Computational evaluation and experimental in vitro antibacterial, antifungal and antiviral activity of bis-Schiff bases of isatin and its derivatives

Article abstract of DOI:10.1007/s00044-012-0127-6

A computational model has been developed for the rational design of bioactive pharmacophore sites as an antibacterial, antifungal and antiviral candidates based on available X-ray structures of bis-Schiff bases (Blagus et al., Maced J Chem Chem Eng 29:117-138, 2010; Nabei et al., Polyhedron 28:1734-1739, 2009; Zhang et al., Inorg Chem Commun 14:1636-1639, 2011; Zhong et al., Eur J Med Chem 41:1090-1092, 2006; Zhou et al., Inorg Chim Acta 359:1442-1448, 2006). A dozen of bis-Schiff bases 3-14 of isatin, benzylisatin and 5-fluoroisatin 1a-c were designed using this model. The compounds were screened for antibacterial, antifugal and antiviral activity against a panel of DNA and RNA viruses. The most potent of these compounds 8 and 11 was tested in viral cultures for their ability to present a potential (O^δ-- N^δ-) antiviral pharmacophore site. Compounds 8 and 11 were the most cytotoxic in HEL cells. All these synthesized bis-Schiff bases were also tested for their antibacterial and antifungal activities. They did not display activity against S. cerevisiae (ATCC 28383) or C. albicans (CIP 1180-79); may be because they did not have an antibacterial pharmacophore site (X ^δ--Y^δ+). The best inhibitors tested in vitro against HIV-1 are genetically predisposed to be inhibited by similar pharmacophore sites. The results from all the aspects of this bioinformatic approaches are discussed as par with our experience with screening candidates. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00044-012-0127-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0127-6
ORIGINAL RESEARCH
Computational evaluation and experimental in vitro antibacterial,
antifungal and antiviral activity of bis-Schiff bases of isatin and its
derivatives
•
Aliasghar Jarrahpour Javed Sheikh
•
•
Ibrahim El Mounsi Harjeet Juneja
•
Taibi Ben Hadda
Received: 31 August 2011 / Accepted: 23 May 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A computational model has been developed for
the rational design of bioactive pharmacophore sites as an
antibacterial, antifungal and antiviral candidates based on
available X-ray structures of bis-Schiff bases (Blagus et al.,
Maced J Chem Chem Eng 29:117–138, 2010; Nabei et al.,
Polyhedron 28:1734–1739, 2009; Zhang et al., Inorg Chem
Commun 14:1636–1639, 2011; Zhong et al., Eur J Med
Chem 41:1090–1092, 2006; Zhou et al., Inorg Chim Acta
359:1442–1448, 2006). A dozen of bis-Schiff bases 3–14
of isatin, benzylisatin and 5-fluoroisatin 1a–c were
designed using this model. The compounds were screened
for antibacterial, antifugal and antiviral activity against a
panel of DNA and RNA viruses. The most potent of these
compounds 8 and 11 was tested in viral cultures for their
ability to present a potential (Od-–Nd-) antiviral pharma-
cophore site. Compounds 8 and 11 were the most cytotoxic
in HEL cells. All these synthesized bis-Schiff bases were
also tested for their antibacterial and antifungal activities.
They did not display activity against S. cerevisiae (ATCC
28383) or C. albicans (CIP 1180-79); may be because
they did not have an antibacterial pharmacophore site
(Xd-–Yd?). The best inhibitors tested in vitro against
HIV-1 are genetically predisposed to be inhibited by
similar pharmacophore sites. The results from all the
aspects of this bioinformatic approaches are discussed as
par with our experience with screening candidates.
Keywords Virtual screening ꢀ Isatin ꢀ Schiff bases ꢀ
Antibacterial ꢀ Antiviral ꢀ Antifungal activity
Introduction
Invasive, all bacterial, fungal and viral infections are a
serious and escalating health issue. They are associated
with a high morbidity, mortality, and economic burden,
especially in immuno-compromised hosts. Current thera-
pies are limited in safety and/or efficacy and resistant
fungi, bacteria, and viruses are an emerging problem
(Jolliffe, 2006). It is widely recognised that there is a need
for the optimization of pharmacological properties or
development of new antifungal drugs that have a different
mode of action to those currently in use.
Pharmacophore sites identification and then optimiza-
tion (Anaflous et al., 2004; Ben Hadda et al., 2003, 2007,
2008; Chohan et al., 2006; Hakkou et al., 2002; Houari
et al., 2008) plays a major role in many steps of the drug
discovery processes. A better understanding and modelling
of the pharmacophore sites could greatly increase the
efficiency for developing new efficient antibacterial
(Anaflous et al., 2004; Ben Hadda et al., 2003, 2007, 2008;
Chohan et al., 2006; Hakkou et al., 2002; Houari et al.,
2008), antitumoral (Zunino et al., 2002) and combined
antitubercular/anti-HIV-1 drugs (Ben Hadda et al., 2005;
Bennani et al., 2007).
A. Jarrahpour
Department of Chemistry, College of Sciences,
Shiraz University, 71454 Shiraz, Iran
J. Sheikh (&) ꢀ H. Juneja
Department of Chemistry, RTM Nagpur University,
Nagpur 440033, India
e-mail: sheikhchemie@gmail.com; javedchemie@gmail.com
I. E. Mounsi ꢀ T. B. Hadda (&)
In pharmacophore site identification, an understanding
of molecular properties is needed. In lead discovery and
optimization, an estimate of electronic factors and
´
Laboratoire Chimie des Materiaux, Universite Mohammed
Premier, 60000 Oujda, Morocco
´
e-mail: tbenhadda@yahoo.fr
123

Med Chem Res
Fig. 1 Structures of SR and
screened candidates 3–14.
Ribavirin is capable of adopting
multiple conformations by
rotating the C3–C6 bond to
mimic both adenosine and
guanine ribonucleosides. So it
has wo different pharmacophore
sites (antibacterial and antiviral)
represented in blue and red
colours, respectively (Color
figure online)
1
1
O
Br
1
O
O
3
1
NH2
1
1
3
NH
HO
NH
N
N
O
N
N
2
2
HO
2
NH2
N 2
O
4
N
N
O
4
HO
OH
OH
O
HO
Ribavirin
Acyclovir
Brivudin
R2
4
R1
N
4
NH
2
O
Z
N
2
1
3
O
2
Y
W
O
NH
N
N
2
3
1
1
3
X
N
N 3
N
N
CH3
1
NH
Y
W
2
N
1
4N
OH
NH
2
1
N
N
1
O
O
Z
4
NH
O
OH
OH
R2
N
2
2
R1
HO
(S)-DHPA
14
Ganciclovir
3-13
crystallographic structure accessibility is desired, molecu-
lar properties have to be calculated, and the synthesis of a
pharmacology library asks for knowledge on the scope and
limitations of a bioactivity type. Further, the knowledge on
the stability of the drugs of a library is necessary.
anti-HIV pharmacophore sites. We have employed this
technology to discover potent viral inhibitors by modelling
the antiviral pharmacophore sites.
In this study, we have exemplified the principles of the
technology with the successful discovery of potent antiviral
activity in vitro against 13 viruses (Fig. 1).
The estimation of heteroatoms charge and their orien-
tation in space and bioavailability properties of resultant
candidate has to model the interaction between drugs and
their target(s) and to predict the drug-likeness values.
Furthermore, many bioactivity modes of action are the
results of drug conformation.
We presented here the results of our virtual screening
investigation into possible alternative structures for these
compounds. A comparison between experimental and
theoretical predictions of the antibacterial and antiviral
activity has enabled us to identify alternative antiviral
structures.
In fact, molecular recognition between a drug and its
receptor is generally dictated by the correct three dimen-
sional presentations of the ‘essential’ functionalities of the
ligand to the binding site of the receptor. The challenge in
peptidomimetic drug discovery lies in placing these phar-
macophoric groups in an identical spatial arrangement to
elicit the desired biological response. Although some
classes of molecules have been discovered that seems to be
privileged structures for at least some drug-receptor inter-
actions, the challenge to design and synthesize small
molecules with high specific affinity to pharmacologically
important targets are still remains. With their high density
of stereo information and their relative rigid Schiff bases of
isatin provides excellent platform to display a number of
substituent in a variety of sterically defined ways, hence
offering the opportunity to explore these unique features
for the drug discovery processes. In collaboration with NCI
and TAACF of United States, we have developed a tech-
nology platform that enables easy access to structurally
diverse libraries based on antibacterial, antitumoral and
Results and discussion
Synthesis
The efficient formal synthesis of various bis-Schiff bases
3–14 have previously been reported by the reaction
between isatin, benzylisatin or 5-fluoroisatin 1a–c and
primary aromatic amines 2a–d (Scheme 1). The chemical
1
structures of the products have been confirmed by H- and
13CNMR, IR and mass spectral data (Jarrahpour et al.,
2007).
The structurally simpler and symmetric diamino-aryl 2d
was used as an initial precursor to allow for the exploration
of a symmetric Schiff base structure 14 and to serve as a
platform for the synthesis of synthetically more challeng-
ing therapeutic agents 3–13. Compounds 3–14 were
obtained in one-step sequence from isatins 1a–c, the
123

Med Chem Res
R2
Y
Y
X
Z
Z
R2
W
N
3
4'
N
N
W
R1
O
O
N
6-7
R1
(3,4'-isomers/X)
Y
Y
Z
Z
X
W
H2N
R1
EtOH/Δ
W
R2
R2
NH2
NH2
N
Z
X
W
W
Z
X
2b
Y
Y
W
O
NH2
NH2
Y
Y
R1
W
N
O
Z
2c
Z
N
N
2a
4
3
W
N
N
Y
O
Y
W
W
Z
Z
R2
NH2
X
O
X
N
EtOH/Δ
EtOH/Δ
Y
O
R1
Y
Z
1a-c
W
4'
N
R1
Z
O
R2
R2
N
H2N
NH2
R1
EtOH/Δ
CH3
3-5
(3,3'-isomers/X)
2d
8-13
(4,4'-isomers/X)
N
N
NH
HN
CH3
O
O
14
(X, Y, Z, W, R1, R2)
7: (O, H, H, H, H, H)
3: (CH2, H, H, H, H, H)
4: (CH2, H, H, H, H, F)
5: (CH2, H, H, H, Bn, H)
6: (CH2, H, H, H, H, H)
11: (O, H, H, H, H, F)
12: (O, H, H, H, Bn, H)
13: (CO, H, H, H, H, H)
8: (CH2, H, H, H, H, F)
9: (CH2, Cl, Et, Et, Et, Et)
10: (CH2, H, H, H, Bn, H)
14: (---, H, H, CH3, H, H)
Scheme 1 General synthesis of bis-Schiff bases 3–14
symmetric structure of 3,30-isomers in (3–5) and 4,40-iso-
mers in (4,40-isomers) was rapidly assembled from a novel
symmetric diamines 2a or 2c via a Keto/amine condensa-
tion. That was extended to dissymmetric structure 3,40-
isomers (6–7) by using dissymmetric diamine 2b. So this
dissymmetric-substituted Schiff bases molecules 3–14 has
been established. The flexibility of the synthesis could
allow for further development of a wide range of deriva-
tives able to coordinate selectively one or two transition
metal centres. The direct impact of structure symmetry and
nature of various substituents at different positions, on
efficient synthesis for
a range of symmetric and
123

Med Chem Res
Table 1 Antibacterial activities of Schiff bases 3–14
Compds.
Substituants
Anibacterial Activity. MIC (lg/mL)
X
Y
Z
W
R1
R2
C=N/X
S. cerevisiae
S. aureus
C. albicans
E. coli
3
CH2
CH2
CH2
CH2
O
H
H
H
H
H
H
Cl
H
H
H
H
–
H
H
H
H
H
H
Et
H
H
H
H
–
H
H
H
H
H
H
Et
H
H
H
H
–
H
H
F
3,30
3,30
3,30
3,40
3,40
4,40
4,40
4,40
4,40
4,40
4,40
–
\50
\50
\50
\50
\50
\50
\50
\50
\50
\50
\50
\100
\50
\50
\50
\50
\50
\50
\50
\50
\50
\50
\50
\100
\50
\50
\50
\50
\50
\50
\50
\50
\50
\50
\50
\100
\50
\50
\50
\50
\50
\50
\50
\50
\50
\50
\50
\100
4
H
5
Bn
H
H
H
H
F
6
7
H
8
CH2
CH2
CH2
O
H
9
H
H
H
F
10
11
12
13
14
Bn
H
O
Bn
H
H
H
–
C=O
–
–
Table 2 Cytotoxic and antiviral activity of bis-Schiff bases 3–14
Compds.
Minimum cytotoxic concentration Minimum virus-inhibitory concentration (lg/mL)
(lg/mL)
HEL
Vero
Hela
A
B
C
D
E
F
G
H
I
J
K
L
M
3
80
80
80
C16
80
[16 [16 [16 [16 [16 [16 [16 [16 [16 [16 9.6
[16 [16 [16 [16 [16 [16 [16 [16 [16 [16 9.6
[16 [16
[16 [16
4
80
5
200
80
200
80
200
C16
C16
80
[40 [40 [40 [40 [40 [40 [40 [40 [40 [40 [40 [40 [40
[16 [16 [16 [16 [16 [16 [16 [16 [16 [16 3.2 [16 [16
6
7
400
16
400
C16
16
[80 [80 [80 [80 [80 [80 [80 [80 [80 [80 [16 [16 [16
[3.2 [3.2 [3.2 [3.2 [3.2 [16 [16 [16 [16 [16 [16 [16 [16
[16 [16 [16 [16 [16 [3.2 [3.2 [3.2 [3.2 [3.2 [3.2 [3.2 [3.2
8
9
80
16
10
40
40
200
C16
80
[8 [8
[8
[8
[8
[8
[8
[8
[8
[8
[8
[8
[8
[8
[40 [40 [40
[16 [16 [16
11
8
40
[1.6 [1.6 [1.6 [1.6 [1.6 [8
12
400
80
80
[80 [80 [80 [80 [80 [80 [80 [80 [80 [80 [16 [16 [16
[16 [16 [16 [16 [16 [16 [16 [16 [16 [16 48 [16 [16
[80 [80 [80 [80 16 [80 [80 [80 [80 [80 [400 [400 [400
0.16 [500 60 [500 500 [100 [100 [100 [100 [100 [500 [500 [500
500 [500 300 [500 [500 300 300 300 [500 60
13
C16
400
500
[500
–
80
14
400
[500
[500
C400
500
[500
–
Brivudin
Ribavirin
60
–
[500 60
Acyclovir [500
Ganciclovir [100
2.4 20
[500 [500 300
[100 [100 12
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
0.48
–
4
–
–
(S)-DHPA
–
500
[500
–
–
–
[100 300 [100 [100
500 [500 [500
A Herpes simplex virus-1(KOS), B herpes simplex virus-2(G) C vaccinia virus, D vesicular stomatitis virus, E herpes simplex virus-1 KOS ACV’
(TK’), F para-influenza-3 virus, G reovirus-1, H sindbis virus, I coxsackie virus B4, J punta Toro virus, K vesicular stomatitis virus, L coxsackie
virus B4, M respiratory syncytial virus
bioactivity was confirmed by antibacterial, antifungal and
antiviral screening results analysis (Tables 1, 2, 3).
these compounds were determined (Jarrahpour et al.,
2007).
The compounds 8 and 11 were the most cytotoxic in
HEL cells. These newly synthesized bis-Schiff bases were
also tested for their antibacterial and antifungal activi-
ties. They did not display activity against S. cerevisiae
(ATCC 28383) or C. albicans (CIP 1180-79) as shown in
Tables 1, 2.
Biological activity
The compounds have been screened for antiviral activity
against a panel of DNA and RNA viruses. Minimum
cytotoxic and minimum virus-inhibitory concentrations of
123

Med Chem Res
Table 3 Selected Petra calculations of references and compounds 3–14 (Sheikh et al., 2011b; Sheikh and Ben Hadda, 2012)
Compds.
Calculated atomic property of partial p-charge of heteroatoms (in e-)
Antiviral
pharmacophore
site
N1
N2
N3
N4
O1
O2
X
3
-0.083
-0.080
-0.082
-0.083
-0.083
-0.080
-0.084
-0.082
-0.082
-0.084
-0.082
-0.072
0.185
0.227
-0.083
-0.080
-0.082
-0.083
-0.085
-0.080
-0.084
-0.082
-0.082
-0.084
-0.082
-0.072
–
0.227
-0.182
-0.181
-0.180
-0.182
-0.180
-0.182
-0.180
-0.181
-0.193
-0.193
-0.178
-0.153
-0.224
-0.186
-0.211
-0.211
–
-0.182
-0.181
-0.180
-0.182
-0.196
-0.182
-0.180
-0.181
-0.109
-0.193
-0.178
-0.153
-0.200
–
0
N=C–C=O
N=C–C=O
N=C–C=O
N=C–C=O
N=C–C=O
N=C–C=O
N=C–C=O
N=C–C=O
N=C–C=O
N=C–C=O
N=C–C=O
N=C–C=O
Tautomers
N=C–C=O
N–C–C=O
N–C–C=O
N–C–C–N
4
0.232
0.221
0.227
0.230
0.231
0.230
0.221
0.232
0.222
0.236
0.202
0.238
-0.116
0.201
0.201
0.134
0.232
0.221
0.227
0.228
0.231
0.230
0.221
0.232
0.222
0.236
0.202
–
0
5
0
6
0
7
0.098
0
8
9
0
10
0
11
0.130
0.122
12
13
-0.18
14
–
–
–
–
–
–
Brivudin
Ribavirin
Acyclovir
Ganciclovir
(S)-DHPA
-0.115
-0.125
-0.125
-0.096
0.138
0.261
-0.212
-0.212
-0.174
0.209
–
0.209
-0.170
–
R2
R2
Fig. 2 Repetition of negative
charge of Nsp2 and Osp2 atoms
R1
N
R2
3
R1
W
O
N
Z
δ -
NH
O
3
N
Z
δ -
N
O
δ -
R1
4
W
Z
X
N
δ -
Y
O
δ -
δ -
3
Y
Y
W
N
N
Y
Y
δ -
X
δ -
X
CH3
W
Y
δ -
W
δ -
δ -
δ -
N
N
4'
Z
O
N
δ -
δ -
δ -
4'
O
N
Z
Z
W
δ -
O
N
R1
R2
O
NH
N
R2
R2
R1
N
R1
3-5
14
8-13
(4,4'-isomers/X)
6-7
(3,4'-isomers/X)
(3,3'-isomers/X)
(2,6-isomer/Me)
Theoretical calculations of molecular properties of 3–14
design specific drug-like or lead-like bis-Schiff bases
products.
Various investigators have used computational methods to
understand differences between natural products and other
sources of drug leads. Modern drug discovery is based in
large part on high throughput screening of small molecules
against macromolecular disease targets requiring that
molecular screening libraries contain drug-like or lead-like
compounds. We have analyzed known standard references
(SR) for drug-like and lead-like properties. With this
information in hand, we have established a strategy to
Petra calculations
The series 3–14 of Schiff bases have been subjected to
delocalised-charge calculations using Petra method of the
non-hydrogen common atoms (Fig. 2), obtained from the
partial pi-charge of heteroatoms, have been used to model
the bioactivity against bacteria, fungal and viruses.
123

Med Chem Res
Table 4 Osiris calculations of
compounds 3–14 and references
(Color table online)
MUT mutagenic, TUMO
tumorigenic, IRR irritant, REP
reproductive effective, CLP
cLogP, S solubility, DL
Druglikness, DS drug-score
PETRA is a program package comprising various
empirical methods for the calculation of physicochemical
properties in organic molecules. All 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
(Sheikh et al., 2011b; Sheikh and Ben Hadda, 2012).
It is found that the negative charges of the nitrogen Nsp2
and oxygen Osp2 contribute positively in favour of an
antiviral activity, more than antibacterial activity, and this
is in good agreement with the mode of antiviral action of
the compounds bearing (Xd-–Yd-) involving coordination
of the metal within the parasite. It was hypothesized that
difference in charges between two heteroatoms of the same
pharmacophore site (Xd-–Yd?) may facilitate the inhibi-
tion of bacteria, more than viruses. It is further found that
the activity increases with increase in negative charge of
the heteroatoms of the common pharmacophore fragment
of the molecule. This is related with possible secondary
electronic interaction with the positively charged side
chains of the virus target(s).
Attempts were 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 sub-
stituents and a three-member pharmacophore site attached to
the isatin/aryl bridge-containing ring are conductive to the
activity. The Petra software calculations confirmed that all
compounds 3–14 have a clear preference for forming anti-
viral pharmacophore sites though their estimated partial p
charges respectively for O and N neighbour atoms are of
negative charges (-0.182 and -0.083 e) for compound 3.
The Petra calculations with the other azo Schiff bases 4–14
are shown and summarised in Table 3.
On the basis of the above observations, it is tentatively
suggested that compounds 3–14 show two antiviral phar-
macophore site in which the N,O heteroatoms act as
123

Med Chem Res
Table 5 Molinspiration calculations of compounds 3–14 and references
Compds.
Molinspiration calculations
Drug-likeness
MW g/mol
cLogP
TPSA
Number
OH–NH
Interract
Number
violation
Volume
GPCRL
ICM
KI
NRL
3
456
492
636
456
458
492
637
636
494
638
470
380
333
244
225
255
209
6.45
4.79
90
2
2
0
2
2
2
2
0
2
0
2
2
3
5
4
5
4
1
0
2
1
1
0
2
2
0
2
1
0
0
0
0
0
0
402
412
579
402
394
412
563
579
404
572
404
331
235
197
187
212
178
-0.17
-0.11
-0.91
-0.17
-0.20
-0.10
-0.65
-0.91
-0.14
-0.93
-0.17
-0.37
-0.46
-0.32
-0.27
-0.21
-0.10
-0.46
-0.55
-2.45
-0.46
-0.47
-0.54
-1.48
-2.44
-0.55
-2.45
-0.54
-0.46
-1.49
-1.35
-1.30
-1.17
-0.73
-0.17
-0.15
-1.64
-0.17
-0.15
-0.16
-0.94
-1.64
-0.14
-1.63
-0.14
-0.27
-0.30
-0.33
-0.32
-0.07
0.39
-0.69
-0.64
-1.95
-0.69
-0.79
-0.64
-1.27
-1.95
-0.63
-1.94
-0.66
-0.96
-2.27
-1.96
-2.63
-2.40
-3.17
4
90
5
9.02
68
6
6.48
90
7
6.27
99
8
4.83
90
9
9.41
90
10
9.04
68
11
4.63
99
12
8.96
78
13
5.99
108
90.45
105
144
119
139
110
14
4.89
Brivudin
Ribavirin
Acyclovir
Ganciclovir
(S)-DHPA
-0.94
-2.77
-1.61
-2.17
-0.97
GPCRL GPCR ligand, ICM ion channel modulator, KI kinase inhibitor, NRL nuclear receptor ligand
ligation centres and possibly accommodate themselves
between metal in such a way that a stable complex of the
pharmacophore site is formed hence, giving a moderate to
inactive structure to the tested antibacterial candidates.
associate with DANN (Sheikh et al., 2011b; Sheikh and
Ben Hadda, 2012).
The OSIRIS Property Explorer shown in this page is an
integral part of Actelion’s (1) inhouse substance registra-
tion system. It lets you draw chemical structures and cal-
culates on-the-fly various drug-relevant properties
whenever a structure is valid. Prediction results are valued
and colour-coded. Properties with high risks of undesired
effects like mutagenicity or a poor intestinal absorption are
shown in red. Whereas a green colour indicates drug-
conform behaviour (Table 4).
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 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 (Sheikh et al.,
2011b; Sheikh and Ben Hadda, 2012).
Molinspiration calculations
CLogP (octanol/water partition coefficient) is calculated by
the methodology developed by Molinspiration as a sum of
fragment-based contributions and correction factors (Ertl
et al., 2000).
With our recent publications on the drug design com-
binations of various pharmacophore sites by using spiro-
heterocyclic structure (Bennani et al., 2007), it is now
possible to predict activity and/or inhibition with increas-
ing success in two targets (bacteria and HIV). This is done
using a combined electronic/structure-docking procedure
and an example will be given here. The remarkably well-
behaved mutagenicity of divers synthetic molecules clas-
sified 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
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. (2000) as a sum of
fragment contributions. O- and N- centered 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
123

Med Chem Res
and N,N,N0,N0-tetra-[(3-substituted-5-methylpyrazol-1yl] para-
phenylenediamines. Lett Drug Des Discov 2:584–589
Ben Hadda T, Badri R, Kerbal A, Baba BF, Akkurt M, Demailly G,
Benazza M (2007) Synthesis and antitubercular activity of
spiroheterocycles: 2,20,40,50-tetra-substituted-1,2,20,40-tetrahy-
dro-4H-spiro[isoquinoline-3,30-pyrazol]-4-ones. Arkivoc XIV:
276–288
compounds 3–14 molecular properties (TPSA, GPCR
ligand and ICM) are valued (Table 5).
Conclusion
Ben Hadda T, Rahima B, Kerbal A, Baba BF, Akkurt M, Demailly G,
Benazza M (2008) Looking for a new antitubercular pharmaco-
phore site: synthesis and bioactivity of spiroheterocycles 2,30,40-
tri-subsituted-1,2-dihydro-4H,40H-spiro[iso-quinoline-3,50-iso-
xazol]-4-ones. Arkivoc ii:1–13
Ben Hadda T, Akkurt M, Baba MF, Daoudi M, Bennani B, Kerbal A,
Chohan ZH (2009) Anti-tubercular activity of ruthenium (II)
complexes with polypyridines. J Enzym Inhib Med Chem
24:457–463
The compounds 3–14, typically could form the highly
stable aromatic pharmacophore sites (O=C–C=N). This
structure leads us to design therapeutically active candi-
dates with remarkable chemical stability in both coordi-
nation chemistry and antiviral activity. Some inactive
series tested previously, in our groups, as antibacterial
agents are in the same undesirable geometry (Jarrahpour
et al., 2011). A number of important points emerge con-
cerning the electronic and steric factors which have direct
impact on antiviral properties. The positive results we have
recorded, while encouraging for purposes of new drug
design, confirm that very likely most of these compounds
could be used as potential antiviral activity after minor
modifications. Based on their structural properties, these
compounds may be useful as chelating agents with poten-
tial activity. These results prompt several pertinent obser-
vations: (i) This type of azo Schiff bases can furnish an
interesting 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 rigid pharmacophore site (s) geometric conformation
enables us to prepare molecules for multi-therapeutic
materials with high selectivity and low molecular weight
(MW \ 400 g/mol). This approach was executed with
success in the case of other series of ligands and their
transition metal complexes (Ben Hadda et al., 2009; Cho-
han et al., 2010a,b; Jarrahpour et al., 2010; Parvez et al.,
2010, 2012; Rauf et al., 2012; Sheikh et al., 2011a,b;
Sheikh and Ben Hadda, 2012).
Bennani B, Kerbal A, Daoudi M, Baba BF, Houari GA, Jalbout AF,
¨
´
´ ´
Mimouni M, Benazza M, Demailly G, Akkurt M, Yyldyrym SO,
Hadda TB (2007) Combined drug design of potential mycobac-
terium tuberculosis and HIV-1 inhibitors: 30,40-di-substituted -
40H-spiro [isothiochromene-3,50-isoxazol]-4(1H)-one. Arkivoc
xvi:19–40
ˇ ´
ˇˇ ´
´
Blagus A, Cincic D, Friscic T, Kaitner B, Stilinovic V (2010) Schiff
bases derived from hydroxyaryl aldehydes: molecular and crystal
structure, tautomerism, quinoid effect, coordination compounds.
Maced J Chem Chem Eng 29:117–138
Chohan ZH, Shaikh AU, Naseer MM (2006) Metal-based isatin-
bearing sulfonamides: their synthesis, characterization and
biological properties. Appl Organomet Chem 20:729–739
Chohan ZH, Sumra SH, Youssoufi MH, Ben Hadda T (2010a) Metal
based biologically active compounds: design, synthesis and
antibacterial/antifungal/cytotoxic properties of triazole derived
Schiff bases and their oxovanadium(IV) complexes. Eur J Med
Chem 45:2739–2747
Chohan ZH, Youssoufi MH, Jarrahpour A, Ben Hadda T (2010b)
Identification of antibacterial and antifungal pharmacophore
sites for potent bacteria and fungi inhibition: indolenyl sulfon-
amide derivatives. Eur J Med Chem 45:1189–1199
Ertl P, Rohde B, Selzer P (2000) Fast calculation of molecular polar
surface area as a sum of fragment-based contributions and its
application to the prediction of drug transport properties. J Med
Chem 43:3714–3717
Hakkou A, Bouakka M, Touzani R, Elkadiri S, Ramdani A,
Kotchevar A, Ellis T, Waring M, Hadda TB (2002) 2,3-
Bifunctionalized quinoxalines: synthesis, DNA interactions and
evaluation of anticancer, antituberculosis and antifungal activity.
Molecules 7:641–656
Acknowledgments The authors are thankful to the Shiraz Univer-
sity Research Council for financial support (Grant No. 87-GR-SC-23).
Prof. T. Ben Hadda would like to thank the ACTELION; the Bio-
pharmaceutical Company of Swiss, for the on-line molecular prop-
erties calculations.
HouariGA, KerbalA,BennaniB,BabaMF,DaoudiM,HaddaTB(2008)
Drug design of new antitubercular agents: 1,3-dipolar cycloaddition
reaction of para-substituted-benzadoximes and 3-para-methoxy-
benzyliden-isochroman-4-ones. Arkivoc xii:42–50
Jarrahpour A, Khalili D, De Clercq E, Salmi C, Brunel JM (2007)
Synthesis, antibacterial, antifungal and antiviral activity evalu-
ation of some new bis-Schiff bases of isatin and their derivatives.
Molecules 12:1720–1730
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