 7.23 6.019 3.009 0.332 − 4.22 4.22 2.967 10.913 2.460 13.373 4.984 5.931

Que(g) − 1.33 − 7.32 5.998 2.999 0.333 − 4.33 4.33 3.126 10.121 2.672 12.793 5.173 7.714
(w) − 1.27 − 7.16 5.888 2.944 0.339 − 4.22 4.22 3.024 11.005 2.564 13.570 7.643 5.895
(eth) − 1.39 − 7.56 5.899 3.084 0.324 − 4.47 4.47 3.249 11.747 2.793 14.540 7.415 5.911

Rhz(g) − 1.05 − 7.32 6.274 3.137 0.318 − 4.19 4.19 2.800 9.665 2.193 11.859 8.619 7.675
(w) − 1.11 − 7.25 6.141 3.070 0.325 − 4.18 4.18 2.850 10.653 2.284 12.938 11.992 5.911
(eth) − 1.08 − 7.24 6.156 3.078 0.324 − 4.16 4.16 2.817 10.568 2.239 12.807 11.721 5.946

Rht(g) − 1.34 − 7.17 5.829 2.914 0.343 − 4.26 4.26 3.118 9.991 2.702 12.693 5.895 7.525
(w) − 1.30 − 7.10 5.806 2.903 0.344 − 4.20 4.20 3.044 11.018 2.610 13.692 8.630 5.814
(eth) − 1.28 − 7.09 5.806 2.903 0.344 − 4.19 4.19 3.027 10.972 2.587 13.560 8.419 5.824
a
Units for the chemical reactivity descriptors are in electron volts (eV) EL: LUMO energy, EH: HOMO energy, Egap: HOMO-LUMO energy gap, η: Chemical hardness,
S: Chemical softness, μ: Chemical potential, χ: Electronegativity, ω: Electrophilicity index, ω-: Electron donating power, ω+: Electron accepting power, Δω±: Net
electrophilicity, μD: Dipole moment, I: Ionization potential, g: gas phase, w: water and eth: ethanol.

4
E.O. Akintemi et al. Computational and Theoretical Chemistry 1210 (2022) 113658

Fig. 3. Comparison of the energy gaps in gas-phase, water and ethanol.

(7) and (8)) respectively [38]. The multiphilic descriptor [39] or net hyperpolarizability (β) are indicators for the application of organic
electrophilicty [1] Δω±, (Eq. (9)) gives a better description of intermo­ compounds as non-linear optical (NLO) materials are reported [43–47].
lecular reactivity [40]. The results show that on average the flavonols The polarizablities and hyperpolarizabilities illustrate the reaction of a
have an electron donating power, ω− of approximately 10 eV which is system in an applied electric field. They are essential features of atomic
much higher than the electron accepting power, ω+ of about 3 eV. This and molecular systems. The donor and acceptor substituents offer the
means that the flavonols are strongly nucleophilic and weakly required ground-state charge asymmetry, while the π-conjugated system
electrophilic. offers a pathway for the reallocation of electric charges as a response to
the control of electric fields [46].
(EL + EH )2 Since there were no experimental NLO values for these flavonols,
ω= (6)
4(EL − EH ) urea and pure tetramethylurea were chosen as the reference compounds
[48,49]. Urea and pure tetramethylurea have first hyperpolarizabilities
(3EH − EL )2 β, 0.32 × 10− 30 esu and 0.41 × 10− 30 esu respectively [50]. Using these
ω− = (7)
16η values as the comparative threshold for the study, it can be inferred that
all these natural flavonols have the capacity for non-linear optical ap­
(EH + 3EL )2 plications, since their β values are greater than those for both urea and
ω+ = (8)
16η pure tetramethylurea. Interestingly, the comparison shows that

Δω± = ω+ + ω− (9)
The ionization potential, I (Eq. (10)) is the difference between the Table 2
positively charged aromatic hydroxyl species (ArOH+) and neutral ar­ Non-linear optical properties.
omatic hydroxyl species (ArOH) [41,42]. Ionization potential is also α (esu) Δα (esu) β (esu)
inversely proportional to reactivity so the lower the ionization potential, 3-Hydroxyflavone − 1.47 × 10− 23
4.05 × 10− 24
0.71 × 10− 30

the higher the chemical reactivity. Generally, the ionization potentials Azaleatin − 1.89 × 10− 23
2.75 × 10− 24
1.41 × 10− 30

in water were the lowest when compared to the other solvents. This Fisetin − 1.65 × 10− 23
5.58 × 10− 24
1.63 × 10− 30
23 24 30
reiterates the fact that the chemical reactivity of the flavonols is best in Galagin − 1.62 × 10− 5.85 × 10− 0.59 × 10−
23 24 30
Gossypetin 1.90 × 10− 3.54 × 10− 2.00 × 10−
water since this medium provides favourable interaction via hydrogen
−
23 24 30
Isorhamnetin − 1.93 × 10− 1.44 × 10− 1.61 × 10−
bonding. Gossypetin has the lowest I value (5.687 eV) in water relative Kaempferide − 1.78 × 10− 23
6.24 × 10− 24
1.13 × 10− 30

to other flavonols thus making it the most chemically reactive molecule. Kaempferol − 1.72 × 10− 23
3.14 × 10− 24
1.30 × 10− 30
23 24 30
Morin − 1.82 × 10− 2.38 × 10− 1.25 × 10−
I = EArOH + − EArOH (10) Myricetin − 1.89 × 10− 23
1.88 × 10− 24
1.60 × 10− 30
23 24 30
Natsudaidain − 2.48 × 10− 3.19 × 10− 0.56 × 10−
The relationship between energy gap and ionization potential is Pachypodol − 2.03 × 10− 23
2.00 × 10− 24
1.16 × 10− 30

presented in the Supporting Information (Table S3). Quercetin − 1.85 × 10− 23

2.17 × 10− 24
1.34 × 10− 30
23 24 30
Rhamnetin − 1.97 × 10− 4.62 × 10− 1.31 × 10−
23 24 30
3.2. Polarizabilties and hyperpolarizabilities Rhamnazin − 2.07 × 10− 2.12 × 10− 2.10 × 10−

α is linear or mean polarizability, Δα is anisotropy of polarizability, and β is first

Polarizabilities (α), anisotropy of polarizability Δα, and first order order hyperpolarizability. See Supporting Information for equations.

5
E.O. Akintemi et al.
Gossypetin and Rhamnazin (β values of 2.00 × 10− 30 esu and 2.10 ×
10− 30 esu, respectively, Table 2) are each around 6 times more active,
Isorhamnetin and Myricetin are 5 times as active, Azaleatin, Kaemp­
feride, Kaempferol, Morin, Quercetin and Rhamnetin are 4 times as
active, Pachypodol is 3 times as active while 3-hydroxyflavone, Galagin
and Natsudaidain are 2 times as active as urea for non-linear optical
applications.
Sankar and Philip [51] described NLO as the study of the interaction
of intense light fields with matter. They state that molecules which are
anisotropic and display a linear anisotropic polarizability tend to show
an optically isotropic behavior in the bulk when their orientation is
randomly distributed. In our study we found that all compounds exhibit
some measure of linear polarizability, α and anisotropy of polarizability,
Δα. Hence, all should have optical isotropic behavior if their orienta­
tions are randomly distributed.
It should be noted that the moderate NLO properties displayed by the
15 flavonols can be improved by derivatisation if materials scientists
consider bioactive compounds for applications in optoelectronics and as
conductors [23,24].
3.3. Atomic charge and electrostatic potential
Electrical charge in the molecule are the driving force of electrostatic
interactions (Fig. 4, see the Supporting Information for all flavonols). It
is proven that electron density or charge are important in chemical re­
actions and physicochemical properties of compounds [52].Charge-
based descriptors are widely employed as chemical reactivity indices or
as a measure of weak intermolecular interactions. Many quantum-
chemical descriptors are derived from the partial charge distribution
in a molecule or from the electron density on specific atoms [52]. The
calculated net atomic charges, Q [53] describe the molecular polarity of
the molecules.
A uniform distribution of charge was found for all molecules. For
Gossypetin, which had the lowest energy gap and was the most reactive,
it had the highest negatively charged atom (− 0.714 a.u.) which is the
oxygen atom of the hydroxyl group at C3′ position (Fig. 4). This charge is
significant for the antioxidant property of the molecules due to the role
the –OH group plays in scavenging radicals. On the other hand, the
highest positively charged atom (0.518 a.u.) is the hydrogen atom of the
hydroxyl (–OH) group at the C5 position of the ring A which is also
important for the reactivity of the compound since the presence of –OH
at position C5 is important for antioxidant activities. Secondly, this
hydrogen atom is involved in free radical inhibition activity because
phenolic compounds inhibit free radicals by transfer of the hydrogen
atom from its hydroxyl group [54].
Water is a polar solvent whereas ethanol is less polar than water due
to its non-polar hydrocarbon. Studies on the effect of solvent polarity on
Fig. 4. Atomic charge distribution in Gossypetin.
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Computational and Theoretical Chemistry 1210 (2022) 113658
the scavenging activity of flavonols reveal that water gives higher con­
centrates than ethanol. Rhaman et al. [55] reported that a water extract
solution of C. asiatica had higher polyphenols and flavonol content than
those of 100% ethanol solution extract. The work of Fang Tian and co-
workers [56] also showed that the total polyphenol (TPP) content ob­
tained from a water extract of Galla chinensis is much more than that
obtained for the ethanol extract. These properties also reflected in their
half maximum effective concentration (EC50) measurements.
3.4. Molecular electrostatic potential surface
The 3-D molecular electrostatic potential (MEP) surfaces (Fig. 5) aid
in determining the reactivity of molecules [57–60]. The blue region
indicates the positive potential of the molecule and hence is the area
where there is proton repulsion. The red region has negative potential
and represents proton attraction [61]. The MEP surfaces for all the fla­
vonols show an overall region of positive potential around protons of the
C7, C4′ and C3′ . Conversely, areas of negative potential are around the
oxygen atoms of the hydroxyl groups C3 and C5 as well as the C4
carbonyl group. This further verifies the necessity of the hydroxyl and
carbonyl groups for effective antioxidant properties of flavonols.
Kumar and Pandey [62] report that the B ring hydroxyl configuration
is important for the reactive oxygen species (ROS) and reactive
hydrogen species (RHS) scavenging ability of flavonols. The reason for
this is that the ring offers a hydrogen and an electron to the hydroxyl as
well as the peroxyl radical, and still maintains a stable flavonoid radical.
Since C4′ and C3′ are on the B ring and have an area of positive potential
it will bind to the negatively charged side groups of amino acids such as
aspartic acid and glutamic acid. Conversely, the areas of negative po­
tential will have an affinity for the positively charged side groups of
amino acids (lysine, arginine and histidine) and sugar moieties to
become β-glycosides.
3.5. UV–vis spectroscopy
UV–visible spectroscopy has emerged as the most favoured tech­
nique to evaluate the phenolic properties and content of bioactive
compounds. The phenolic ring in bioactive molecules have the ability to
absorb UV light. Some phenolic compounds also show absorption in the
visible region since they are coloured. Hence, these features, make
UV–visible spectroscopy the appropriate technique to examine bioactive
phenolic compounds. [63]. To determine the total antioxidant activity,
in bioactive compounds, the absorbance is measured against water and
used to calculate the inhibition percent. The absorbance value is also
used to calculate total phenol content and total flavonoid [64]. In this
study a single-point (SP) energy calculation provides the HOMO and
LUMO energies (Table 1). All the flavonols have two or three charac­
teristic absorption peaks in each medium (gas-phase, ethanol or water).
Each absorption peak is associated with an electron transition from the
ground state to its excited state and has a corresponding excitation
energy.
It has been reported that ethanol and water or a mixture of these
solvents is suitable since the hydroxyl groups are soluble in the solvents
[65–67]. We chose water as the solvent for the UV–vis calculation since
this is preferred medium for drug delivery. The maximum absorption
wavelength, λmax, of the flavonols in water and the excitation energies
are presented in the Supporting Information (Table S4). This study
shows that the maximum wavelength of absorption is inversely pro­
portional to the excitation energy (Fig. 6). Hence, the promotion of an
electron from the ground state to the excited state at longer wavelengths
require low energy, and vice versa. Gossypetin with the lowest excita­
tion energy and the highest wavelength, implies that the compound is
the most active flavonol. Azaleatin, Natsudaidain and 3-hydroxyflavone
have high excitation energies indicating low activity.
Time-dependent density functional theory (TD-DFT) calculations
gave information on electronic transitions such as which orbital was
E.O. Akintemi et al.
Fig. 5. Molecular electrostatic potential (MEP) surface for the 15 flavonols.
involved in the transitions, extinction coefficient, oscillator strength,
excitation state energies and the electronic states of the transitions. The
strongest transitions for each molecule in the aqueous medium is pre­
sented (Table 3).
Molar extinction coefficient, also known as molar absorptivity, is a
measure of how strongly a chemical species attenuates light at a given
wavelength [68]. All molecules have high molar absorptivity hence,
they strongly attenuate light.
Oscillator strength is a measure of the probability of excitation [69].
The strongest transitions (which are presented in Table 3) were chosen
based on the highest oscillator strengths compared to other transitions.
Oscillator strength values >0.1 were obtained for all the flavonols
indicating the high probability of excited states. Ferry et al. [70] re­
ported that electronic excitation produces molecules which may relax to
give radicals through homolytic bond splitting as follows:
7
Computational and Theoretical Chemistry 1210 (2022) 113658
AB → AB*, AB** → A* + B*
where A* and B* are the resulting radicals. For flavonols, the resulting
radical is the flavonol radical (Ar*) and the hydroxyl radical (OH*)
[71,72]. The flavonol radical is very reactive. It binds to appropriate
sites to decrease lipid peroxidation and suppresses other scavenging
species.
3.6. Molecular and physicochemical properties
The protocol of adsorption, distribution, metabolism and excretion
(ADME) are very important considerations in the development of new
drug molecules. These are the parameters that play a critical part in
outlining the dose amounts, dosing intervals and overall safety of oral
E.O. Akintemi et al. Computational and Theoretical Chemistry 1210 (2022) 113658

Fig. 6. Relationship between excitation energy and maximum absorption wavelength.

Table 3
Strongest transitions of electronic absorptions in water.
Orbitals Extinction coefficient Oscillator strength 1st Excitation state energy (eV) Electronic state

3-Hydroxyflavone 62 → 63 0.69593 0.5853 4.0629 1– A′

Azaleatin 82 → 83 0.67399 0.6304 4.0893 1– A
Fisetin 74 → 75 0.68233 0.7263 3.9648 1– A′
Galagin 70 → 71 0.69162 0.5167 3.8835 1– A′
Gossypetin 82 → 83 0.69094 0.4697 3.6362 1– A′
Isorhamnetin 82 → 83 0.67397 0.5832 3.9387 1– A
Kaempferide 78 → 79 0.68557 0.5917 3.9739 1– A
Kaempferol 74 → 75 0.68985 0.6727 3.8482 1– A′
Morin 78 → 79 0.69057 0.7088 3.7732 1– A′
Myricetin 82 → 83 0.68062 0.6660 3.8173 1– A′
Natsudaidain 110 → 111 0.67673 0.5571 4.0803 1– A
Pachypodol 90 → 91 0.66378 0.6832 3.9156 1– A
Quercetin 78 → 79 0.68405 0.6886 3.8101 1– A′
Rhamnetin 82 → 83 0.68520 0.7309 3.7401 1– A
Rhamnazin 86 → 87 0.67131 0.5721 3.9819 1– A

drug administration [73]. Hence determining physicochemical proper­
ties are vital [74] because these properties have an impact on various
ADME attributes and can be easily controlled by medicinal chemists.
The primary objective is to find the desirable balance of physicochem­
ical properties for safe drug administration [75].
The logarithm of octanol–water partition coefficient (log POW) is a
broadly acknowledged measure of lipophilicity and is determined for
numerous compounds [76]. POW is the concentration ratio of the com­
pound distributed between n-octanol and water [77,78]. Note: in this
report, the subscript OW for the octanol–water partition coefficient, is
omitted. The partition coefficient is an exceedingly important physico­
chemical parameter in medicinal chemistry, beneficial in pharmacology
and toxicology, as long-established by a large numeral of literature data
[79,80].
In a study from Li et al. [81] they report that for active flavonols the
log P value is principally 1.6 upward. So, values below this imply a
reduced inhibitory activity. Gossypetin and Myricetin, which are
structural isomers with the molecular formula C15H10O8, have low
miLogP values (miLogP refers to the octanol–water partition coefficient
as reported in Molinspiration) (1.42 and 1.39, respectively) (Table 4).
Despite the value implying reduced inhibitory activity they display
strong chemical reactivity as already discussed.
Vlahovic et al. [82] as well as Keen [83] and Shargel et al. [84] report
that hydrophobic substances have a high octanol–water partition

8
E.O. Akintemi et al. Computational and Theoretical Chemistry 1210 (2022) 113658

Table 4
Physicochemical parameters for flavonols.
miLogPa TPSAb Natomsc MWd nONe nOHNHf nviolationsg nrotbh Volumei

3-Hydroxyflavone 3.45 50.44 18 238.24 3 1 0 1 208.01

Azaleatin 1.96 120.36 23 316.26 7 4 0 2 257.61
Fisetin 1.97 111.12 21 286.24 6 4 0 1 232.07
Galagin 2.65 90.89 20 270.24 5 3 0 1 224.05
Gossypetin 1.42 151.58 23 318.24 8 6 1 1 248.10
Isorhamnetin 2.71 100.13 22 300.27 6 3 0 2 249.59
Kaempferide 2.17 111.12 21 286.24 6 4 0 1 232.07
Kaempferol 1.99 120.36 23 316.26 7 4 0 2 257.61
Morin 1.88 131.35 22 302.24 7 5 0 1 240.08
Myricetin 1.39 151.58 23 318.24 8 6 1 1 248.10
Natsudaidain 3.08 105.84 30 418.40 9 1 0 7 361.29
Pachypodol 2.80 98.37 25 344.32 7 2 0 4 292.67
Quercetin 1.68 131.35 22 302.24 7 5 0 1 240.08
Rhamnetin 2.53 109.36 24 330.29 7 3 0 3 275.14
Rhamnazin 2.22 120.36 23 316.26 7 4 0 2 257.61
a
Octanol–water partition coefficient as reported in Molinspiration.
b
Total polar surface area in Å2.
c
Total number of atoms.
d
Molecular Weight in g mol− 1.
e
Number of hydrogen bond acceptors.
f
Number of hydrogen bond donors.
g
Number of violations to Lipinski’s rule of 5.
h
Number of rotatable bonds.
i
Volume in in Å3. Formulae and total energy are presented in Table S2.

coefficient which is distributed primarily in the lipid bilayers of cells.
Hydrophilic substances on the other hand have a low octanol–water
partition co-efficient and are distributed in blood plasma. They also
showed the linear relationship of the octanol–water partition coefficient
with log P. This explains the high miLogP values obtained for Natsu­
daidain and 3-hydroxyflavone (3.08 and 3.45, respectively) (Table 3).
Our deduction is that these two compounds are hydrophobic and are
easily distributed in the lipid bilayers. On the other hand, Gossypetin
and Myricetin with low miLogP values (1.42 and 1.39 respectively)
(Table 4) are hydrophilic and will be readily distributed in blood
plasma. This also conforms to the high reactivity observed for Gossy­
petin and Myricetin in water.
3.7. Drug likeness/bioactivity score
In drug discovery the critical phase is the hit-to-lead optimization.
Medicinal chemists use drug-likeness as the essential guide for drug
discovery [85,86]. The ADME parameters referred to as the pharmaco­
kinetic properties are also strongly affected by the physicochemical
properties of a drug [87,88]. As already stated a drug-like molecule must
be soluble in water as well as fat. This is necessary since after ingestion,
an orally administered drug passes through the intestinal lining into the
bloodstream and is carried to the target. The molecule then penetrates
the lipid-based cell membrane to get into the target cell [85]. Hydrogen
bonds have an important role in water solubility since to enable the
molecule to permeate into and through the lipid bilayer membrane, this
bond must break. Additionally, increased hydrogen bonds results in
increased aqueous solubility. The molecule is hence less hydrophobic,
which reduces partitioning [89].
Bioavailability refers to the rate and extent to which the flavonol is
absorbed from the fruit or vegetable and is available at the site of action.
Veber and co-workers [90] carried out oral bioavailability measure­
ments on over a thousand possible drug candidates and report that
compounds will have a high probability of good oral bioavailability if
they meet following criteria: (1) a total polar surface area (TPSA) ≤ 140
Å2 and, (2) if the number of rotatable bonds (nrotb) ≤ 10. All the fla­
vonols fulfil this criteria with the exception of Gossypetin and Myricetin
that have high total polar surface area (151.58 Å2) (Table 4) implying
they have reduced permeability in lipid membranes.
The Lipinski’s rule of 5 states that for a drug molecule to be orally
active it should obey the following rules: number of hydrogen bond
donors (nOHNH) ≤ 5, number of hydrogen bond acceptors (nON) ≤ 10,
molecular weight (MW) ≤ 500, partition coefficient (miLogP) ≤ 5, and
number of violations (nviolations) ≤ 2 [91]. All the flavonols comply
with the Lipinski rule of 5 (Table 4), confirming that all are orally active
drug molecules. We found that the molecular weight of the flavonols is
directly proportional to the volume of the compounds (Fig. 7). The
Pearson correlation co-efficient (r) of 0.97 and R2 value of 0.94 verify
this.
For an average organic molecule, if the bioactivity score is more than
0 then it is active, a score ranging from − 0.50 to 0.0 indicates moder­
ately active and a score of less than − 0.50 denotes inactivity [92]. The
results are presented in Table S5 (Supporting Information) but are
depicted in Fig. 8.
All 15 compounds are excellently active (Fig. 8) as enzyme inhibitors
(EI). Although 3-hydroxyflavone (1) is a synthesized compound, it is a
strong enzyme inhibitor (0.31). The two natural flavonols that are
closest to this is Gossypetin (5) and Myricetin (10) which have enzyme
inhibitor values of 0.30. Galagin (4), Morin (9), and Quercetin (13) with
an enzyme inhibitor values of 0.28 is also good. Flavonol (1) is inactive
as a nuclear receptor ligand (NRL). Morin (9) and Natsudaidain (11) are
moderately active, while the remaining 9 are strongly active as kinase
inhibitors (KI). In addition, all demonstrate moderate activity as G-
protein-coupled receptors (GPCR), ion channel modulators (ICM) and
Fig. 7. Relationship between volume and molecular weight.

9
E.O. Akintemi et al.
Fig. 8. Profile depicting bioactivity score.
protease inhibitors (PI).
4. Conclusion
All the flavonols investigated are chemically reactive. We have
shown that the highest negative charge for the oxygen atom on C-3′
hydroxyl and highest positive charge on the H atom of C5-OH to be
crucial for antioxidant activity. The energy gap is lower in water and this
is important because water is the medium for drug delivery. All the
flavonols are reactive with Gossypetin having the lowest Egap. This also
highlights the hydrophilic property of flavonols. The potential distri­
butions on the MEP surfaces of the flavonols showed the hydroxyl and
carbonyl groups are required for effective antioxidant properties.
Although the flavonols investigated exhibit moderate NLO properties,
this value can be improved by derivatisation for application in materials
science.
The quantum chemical calculations of their physicochemical prop­
erties showed they have good bioavailability. All the compounds agree
with the Lipinski rule of 5, indicating potential use as oral active drugs
and promising drug likeness. All the flavonols are active as enzyme in­
hibitors and moderately active as G-protein-coupled receptors, ion
channel modulators and protease inhibitors. The results presented here
can be used to further evaluate and test these flavonols in molecular
docking studies against infections and diseases.
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.
Acknowledgement
Thishana Singh acknowledges the National Research Foundation
(NRF) South Africa for the Post-PhD Thuthuka grant, the UKZN RO Fund
and RSC Research Fund Grant (R20-2009) for financial support. All
computations were carried out using the computational cluster re­
sources at the Centre for High Performance Computing (CHPC), Cape
Town, South Africa.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.comptc.2022.113658.
10
Computational and Theoretical Chemistry 1210 (2022) 113658
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