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Chemical Reactivity, Drug-Likeness and Structure Activity/Property

Relationship Studies of 2,1,3-Benzoxadiazole Derivatives as Anti-Cancer
Activity

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DOI: 10.1166/jbns.2018.1503

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 Copyright © 2018 American Scientific Publishers Journal of
All rights reserved Bionanoscience
Printed in the United States of America Vol. 12, 1–9, 2018

Chemical Reactivity, Drug-Likeness and

Structure Activity/Property Relationship Studies of
2,1,3-Benzoxadiazole Derivatives as Anti-Cancer Activity
Imane Almi1 , Salah Belaidi1 ∗ , Nadjib Melkemi1 , and Djemoui Bouzidi2
1
Group of Computational and Pharmaceutical Chemistry, LMCE Laboratory, University of Biskra, BP 145 Biskra 07000, Algeria
2
East Central College, 1964 Prairie Dell Road, Union, Missouri 63084, USA

In this paper, we evaluate the ability of three methods (HF, DFT, and MP2) using a collection of
basis sets to determine atomic and molecular properties for 2,1,3-benzoxadiazole. We have cal-
culated DFT reactivity descriptors of the system (chemical potential (), chemical hardness (),
electrophilicity (), condensed Fukui function and Dual descriptor) at B3LYP/6-311++G (d,p) to
identify changes in the reactivity of the system in gas and aqueous phases. The molecular elec-
trostatic surface potential (MESP) was determined to show the most active center in a molecule.
The Rules-of-Thumb, analyses of Golden triangle, and structure activity/property relationship also
have been applied in a series of twenty derivatives of 2,1,3-benzoxadiazoleto identify successfully
the compounds related to good oral absorption.
Keywords: 2,1,3-Benzoxadiazole, Reactivity, DFT, Drug-Likeness, MESP, SAR/SPR.

1. INTRODUCTION
The molecular modeling1 is used in many fields specially,
physics, chemistry, ecology, material science as well as tis-
sue engineering, and drug design.2 3 It is the science that
deals with the discovery and design of new therapeutic
chemicals or biochemical and their development into use-
ful medicines.4 The chemistry and biological study of het-
erocyclic compounds have been an interesting field for a
long time in medicinal chemistry. Many heterocyclic com-
pounds containing heteroatoms such as nitrogen and sulfur
atom serve as a unique and versatile scaffold for experi-
mental drug design.5
Concerning bioactive compounds, benzoxadiazole
derivatives have been widely studied for their differ-
ent biological activities and clinical applications. The
2,1,3-benzoxadiazole moiety has Antibacterial, Antipara-
sitical, Treatment of Neuronal Disorders,6 antiviral,6 and
Antitumoral activities.6 7
Cancer is one of the leading causes of morbidity and
mortality. It is a major public health problem in the world,
and the second leading cause of death globally, and was
responsible for 8.8 million deaths in 2015.8 Chemotherapy
is one of the commonly-used strategies in cancer treat-
ment. A number of drugs can be used in treatment of
∗
Author to whom correspondence should be addressed.
RESEARCH ARTICLE
cancer. However these drugs can’t play their role because
the enzyme of detoxification will attack these drugs. The
2,1,3-benzoxadiazole and its derivatives have a consider-
able attention to inhibit this enzyme of detoxification and
to enhance the anticancer activity of drugs.
Many useful and important concepts in chemistry have
been identified by and derived from density functional the-
ory (DFT).9–11 To study these biologically important type
of compounds, we use DFT method. It is a very use-
ful convenient framework for the discussion of chemical
reactivity.12
Absorption-Distribution-Metabolism-Excretion (ADME)
parameters are of critical importance in the development
of new drug molecules due to their role in defining dose
amounts, dosing intervals and overall safety margins.13
Attention has been paid to physicochemical parameters14
because manipulation of these parameters is something
medicinal chemists can relate to easily, and more-
over, these parameters have a direct bearing on various
ADME attributes. The goal is to find the right balance
of physicochemical properties because some parame-
ters have an orthogonal dependence on physiochemical
parameters.15
The aim of this work is the comparison of different
methods and basis sets in order to find a more suitable
method and basis set in predicting geometry and electronic
of 2,1,3-benzoxadiazole. We studied the effect of solvent

J. Bionanosci. 2018, Vol. 12, No. xx 1557-7910/2018/12/001/009 doi:10.1166/jbns.2018.1503 1

 Chemical Reactivity, Drug-Likeness and Structure Activity/Property Relationship Studies Almi et al.

on the system of 2,1,3-benzoxadiazole. Therefore, we con-

sider that this kind of study will contribute to get a better
understanding of the chemical behavior, in the gas and
solution phases, of this important compound. In the second
part we used the Rule-of-Thumb, Golden Triangle, and the
study of structure-activity/property relationship to identify
compounds with high proprieties.
The rest of this paper is organized as follows: the second
part presents the programs and methods used. The third
part contains a detailed description and discussion about
the calculated results.

2. MATERIALS AND METHODS Fig. 1. 3D structure of 2,1,3-Benzoxadiazole (GaussView 5.0).

During this study, a package of programs are used to
do the molecular modeling calculation for the deriva- (A%) between the calculated and experimental values for
tives of 2,1,3-Benzoxadiazole. Initially the molecules were each method are given in Table I. These results indicate
pre-optimized using the Molecular Mechanics force field that of all the methods tested, DFT/B3LYP method is
(MM+ with HyperChem version 7.0.16 the most suitable for predicting the bond length of 2,1,3-
After that, we calculated the geometric and electronic benzoxadiazole. Therefore it is chosen to proceed the other
parameters using three different methods. Hartree-Forck parts of this work.
(HF), density functional theory with the Becke’s three—
parameter exchange functional and the gradient—corrected
3.2. Comparison of Atomic Charges Methods
functional of Lee, Yang and Parr (DFT/B3LYP) and
In quantum mechanical calculations, the calculation of
Möller-Plesset second order (MP2) level. With two basis
atomic charges in any molecule plays an important role in
set 6-311++G (d,p), and cc-pVDZ using Gaussian 09.17
molecular system. The Mulliken, ChelpG and NBO meth-
In this study, we use DFT to define molecular stability
ods represent reasonable atom charges for use in molecular
and reactivity descriptors, to determine a reactive site of
modeling. However, there are still some issues that remain
the molecule. We have calculated the Fukui function and
RESEARCH ARTICLE

to be explored in choosing the most appropriate partial

Dual descriptor as a descriptor of reactivity followed by
the visualization of MESP using molecular visualization
software (Gaussian graphical interface GaussView 5.0.8).
Finally, a study of structure activity/property relationship
was done. The calculated parameters of drug-likeness real-
ized with the Calculator Plugins of MarvinSketch 6.2.118
software according to the rule of five and Veber’s rules.
3. RESULTS AND DISCUSSION
3.1. Validation of Methods
In the molecular case, the choice of method and basis set
is of great importance to the accuracy of calculations. The
present geometric optimization of 2,1,3-benzoxadiazole
(Fig. 1) was made by ab initio/HF, DFT/B3LYP, and ab ini-
tio/MP2methods and are listed in Table I. These values are
compared to the experimental results19 of bond lengths, to
determining the best method and basis set to complete our
study with it. Also, the values of dihedral angle are calcu-
lated which equals zero and 180, which explains that the
geometry of 2,1,3-benzoxadiazole is planar.
A comparison of bond lengths calculated with vari-
ous methods using the 6-311++G (d,p), and cc-pVDZ
basis set for the molecular of 2,1,3-benzoxadiazole is
shown in Table I. These results show that DFT/B3LYP
method in better agreement with experimental19 data than
all other methods used. The mean absolute deviations
atomic charges for modeling of periodic systems. A major
aim of this part is to propose the most efficient method
that gives rise to the most reliable charge values for the
molecular modeling.20
Therefore, we test the performance of the different
methods Mulliken, ChelpG, and NBO. partial charges
were calculated for 2,1,3-benzoxadiazole (Table II)
with six basis sets B3LYP/6-31G, 6-311G, 6-31+G(d),
6-311+G(d), 6-31++G(d,p) and 6-311++G(d,p). The
quality of the charges was estimated from the standard
error mean (Fig. 2). It follows from these results that the
ChelpG shows the smallest standard error mean comparing
with Mulliken and NBO methods. Therefore, the ChelpG
method gives best results, according to that, we have cho-
sen ChelpG method to perform the next part of the elec-
tronic properties study.
3.3. Determined of Changes in the Reactivity
of 2,1,3-Benzoxadiazole in the Gas and
Aqueous Phases
3.3.1. Effect of Solvent on the Geometric Parameter
Theoretical studies on the effect of the solvent on the
properties and behavior of molecules are today performed
according to a large variety of methods.21 In this part
of the study, we are interested in the effect of sol-
vent on the geometric parameter of 2,1,3-benzoxadiazole.

2 J. Bionanosci. 12, 1–9, 2018

Almi et al. Chemical Reactivity, Drug-Likeness and Structure Activity/Property Relationship Studies

Table I. Bonds lengths experimental and calculated values of 2,1,3-benzoxadiazole.

ab initio/HF DFT/B3LYP ab initio/MP2

19
Parameters EXP 6-311++ G(d,p) cc-pVDZ 6-311++ G(d,p) cc-pVDZ 6-311++ G(d,p) cc-pVDZ

Bond length (Å)

O1-N2 1.371 1,325 1,325 1.366 1,363 1.359 1.359
N2-C3 1.312 1,282 1,287 1.319 1,325 1.353 1.353
C3-C8 1.424 1,427 1,428 1.436 1,438 1.421 1.421
C3-C4 1.426 1,441 1,442 1.425 1,428 1.415 1.415
C4-C5 1.346 1,339 1,343 1.365 1,371 1.384 1.384
C5-C6 1.428 1,461 1,462 1.441 1,442 1.429 1.429
A% – 1.600 1.500 0.686 0.915 1.276 1.276

Note: mean absolute deviations of bond length

A% × 100
mean bond length of experimental value

This molecule is studied in the gas phase and the aque- surface of the solute and it is characterized only by its
ous phase with the PCM (Polarizable Continuum Model) dielectric constant which is 78.5 for water at 25  C.22 The
solvation model. In this model, the solvent is treated as geometrics parameters of 2,1,3-benzoxadiazole are listed
an unstructured continuum outside the solvent-accessible in Table III.

Table II. Calculated partial charges of 2,1,3-benzoxadiazole using DFT.

DFT/B3LYP Atoms 6-31G 6-311G 6-31+ G(d) 6-311+ G(d) 6-31++ G(d,p) 6-311++ G(d,p) Standard error mean

Mulliken O1 −0241 −0217 0227 0308 0254 0315 0.107

N2 −0156 −0111 −0344 −0274 −0324 −0243 0.038
C3 0140 0023 0385 −0036 −0383 −0365 0.121
C4 −0041 −0010 −0360 −0110 0472 0335 0.124
C5 −0141 −0155 −0200 −0216 −0204 −0280 0.020
C6 −0141 −0155 −0199 −0216 −0204 −0281 0.020
C7 −0041 −0010 −0360 −0110 0471 0336 0.124
C8 0140 0023 0384 −0036 −0384 −0365 0.121

RESEARCH ARTICLE
N9 −0156 −0111 −0343 −0274 −0324 −0243 0.038
H10 0170 0192 0212 0247 0185 0217 0.011
H11 0148 0169 0193 0235 0128 0179 0.015
H12 0148 0169 0193 0235 0128 0179 0.015
H13 0170 0192 0212 0247 0185 0217 0.011
NBO O1 −0172 −0170 −0139 −0140 −0139 −0140 0.007
N2 −0067 −0069 −0076 −0080 −0077 −0080 0.002
C3 0081 0081 0082 0086 0082 0087 0.001
C4 −0228 −0190 −0226 −0191 −0223 −0192 0.008
C5 −0224 −0179 −0226 −0183 −0220 −0184 0.009
C6 −0224 −0179 −0226 −0183 −0220 −0184 0.009
C7 −0228 −0190 −0226 −0191 −0223 −0192 0.008
C8 0081 0081 0082 0086 0082 0087 0.001
N9 −0067 −0069 −0076 −0080 −0077 −0080 0.002
H10 0267 0228 0263 0226 0260 0226 0.008
H11 0257 0214 0253 0212 0248 0213 0.009
H12 0257 0214 0253 0212 0248 0213 0.009
H13 0267 0228 0263 0226 0260 0226 0.008
ChelpG O1 0027 0036 0104 0103 0105 0103 0.015
N2 −0390 −0404 −0405 −0412 −0405 −0411 0.003
C3 0492 0513 0459 0478 0458 0478 0.009
C4 −0378 −0392 −0342 −0369 −0339 −0383 0.008
C5 −0043 −0052 −0061 −0055 −0059 −0038 0.004
C6 −0043 −0031 −0029 −0038 −0028 −0055 0.004
C7 −0361 −0381 −0358 −0383 −0354 −0369 0.005
C8 0466 0483 0459 0478 0457 0478 0.004
N9 −0385 −0396 −0404 −0411 −0404 −0412 0.004
H10 0196 0199 0181 0191 0179 0196 0.003
H11 0115 0119 0110 0113 0107 0109 0.002
H12 0111 0108 0101 0109 0099 0113 0.002
H13 0193 0197 0185 0196 0183 0191 0.002

J. Bionanosci. 12, 1–9, 2018 3

 Chemical Reactivity, Drug-Likeness and Structure Activity/Property Relationship Studies Almi et al.

Standard Error Mean in determining molecular reactivity. The frontier orbitals

.140
oxygen1 of HOMO and LUMO play the role of electron donor
nitrogen2
.120
carbon3 and electron acceptor respectively. The energies of HOMO
carbon4
.100 carbon5 and LUMO and their neighboring orbitals are all negative,
carbon6
.080 carbon7 which indicate the title molecule is stable.24 The calcu-
.060
carbon8
nitrogen9 lated electronic parameters such as energy gap ( Egap ,
hydrogen10
.040 hydrogen11 Chemical potential (), Chemical hardness (, and Elec-
.020 hydrogen12 trophilicity ( ) are listed in (Table IV) and are calculated
hydrogen13
.000 at B3LYP/6-311++G (d,p) level.
Mulliken NBO ChelpG
The energy gap ( Egap  is an important stability index
Fig. 2. Standard error mean of partial charges of 2,1,3-benzoxadiazole which determines the chemical reactivity of the molecule.
by different methods. From the values reported in Table IV, it may be observed
that the energy gap ( Egap  are small in aqueous phase
From the Table III, we can see that the total energy which makes the system more reactive compared with gas
decreases in the aqueous phase to make the system more phase. The electronic chemical potential () decreases in
stable in water, the energy difference between the molecule gas phase as well as the indices of electrophilicity ( .
in gas and aqueous phases is (−022 eV) which corre- Furthermore, the 2,1,3-benzoxadiazole have electrophilic
sponds to the solvation energy of 2,1,3-benzoxadiazole. nature in aqueous phase than the gas phase. Hardness (
Thedipole moment value increases in aqueous phase so we and softness (S) are a useful concept for understanding
can say that the solvent (water) effects the polarity of the the behavior of chemical systems. Thus, the global hard-
molecule. ness ( decreases when the solvent effect is considered
so the molecule in the gas phase is harder than aque-
3.3.2. Global Reactivity Descriptors ous phase. These results may suggest a bigger stability of
The density functional theory (DFT) defined many impor- 2,1,3-benzoxdiazole in the aqueous phase.
tant concepts of chemical reactivity via electron density
of the chemical system.23 Electronegativity (, chemi- 3.3.3. Local Reactivity Descriptors
cal potential (), chemical hardness (, chemical soft- Local and global reactivity descriptors both have been
ness (S), nucleophilicity (N), and electrophilicity ( ) are used to understand the chemical reactivity and site
the global descriptors used to understand the various qual-
RESEARCH ARTICLE

selectivity.25 26 To analyze selective site in a molecule Parr

itative concepts in chemical reactivity21 22 were calculated
using the following formulas.
 = − = −1/2 I + A S = 1/2 N = I TCE − I
 = 1/2 I − A = 2/2
Where, I and A are the vertical ionization potential energy
and the vertical electron affinity respectively, it can be
expressed as: I = −EHOMO , and A = −ELUMO , and I (TCE)
is ionization potential energy of Tetra Cyano Ethylene.
According to its definition, this index measures the
propensity of chemical species to accept electrons. Thus,
a good nucleophile is characterized by low values of 
and . Otherwise, a good electrophile is characterized by
high values of  and 23
The values of the calculated quantum chemical param-
eters such as the energy of the highest occupied molecu-
lar orbital (EHOMO , the energy of the lowest unoccupied
molecular orbital (ELUMO , and energy gap E are pre-
sented in Table IV and Figure 3. The FMOs are important
and Yang,27 define the local descriptors such as the Fukui
function. Thus, calculating Fukui functions helps us to
determine the active sites of a molecule, based on the elec-
tronic density changes experienced by it during a reaction.
Fukui functions f + r, f − r and f 0 r are calculated
using the following equations as:28 29
f − r = qk N  − qk N − 1 Electrophilic attack
f + r = qk N + 1 − qk N  Nucleophilic attack
f 0 r = 1/2 qk N + 1 − qk N − 1 Radical attack
Where qk N  the atomic population on the kth atom
for neutral molecule while qk N + 1 and qk N − 1 are
the same for its anionic and cationic species, respectively.
The values of descriptors calculated at B3LYP/6-311++G
Table IV. Reactivity descriptors for 2,1,3-Benzoxadiazole at the level
B3LYP/6-311++G (d,p).

Table III. Electronic energies and dipole moment at the level B3LYP/6- -HOMO = I -LUMO = A E  
311++ G(d,p). Phases (eV) (eV) (eV) (eV) (eV) (eV)

Phases  (D) Total energy (eV) Gas 7.2264 2.8413 4.3852 −50339 2.1926 5.7785
phase
Gas phase 4.394 −11313.46 Aqueous 7.1448 2.8535 4.2913 −49992 2.1456 5.8238
Aqueous phase 5.944 −11313.67 phase

4 J. Bionanosci. 12, 1–9, 2018

Almi et al. Chemical Reactivity, Drug-Likeness and Structure Activity/Property Relationship Studies

Fig. 3. Highest occupied molecular orbitals and lowest unoccupied molecular orbitals of 2,1,3-benzoxadiazole (a) in gas and (b) aqueous phases.

(d,p) level using ChelpG charges on atoms in molecules
are presented in Table V.
In addition to the information regarding electrophilic
and nucleophilic power of a given atomic site in the
molecule Labbe et al.30 proposed a Dual descriptor
( f r) which is given by:
f r = f + rf − r
f r is defined as the difference between the nucle-
ophilic and electrophilic Fukui function, if f r > 0,
then the site is favored for a nucleophilic attack, whereas
if f r < 0, then the site may be favored for an elec-
trophilic attack.
The calculation of Fukui functions indices and Dual
descriptor of 2,1,3-benxoadiazole obtained from ChelpG
charges in the gas and aqueous phases and at the level
B3LYP/6-311++G (d,p). From the values of Fukui func-
tions reported in Table V, in the gas phase the most elec-
to N2 and N9 . These results indicate a strong influence
of water on the reactivity showed by 2,1,3-benxoadiazole.
We can deduce the same results from the Wang et al.
works.31
3.4. Molecular Electrostatic Potential (MEP) Surface
of 2,1,3-Benzoxadiazole
The molecular electrostatic surface potential (MESP) is
related to the electronic density which can be calculated
from theoretically derived electron density or measured
experimentally has been proven useful in understanding
the interactive behavior and properties of molecules.32 It
is a very useful descriptor to predict reactive sites for
electrophilic and nucleophilic attack reactions as well as
hydrogen-bonding interactions.33 34
The MESP map (Fig. 4) is showing a region character-
ized by a red color around the nitrogen atom that refers to
a negative potential (electrophilic attack), in additional to

trophilic active site is located on C4 and C7 . In the case of
nucleophilic attacks, the most active site is on N2 and N9 .
In the aqueous phase, we can see an increase of the Fukui
function and also locate in N2 and N9 for the nucle-
ophilic attack, C4 , and C7 for the electrophilic attack, the
same conclusion will be done with the Dual descriptor in
the case of electrophilic attack. On the other hand, the
nucleophilic attack orients towards C4 and C5 in the gas
phase, whereas in aqueous phase the attack is oriented
Table V. Values of the Fukui function and Dual descriptor considering
ChelpG charges.
Gas Solvent
RESEARCH ARTICLE
that another region characterized by a blue color around
the four hydrogen atoms that refers to a positive potential
(nucleophilic attack). The green color refers to a neutral
electrostatic potential. The information contained in the
MESP is used in a variety of different classical and quan-
tum chemical models. Typical applications of the MESP
are the interpretation of molecular electronic structure,
reactivity, and structure-activity relationships.35
3.5. Drug-Likeness and Rules of Thumb
Drug-likeness is useful to medicinal chemists as a guide
for molecule design in a hit and lead optimization.36 37
In vivo38 39 pharmacokinetic parameters, such as absorption,

Atoms f+ f− f f+ f− f

O1 0074 0061 0014 0063 0046 0018

N2 0224 0193 0030 0234 0169 0064
C3 −0072 −0113 0041 −0038 −0098 0061
C4 0103 0275 −0172 0095 0308 −0213
C5 0096 0045 0051 0116 0055 0061
C6 0104 0049 0055 0105 0050 0055
C7 0097 0271 −0174 0099 0313 −0214
C8 −0066 −0114 0048 −0040 −0097 0057
N9 0221 0194 0028 0234 0169 0066
H10 0055 0016 0038 0034 0005 0030
H11 0056 0053 0002 0030 0038 −0008
H12 0054 0052 0001 0033 0040 −0006
H13 0056 0018 0038 0034 0003 0031 Fig. 4. 2D and 3D Molecular electrostatic potential surface of 2,1,3-
benzoxadiazole.

J. Bionanosci. 12, 1–9, 2018 5

 Chemical Reactivity, Drug-Likeness and Structure Activity/Property Relationship Studies Almi et al.
RESEARCH ARTICLE

Fig. 5. 2D structures of 2,1,3-benzoxadiazole derivatives.

distribution, metabolism, and excretion are strongly water/octanol partition coefficient (log P) (Fig. 6). It was
affected by the physicochemical properties of a drug. The determined that compounds which fail two or more of
analyses of ADME propriety are made by Thumb.40 these rules should probably be excluded from further
Whereas this part involves calculation of the rules development.41
of Lipinski, Veber, and analyzes of Golden Triangle of
twenty derivatives of 2,1,3-benzoxadiazole (Fig. 5) char- 1. H-bond donors ≤ 5
2. Molecular weight ≤
acterized with anti-cancer activity.7 Partition coefficient (expressed as the
500 DA
octanol/water (log P), octanol: buffer (pH 7.4) distribu- sum of OHs and NHs)
tion coefficients (logD74 , molecular weight (MW), hydro-
gen bond donors (HBD), hydrogen bond acceptors (HBA), Good in vivo drug
number of rotatable bonds (rot ) and polar surface area absorption and
permeation
(PSA) are the properties studied in the present work. The
results (Table VII) are obtained by HyperChem 7.0 and
MarvinSketch 6.2.1 software. 4. H-bond acceptors
3. log P ≤ 5 ≤ 10 (expressed as
The Lipinski rule thus proposes threshold values for the sum of Ns and Os)
the molecular weight (MW), the number of hydrogen
bond acceptors and donors (HBA and HBD) and the Fig. 6. Lipinski’s “Rule of five.”

6 J. Bionanosci. 12, 1–9, 2018

Almi et al. Chemical Reactivity, Drug-Likeness and Structure Activity/Property Relationship Studies

A drug-like molecule must have some solubility in both 500

water and fat since phases an orally administered drug 450 19

needs to pass through the intestinal lining after inges- 13 14
400
tion, be carried in aqueous blood and penetrate the lipid- 16

based cell membrane to reach the inside of a cell.36 Also, 350 15 12

MW
17 20 18 11 8
10
Hydrogen bonds play an important role in the water space 5
300 6
7 9
3
4

solubility. This bond must be broken so the molecule is 2

1
able to permeate into and through the lipid bilayer mem- 250

brane. In addition, the increase in the number of hydro- 200

gen bonds causes the increase of the aqueous solubility,
which makes the molecule less hydrophobic, and this
reduces partitioning from the aqueous phase into the lipid
bilayer membrane for permeation by passive diffusion.
The molecular weight is commensurate with the size of
the molecule, when the size increases, it can induce the
reduction of compound concentration at the surface of the
intestinal epithelium, thus reducing absorption. Increas-
ing size also impedes passive diffusion through the tightly
packed aliphatic side chains of the bilayer membrane.42
All compounds agreed with all Lipinski’s rules, which
means that the 2,1,3-benxoadiazole derivatives have a good
absorption and permeation; suggesting that these com-
pounds theoretically would not have problems with oral
bioavailability.
In contrast to the Rule of 5, Veber and coworkers found
that reduced molecular flexibility, as determined by the
number of rotatable bonds (rot < 10), and low polar sur-
face area (PSA < 140 Å2 the sum of surfaces of polar
atoms, usually oxygen, nitrogen, and attached hydrogen in
150
–3 –2 –1 0 1 2 3 4 5 6
logD
Fig. 7. Golden triangle.
3.6. Structure Activity/Property Relationships
This section involves a calculation of physicochemical
properties of 2,1,3-benxoadiazole derivatives that are illus-
trated in the Tables VI and VII with respect to their
anticancer activity.7 The properties are Surface area grid
(SAG), molar volume (V), hydration energy (HE), partition
coefficient octanol/water (logP), molar refractivity (MR),
polarizability (Pol) and molecular weight (MW). We per-
form the calculations using HyperChem 8.0.
Tables VI and VII show that there are proportional
relationships between molecular reactivity, polarizability,
molecular weight, volume, and surface. This explains that
the results are agreeing with Lorentz–Lorenz equation.47
Where compound 20 has the biggest molecular reac-

RESEARCH ARTICLE
a molecule) or a total hydrogen bond count (≤ a total of tivity and polarizability (130.55 Å3 , 45.93 Å3 ) respec-
12 number of hydrogen bond donors and acceptors) are tively. In contrast, compound 1 has the smallest values
important predictors of good oral bioavailability indepen- (78.31 Å3 , 26.86 Å3 ). By the contrary, the most active
dent of MW.43
The number of polar surface areas and rotatable bonds Table VI. Calculated pharmacological activities and properties for
or total hydrogen bond count are found to be important 2,1,3-benzoxadiazole derivatives.
predictors of good oral bioavailability.44 The polar sur- Lipinski
face area (PSA) has been used successfully to predict the MW score
absorption of drugs.45 The term polar surface area suggests Compounds logP (DA) HBD HBA of 4 PSA nrot logD
that the absorption is related to the physical interaction
1 037 27327 0 4 4 8206 3 345
of surfaces through their electrostatic potential. The series 2 090 28729 0 4 4 8206 4 351
of 2,1,3-benzoxadiazole show a value of PSA < 140 Å2 3 115 30132 0 4 4 8206 5 380
which reduces the absorption of the compounds. 4 154 31535 0 4 4 8206 6 425
Johnson and co-workers reported that molecular weight 5 −024 31728 1 6 4 11936 4 −032
(MW) and lipophilicity (LogD at pH 7.4) act as surrogates 6 −024 31728 1 6 4 11936 4 −008
7 −024 31728 1 6 4 11936 4 −003
of many different molecular descriptors and have been
8 013 34533 0 5 4 10836 6 381
used to develop a useful visualization tool of the Golden 9 −111 31629 1 5 4 12515 4 230
Triangle. Compounds that reside inside the Golden Trian- 10 −062 33229 2 6 4 13139 4 229
gle are more likely to be both metabolically stable and to 11 −061 34434 0 5 4 10237 4 275
possess good membrane permeability than those outside. 12 −069 34632 1 6 4 12039 5 268
13 001 41641 1 7 4 12962 6 358
The golden Triangle (Fig. 7) shows that the compounds 3,
14 033 42241 1 6 4 12039 7 440
4, 8, 13, 14, 17 and 19 sit outside of the triangle therefore 15 −130 36034 2 6 4 13139 6 184
these derivatives have poor permeability and clearance. 16 −088 38741 1 6 4 11440 7 141
Also, the other compounds are the inverse.36 In general, 17 −031 33130 1 6 4 11936 5 −021
lower log D and higher molecular weight molecules fail 18 009 34533 1 6 4 11936 6 034
due to low permeability while higher log D and higher 19 065 45047 1 6 4 12039 9 477
20 028 33130 1 6 4 11936 5 005
MW compounds fail due to elevated in vitro clearance.46

J. Bionanosci. 12, 1–9, 2018 7

 Chemical Reactivity, Drug-Likeness and Structure Activity/Property Relationship Studies Almi et al.

Table VII. Activity and physicochemical properties of 2,1,3- and aqueous phases. The results suggest that the interac-
benzoxadiazole derivatives.
tion of the solvation modifies the values of the reactiv-
S V HE Ref Pol ity descriptors of 2,1,3-benzoxadiazole. The values of the
Compounds pIC50 (Å2 ) (Å3 ) (Kcal/mol) (Å3 ) (Å3 ) Dual descriptor and Fukui function that indicate a strong
1 6.222 440.40 70637 −1463 7831 2686 influence of water on the reactivity of 2,1,3-benxoadiazole,
2 6.000 469.00 75527 −1407 8248 2869 and present more active sites suffered attacks electrophilic
3 6.699 497.76 81205 −1399 8723 3053 and nucleophilic. The study involves the molecular elec-
4 6.301 513.62 85390 −1351 9183 3236 trostatic potential surface to be used in predestining for
5 5.509 468.95 77132 −1940 8431 2942
binding of a drug to its actives sites.
6 5.854 482.36 78489 −1969 8431 2942
7 5.770 483.08 78428 −1966 8431 2942 The application of the rules-of-Thumb and analyses of
8 5.745 552.00 90069 −1424 9383 3309 Golden triangle on the studied benzoxadiazole derivatives
9 6.097 492.05 79587 −1912 8614 3013 shows that these compounds theoretically will not have
10 5.921 505.05 82353 −2676 8761 3077 problems with the oral bioavailability, and the most of
11 6.222 540.26 90266 −1327 9593 3380
them are more likely to be both metabolically stable and
12 6.301 547.20 88589 −2006 9265 326
13 5.921 656.78 108000 −1876 11068 3981 to possess a good membrane permeability. This well estab-
14 6.000 664.86 110278 −1997 12140 4226 lishes that successful drugs require a delicate balance of
15 5.678 568.23 93501 −2271 9733 3444 many factors relating to their biological and physicochem-
16 6.000 630.62 104926 −1507 10905 3882 ical properties.
17 6.398 511.26 83532 −2104 8886 3125
18 6.155 545.62 89257 −2088 9346 3309
19 7.000 739.86 121813 −2034 13055 4593 References and Notes
20 5.796 520.74 84371 −1931 8848 3125 1. S. Khamouli, S. Belaidi, Z. Almi, S. Medjahed, and H. Belaidi,
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2. C. Romagnoli, R. Zonefrati, D. Puppi, C. Rosati, A. Aldinucci,
compound against GSTP 1–1 is the 19th one in the 2,1,3- G. Palmini, G. Galli, F. Chiellini, F. S. Martelli, A. Tanini, and M. L.
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RESEARCH ARTICLE

change in values of hydration energy affected by the
increase or also the decrease in the number of hydrogen
bond donor and acceptor. Tables VI and VII illustrate that
compound 10 has the biggest value of hydration energy
in absolute value (−26.76 Kcal/mol) and characterized by
high value of hydrogen bonds donor and acceptor. This
property supports that this compound, not only by fixing
on the receiver, but also activates it more. Thus it is an ago-
nist, and as a consequence a better distribution in fabrics.
Lipophilicity is a major determinant of many ADME
properties. Compounds with a lower Log P are more polar
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aqueous solubility.42 For that, compound 9 has a good
aqueous solubility and a bad absorption and permeability
and vice versa for compound 4. Furthermore, Log P val-
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in the field of optimal values (0 < Log P < 3).48 To that
end, we can say that these compounds have a good oral
bioavailability and an optimal biological activity.
4. CONCLUSION
The present work includes a comparison of different cal-
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RESEARCH ARTICLE
Received: xx Xxxx xxxx. Accepted: xx Xxxx xxxx.
9