Tautomeric origin of dual effects of N1-nicotinoyl-3-(4′-hydroxy- 3′-methyl phenyl)-5-[(sub)phenyl]-2-pyrazolines on bacterial and viral strains: POM analyses as new efficient bioinformatics' platform to predict and optimize bioactivity of drugs

Article abstract of DOI:10.1007/s00044-012-0143-6

In this study, we have amalgamated computational methodologies, viz. Petra, Osiris and Molinspiration (POM) to identify pharmacophores and antipharmacophores for antibacterial/antiviral activities of some 2-pyrazolines derivatives. Lipophilicity and the p

Full text of DOI:10.1007/s00044-012-0143-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:1438–1449
DOI 10.1007/s00044-012-0143-6
ORIGINAL RESEARCH
Tautomeric origin of dual effects of N1-nicotinoyl-3-(40-hydroxy-
30-methyl phenyl)-5-[(sub)phenyl]-2-pyrazolines on bacterial
and viral strains: POM analyses as new efficient bioinformatics’
platform to predict and optimize bioactivity of drugs
•
Taibi Ben Hadda Mohamed A. Ali Vijay Masand
•
•
•
Said Gharby Teffaha Fergoug Ismail Warad
•
Received: 14 January 2012 / Accepted: 5 June 2012 / Published online: 17 June 2012
Ó Springer Science+Business Media, LLC 2012
Abstract In this study, we have amalgamated computa-
tional methodologies, viz. Petra, Osiris and Molinspiration
(POM) to identify pharmacophores and antipharmaco-
phores for antibacterial/antiviral activities of some 2-pyr-
azolines derivatives. Lipophilicity and the presence of
tautomerism process are the major factors that govern the
orientation to antibacterial and/or antiviral activity. On
other hand, it was observed that these compounds have two
different active sites and can inhibit both antiviral and
antibacterial strains. Further, we have carried out receptor-
based electrostatic analysis to confirm the electronic, steric
and hydrophobic requirements for future modifications.
The analyses provide substantial idea about the structural
features responsible for their combined antibacterial/anti-
viral activity and provide guidelines for further modifica-
tions, with the aim of improving the activity and selectivity
of designed drugs targeting HIV and tuberculosis
microorganisms.
T. B. Hadda (&)
Keywords 2-Pyrazolines ꢀ Tautomerism ꢀ
´
´
Laboratoire Chimie Materiaux, Faculte des Sciences,
Mohammed First University, 60000 Oujda, Morocco
e-mail: tbenhadda@yahoo.fr; taibi.ben.hadda@gmail.com
Virtual screening ꢀ Petra/Osiris/Molinspiration (POM)
M. A. Ali
New Drug Discovery Research, Department of Medicinal
Chemistry, Sunrise University, Alwar 301030, Rajasthan, India
Introduction
The chemistry of pyrazolines derivatives has attracted much
attention because of their interesting structural properties
and their potentials as antibacterial (Ali et al., 2007a, b;
Chimenti et al., 2005; Rani et al., 2011a, b, c; Abdel-Wahab
et al., 2009; Yar et al., 2006; Ferreras et al., 2011; Sha-
haryar et al., 2006; Ahsan et al., 2011), antifungal (Maty-
siak and Niewiadomy, 2003; Dawane et al., 2010),
cyclooxygenase (COX-2) (Fioravanti et al., 2010), antiin-
flammatory (Shoman et al., 2009; Amir et al., 2008; Girisha
et al., 2011; Rathish et al., 2009; Joshi et al., 2010; Ahn
et al., 2004), antidiabetic (Chohan et al., 2010), antiMAO
(Mishra and Sasmal, 2011; Jagrat et al., 2011; Jayaprakash
et al., 2008; Sahoo et al., 2010; Karuppasamy et al., 2011;
Chimenti et al., 2008), anticonvulsant (Amnerkar and
Bhusari, 2010; Siddiqui et al., 2010), antitumoral (Ly et al.,
2011; Jun et al., 2008; Havrylyuk et al., 2009; Choudhary
et al., 2011; Banday et al., 2010; Manna and Agrawal, 2010;
Bashir et al., 2011; Bano et al., 2011; Lee et al., 2011;
V. Masand
Department of Chemistry, Vidya Bharati College,
Amravati 444602, Maharashtra, India
S. Gharby
Laboratoire Chimie Plantes Synthese Organique et
`
Bioorganique, Faculte des Sciences, Universite Mohammed
´
V-Agdal, Rabat, Morocco
´
T. Fergoug
Laboratoire de Chimie Physique des Biomolecules et Interfaces
´
Biologiques, Faculte des Sciences de la Nature et de la Vie,
´
Universite de Mascara, 29000 Mascara, Algeria
´
I. Warad
Department of Chemistry, King Saud University, Riyadh 11451,
Saudi Arabia
M. A. Ali
Institute for Research in Molecular Medicine, Universiti Sains
Malaysia, 11800 Minden, Penang, Malaysia
123

Med Chem Res (2013) 22:1438–1449
1439
Parekh et al., 2011) and antiHIV agents (Ali et al.,
2007a, b).
nature is accomplished by defining the active pharmaco-
phore site with the aid of pre-existing drugs.
Amongst bioactivities cited above, 2-pyrazoline deriv-
atives have been found to possess a broad spectrum of
other biological activities such as tranquillizing, muscle
relaxant, antihypertensive and antidepressant activities
(Rajendra et al., 2005; Soni et al., 1987; Turan-Zitouni
et al., 2000).
Recently, some 2-pyrazolines bases from isoniazid
(INH) and chalcones were prepared and their molecular
structures were determined. These ligands can exist in two
major tautomeric forms: keto-imine, and keto-enamine,
although the keto-imine form is predominant in the solid
state.
Although many of these drugs exhibit tautomerism,
isomerism and opening closing pyrazolic ring, there is no
study elucidating the impact of tautomerism on resulting
bioactivity of 2-pyrazolines and because of this, they show
interesting structural and spectroscopic properties which
are the subject matter of this contribution.
As a continuation of our bioinformatics studies, we were
interested to Petra/Osiris/Molinspiration (POM) analyses
of bioactive pyrazoline-based isoniazid ligands, which can
furnish interesting model and may find some application in
chemotherapy. With this view, we have analysed a series of
ligands bearing dual bioactivities. The POM analyses of
these ligands resulted in the identification of coexisting
antibacterial and antiviral O,N-pharmacophore sites. We
have included the synthesized compounds into the dataset
and referred a previous data (Chohan et al., 2010) to
establish or evaluate the current study.
Tautomerism/mesomerism/isomerism and opining/clos-
ing heterocyclic rings in bioactive compounds have played
and continue to play a key role in orientation of bioactivity
of drugs that have found wide application in drug design,
from new medicinal materials to antibacterial imidazo[1,2-
a]pyrimidine (-pyridine) (Anaflous et al., 2004; Ben Hadda
et al., 2003), as sulphonamides in the antifungal agents
(Chohan et al., 2010) and as potential antiHIV spirohet-
erocycles (Bennani et al., 2007).
Results and discussion
Amongst the compounds, acyl/sulfonyl pyrazolines have
been studied extensively owing to their effective properties
with respect to inhibiting various pathogenic strains, but on
the other hand pyrazoline-based isoniazid chemistry is less
extensive and has not been analysed rigorously by bioin-
formatic methods.
Chemistry
The 2-pyrazolines derivatives 3a–3k have been previously
(Ali et al., 2007a, b) synthesized in good yields (85–95 %)
by condensation of aryl-methylketone 1 with various
substituted aromatic aldehydes 2 and then with ison-
icotinylhydrazide (Scheme 1).
We have previously published the Petra, Osiris and
Molinspiration (POM) methods for antibacterial (Chohan
et al., 2010; Fathi et al., 2011; Jarrahpour et al., 2011;
Parvez et al., 2011; Sheikh et al., 2011; Ali et al., 2010;
Chohan et al., 2010; Parvez et al., 2010), antifungal (Fathi
et al., 2011) and antiviral (Bennani et al., 2007) pharma-
cophore sites identification. The control of different phys-
icochemical and pharmacological parameters leads us to
seek suitable hits in various areas (Fig. 1).
The structures of the title compounds were determined
1
by IR, H NMR, mass spectrometry and elemental data.
The spectroscopic properties and analytical data were in
1
accord with the proposed structures. The H NMR spec-
trum for compounds 3a–3k showed a multiplet peak for the
two methylenyl –CH2– protons. Such values are very
similar to those found in the literature for similar 2-pyr-
azoline system (Ali et al., 2007a, b).
Constraint parameters used for ligand preparation are
ionization change, tautomer and isomer generation; POM
analyses using Lipinski filter and 3D generator albeit all the
duplicate structures are removed. Prediction of bioactivity
On other hand, the pharmacological complexity of the
2-pyrazolines products 3a–3k may be explained by the fact
that pyrazolines, example those derived from alkyl acry-
lates (Horna et al., 1986), are rather unstable, there being
Fig. 1 Drugs/bacterial and viral
targets interactions
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Med Chem Res (2013) 22:1438–1449
Scheme 1 Synthesis of
compounds 3a–3k
CH3
OH
N
H3C
CH3
O
O
O
(1)
Aryl
OH
Aryl
N
NaOH/
EtOH
Isonicotinyl
hydrazide
N
+
Aryl
H
O
(2)
3a-3k
H3C
O
3a : Aryl = 4-CH3-O-Ph ;
3b: Aryl = 4-Cl-Ph ;
3d : Aryl = Ph ;
H
3c : Aryl = 4-(CH3)2N-Ph ;
3a-3k
3e : Aryl = 3,4-(CH3)2-Ph ;
3g : Aryl = Furyl ;
3f : Aryl = 3,4,5-(CH3)3-Ph ;
3h : Aryl = 4-F-Ph;
3i : Aryl = 2-Cl-Ph ;
3j : Aryl = 2,6-(Cl)2-Ph ;
3k: Aryl = 4-NO2-Ph
three possible tautomeric forms, or which the 3-alkox-
ycarbonyl-2-pyrazoline (Tautomer-II) is the most sable
(Scheme 2).
indoline ring at the spirocyclic carbon affording pyrazole
(g). The X-ray crystal data have been explored to prove the
mechanism in Scheme 6).
Note that tautomerization of the 1-pyrazoline (Tauto-
mer-I) to the thermodynamically more stable 2-pyrazoline
(Tautomer-II) has taken place (Rispens et al., 1994), due to
the acidic nature of the proton to the ester moiety
(Scheme 3).
More interesting and once again, it is known, that
5-hydroxy-2-pyrazolines in the solutions can exist in
equilibrium (Kuzmenok et al., 2008) with acyclic tautom-
ers (Scheme 7).
The tautomerism/isomerism and opening/closing
2-pyrazolines system is well documented by Sanderefer
(1965). Unfortunately, there are few and very limited
pharmacologists who really use these important observa-
tions of Sanderefer to explain the origin of various bioac-
tivities of 2-pyrazolines.
Tautomerization of compound (c) (Shekarchi et al.,
2008), a closely analogue of compounds 3a–3k, results in
the formation of its second tautomeric form (Scheme 4).
In general, 1-pyrazolines series tend to be unstable and
isomerizes to the 2-pyrazolines with the regioselectivity of
the isomerization dependent on the substituents R1 and R2
(Simovic et al., 2007), as shown in Scheme 5.
Molecular properties calculations
Another interesting proposed mechanism for formation
of the pyrazole via spiropyrazoline ring opening (Dadi-
boyena et al., 2009) is shown in Scheme 6. After the for-
mation of the cycloadduct (f-I), an imine to enamine
tautomerization occurs to form the enamine tautomer (f-II).
Instead of compound (f-II) reverting to (f-I), the enamine
tautomer undergoes an eliminatory ring cleavage of the
For compounds 2-pyrazolines and certainly for its ana-
logues 3a–3k, depending on the pH and position of the
dissociate amidogen hydrogen atom, two possible tauto-
meric forms can be described for neutral forms. These
relevant structures are sketched in Scheme 8.
Scheme 2 Tautomerism of
pyrazoline with alkylacrylate
H
O
O
O
N
N
N
H
N
N
N
RO
RO
RO
(a)-Tautomer-I
(a)-Tautomer-II
(a)-Tautomer-III
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Med Chem Res (2013) 22:1438–1449
1441
Scheme 3 Tautomeric
equilibrium between 1- and
2-pyrazoline
O
O
N
O
N
O
H
N
N
O
O
H3C
H3C
CH3
CH3
O
O
O
O
H3C
H3C
CH3
CH3
(b)-Tautomer I
(b)-Tautomer II
Scheme 4 Tautomeric
equilibrium between 1- and
2-pyrazoline
S
S
H
H2N
H2N
N
N
N
N
N
N
(c)-Tautomer I
(c)-Tautomer II
Scheme 5 Isomerization/
tautomerization of 1- to
2-pyrazolines
H
N
N
tautmerisation
N
N
N
NH
isomerisation
R2
R1
R2
R1
R2
R1
(e) Tautomer II
(d)
1-pyrazolines
(e) Tautomer I
2-pyrazolines
H
N
N
N
N
N
N
H3C
H3C
H3C
N
NH
N
R
R
CH3
CH3
H3C
R
CH3
H3C
H3C
(f)-Tautomer I
(f)-Tautomer II
(g)
Scheme 6 Proposed mechanism for the spiropyrazoline ring fragmentation of (f) to form the corresponding pyrazole (g)
In the literature described above, attention was mainly
drawn to the Tautomer-I structure. However, from a
chemical point of view, another tautomeric structure is
possible (Tautomer-II). For the development of binding
approaches for 2-pyrazolines and its analogues 3a–3k in
the environment, the identification of the active tautomeric
structures present is important. Neither experimental nor
theoretical data is available for the identification of water-
solved 2-pyrazoline species. Theoretically, NMR spec-
troscopy could be useful for identifying chemical struc-
tures. Theoretical ab initio studies could supplement these
measurements. Additionally, calculations of energetics,
atomic charges, minimum energy structures, geometry and
natural bond orbital (NBO) could indicate the electronic
density distribution of each atom. These systematic data,
regarding the variation of molecular properties, are
123

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Med Chem Res (2013) 22:1438–1449
H3C
H3C
H3C
H3C
H3C
NHR
NHR
NHR
NH
H3C
H3C
N
N
N
N
R
H3C
H3C
H3C
O
OH
O
OH
H3C
H3C
(h)
(i) Tautomer I
(i) Tautomer II
(i) Tautomer III
Scheme 7 Opening/closing 2-pyrazolinyl ring and tautomerization of 2-pyrazolines bearing 2-hydroxyl group
δ-
O
Scheme 8 Potential
antibacterial/antiviral
pharmacophores sites of
compounds 3a–3k
δ-
δ+
H
O
δ-
N
N
N
N
O
H
O
N
N
H
Aryl
Aryl
CH3
CH3
3a-3k
3a-3k
(Tautomer-II)
(Tautomer-I)
δ-
δ-
δ-
: Antibacterial pharmacophore site
: Antiviral pharmacophore site
δ+
important for the chemical structure and could therefore
provide first insights into the still poorly understood
chemical bonding of 2-pyrazolines complexes to soil.
In brief, the objective of this study is to investigate the
potential pharmacophore sites of 2-pyrazolines species
using antibacterial and antiviral screenings dependence on
pH and comparison with the calculated molecular proper-
ties. To verify these structures, further Petra/Osiris/
Molinspiration (POM) analyses were carried out for
example calculation of net atomic charges, bond polarity,
atomic valence, electron delocalization and lipophilicity.
Finally, to investigate the combined antibacterial/anti-
viral bioactivity of the 2-pyrazolines species, tautomeric
structure were performed (Scheme 9).
molecular properties that make them favourable as lead and
standard reference (SR) structures for drug discovery, and
which serve to differentiate them from libraries of synthetic
and combinatorial compounds.
Various investigators have used computational methods
to understand differences between natural products and
other sources of drug leads. Modern drug discovery is
based on large part on high throughput screening of small
molecules against macromolecular disease targets requir-
ing that molecular screening libraries contain drug-like or
lead-like compounds. We have analysed known SRs for
drug-like and lead-like properties. With this information in
hand, we have established a strategy to design specific
drug-like or lead-like 2-pyrazoline derivatives 3a–3k con-
taining various aryl groups (Table 1).
Current thinking in the generation of specific drug leads
embodies the concept of achieving high molecular diver-
sity within the boundaries of reasonable drug-like proper-
ties. Natural and semi-natural products, examples ofloxacin
(OFL), fluconazole (FLN) and niverapine (NVP) have high
chemical diversity, biochemical specificity and other
Petra calculations
Petra is a program package comprising various empirical
methods for the calculation of physicochemical properties
Scheme 9 Proposed tautomeric
structures of 2-pyrazolines
3a–3k
O
O
H
H
H
N
CH3
CH3
N
O
N
O
N
H
Aryl2
Aryl2
(II)
(I)
H
Aryl1
Aryl1
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Med Chem Res (2013) 22:1438–1449
1443
Table 1 Antibacterial and antiviral activities of compounds 3a–3k
Compounds Aryl
Antibacterial activity
Antiviral activity
IC50 (lM) % Protec.
A
B
C
D
E
F
G
3a
4-CH3O-Ph
?
??
?
-
-
-
-
[125
[36
6.0
24
42
102
13
24
26
86
08
24
24
40
ND
ND
98
3b
4-Cl-Ph
???
????
?
????
????
?
???
???
?
???
???
-
-
-
-
3c
4-(CH3)2N-Ph
??
-
??
-
?
3d
Ph
-
[11
[14
[66
7.0
3e
3,4-di-CH3O-Ph
??
??
??
?
-
-
-
3f
3,4,5-tri-CH3O-Ph
?
?
?
?
-
-
-
3g
Furyl
?????
????
???
???
????
?????
????
???
????
????
???
???
???
?
-
-
-
3h
4-F-Ph
2-Cl-Ph
2,2-di-Cl-Ph
3-NO2-Ph
-
???
-
-
-
--
-
[68
[53
[14
[11
ND
3i
-
-
3j
???? ???? ??? ??
?
3k
???
-
-
-
-
-
-
-
-
OFL
FLN
NVP
?????? ??????
--
-
-
-
???? ???? ??? ??? ??? ND
ND ND ND ND ND 0.10
-
ND
ND
OFL ofloxacin, FLN fluconazole, NVP niverapine, A S. aureus-209P, B E. coli-2231, C A. fumigatus, D C. albicans, E C. albicans-ATCC-10231,
F C. glabrata-H05, F C. krusi-G03
- Inactive (inhibition zone \5 mm), ? slightly active (inhibition zone 5–10 mm), ?? moderately active (inhibition zone 10–15 mm), ???
highly active (inhibition zone [15 mm)
in organic molecules. All the methods are empirical in
nature and have been developed over the last 20 years in
the research group of Prof. J. Gasteiger. The following
chemical effects can be quantified: heats of formation,
bond dissociation energies, sigma charge distribution,
p-charge distribution, inductive effect, resonance effect
and delocalization energies and polarizability effect.
The series 3a–3k of 2-pyrazolines have been subjected
to delocalized-charge calculations using Petra method of
the non-hydrogen common atoms obtained from the partial
p-charge of the heteroatoms, have been used to model the
bioactivity against bacteria and HIV virus (Scheme 9).
It is found that the negative charges of the oxygen of
C=O group and NH contribute positively in favour of an
antibacterial activity, more, and this is in good agreement
with the mode of antibacterial action of the compounds
bearing (Xd-–Yd?) pharmacophore site. It was hypothe-
sized that difference in charges between two heteroatoms
of the same dipolar pharmacophore site (Xd-–Yd?) may
facilitate the inhibition of bacteria, more than viruses. It is
further found that the activity increases with increase in
negative charge of one heteroatom of the common phar-
macophore fragment of the potential tautomer (I). The
presence of tautomerism phenomena in 2-pyrazoline ana-
logues was presented previously since 1965, in many
papers by most of the authors involved in this chemistry.
On the basis of these analogues systems described
above, in compounds 3, sets of isomeric and tautomeric
pyrazoline derivatives I–II could be generated in situ in the
presence of bacteria of virus. This synergistic and
streamlined working procedure led to highly active iso-
meric/tautomeric Gram( ) and virus receptor ligands.
However, a little difference in their respective binding
affinities was consistently found for all isomeric pairs I–II.
The analysis of conformational differences due to hetero-
atom interactions in Tautomers-I–II revealed a favourable
(C=O–NH) interaction in Tautomer-I, where as Tautomer-
II showed a repulsive (C=O–N) interaction.
So the antiviral activity is related with possible sec-
ondary electronic interaction with the positively charged
side chains of the virus target(s). Attempt was made to
evaluate steric and indicator parameters which emerged as
important contributors from previous pharmacologic anal-
ysis. The present results support the previous observations
that heterocyclic ring in adjacent position of NH could
generate two tautomeric forms, in less and two distinct
four-membered pharmacophore sites are conducive to the
activity of both antibacterial (Od-–NHd?) and antiviral
activity (Od-–Nd-).
Osiris calculations
Structure-based design is now fairly routine, but many
potential drugs fail to reach the clinic because of ADME-
Tox liabilities. One very important class of enzymes,
responsible for many ADMET problems is the
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Med Chem Res (2013) 22:1438–1449
cytochromes P450. Inhibition of these or production of
unwanted metabolites can result in many adverse drug
reactions. Of the most important program, Osiris is already
available online.
(OFL), fluconazole (FLN) and niverapine (NVP) is calcu-
lated by the methodology developed by Molinspiration as a
sum of fragment-based contributions and correction fac-
tors. There is no violation of Lipinski rules (Table 4).
The method is very robust and is able to process prac-
tically all organic and most organometallic molecules.
Molecular Polar Surface Area TPSA is calculated based on
the methodology published by Ertl et al. as a sum of
fragment contributions. O– and N– centred polar fragments
are considered. PSA has been shown to be a very good
descriptor characterizing drug absorption, including intes-
tinal absorption, bioavailability, Caco-2 permeability and
blood–brain barrier penetration. Prediction results of
compounds 3a–3k molecular properties (TPSA, GPCR
ligand and ICM) are valued (Table 5).
With our recent publication of the drug design combi-
nation of various pharmacophore sites using spirohetero-
cyclic structure, it is now possible to predict activity and/or
inhibition with increasing success in two targets (bacteria
and HIV). This is done using a combined electronic/struc-
ture docking procedure and an example will be given here.
The remarkably well-behaved mutagenicity of diverse
synthetic molecules classified in data base of CELERON
Company of Swiss can be used to quantify the role played
by various organic groups in promoting or interfering with
the way a drug can associate with DNA. Interestingly,
compounds 3a–3k show encouraging drug-score, more
important of those of standard drugs (Table 2). In contrast
to compounds 3c and 3e, the rest of series 3a–3k show no
toxicity risks (Table 3).
Attempt was made to incorporate steric and indicator
parameters which emerged as important contributors from
previous pharmacologic analysis. The present results sup-
port the previous observations that bulky phenyl ring
substituents and a three-membered pharmacophore site
attached to the 2-pyrazolines/aryl containing ring are
conducive to the activity. The Petra software calculations
confirmed that all compounds 3a–3k do not have the same
and a clear preference for forming antiviral pharmacophore
Molinspiration calculations
CLogP (octanol/water partition coefficient) of compounds
3a–3k and standard drugs references (Fig. 2); ofloxacin
Table 2 Osiris calculations of
drug-score of compounds 3a–3k
Compounds
MW
387
R
Tautomers
cLogP
S
DL
2.54
D-S
3a
4-CH3O-Ph
I
2.36
3.60
3.08
4.32
2.46
3.70
2.46
3.70
3.09
4.34
3.41
4.65
1.57
2.81
2.52
3.76
3.08
4.32
3.69
4.93
2.33
3.57
-0.26
-0.21
2.91
-3.44
-4.06
-4.16
-4.78
-3.46
-4.08
-3.43
-4.04
-4.11
-4.73
-4.46
-5.07
-3.11
-3.72
-3.74
-4.35
-4.16
-4.78
-4.90
-5.51
-3.89
-4.50
-2.74
-2.17
-4.67
0.76
0.68
0.70
0.58
0.42
0.39
0.78
0.70
0.40
0.34
0.56
0.46
0.81
0.75
0.73
0.66
0.58
0.56
0.56
0.43
0.37
0.32
0.42
0.46
0.71
II
I
3.37
3.68
4.92
1.39
2.22
2.39
3.20
0.99
1.35
0.83
1.19
2.02
2.38
1.96
3.38
2.53
2.87
2.55
2.89
-7.68
-6.82
5.77
-1.13
3.02
3b
3c
3d
3e
3f
391
400
357
385
399
347
375
391
425
402
4-Cl-Ph
II
I
4-(CH3)2N-Ph
Ph
II
I
II
I
3,4-di-CH3O-Ph
3,4,5-tri- CH3O-Ph
Furyl
II
I
II
I
3g
3h
3i
II
I
4-F-Ph
II
I
2-Cl-Ph
II
I
3j
2,6-di-Cl-Ph
3-NO2-Ph
II
I
3k
II
–
–
–
OFL
FLN
NVP
361
306
266
–
–
–
OFL ofloxacin, FLN
fluconazole, NVP niverapine
123

Med Chem Res (2013) 22:1438–1449
1445
Table 3 Osiris calculations of toxicity risks of compounds 3a–3k
Compounds MW
R
Tautomers MUT
TUMO
IRRI
REP
3a
3b
3c
4-CH3O-Ph
I
387
391
400
357
385
399
347
375
391
425
402
II
I
4-Cl-Ph
4-(CH3)2N-Ph
Ph
II
I
II
I
3d
3e
3f
II
I
3,4-di-CH3O-
Ph
II
I
3,4,5-tri-CH3O-
Ph
II
I
3g
3h
3i
Furyl
II
I
4-F-Ph
II
I
2-Cl-Ph
II
I
3j
2,6-di-Cl-Ph
3-NO2-Ph
II
I
3k
II
OFL
FLN
NVP
361
306
266
–
–
–
–
–
–
OFL ofloxacin, FLN fluconazole, NVP niverapine
123

1446
Med Chem Res (2013) 22:1438–1449
Ofloxacin (antibacterial drug)
Fluconazole (anti-fungal drug)
Niverapine (anti-HIV drug)
Fig. 2 Chemical structures of Ofloxacin (OFL), Fluconazole (FLN) and Niverapine (NVP)
indicative; D-S is 0.42 and 0.37 for 3c and 3k, respectively,
as shown and summarized in Table 2.
Table 4 Molinspiration calculations of compounds 3a–3k
Compounds MW Tautomers TPSA OH–
NH
N
Viol.
NROTB Vol.
For each compound, the Tautomer-I has better drug
score than Tautomer-II. The Osiris calculations (Table 3)
reveal that the compounds have low toxicity profile. The
compound 3c possesses good antibacterial and antifungal
profiles.
3a
3b
3c
3d
3e
3f
387
I
75
75
65
66
69
69
65
66
65
66
65
66
79
79
65
66
65
66
65
66
111
112
75
81
64
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
4
4
3
3
4
4
3
3
3
3
3
3
3
3
3
3
3
3
3
3
4
4
2
5
1
350
351
338
339
371
371
325
325
358
358
375
375
306
307
330
330
338
339
352
352
348
348
311
249
237
II
I
II
I
400
357
385
399
347
375
392
426
402
II
I
Conclusions
II
I
The results of present investigation support the suggested
structures of 2-pyrazolines. It has been suggested that some
functional groups such as azomethine or heteroaromatics
present in these compounds displayed role of biological
activity that may be responsible for the increase of
hydrophobic character and liposolubility of the molecules.
This in turn, enhances activity of the compounds and
biological absorbance, so as, all the synthesized 2-pyraz-
olines have good antibacterial and antiviral properties.
A number of important points emerge concerning the
electronic and steric factors which have direct impact on
bioactivity properties. The positive results we have recor-
ded, while encouraging for purposes of new drug design,
confirm that very likely most of these compounds could be
used as potential antibacterial activity after minor modifi-
cations. Based on their structural properties, these com-
pounds may be useful as chelating agents with potential
activity. These results prompt several pertinent observa-
tions: (i) this type of 2-pyrazolines can furnish an inter-
esting model for studying the interaction of antibiotics with
viral target because the possible charge modification of
substituents and O/N of pharmacophore group; (ii) the
future flexible pharmacophore site(s) geometric confor-
mation enables us to prepare molecules for multi-thera-
peutic materials with high selectivity.
II
I
II
I
3g
3h
3i
II
I
II
I
II
I
3j
II
I
3k
II
–
–
–
OFL
FLN
NVP
361
306
266
OFL ofloxacin, FLN fluconazole, NVP niverapine
sites though their estimated partial p charges, respectively,
for O and N neighbour atoms are of negative charges
(Scheme 9) for compounds 3c (Aryl = 4-(CH3)2N-Ph) and
3k (Aryl = 3-NO2-Ph), for example. The drug-score is
123

Med Chem Res (2013) 22:1438–1449
1447
Table 5 Drug likeness of
compounds 3a–3k
Compounds
Tautomers
GPCRL
ICM
KI
-0.25
NRL
PI
-0.45
EN
3a
3b
3c
3d
3e
3f
I
-0.33
-0.33
-0.31
-0.31
-0.28
-0.29
-0.31
--0.31
-0.30
--0.30
-0.29
-0.29
-0.40
-0.48
-0.30
-0.30
-0.32
-0.32
-0.34
-0.34
-0.42
-0.42
0.23
-0.57
-0.74
-0.55
-0.72
-0.53
-0.69
-0.56
-0.74
-0.55
-0.71
-0.62
-0.78
-0.72
-1.02
-0.56
-0.73
-0.58
-0.75
-0.57
-0.74
-0.56
-0.72
-0.14
0.01
-0.37
-0.37
-0.38
-0.38
-0.33
-0.32
-0.38
-0.37
-0.35
-0.35
-0.34
-0.34
-0.48
-0.50
-0.34
-0.34
-0.36
-0.35
-0.30
-0.30
-0.42
-0.42
-0.13
-0.23
-0.72
-0.44
-0.26
-0.41
-0.27
-0.37
-0.24
-0.39
-0.25
-0.38
-0.25
-0.38
-0.25
-0.48
-0.37
-0.39
-0.25
-0.45
-0.31
-0.43
-0.30
-0.45
-0.32
0.35
II
I
-0.33
-0.25
-0.33
-0.19
-0.27
-0.24
-0.33
--0.24
-0.32
-0.24
-0.32
-0.45
-0.65
-0.21
-0.29
-0.34
-0.43
-0.28
-0.36
-0.34
-0.42
-0.06
-0.09
0.08
--0.43
--0.45
-0.42
-0.42
-0.41
-0.43
--0.42
-0.42
-0.41
-0.43
-0.42
-0.65
-0.71
-0.44
-0.43
-0.51
-0.50
-0.44
-0.43
-0.52
-0.51
-0.26
-0.09
-0.52
II
I
II
I
II
I
II
I
II
I
3g
3h
3i
II
I
II
I
II
I
3j
II
I
GPCRL GPCR ligand, ICM ion
channel modulator, KI kinase
inhibitor, NRL nuclear receptor
ligand, PI protease inhibitor,
EN enzyme inhibitor,
3k
II
–
–
–
OFL
FLN
NVP
0.04
0.03
OFL ofloxacin, FLN
fluconazole, NVP niverapine
-0.12
-0.14
0.58
Acknowledgments Prof. T. Ben Hadda would like to thank the
ACTELION; the Biopharmaceutical Company of Swiss, for the on-
line molecular properties calculations and to Ministry of High Science
and Education of Rabat (Morocco) for financial support.
Ali P, Meshram J, Youssoufi MH, Ben Hadda T (2010) Theoretical
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and 3D-QSAR study of some prop-2-eneamido and 1-acetyl-
pyrazolin derivatives of aminobenzothiazole. Eur J Med Chem
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