Computational evaluation and experimental verification of antibacterial and antioxidant activity of 7-hydroxy-3-pyrazolyl-4H-chromen-4-ones and their o-glucosides: Identification of pharmacophore sites

Article abstract of DOI:10.1007/s00044-013-0621-5

This paper reports the computational evaluation and experimental verification of 7-hydroxy-3-(1-phenyl-3-aryl-1H-pyrazol-5-yl)-4H-chromen-4-ones 3 and their o-β-d-glucopyranosides 5 for their antimicrobial and antioxidant activity. The prepared compounds

Full text of DOI:10.1007/s00044-013-0621-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0621-5
ORIGINAL RESEARCH
Computational evaluation and experimental verification
of antibacterial and antioxidant activity of 7-hydroxy-3-
pyrazolyl-4H-chromen-4-ones and their O-glucosides:
identification of pharmacophore sites
•
Javed Sheikh Kishor Hatzade Ammar Bader
•
•
•
•
Usama Shaheen Thomas Sander Taibi Ben Hadda
Received: 7 January 2013 / Accepted: 6 May 2013
Ó Springer Science+Business Media New York 2013
Abstract This paper reports the computational evaluation
and experimental verification of 7-hydroxy-3-(1-phenyl-3-
microbial activity (Billeret et al., 1993; Cingolani et al.,
1969). The widespread flavonoids act as various functional
secondary metabolites in plants. Literature survey reveals
that chromones show anticancer (Atassi et al., 1985; Birt
aryl-1H-pyrazol-5-yl)-4H-chromen-4-ones
3 and their
O-b-D-glucopyranosides 5 for their antimicrobial and anti-
oxidant activity. The prepared compounds were tested
against various Gram-positive and Gram-negative bacteria
species. Some of the synthesized compounds have shown
potential antimicrobial and antioxidant activity. This POM
bioinformatic study could greatly help to pharmacomodu-
late the potential antibiotics and antioxidants.
´
´
et al., 2001; Lopez-Lazaro, 2002; Pouget et al., 2001;
Zheng et al., 2003), anti-HIV (Yu et al., 2004), and anti-
oxidant properties (Burda and Oleszek, 2001; Rackova
et al., 2005). Pyrazoles are quite popular in the field of
medicine and agro chemistry. A number of pyrazole
derivatives have been reported to possess interesting bio-
logical activities like anti-inflammatory (Bernard et al.,
1986), antimicrobial and antiprotozoal (Bochis et al.,
1986). In addition, pyrazole is found widely as a core
structure in a large variety of compounds that exhibit
important biological activity (Pevarello et al., 2005). Many
organic compounds containing carbohydrate exhibit a wide
variety of biological and therapeutic properties (Dwek,
1996). Another group of carbohydrate exhibiting potential
therapeutic uses is nucleoside analogs. Nucleosides are also
glycosides that occur in nucleic acids. Several O-, N-, and
C-glycosides have been isolated from other natural sources
(The Merck Index, 1989). These compounds have a wide
range of biological relevance including antibacterial, anti-
fungal, antiviral, and antitumoral activities. As a result, the
formation of the glycosidic linkage continues to be a pre-
dominant theme in carbohydrate chemistry (Boons, 1996).
Carbohydrates play important roles in a variety of biolog-
ical processes, such as signaling, cell–cell communications,
molecular and cellular targeting (Sears and Wong, 1999).
In view of these pertinent observations and in continu-
ation to our work (Ingle et al., 2007) on chromone-based
heterocycles, it was considered to synthesize chemical
entities incorporating three active pharmacophores namely
chromone, pyrazole, and glucose moiety in a single
molecular framework so as to get biologically active
Keywords Chromones ꢀ Pyrazoles ꢀ O-b-D-Glucosides ꢀ
Virtual screening ꢀ Petra, Osiris, and molinspiration (POM) ꢀ
Chemoinformatics
Introduction
Flavonoids constitute one of the most active classes of
compounds possessing diverse pharmacological and
J. Sheikh (&) ꢀ K. Hatzade
Department of Chemistry, Dhote Bandhu Science College,
Gondia 441614, India
e-mail: sheikhchemie@gmail.com
A. Bader ꢀ U. Shaheen
Department of Pharmacognosy, Faculty of Pharmacy,
Umm Al-Qura University, Mecca 21955, Saudi Arabia
T. Sander
Actelion Pharmaceuticals Ltd., Gewerbestrasse 16,
4123 Allschwil, Switzerland
T. Ben Hadda
Laboratoire Chimie Materiaux, FSO, Universite Mohammed
´
1ER, 6000 Oujda, Morocco
e-mail: taibi.ben.hadda@gmail.com
´
123

Med Chem Res
H2N
O
N
OH
Fig. 1 Structures of standard
drugs and POM analyzed 3a–3i
and 5a–5i compounds
O
O
OH
CH3
NH
F
S
O
O
O
HO
H3C
N
CH3
NH2
CH3
HO
O
O
N
H2N
H3C
HN
NH
OH
NH2
Ciprofloxacin
Sulphacetamide
Gentamycin
(Antibacterial agent)
(Antibacterial agent)
(antifungal agent)
HO
Cl
R'
O
HO
O
N
O
N
O
H
N
3-5
HO
OH
N
R
Clotrimazole
ascorbic Acid
(anti-oxidant agent)
3a-3i & 5a-5i
(POM analyzed compounds)
(antifungal agent)
compounds (Hatzade et al., 2008). Herein, we report the
computational evaluation of chromones/pyrazoles gluco-
side using Petra/Osiris/Molinspiration (POM) approach
and their experimental verification (Fig. 1).
antifungal activity against A. niger and C. albicans fungi
using the cup plate diffusion method (Vagdevi et al., 2001)
by measuring the inhibition zones in mm. The comparative
studies of the aglycones and glucosides have been observed
by using standard ciprofloxacin, sulfacetamide for bacteria
and gentamycin, clotrimazole (100 lg/mL) for fungi. The
test compounds were dissolved in DMSO at a concentra-
tion of 100 lg/mL. Most of the compounds exhibited mild
to moderate antibacterial activity as well as antifungal
activity against all the microbes tested (Table 1). Similarly
in vitro free radical scavenging activities of glucosides
were evaluated by DPPH assay method and most of the
compounds were found to be active at 1 mg/mL concen-
tration. Percentage scavenging of DPPH radical was cal-
culated using the formula:
Results and discussion
Synthesis of compounds 3–5
7-Hydoxy-3-formyl chromen-4H-one 1 on condensation
with substituted acetophenones in the presence of piperi-
dine in dry alcohol affords 7-hydroxy-3-(3-oxo-3-arylprop-
1-enyl)-4H-chromen-4-ones 2 which on cyclization with
phenyl hydrazine hydrochloride leads to the formation of
7-hydroxy-3-(1-phenyl-3-aryl-1H-pyrazol-5-yl)-4H-chro-
men-4-ones 3. 7-O-b-D-Glucopyranosyloxy-3-(1-phenyl-3-
aryl-1H-pyrazol-5-yl)-4H-chromen-4-ones 5 have been
synthesized by the reaction of 2,3,4,6-tetra-O-acetyl-a-D-
glucopyranosyl bromide with potassium salt of 3 followed
by deacetylation with Zn(CH3COO)2 in absolute methanol.
All the compounds described have been previously pre-
pared and well characterized by NMR, Mass and IR
spectroscopic methods (Hatzade et al., 2008) (Scheme 1).
% Scavenging of DPPH ¼ ½ðControl ꢁ TestÞ=Controlꢂ
ꢃ 100:
Theoretical calculations of molecular properties
of 3a–3i and 5a–5i
The aqueous and/or ethanol extraction of flavonoids have
often been used in traditional medicine, and also have,
therefore, been studied for their antitumor, antioxidant,
antiviral, anti-algal, antimicrobial, cytotoxic, and anti-
inflammatory, significant hepatoprotective and cardiovas-
cular activity without any criteria of selection.
Biological activity
In continuation of our first POM analyses (Ben Hadda
et al., 2012), on Natural Flavonoids (Fig. 2), as potential
antibacterial/antiviral drugs, the present study furnishes an
overview of the 20 synthetic flavonoids and antifungal/
antibacterial activity of their metabolite species. Here, on
the basis of POM analyses, a simple, economic, quick and
Compounds 3a–3i and 5a–5i were evaluated for various
biological screening programs. The various screening
programs carried out includes the in vitro antibacterial
activity against Escherichia coli, Klebisilla aerogens,
Staphyllococcus aureus, and Bacillus substilis and in vitro
123

Med Chem Res
Scheme 1 Synthetic protocol
for compounds 3–5 (Hatzade
et al., 2008)
R
R
HO
O
H
C
3
HO
O
O
O
O
C5H11N, Absol. EtOH
O
H
O
1
2
2-5
HO
O
a : R = H
N
N
b : R = 4-Cl
c : R = 4-Br
O
C6H5NHNH2/ HCl/ DMF
3
d : R = 4-CH3
e : R = 4-OCH3
f : R = 2,4-Cl2
g : R = 3,4-Cl2
h : R = 3-NO2
i : R = 4-NO2
R
AcGlu
O
N
N
O
i) K2CO3/ CH3CN, inert Atmos.
4
ii) α-acetobromoglucose, 18-crown-6
OAc
R
O
AcO
AcO
O-------
OAc
AcGlu :
Glu
O
O
N
N
Zn(OAc)2, MeOH
5
R
efficient bioinformatic platform, it now becomes easy and
possible to predict and optimize the flavonoids bioactivity.
For antibacterial activity, the compound should possess
(Xd-–Yd?) pharmacophore site and also it was hypothe-
sized that the difference in charge between X and Y of the
same dipolar pharmacophoric site should facilitate the
inhibition of bacteria more than viruses. In contrast to
Petra calculations
antibacterial agent, the antiviral drug should have (Xd-
–
During the past 15 years, our group investigated the
potential pharmacophores of various heterocycles for their
possible antiviral and/or antibacterial activity and verified
them further with Petra/Osiris/Molinspiration (POM)
analyses (Chohan et al., 2010; Jarrahpour et al., 2010,
2011; Masand et al., 2012; Parvez et al., 2010a, b; Rauf
et al., 2011; Sheikh et al., 2011; Sheikh and Hadda, 2012).
On the basis of the new findings, we can conclude that
series 3a–3i and 5a–5i engage in opening/closing of B ring
showing that 3–5 act as prodrugs and, in the presence of
bacteria, can furnish active metabolites bearing keto and
two hydroxyl groups containing a potential antibacterial/
antiviral/antifungal O,O,O-pharmacophore site (Fig. 3).
Yd-) pharmacophore site with respect of some architec-
tural parameters (dihedral angle = 0–10° and distance
dx-y = 3–3.5 A°) (Chohan et al., 2010; Jarrahpour et al.,
2010, 2011; Masand et al., 2012; Parvez et al., 2010a, b;
Rauf et al., 2011; Sheikh et al., 2011; Sheikh and Hadda,
2012). POM analyses confirm the existence of a combined
antibacterial/antifungal pharmacophore site (Fig. 4).
Osiris calculations
The remarkably well-behaved mutagenicity of divers syn-
thetic molecules classified in database of Celeron Company
of Swiss can be used to quantify the role played by various
123

Med Chem Res
% Inhibition
Table 1 Antimicrobial and antioxidant activity of compounds 3a–i and 5a–i
Zone of inhibition (mm) (Activity index)std
Sr. No.
Antibacterial activity
Gram-positive
Antifungal activity
Antioxidant
activity
Gram-negative
C. albicans
A. niger
S. aureus
B. substilis
E. coli
K. aerogens
DPPH
3a
3b
3c
3d
3e
3f
20 (0.58)a
(0.65)b
21 (0.62)a
(0.68)b
20 (0.58)a
(0.65)b
21 (0.62)a
(0.68)b
24 (0.71)a
(0.77)b
23 (0.68)a
(0.74)b
23 (0.68)a
(0.74)b
22 (0.65)a
(0.71)b
17 (0.59)a
(0.65)b
19 (0.66)a
(0.73)b
19 (0.66)a
(0.73)b
18 (0.62)a
(0.69)b
20 (0.69)a
(0.77)b
17 (0.59)a
(0.65)b
22 (0.76)a
(0.85)b
18 (0.62)a
(0.69)b
17 (0.49)a
(0.59)b
19 (0.54)a
(0.66)b
22 (0.63)a
(0.76)b
17 (0.49)a
(0.59)b
20 (0.57)a
(0.69)b
21 (0.60)a
(0.72)b
20 (0.57)a
(0.69)b
16 (0.46)a
(0.55)b
22 (1.00)a
(1.04)b
19 (0.86)a
(0.90)b
20 (0.91)a
(0.95)b
17 (0.77)a
(0.81)b
19 (0.86)a
(0.90)b
24 (1.09)a
(1.14)b
22 (1.00)a
(1.04)b
17 (0.77)a
(0.81)b
30 (1.43)a
(1.30)b
27 (1.29)a
(1.17)b
23 (1.09)a
(1.00)b
23 (1.09)a
(1.00)b
25 (1.19)a
(1.07)b
23 (1.09)a
(1.00)b
29 (1.38)a
(1.26)b
19 (0.90)a
(0.83)b
19 (0.76)a
(0.79)b
20 (0.80)a
(0.83)b
16 (0.64)a
(0.66)b
18 (0.72)a
(0.75)b
20 (0.80)a
(0.83)b
22 (0.88)a
(0.92)b
19 (0.76)a
(0.79)b
16 (0.64)a
(0.66)b
86.56
(0.88)a
88.73
(0.90)a
86.10
(0.86)a
79.87
(0.81)a
80.56
(0.87)a
86.13
(0.86)a
85.56
(0.87)a
3g
3h
3i
88.75
(0.90)a
86.45
25 (0.74)a
(0.81)b
20 (0.69)a
(0.77)b
21 (0.60)a
(0.72)b
19 (0.86)a
(0.90)b
20 (0.95)a
(0.87)b
20 (0.80)a
(0.83)b
(0.88)a
5a
5b
5c
5d
5e
5f
28 (0.82)a
(0.90)b
26 (0.76)a
(0.84)b
22 (0.65)a
(0.71)b
25 (0.74)a
(0.81)b
31 (0.91)a
(1.00)b
33 (0.97)a
(1.06)b
30 (0.88)a
(0.97)b
25 (0.74)a
(0.81)b
20 (0.69)a
(0.77)b
18 (0.62)a
(0.69)b
22 (0.76)a
(0.85)b
21 (0.72)a (0.81)b
18 (0.51)a
(0.62)b
20 (0.57)a
(0.69)b
24 (0.69)a
(0.83)b
18 (0.51)a
(0.62)b
22 (0.63)a
(0.76)b
20 (0.57)a
(0.69)b
19 (0.54)a
(0.66)b
17 (0.49)a
(0.59)b
24 (1.09)a
(1.14)b
20 (0.91)a
(0.95)b
22 (1.00)a
(1.04)b
19 (0.86)a
(0.90)b
22 (1.00)a
(1.04)b
27 (1.23)a
(1.29)b
24 (1.09)a
(1.14)b
17 (0.77)a
(0.81)b
34 (1.62)a
(1.48)b
29 (1.38)a
(1.26)b
22 (1.04)a
(0.96)b
25 (1.19)a
(1.09)b
27 (1.29)a
(1.17)b
25 (1.19)a
(1.07)b
30 (1.43)a
(1.30)b
20 (0.95)a
(0.87)b
21 (0.84)a
(0.88)b
21 (0.84)a
(0.88)b
18 (0.72)a
(0.75)b
19 (0.76)a
(0.79)b
22 (0.88)a
(0.92)b
23 (0.92)a
(0.96)b
22 (0.88)a
(0.92)b
16 (0.64)a
(0.66)b
88.68
(0.90)a
90.76
(0.93)a
87.19
(0.89)a
80.57
(0.82)a
24 (0.83)a
(0.92)b
22 (0.76)a
(0.85)b
27 (0.93)a
(1.04)b
19 (0.66)a
(0.73)b
23 (0.79)a
(0.88)b
29
82.45
(0.84)a
88.73
(0.90)a
5g
5h
5i
86.12
(0.88)a
91.65
(0.93)a
31 (0.91)a
(1.00)b
23 (0.66)a
(0.79)b
20 (0.91)a
(0.95)b
23 (1.09)a
(1.00)b
21 (0.84)a
(0.88)b
86.56
(0.88)a
98.03
Std. 1
Std. 2
34
35
22
21
25
31
26
29
21
23
24
(Activity index) = Inhibition zone of the sample/Inhibition zone of the standard. For antibacterial activity: Std. 1 = ciprofloxacin and Std.
2 = sulfacetamide, For antifungal activity: Std. 1 = gentamycin and Std. 2 = clotrimazole. For antioxidant activity: Std. 1 = ascorbic Acid
a
Activity index against Std. 1
b
Activity index against Std. 2
123

Med Chem Res
Fig. 2 Opening of C ring of
prodrug (Flavonoids) followed
by a conformational
rearrangement. The formation
of tautomeric forms is crucial in
the orientation/preparation of
hypothetical anti-HIV-IN
O,O,O-pharmacophore site
(Marchand et al., 2006)
HIV-IN catalytic site
O
δ–
O
O
M
R1
R2
R1
H
H
R1
A
A
δ–
A
O
O
O
O
B
M
O
H
δ–
R1
O
O
A
C
O
H
R2
R2
R2
O
B
B
B
IN/Metabolite complex
Flavonoids
Metabolite
(Tautomer-01)
Metabolite
(M = Mn2+, Mg2+
)
(prodrugs)
(Tautomer-02)
Fig. 3 Plausible mechanism for
opening of C ring of prodrugs
3–5 followed by the
regeneration of bioactive
metabolites 30–50 bearing
O,O,O-pharmacophore
+
δ
O
H
R3
A
–
δ
O
O
+
δ
O
R1
H
H3O+
R3
H
+
δ
bacteria
R3
A
A
–
δ
B
O
O
R2
R2
R1
O
R2
Metabolite-II
3-5
R1
(keto-diol)
(prodrugs)
Metabolite-I
(keto-ol)
Fig. 4 Structure of dual
antibacterial/antifungal
pharmacophore site
of prodrugs 3–5
–
δ
M2+
+
δ
O
–
δ
O
H
R3
bacteria
A
R3
A
–
δ
O
B
R1
–
δ
O
O
M2+
H
O
R3
A
+
bacteria
δ
O
–
δ
R2
R2
R2
R1
R1
M = Mn, Mg
(Bacteria Inhibition)
O
3'-5'
3-5
(prodrugs)
(metabolites)
organic groups in promoting or interfering with the way a
drug can associate with DNA. The Osiris calculations are
tabulated in Tables 2 and 3. Toxicity risks (mutagenicity,
tumorogenicity, irritation, reproduction) and physico-
chemical properties (CLogP, solubility, drug-likeness, and
drug-score) of prodrugs 3–5 and their metabolites 30–50
were calculated by the methodology developed by Osiris.
The toxicity risk predictor locates fragments within a
molecule, which indicate a potential toxicity risk. Toxicity
risk alerts are an indication that the drawn structure may be
harmful concerning the risk category specified. From the
data evaluated in Tables 2 and 3 it is obvious that, majority
of structures are supposed to be non-mutagenic, non-irri-
tating with no reproductive effects when run through the
mutagenicity assessment system in comparison with the
standard drug. Low hydrophilicities and, therefore, high
log P values may cause poor absorption or permeation. It
has been shown that for compounds to have a reasonable
probability of good absorption, their log P value must not
be greater than 5.0. On this basis, all the prodrugs 3–5 and
their metabolites 30–50 possessed log P values in the
acceptable range.
The aqueous solubility of a compound significantly
affects its absorption and distribution characteristics.
Typically, a low solubility goes along with a bad absorp-
tion and, therefore, the general aim is to avoid poorly
soluble compounds. Our estimated log S value is a unit
stripped logarithm (base 10) of a compound’s solubility in
mol/L. There are more than 80 % of the drugs in the
market that have an (estimated) log S value greater than
-4. In case of compounds 3–5 and 30–50, values of log
S are around (-4)-(-5). Further, Tables 2 and 3 show
drug-likeness of compounds 3–5 and 30–50 which is in the
comparable zone with that of standard drugs used for
comparison. The reported compounds 3–5 and 30–50
(except 3h, 5h, 3h0, and 5h0) showed no toxicity risk and
have good drug-score as compared with the two standard
drugs used.
123

Med Chem Res
Table 2 Osiris calculations of
compounds 3a–3i and 5a–5i
Compd. MW
Toxicity risk
Osiris calculations
D-L D-S
MUT TUMO IRRI REP CLP
S
3a
3b
3c
380
414
458
394
410
448
448
425
425
542
576
620
556
572
610
610
587
587
330
3.51 −4.86 −0.83 0.41
4.12 −5.59 0.26 0.39
4.21 −5.69 −2.63 0.24
3.83 −5.20 −2.06 0.32
3.41 −4.87 −0.31 0.44
3d
3e
3f
4.74 −6.33
4.74 −6.33
0.44
0.31
0.27
3g
3h
3i
−046
3.38 −5.32 −5.93 0.22
3.38 −5.32 −10.80 0.28
1.40 −4.74 −3.89 0.27
2.01 −5.48 −3.01 0.23
2.10 −5.58 −5.60 0.20
5a
5b
5c
5d
5e
1.72 −5.09 −5.04
0.24
1.30 −4.76 −3.32 0.26
2.63 −6.21 −2.90 0.19
2.63 −6.21 −3.57 0.18
1.27 −5.20 −8.81 0.18
1.27 −5.20 −13.82 0.23
5f
5g
5h
5i
Ciprof
1.63 −3.42
0.17 −1.53
−4.03 −1.18
2.33
5.46
4.88
0.65
0.35
0.77
MUT mutagenic, TUMO
tumorigenic, IRRI irritant, REP
reproductive effective, CLP
CLogP, S solubility, DL
druglikness, DS drug-score,
Ciprof ciprofloxacin, Sulpha
sulfacetamide, Genta
gentamycin, Clotri
clotrimazole, Ascorb ascorbic
acid
Sulpha 214
Genta
Clotri
477
344
4.97 −7.72 −0.10 0.28
−2.23 −0.35 0.02 0.44
Ascorb 176
Molinspiration calculations
Molecular Polar Surface Area TPSA is calculated based on
the corresponding methodology as a sum of fragment
contributions (Chohan et al., 2010; Jarrahpour et al., 2010,
2011; Parvez et al., 2010a, b; Rauf et al., 2011; Sheikh
This method is very robust and is able to process practi-
cally all organic and most organometallic molecules.
123

Med Chem Res
Table 3 Osiris calculations of
compounds 3a0–3i0 and 5a0–5i0
resulting from opening of ring B
of flavonoids/prodrugs 3a–3i
and 5a–5i
Compd. MW
Toxicity risk
Osiris calculations
MUT TUMO IRRI REP CLP
S
D-L
D-S
3a
3b
3c
3d
3e
3f
3g
3h
3i
5a
5b
5c
5d
5e
5f
5g
5h
5i
400
434
478
414
430
468
468
445
445
561
596
640
576
592
630
630
607
605
3.02 −4.24
3.64 −4.98
0.56
1.67
0.57
0.53
3.72 −5.08 −1.26 0.32
3.34 −4.59 −0.70 0.43
2.92 −4.26
4.25 −5.71
4.25 −5.71
1.06
1.95
0.93
0.59
0.41
0.38
2.89 −4.70 −4.57 0.25
2.89 −4.70 −9.54 0.31
0.91 −4.13 −2.61 0.30
1.53 −4.86 −1.73 0.27
1.61 −4.96 −4.33 0.22
1.23 −4.47 −3.77
0.81 −4.15 −2.05 0.29
2.14 −5.60 −1.61 0.23
0.26
MUT mutagenic, TUMO
tumorigenic, IRRI irritant, REP
reproductive effective, CLP
CLogP, S solubility, DL
2.14 −5.6
−2.29 0.21
0.78 −4.59 −7.57 0.19
1.42 −5.05 −11.15 0.13
druglikness, DS drug-score
Table 4 Molinspiration calculations of compounds 3a–3i and 5a–5i
Compd.
R
Molinspiration calculations
Drug-likeness
TPSA
NONI
NV
nrotb
VOL
GPCR
ICM
KI
NRL
PI
EI
3a
H
68
68
1
1
1
1
1
1
1
1
1
4
4
4
4
4
4
4
4
4
2
3
11
0
0
0
1
0
0
1
1
0
0
1
1
1
1
2
1
1
2
2
0
0
2
1
3
3
3
3
4
3
3
4
4
6
6
6
6
7
6
6
7
7
3
2
7
4
332
346
350
349
358
359
359
355
355
464
478
482
481
490
491
491
483
483
290
175
451
310
-0.14
-0.14
-0.22
-0.17
-0.17
-0.10
-0.13
-0.25
-0.25
-0.06
-0.08
-0.14
-0.11
-0.12
-0.09
-0.10
-0.27
-0.27
0.36
-0.58
-0.57
-0.62
-0.63
-0.59
-0.54
-0.55
-0.58
-0.57
-0.64
-0.71
-0.75
-0.75
-0.81
-0.78
-0.79
-0.93
-0.93
0.09
-0.06
-0.08
-0.10
-0.10
-0.08
-0.06
-0.07
-0.15
-0.17
-0.15
-0.20
-0.22
-0.22
-0.25
-0.25
-0.25
-0.40
-0.42
-0.05
-0.70
0.18
-0.03
-0.05
-0.13
-0.06
-0.05
-0.04
-0.03
-0.11
-0.12
-0.13
-0.20
-0.25
-0.20
-0.26
-0.25
-0.24
-0.36
-0.37
0.01
-0.67
-0.69
-0.75
-0.70
-0.67
-0.65
-0.68
-0.73
-0.73
-0.43
-0.45
-0.50
-0.46
-0.44
-0.43
-0.45
-0.51
-0.51
0.14
-0.03
-0.06
-0.09
-0.08
-0.07
-0.08
-0.05
-0.11
-0.12
0.08
3b
4-Cl
3c
4-Br
68
3d
4-CH3
4-OCH3
2,5-Cl2
3,5-Cl2
3-NO2
4-NO2
H
68
3e
77
3f
68
3g
68
3h
114
114
147
147
147
147
157
147
147
199
199
70
3i
5a
5b
4-Cl
0.01
5c
4-Br
-0.01
-0.01
-0.04
-0.06
-0.04
-0.27
-0.28
0.18
5d
4-CH3
4-OCH3
2,5-Cl2
3,5-Cl2
3-NO2
4-NO2
–
5e
5f
5g
5h
5i
Std. 1
Std. 2
Std. 3
Std. 4
–
89
-0.46
0.34
-0.48
0.19
-1.28
-0.06
-0.21
-0.36
0.66
-0.12
0.46
–
200
18
–
0.17
0.30
0.14
-0.13
0.42
TPSA total polar surface area, VOL volume, ONI OH–NH interaction, NV number of violation, GPCR GPCR ligand, ICM ion channel modulator,
KI kinase inhibitor, NRL nuclear receptor ligand, Std. 1 ciprofloxacin, Std. 2 sulfacetamide, Std. 3 gentamycin, Std. 4 clotrimazole
123

Med Chem Res
Table 5 Molinspiration calculations of compounds 3a0–3i0 and 5a0–5i0 resulting from opening of ring B of flavonoids/prodrugs 3a–3i and 5a–5i,
respectively
Compd.
R
Molinspiration calculations
Drug-likeness
TPSA
NONI
NV
nrotb
VOL
GPCR
ICM
KI
NRL
0.21
PI
EI
0.06
3a0
H
96
96
3
3
3
3
3
3
3
3
3
6
6
6
6
6
6
6
6
6
2
3
11
0
4
0
0
0
0
0
0
0
0
0
3
3
3
3
3
3
3
3
3
0
0
2
1
0
6
6
356
370
374
372
382
383
383
379
379
488
502
506
505
514
515
515
511
512
290
175
451
310
140
0.02
0.02
-0.21
-0.21
-0.27
-0.26
-0.25
-0.20
-0.21
-0.24
-0.24
-0.44
-0.52
-0.56
-0.56
-0.64
-0.61
-0.62
-0.75
-0.75
0.09
-0.06
-0.08
-0.01
-0.10
-0.09
-0.06
-0.07
-0.15
-0.17
-0.20
-0.26
-0.28
-0.28
-0.32
-0.32
-0.32
-0.46
-0.48
-0.05
-0.70
0.18
-0.17
-0.20
-0.26
-0.22
-0.20
-0.18
-0.21
-0.28
-0.27
-0.10
-0.12
-0.17
-0.13
-0.13
-0.12
-0.14
-0.21
-0.21
0.14
3b0
4-Cl
0.18
0.11
0.03
-0.01
0.01
3c0
3d0
3e0
3f0
3g0
3h0
3i0
5a0
4-Br
4-CH3
4-OCH3
2,5-Cl2
3,5-Cl2
3-NO2
4-NO2
H
96
6
-0.06
-0.01
-0.01
0.05
96
6
0.18
105
96
7
0.17
0.02
6
0.18
0.00
96
6
0.03
0.20
0.03
141
141
175
175
174
175
184
175
175
221
221
70
7
-0.10
-0.10
0.03
0.11
-0.03
-0.04
0.09
7
0.10
9
0.00
5b0
4-Cl
9
0.00
-0.07
-0.13
-0.08
-0.16
-0.14
-0.153
-0.28
-0.28
0.01
0.01
5c0
5d0
5e0
5f0
5g0
5h0
5i0
4-Br
4-CH3
4-OCH3
2,5-Cl2
3,5-Cl2
3-NO2
4-NO2
–
9
-0.06
-0.03
-0.06
-0.02
-0.04
-0.18
-0.18
0.36
-0.01
-0.00
-0.06
-0.08
-0.05
-0.18
-0.19
0.18
9
10
9
9
10
10
3
Std. 1
Std. 2
Std. 3
Std. 4
Std. 5
–
89
2
-0.46
0.34
-0.48
0.19
-1.28
-0.06
-0.21
-1.01
-0.36
0.66
-0.12
0.46
–
200
18
7
–
4
0.17
0.30
0.14
-0.13
-0.81
0.42
–
107
2
-0.53
-0.24
-1.01
0.20
TPSA total polar surface area, VOL volume, ONI OH–NH interaction, NV number of violation, GPCR GPCR ligand, ICM ion channel modulator,
KI kinase inhibitor, NRL nuclear receptor ligand, Std. 1 ciprofloxacin, Std. 2 sulfacetamide, Std. 3 gentamycin, Std. 4 clotrimazole, Std. 5 ascorbic
acid
Acknowledgments The authors are sincerely thankful to the Prin-
et al., 2011; Sheikh and Hadda, 2012). O-centered polar
cipal, Dhote Bandhu Science College, Gondia for providing necessary
help. Prof. Dr. J. Sheikh and Prof. Dr. T. B. Hadda would like to thank
ACTELION; the Biopharmaceutical Company of Swiss, for the
molecular properties calculations.
fragments are considered. PSA has been shown to be a
very good descriptor characterizing drug absorption,
including intestinal absorption, bioavailability, Caco-2
permeability, and blood–brain barrier penetration. CLogP
(octanol/water partition coefficient) is calculated by the
methodology developed by Molinspiration as a sum of
fragment-based contributions and correction factors
(Tables 4 and 5).
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