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DFT and QSAR investigations of substituent effects in pyrazolooxazine

derivatives: Activity prediction, . , Journal of Theoretical and Computational
Chemistry, Vol. 18, No. 1 (2019...

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DOI: 10.1142/S021963361950001

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Journal of Theoretical and Computational Chemistry
Vol. 18, No. 1 (2019) 1950001 (15 pages)
.c World Scienti¯c Publishing Company
#
DOI: 10.1142/S0219633619500019

DFT and QSAR investigations of substituent e®ects

in pyrazolooxazine derivatives: Activity prediction

Zehira Haddadi*, Hacene Meghezzi† and Anissa Amar‡

Laboratoire de Thermodynamique et Mod
elisation Mol
eculaire
Facult
e de Chimie, U.S.T.H.B., B.P.N
32 El Alia
16111 Bab Ezzouar, Alger, Algeria
*haddadizehira@yahoo.fr
†
hmeghezzih@yahoo.fr
‡amaranissa2005@yahoo.fr

Abdou Boucekkine
Univ Rennes, CNRS, ISCR – UMR 6226
F-35000 Rennes, France
abdou.boucekkine@univ-rennes1.fr

Norah Bennamane§ and Bellara Nedjar-Kolli¶

Laboratoire de Chimie Organique Appliqu
ee
Facult
e de Chimie, U.S.T.H.B., B.P. 32 El Alia
16111 Bab Ezzouar, Alger, Algeria
§
benamanenoura@yahoo.fr
¶
Bellara _Kolli@yahoo.fr

Salah Belaidi|| and Aicha Kerassa**

Group of Computational and Pharmaceutical Chemistry
LMCE Laboratory, University of Biskra
BP 145, 07000 Biskra, Algeria
||salah _belaidi@hotmail.com

**aichachimie1@gmail.com

Received 16 August 2018

Accepted 16 December 2018
Published 1 March 2019

The theoretical investigation of the physico-chemical properties of pyrazolooxazine derivatives,

which could exhibit anti-in°ammatory activity, has been carried out using DFT computations
at the B3LYP/6-311þþG (d, p) level. It appears that both pyrazolooxazin-2-one (1) and
pyrazolooxazin-2-thione (2) exhibit thermal stability whereas the electron donating character of
the latter is higher than that of the former species. Molecular electrostatic potential surfaces
(MESP) have been used in order to determine the activity sites of these species. The HSAB
(Hard and Soft Acids and Bases) principle helped to determine the reactivity as well as the e®ect
of substituting groups on the molecules. The stability of these compounds has been analyzed

†Corresponding author.

1950001-1
Z. Haddadi et al.

using natural bond orbital analyses NBO. Then, the structure-activity properties of a large
series of derivatives were investigated using the HyperChem 8.0.6 software considering the
Lipinski's \rule of ¯ve". The results of QSAR analyses showed that the most promising com-
pound among others, named f1 (a thiophen ring being attached to the nitrogen atom 3 of 1)
should be a good candidate for experimental testing.

Keywords: Pyrazolooxazine; DFT; NBO; electrostatic potential; structure-activity relationship;

QSAR.

1. Introduction
Oxazinones are important heterocyclic compounds because of their broad biological
activities. Considerable attention has been given to these compounds since the dis-
covery of efavirenz, a tri°uoromethyl-1, 3-oxazin-2-one compound which is a non-
nucleoside reverse transcriptase inhibitor and a selective anti-HIV drug. Several
benzoxazinones exhibit various pharmacological properties, such as progesterone
receptor antagonist, with antitumor, antiviral, antithrombotic, antimycobacterial,
anti-in°ammatory, antidiabetic and hypolipidemic activities. Indeed, recently,
some synthesized oxazinones have shown good antibacterial and antifungal ac-
tivities.1 For our part, we synthesized several pyrazolooxazines derivatives; the
evaluation of their pharmacological properties showed that some of these com-
pounds exhibit an interesting anti-in°ammatory activity.2,3 In the continuation
of this work, we plan to investigate theoretically pyrazolooxazines derivatives, using
Density Functional Theory (DFT) as well as QSAR calculations, in order to bring to
light for these derivatives structure-reactivity relationships, and ¯nally help to the
design of molecules with the best anti-in°ammatory activity (a weak IC50).The syn-
thesis reactions of oxazin-2-ones 1 and oxazin-2-thiones 2 are given in Fig. 1.
The theoretical prediction of various properties among them biological ones often
needs accurate ab initio and DFT computations.4–7 Understanding of fundamental
processes and phenomena in medicinal chemistry and drug design is based on the
calculation of relevant descriptors able to bring to light quantitative structure-ac-
tivity relationships.8 Basic molecular descriptors, such as log P (partition coe±-
cient), molecular weight (MW), acceptors and hydrogen-bonding donors in a
molecule, may characterize the molecular properties such as membrane permeability
and oral bioavailability. By using these molecular properties, Lipinski et al. intro-
duced a well-known rule for drug design.9 Lipinski's \rule of ¯ve" with parameters
such as Lipophilic E±cacy (LipE) has been demonstrated to be a useful tool in the
process of drug selection for oral medications.10,11
In the present work, large series of pyrazolooxazine derivatives are investigated
for their physico-chemical properties related to their biological activity. For this aim,
DFT computations have been carried out to estimate HOMO-LUMO energy gaps,
ionization potential (I), electron a±nity (A), electrophilicity index (!), nucleophi-
licity index (N), chemical potential (
), hardness () and softness (S) of the con-
sidered pyrazolooxazine derivatives. The determination of their optimized molecular

1950001-2
 DFT and QSAR investigations of substituent e®ects

Fig. 1. Synthesis reaction of oxazin-2-ones (1) and oxazin-2-thiones (2).

electrostatic potential (MEP) Surfaces, in order to characterize the in°uence of the

di®erent substituting groups has also been done. Finally, the study was carried out
for QSAR and drug resemblance properties of the considered series of molecules.

2. Computational Details
The Gaussian 09 program, HyperChem8.0.6 software and the Mol inspiration online
database have been used for all calculations presented in this work.12–14 In a ¯rst
step, the geometries of the considered pyrazolooxazines derivatives were fully opti-
mized at the B3LYP/6-311þþG (d, p) level using the Gaussian 09 program package.
In the literature, the largely used B3LYP DFT functional is presented to give reliable
results regarding the ground state properties of organic molecules.7 The normal
modes of vibration calculations which have been carried out using the optimized
geometries, led to real frequencies indicating that these geometries are minima on the
potential energy surfaces. NBO15,16 calculations have then been done as well as the
computation of di®erent indexes of chemical reactivity at the same level of theory.
In the case of NBO computations, the stabilization energy E2 associated with a pair
of a donor (i) and acceptor (j) natural orbitals is given by:
E 2 ¼ Eij ¼ qi F ði; jÞ2 =ð"j  "i Þ; ð1Þ
where F (i; j) is the corresponding Fock matrix element, qi is the donor
orbital occupancy and "i;j are the orbital energy. Finally, in order to select optimal

1950001-3
Z. Haddadi et al.

compounds, the module QSAR Properties (version 8.0.6) has been used with
HyperChem, allowing to evaluate several properties commonly used in QSAR
studies.

3. Results and Discussion

3.1. Analysis of the frontier molecular orbitals (FMO)
The HOMO-LUMO gap is a determining factor in quantum chemistry; it allows
characterizing the stability of a molecule whereas these frontier MOs play an im-
portant role, driving the chemical reactivity of the molecule.17,18 Molecules exhi-
biting a small HOMO-LUMO energy gap could undergo distortions in order to
increase this gap. The DFT computed descriptors (Table 1) are the HOMO and
LUMO energies, the estimated ionization energy (I) and electron a±nity (A), the
hardness () and the chemical potential (
) given by the following formula,
respectively:
I ¼ EHOMO ; ð2Þ
A ¼ ELUMO ; ð3Þ
 ¼ ðEHOMO þ ELUMO Þ=2; ð4Þ

¼ ðEHOMO þ ELUMO Þ=2: ð5Þ
In Table 1, both 1 and 2 exhibit a high HOMO-LUMO gap indicating their thermal
stability; although this gap is lower for pyrazolooxazine-2-thione 2 than for pyr-
azolooxazin-2-one 1 (2.961 versus 3.211 eV). Pyrazolooxazine-2-thione 2 is the most
reactive and more electron-donating than 1 since its ionization energy (5.533 eV) is
lower than that of 1 (5.929 eV). On the contrary, the electrophilic character of 1 is
higher than that of 2, since its electron a±nity A is slightly higher, (2.717 versus
2.572 eV). 2 exhibits also a low hardness () (1.480 eV) and greater overall softness
(S) (0.338 eV). Both 1 and 2 are characterized by negative chemical potential values
in relation to their stability. The low value of the chemical potential (4.323 eV) and
the high value of the electrophilic index (5.819 eV) of 1 favor its electrophilic be-
havior. Similarly, the high chemical potential (4.053 eV) and low electrophilic
index value (5.547 eV) for 2 favor its nucleophilic behavior.19
The HOMO and LUMO of pyrazolooxazin-2-one 1 and pyrazolooxazin-2-thione
2 are displayed in Fig. 2 (The positive phase is shown with the red color and the

Table 1. Calculated global reactivity descriptors for pyrazolooxazin-2-one 1 and pyrazolooxazin-2-thione

2 using B3LYP/6-311þþG (d, p).

EHOMO ELUMO E S 
! N A I
Compounds (eV) (eV) (eV) (eV) (eV) (eV) (eV) (eV) (eV) (eV)

1 5:929 2:717 3.211 0.311 1.606 4:323 5.819 4.323 2.717 5.929
2 5:533 2:572 2.961 0.338 1.480 4:053 5.547 4.053 2.572 5.533

1950001-4
 DFT and QSAR investigations of substituent e®ects

Fig. 2. HOMO and LUMO of pyrazolooxazin-2-one (1, left) andpyrazolooxazin-2-thione (2, right). The atom
colors are gray for carbon, blue for nitrogen, red for oxygen, yellow for sulfur and white for hydrogen atoms.

negative phase with the green one). As expected, they are very similar, especially the
HOMOs; these frontier MOs exhibit a  character, the HOMO being mainly localized
on the donating part of the molecule including the phenyl group and the LUMO on
the electron with drawing moiety of the molecules. The electrostatic potential sur-
faces considered below will indicate more precisely the electron rich or poor sites of
the molecules.

3.2. NBO analysis of pyrazolooxazine systems

NBO analysis considers the possible interactions between donor natural orbitals (i)
and acceptor (j) ones.15,16 The corresponding stabilization energy E 2 is calculated
using perturbation theory. This energy is associated with electronic delocalization
between the donors's orbital and the acceptor's orbital; high E 2 values indicate a
strong stabilizing interaction between these orbitals.
The results obtained for the stabilization energies reported in Table 2. An
important interaction is relative to the nitrogen atom lone pair n (LP2N1) interacting
with the antibonding orbital  (C5–O6). This interaction is strong and stabilizes 1
by 62.8 kcal/mol and 2 by 62.7 kcal/mol. Molecule 1 is also stabilized by the
interactions between n (LP1N3 Þ $  (C2–O7), and between n (LP1O1 Þ $  (C2–O7)
with the corresponding energies are 57.6 kcal/mol and 40.4 kcal/mol, respectively,
but which are weaker compared to the same interactions for 2. Indeed, the results of
the NBO analysis show that 2 is highly stabilized by the interactions between
n (LP1N3 Þ $  (C2–S7) and n (LP1O1 Þ $  (C2–S7) the corresponding energies
being equal to 70.0 kcal/mol and 45.9 kcal/mol, respectively. The high values of the
E 2 energies found in 1 and 2 indicate that the interactions involving the heteroatoms
lone pairs play an important role in the stabilization of these compounds.

1950001-5
Z. Haddadi et al.

Table 2. NBO analysis results using B3LYP/6-311þþG (d, p).

1 2

Donor (i) Acceptor (j) E2 (kcal/mol) Donor (i) Acceptor (j) E2 (kcal/mol)

 (C4 –C5 )  (C6 –C4 ) 21.6  (C4 –C5 )  (C6 –C4 ) 21.4
 (C6 –C4 )  (C3 –C2 ) 19.7  (C6 –C4 )  (C3 –C2 ) 19. 6
 (C6 –C4 Þ  (C5 –O4 Þ 22.0  (C6 –C4 )  (C5 –O4 ) 21.8
n (LP2 N1 )  (N2 –C3 ) 22.5 n (LP2 N1 )  (N2 – C3 ) 22.5
n (LP2 N1 )  (C5 –O6 ) 62.8 n (LP2 N1 )  (C5 –O6 ) 62.7
n (LP2 O7 )  (C2 –O1 ) 36.7 n (LP2 S7 )  (C2 –O1 ) 17.5
n (LP2 O7 )  (O1 –N3 ) 25.3 n (LP2 S7 )  (O1 –N3 ) 11.5
n (LP1 O1 )  (C2 –O7 ) 40.4 n (LP1 O1 )  (C2 –S7 ) 45.9
n (LP1 O1 )  (C6 –C4 ) 29.0 n (LP1 O1 )  (C6 –C4 ) 27.1
n (LP1 N3 )  (C2 –O7 ) 57.3 n (LP1 N3 )  (C2 –S7 ) 70.0
n (LP1 N3 )  (C4 –C5 ) 37.6 n (LP1 N3 )  (C4 –C5 ) 36.1

3.3. Molecular electrostatic potential (MEP) surfaces

of pyrazolooxazines
Among the descriptors permitting correlations between the molecular structure and
the physico-chemical properties of molecules, one can use MEPs which permit to
distinguish electron rich zones (sites of an electrophilic attack) from electron-poor
ones (nucleophilic attack).20,21 MEP has been determined as well as the electron
density (ED) of both species.22 MEP and ED of 1 and 2 are displayed on Fig. 3.
MEPs are useful tools to predict the biological processes, especially sites for an
electrophilic or nucleophilic attack by a reagent. In Fig. 3, the di®erent magnitudes
of the MEP are given by di®erent colors, as follows: red < orange < yellow <
green < blue.23 The region near the nitrogen atoms of the pyrazole ring and the
oxygen atom of the oxazine ring is characterized by the red color and exhibit a high
ED, thus refers to a negative potential; therefore, an electrophilic attack is preferred
on these sites. On the other hand, the region around the oxygen atoms and the
benzene ring is more yellow, indicating a less negative potential than the previous
one. The green region refers to a neutral electrostatic potential. On the MEP of the
pyrazolooxazine-2-thione, the same regions of negative potential and positive po-
tential are the same as for 1, knowing that the sulfur has a negative potential
(Fig. 3). Considering the ED map, it can be seen that the hydrogen atom of the
pyrazole ring bears a large positive charge implying a strong attraction (dark blue
color), a light blue color surrounds the hydrogen atoms of the methyl group in the
oxazine ring, indicating a less positive potential than for the methyl group in the oxazine
ring; therefore, the nucleophilic attack is preferred in these sites for 1 and 2 (Fig. 3).

3.4. Qualitative study of the structure-activity relationship

of pyrazolooxazine derivatives
QSAR relates structural descriptors or properties of a series of compounds with
their biological activities. For our part, the QSAR approach will be used to compare

1950001-6
 DFT and QSAR investigations of substituent e®ects

Fig. 3. Molecular electrostatic potential and electron density ED contour maps of pyrazolooxazin-2-one
(1) and pyrazolooxazin-2-thione (2). The atom colors are gray for carbon, blue for nitrogen, red for oxygen,
yellow for sulfur and white for hydrogen atoms.

the properties of pyrazolooxazine derivatives di®ering by the substituting group

R attached to the nitrogen atom number 3 (Fig. 4), knowing that these molecules
could exhibit an anti-in°ammatory biological activity.1,2 Some physico-chemical
properties were calculated using HyperChem 8.03 (Surface, Volume, Polarizability,
Refractivity and Hydration Energy and Mass) and others were calculated using the
Molinspiration online database [Molecular Polar Surface Area TPSA, Number of
Rotatable Bondsnrotb, nON of hydrogen acceptors (O, N atoms) and nOHNH of
hydrogen donors (OH, NH groups)].The formula of the di®erent derivatives to study
is given in Fig. 4, whereas the structure in space of one of these derivatives, namely
compound a2 is shown in Fig. 5.

3.5. Descriptors for the structure-activity relationships determination

The consideration of molecular volumes in QSAR studies is essential because it is a
means of determining the transport characteristics of the molecules (in relation
within testinal absorption or blood–brain barrier penetration). Regarding the molar
refractivity, it is related to the volume of the molecules and to the London dispersive
forces that act in the drug–receptor interaction; it is a steric parameter that is
essential to study the interaction of the ligand with the receptor.24 The molecular
polarizability drives the ability of a molecule to undergo electronic distortions which
are of importance regarding intermolecular forces.25
The determination of the stability of di®erent molecular conformations in water
solutions is based on their hydration energy, whereas the prediction of drug transport

1950001-7
Z. Haddadi et al.

Fig. 4. Studied Pyrazolooxazin-2-ones and Pyrazolooxazin-2-thiones derivatives. R is the substituting

group attached to the nitrogen atom 3.

1950001-8
 DFT and QSAR investigations of substituent e®ects

Fig. 5. 3D Conformation of a2 . The atom colors are green for carbon, cyan for nitrogen, red for oxygen,
yellow for sulfur and white for hydrogen atoms.

properties is based on total polar surface area (TPSA).26 The latter descriptor is
de¯ned as the sum of the surfaces of the polar atoms (usually oxygen, nitrogen and
bound hydrogen) in a molecule. It is a parameter that has a good correlation with
human intestinal absorption, the single-layer permeability of Caco-2 and the pene-
tration of the blood–brain barrier.27 Molecules with TPSA values of 140  A2 or more
28
should exhibit poor intestinal absorption. The number of rotating bonds (nrotb) is
a descriptor of the oral bioavailability of the drugs; it measures the molecular °ex-
ibility.29 The rotator links are de¯ned as a single non-ring bond, bound to the non-
hydrogen charges. Amide C–N bonds are not considered due to their high energy
barrier in the rotation. The computed QSAR descriptors are given in Table 3.
In Table 3, the decreasing order of the polarizability magnitude of the studied
derivatives of 1: h > e > f > g > b > a > c whereas for the 2 derivatives, it is:
h > c ¼ e > g > b > a. The polarizability order is approximately the same for the
volume and surface for the two series of derivatives. In the derivatives of 1, the
surfaces vary from 560.890  A2 to 634.794 A2. The derivatives of 1 exhibit a large

Table 3. QSAR descriptors of pyrazolooxazines derivatives.

Surface Volume Polarizability Refractivity Hydration

Compounds Mass A2 )
area ( A3 )
( A3 )
( A3 )
( (kcal/mol) TPSA Nrotb

1 Derivatives
a1 325.367 560.890 943.667 34.967 92.510 3:2 70.04 2
b1 339.394 585.903 990.414 36.802 96.982 2:8 70.04 3
c1 339.394 585.903 585.903 36.802 96.982 2:8 70.04 3
e1 373.411 620.575 1056.315 40.957 116.798 5:5 70.04 3
f1 379.433 608.15 1025.246 40.479 114.094 6:0 70.04 3
g1 359.384 605.139 1017.873 39.122 112.634 5:8 70.04 2
h1 373.411 634.794 1070.789 40.957 116.916 4:7 70.04 2
2 Derivatives
a2 341.428 574.020 968.144 38.127 100.797 4:2 70.04 2
b2 355.454 599.146 1019.433 39.962 105.268 3:7 52.97 2
c2 378.468 617.577 1050.370 40.636 107.113 4:2 52.97 3
d2 378.468 611.646 1045.480 40.636 107.113 5:6 52.97 3
e2 372.421 608.729 1027.783 40.060 106.701 7:2 70.04 2
g2 389.472 647.978 1100.222 44.117 117.166 5:3 52.97 2

1950001-9
Z. Haddadi et al.

Fig. 6. Attack sites for f 1 and e2 .

variation of the volume distribution, the h1 and e1 species showing the highest
volumes, respectively 1070.789  A3 and 1056. 315  A3 (Table 3). In the case of the
derivatives of 2, g2 and c2 exhibit the highest volumes; respectively 1100.222 A3 and
3
1050.370 A (Table 3).
The highest absolute hydration energy for the derivatives of 1 is that of f 1
(6.0 kcal/mol) and the lowest is that of b1 (2.8 kcal/mol) (Table 3). In the case of the
derivatives of 2, the most important energy of hydration is that of e2 (7.2 kcal/mol)
and the lowest absolute hydration energy is that of b2 (3.7 kcal/mol) (Table 3).
In the biological environment, polar molecules are surrounded by water molecules;
thus, hydrogen bonds could occur between the water molecules and the solute. The
proton donor sites interact with the oxygen atom of the water and the proton ac-
ceptor sites interact with the hydrogen atom of the water molecule. The ¯rst ones
lead to complexes with a strong hydrogen bond. These hydrated molecules are
dehydrated at least partially before and during the biological interaction. Low energy
interactions are reversible.30 The same TPSA value for the derivatives of 1 (70.04 A 2)
2
is observed and it is well below 140 
A ; we also observe for the derivatives of 2 that
the TPSA is in the range of 52.97–70.04  A2. The entire screened compounds are
weakly °exible. Attack sites [acceptors H (HBA)] are shown in Fig. 6.

3.6. Determination of drug-likeness properties and lipophilic

e±ciency calculation (LipE )
The structures of all pyrazolooxazines derivatives (Fig. 4) were designed to be used
with the Molinspiration online version (www.molinspiration.com) for the calculation
of molecular properties (number of hydrogen bond donors and acceptors, molecular
weights) (Table 4). The point of comparison between drugs appears to be a desirable
reference model for coding the balance between the molecular properties of a com-
pound that in°uences its pharmacodynamics and pharmacokinetics in the ¯nal
analysis, optimizes their absorption, distribution, metabolism and excretion
(ADME) in the human body as a drug.31 These parameters allow identifying the oral

1950001-10
 DFT and QSAR investigations of substituent e®ects

Table 4. Lipophilic e±ciency and Lipinski's rule of ¯ve for drug likeness of pyrazolooxazine
derivatives.

Compounds PIC50a LipEb Log Pc MW nON nOHNH n Violations

1 Derivatives
a1 3.699 1.819 1.880 325.367 6 0 0
b1 3.699 1.416 2.283 339.394 6 0 0
c1 3.699 1.416 2.283 339.394 6 0 0
e1 4.602 3.710 0.892 373.411 6 0 0
f1 3.699 4.196 -0.497 379.433 6 0 0
g1 4.100 3.729 0.371 359.384 6 0 0
h1 4.040 3.516 0.524 373.411 6 0 0
2 Derivatives
a2 3.699 0.698 3.001 341.428 5 0 0
b2 3.699 0.295 3.404 355.454 5 0 0
c2 3.699 -0.123 3.822 378.468 5 0 0
e2 4.602 0.780 3.822 378.468 6 0 0
g2 4.750 0.383 4.367 372.421 5 0 0
h2 4.670 -0.117 4.787 389.472 5 0 0

nON   of hydrogen acceptors (O, N atoms)

nOHNH  
 of hydrogen donors (OH, NH groups)
n violations: number of parameters violation
a pIC50 ¼ log IC50, IC50 anti-in°ammatory activities
b LipE ¼ pIC50  c Log P
c Calculated by HyperChem program.

absorption or membrane permeability that occurs when the considered molecule

meets the Lipinski's \rule of ¯ve" (molecular weight (MW)  500 Da, log P  5, H
donor (HBD)  5 and acceptors H (HBA)  10). The molecules which do not follow
more than one of these conditions may have bioavailability di±culties and a high
probability of surpassing drug diversity.32 A compound is likely to be active orally if
it follows the Lipinski rule; however, it is worth signaling some oral drugs which do
not respect the rule such as atorvastatin, cyclosporine. The partition coe±cient
(Log P) of Octanol/water is widely used for an estimation of membrane penetration
and permeability, including gastrointestinal absorption, brain–brain crossing (BBC),
and correlations with pharmacokinetic properties.33–36 In other words, Low molec-
ular weight drug molecules (< 500) are easily transported, di®used and absorbed in
relation to heavy molecules. The amounts of hydrogen bond acceptors (O and N
atoms) and hydrogen-bonding donors (NH and OH) are found to be critical in drug
development because they have an in°uence on absorption and permeation.37 The
considered compounds are within Lipinski et al. limit, namely less than 10 and 5,
respectively. LipE is an imperative parameter to normalize the lipophilic character; it
is used to compare compounds of di®erent powers (pIC50) and lipophilicity (Log P).
On the other hand, lipophilic e±cacy is de¯ned as the pIC50 (or pEC50) which is of
lesser interest than the logP of the compound.38 The potency in vitro and lipophi-
licity of the compounds are important parameters to be evaluated explaining the
search for a balanced relationship between the observed potency in vitro and the

1950001-11
Z. Haddadi et al.

lipophilic properties of the chemical compounds evaluated on the basis of the concept
of Lipophilic E±cacy (LipE). Ryckmans et al. reported that high quality compounds
have higher LipE values.39 The results of calculations relative to these properties are
given in Table 4.
Our calculations show that the Log P values are found to be in the range
(0.497)–(2.283) for the derivatives of 1 and (3.001)–(4.787), for derivatives of 2.
The compounds c1 , b1 derivatives of 1 and h2 derivative of 2 have the greatest
hydrophilicity based on their signi¯cant log P values, while f 1 and a2 are the most
lipophilic. This implies that these compounds will have low permeability across the
cell membrane. For a good improvement in their absorption, bioavailability and oral
permeability, some structural changes should be done. The result of the calculations
shows that all the compounds meet the Lipinski's \rule of ¯ve", suggesting that these
compounds theoretically should not have problems with oral bioavailability. The
results reported in Table 4 show that f 1 exhibits the highest LipE value (4.196) in the
dataset; therefore, it can be considered to be one of the most interesting species
regarding the biological activity.

4. Conclusion
The theoretical study of the molecular properties of pyrazolooxazine derivatives
likely to exhibit anti-in°ammatory activities have been carried out. DFT compu-
tations indicate that Pyrazolooxazine-2-thione 2 has a smaller HOMO-LUMO en-
ergy gap than pyrazolooxazin-2-one 1. NBO analysis showed that strong
intramolecular interactions taking place in pyrazolooxazin-2-one 1 and pyrazoloox-
azin-2-thione 2 contribute to their stabilities. Compound 2 is more reactive and more
electron-donating than 1 since its ionization energy (5.533 eV) is lower than that of 1
(5.929 eV). The electrophilic character of 1 is higher than that of 2, since its electron
a±nity A is slightly higher, (2.717 versus 2.572 eV); moreover, its electrophilicity
index is also higher.
A series of di®erently substituted pyrazolooxazine has been considered in order to
check their potential biological activity. It has been found that these compounds
should exhibit good cell plasma membrane permeability. Furthermore, they satisfy
the Lipinski's \rule of ¯ve", indicating that these compounds theoretically would not
have oral bioavailability problems. In particular, f 1 (a thiophen ring attached to the
nitrogen atom 3 of 1) which has the highest LipE value of the dataset could be
considered as a good candidate for biological testing.

Acknowledgment
This work was supported by the University of Sciences and Technology Houari
Boumediene of the Ministry of Higher Education and Scienti¯c Research, ALGERIA
(research project number CNEPRU : E00220120042).

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