Antibacterial, antifungal and antioxidant activity of some new water-soluble β-diketones

Article abstract of DOI:10.1007/s00044-012-0089-8

A new series of eight compounds 1-(4′-O-β-d-glucopyranosyloxy- 2′-hydroxy-5′-substituted phenyl)-3-heteroaryl-propane-1,3-diones (DKG) were prepared by the interaction of α-acetobromoglucose with 1-(2′,4′-dihydroxy-5′-substituted phenyl)-3-heteroaryl- propane-1,3-diones under anhydrous condition at lower temperature. The structures of these O-β-d-glucopyranosides were established on the basis of chemical, elemental, and spectral analyses. Further, the compounds were tested for their antibacterial, antifungal, and antioxidant properties. A correlation of structure and activities relationship of these compounds with respect to molecular modeling, Lipinski rule of five, drug-likeness, toxicity profiles, and other physico-chemical properties of drugs are described and verified experimentally.

Full text of DOI:10.1007/s00044-012-0089-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:964–975
DOI 10.1007/s00044-012-0089-8
ORIGINAL RESEARCH
Antibacterial, antifungal and antioxidant activity of some new
water-soluble b-diketones
•
Javed Sheikh Taibi Ben Hadda
Received: 20 May 2011 / Accepted: 10 May 2012 / Published online: 27 May 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A new series of eight compounds 1-(40-O-b-D-
glucopyranosyloxy-20-hydroxy-50-substituted phenyl)-3-
heteroaryl-propane-1,3-diones (DKG) were prepared by the
interaction of a-acetobromoglucose with 1-(20,40-dihydroxy-
50-substituted phenyl)-3-heteroaryl-propane-1,3-diones under
anhydrous condition at lower temperature. The structures
of these O-b-D-glucopyranosides were established on the
basis of chemical, elemental, and spectral analyses. Fur-
ther, the compounds were tested for their antibacterial,
antifungal, and antioxidant properties. A correlation of
structure and activities relationship of these compounds
with respect to molecular modeling, Lipinski rule of
five, drug-likeness, toxicity profiles, and other physico-
chemical properties of drugs are described and verified
experimentally.
b-diketones bearing potential O,O,O-pharmacophore site,
in which the known side effects are thought to be reduced
and which can be used in a simple manner. The b-dike-
tones and carbohydrates have broad spectrum medicinal
values. b-Diketones exhibits number of pharmacological
activities like antibacterial (Bennett et al., 1999; Sheikh
et al., 2009a, 2011), antiviral (Diana et al., 1978), insec-
ticidal (Crouse et al., 1989), antioxidant (Nishiyama et al.,
2002), and potential prophylactic antitumor activity (Acton
et al., 1980). It has also been used as an anti-sunscreen
agent (Andrae et al., 1997). In liquid solutions (Tobita
et al., 1995) as well as in the solid state (Kaitner and
Mestrovic, 1993) b-diketones exists almost exclusively as
the enol tautomer, which is stabilized by the intramolecular
hydrogen bonding.
Similarly, carbohydrates play important structural and
functional roles in numerous physiological processes,
including various disease states (Dwek, 1996; Sears and
Wong, 1998; Varki, 1993). The relatively recent recogni-
tion of carbohydrates as a medicinally relevant class of
biomolecules has led to the investigation of therapeutic
agents based on either glycan structure or mimics thereof
(Sears and Wong, 1999). For example, cancer cell metas-
tasis (Hakomori and Zhang, 1997) and cell–cell adhesion in
the inflammatory response (Kanas, 1996) are dependent on
cell surface presentation of specific glycans. Synthetic
carbohydrates-based cancer vaccines (Danishefsky and
Allen, 2000) and small molecules selective inhibitors
(Simanek et al., 1998) are thereof being pursued as potential
medicinal agents, respectively. Likewise, the initial stages
of bacterial or viral infection often rely on the recognition
of host cell glycoconjugates by the invading organism
(Karlsson, 1995).
Keywords b-Diketones glucosides (DKG) ꢀ
Antibacterial ꢀ Antifungal ꢀ Antioxidant activity
Introduction
This research communication relates to novel pharmaceu-
tical forms for antibiotics containing hydroxyl sugar and
J. Sheikh (&)
National Environmental Engineering Research Institute,
Nehru Marg, Nagpur 440020, India
e-mail: sheikhchemie@gmail.com; javedchemie@gmail.com
J. Sheikh
Department of Chemistry, RTM Nagpur University,
Nagpur 440033, India
T. B. Hadda
Laboratoire Chimie des Materiaux, FSO,
In this study, we report the synthesis, antibacterial,
antifungal, and antioxidant activity of O-b-D-glucosyl
´
Universite Mohammed I, 60000 Oujda, Morocco
´
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Med Chem Res (2013) 22:964–975
965
derivatives of b-diketones. In addition, we have performed
molecular properties calculations of synthesized com-
pounds by using Petra/Osiris/Molinspiration (POM) theory
to understand the characteristic features responsible for
their bioactivity.
to afford 1-(40-O-b-D-glucopyranosyloxy-20-hydroxy-50-
substitutedphenyl)-3-heteroaryl-propane-1,3-diones(3a–h).
The structures of synthesized compounds were confirmed by
the spectral methods (FT-IR, 1H NMR, 13C NMR, mass) and
elemental analyses. The detailed synthetic strategy is out-
lined in Scheme 1.
Chemistry
The present communication is featured on the synthesis of
1-(40-O-b-D-glucopyranosyloxy-20-hydroxy-50-substituted
phenyl)-3-heteroaryl-propane-1,3-diones (3a–h). The com-
pounds (1a–h) have been prepared by the Baker–Venkatar-
aman transformation of a substituted aroyloxyacetophenones
with base (Sheikh et al., 2009b).
The 1-(20,40-dihydroxy-50-substituted phenyl)-3-hetero-
aryl-propane-1,3-diones (1a–h) in 2.5 % methanolic KOH
solution were coupled with a-acetobromoglucose (glucosyl
donor used for glucosylation) under nitrogen atmosphere
to give 1-[20-hydroxy-40-(2000,3000,4000,6000-tetra-O-acetyl-O-b-
D-glucopyranosyloxy)-50-substituted phenyl]-3-heteroaryl-
propane-1,3-diones (2a–h). In final stage, tetra-O-acetyl-O-
b-D-glucosides (2a–h) were deacetylated in dry methanol
with sodium methoxide solution under nitrogen atmosphere
Results and discussion
Spectroscopic characterizations of compounds
IR spectra
The IR spectra of 1-(40-O-b-D-glucopyranosyloxy-20-
hydroxyphenyl)-3-furyl-propane-1,3-dione (3a) shown a
stretching frequency at 3,422 and 1,735 cm-1 corresponds
to OH and C=O, respectively. Further, (3a) posses the
characteristic bands at 3,401 cm-1 (OH peak of carbohy-
drate residue) and 2,857 cm-1 (glucosidic CH) indicating
the presence of O-b-D-glucosyl moiety in the molecule
(Fig. 1). It was also confirmed by its H- and 13C NMR,
1
and mass spectral data (Table 1).
H
H
H
H
O
O
O
O
O
R
O
O
O
H
O
O
O
S
O
R
O
O
H
H
O
O
O
O
O
H
H
H
3b, 3f
3a, 3e
3b : R = H
3f : R = Cl
(i)
(i)
3a : R = H
3e : R = Cl
Aryl
O
O
O
H
(i)
(i)
R
O
H
H
H
H
H
O
O
O
R
O
O
O
O
O
O
H
N
O
1a-1h
O
R
N
H
O
O
H
O
O
O
3d, 3h
O
H
H
O
H
3c, 3g
3d : R = H
3h : R = Cl
3c : R = H
3g : R = Cl
Scheme 1 Synthesis of 1-(40-O-b-D-glucopyranosyloxy-20-hydroxy-50-substituted phenyl)-3-heteroaryl-propane-1,3-diones (3a–h). (i) glucosylation
123

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Med Chem Res (2013) 22:964–975
1H and 13C NMR spectra
antioxidant activities. The minimal inhibitory concentra-
tions (MICs, mg/mL) of tested compounds against certain
bacteria and fungi are shown in Tables 2 and 3. The com-
pounds (3a–h) were tested for their in vitro antimicrobial
activity against four strains of bacteria (gram ?ve and gram
-ve), and two strains of fungi (C. albicans and C. glabrata).
The four compounds of the series have shown relatively high
in vitro antimicrobial activity. The compound 1-(50-chloro-
40-O-b-D-glucopyranosyloxy-20-hydroxyphenyl)-3-(2-pyri-
dyl)-propane-1,3-dione (3g) shown excellent activity against
E. coli and P. aeruginosa, and excellent activity against
C. albicans indicated in vitro antifungal activity comparable
to slightly lower than fluconazole. 1-(40-O-b-D-glucopyrano-
syloxy-20-hydroxyphenyl)-3-(2-pyridyl)-propane-1,3-dione
(3c) and 1-(50-chloro-40-O-b-D-glucopyranosyloxy-20-hydro
xyphenyl)-3-furyl-propane-1,3-dione (3e) shown excellent
activity against P. aeruginosa indicated in vitro antibacterial
activity comparable to slightly lower than ampicillin. The
compound (3f) shown excellent activity against C. glabrata
The presence of characteristic H and 13C NMR peaks are
consistent with the structure of 1-(40-O-b-D-glucopyrano-
syloxy-20-hydroxyphenyl)-3-furyl-propane-1,3-dione (3a).
1
1
The (3a) exhibited H NMR peaks at d 3.44–4.86 (m, 6H,
b-D-glucopyranosyl ring), 2.5 (s, 4H, glucosidic OH) and
b-linkage at 5.91 (d, 1000-H, anomeric proton, J1,2 = 8.2 Hz)
ppm indicating the linkage of the carbohydrate unit to the
C-40’ position of the aglycone moiety (Table 1).
The anomeric carbon in 13C NMR is confirmed at d
106.4 ppm (s, C-1000, anomeric C-atom). Further, the mass
spectrum shown a molecular ion peak at 408 (M?), con-
firms the molecular formula C19H20O10 of (3a).
In vitro antimicrobial and antioxidant activity
The water-soluble functionalized sugar based b-diketones
(3a–h) are evaluated for the antibacterial, antifungal, and
N
H
O
H
N
H
N+
O
O
O
O
H
O
O-
H
H
O
O
R
H
H
O
O
O
H
R
H
O
O
H
R
O
H
O
O
O
O
O
H
O
O
O
O
H
O
H
H
O
H
O
H
Fig. 1 Intervention of heterocyclic aryl in tautomerism
1
Table 1 IR and H NMR data of compounds (3a–h)
Compounds IR (KBr)
1H NMR (DMSO d6, d, 300 MHz)
OH (carbohyd) =C–OH (enol) C=O (keto) C–O (Moieties) OH (Enolic) 20-OH (phenol) H (gluco) OH (gluco)
3a
3b
3c
3d
3e
3f
3,401
3,408
3,410
3,413
3,410
3,404
3,413
3,417
3,422
3,426
3,435
3,429
3,431
3,429
3,431
3,437
1,735
1,735
1,742
1,734
1,732
1,735
1,742
1,734
1,146
1,146
1,145
1,151
1,141
1,144
1,142
1,155
15.91
16.01
15.96
15.98
15.94
16.11
15.99
16.11
12.22
12.20
12.03
12.13
12.09
12.07
12.13
12.10
3.44–4.86 2.5
3.45–4.88 2.8
3.35–4.97 2.9
3.43–4.97 2.2
3.47–4.89 2.6
3.51–4.98 2.7
3.41–4.99 2.8
3.51–4.98 2.5
3g
3h
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Med Chem Res (2013) 22:964–975
967
Table 2 Antibacterial activity of compounds (3a–h)
Compounds
R
Aryl
Antibacterial activitya
S. aureus
ATCC 25923
B. subtilis
ATCC 6633
E. coli
ATCC 27853
P. aeruginosa
ATCC 27853
3a
H
0.625
0.15
0.15
0.3
2.5
5.0
O
3b
H
0.3
1.25
0.07
0.3
0.15
0.019
1.25
0.019
0.03
0.019
5.0
S
3c
H
0.15
0.15
0.15
0.3
N
3d
H
0.625
0.3
N
3e
Cl
Cl
Cl
Cl
–
0.07
O
S
3f
0.625
1.25
0.3
5
3g
0.15
5.0
0.019
5.0
N
3h
N
Ampicillin
–
0.019
0.005
0.01
0.005
Minimum inhibitory concentrations (MICs, mg/mL)
a
Antibacterial activity: in present protocol 1.25 mg/mL is considered as moderate activity, 0.07 mg/mL is considered as good activity and
0.019 mg/mL is considered as excellent activity compared to the standard drug ampicillin
indicated in vitro antifungal activity comparable to slightly
lower than fluconazole. The presence of electron-withdraw-
ing group on the aromatic ring in general increases the anti-
microbial activities of the tested compounds compared to
compounds having no substitution/electron donating group.
Based upon the results it may also be necessary to
optimize the lead compound by substitution at C-5 position
of the phenyl ring by chloro and polar group, and hetero-
cyclic substitution at C-3 carbon of b-diketones seems to
be very important for the antibacterial effect; as well as the
presence of glucosidic moiety on the aromatic ring seems
to be very important for the antibacterial effect and
cell–cell recognition. Moreover, the glucosidic moiety on
the aromatic ring acts as a drug handle to guide the aglycon
molecule through the drug metabolism.
These results (Table 2) suggested that O-b-D-glucosides
have effective improvement of bioavailability and the
electro-acceptor or electro-donor nature of substituent
(R) have effective and direct impact on selective antimi-
crobial activities against both bacteria and fungi. Table 3
also summarizes free radical scavenging activity (antioxi-
dant activity) using the DPPH assay method. According to
these results, the newly synthesized O-b-D-glucosides have
more promising antioxidant activity.
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Med Chem Res (2013) 22:964–975
For the development of binding approaches for DKG
environment, the identification of the active diketo struc-
tures present is important. Neither experimental nor
theoretical data is available for the identification of water-
solved DKG species. Theoretically, NMR spectroscopy
could be useful for identifying chemical structures. Theo-
retical ab initio studies could supplement these measure-
ments. In addition, calculations of energetics, atomic
charges, minimum energy structures, geometry, and natural
bond orbital (NBO) could indicate the electronic density
distribution of each atom. Finally, by taking NBO results
showing the presence of C–O single bonds in consider-
ation, realistic Lewis structures can be determined. These
systematic data, regarding the variation of molecular
properties, are important for the chemical structure and
could therefore provide first insights into the still poorly
understood chemical bonding of DKG complexes.
Table 3 Antifungal and antioxidant activity of compounds (3a–h)
Compounds
Antifungal activitya
Antioxidant activity
C. albicans C. glabrata DPPH
ATCC 10231 ATCC 36583 % Inhib. antioxidant
3a
5.0
2.5
2.5
10
5.0
5.0
5.0
5.0
5.0
0.15
2.5
10.0
0.01
–
84.34
74.21
79.02
74.21
77.01
81.15
85.53
79.54
–
3b
3c
3d
3e
2.5
5.0
0.15
10.0
0.01
–
3f
3g
3h
Fluconazole
Ascorbic acid
98.03
Minimum inhibitory concentration (MICs, mg/mL)
a
Antifungal activity: in present protocol 0.15 mg/mL is considered
as excellent activity compared to the standard drug fluconazole
In brief, the objective of this study is to investigate the
potential pharmacophore sites of DKG species using anti-
bacterial and antifungal screenings dependence on pH and
comparison with the calculated molecular properties. To
verifythesestructures, furtherPOManalyseswerecarriedout;
for example calculation of net atomic charges, bond polarity,
atomic valence, electron delocalization, and lipophilicity.
Finally, to investigate the combined antibacterial/anti-
fungal bioactivity of the DKG species, tautomeric structures
were performed. Current thinking in the generation of spe-
cific drug leads embodies the concept of achieving high
molecular diversitywithintheboundariesof reasonable drug-
like properties. Natural and semi-natural products, examples,
penicillin, and synthetic fluconazole have high chemical
Molecular properties calculations (Parvez et al., 2010;
Sheikh et al., 2011)
For the compounds (3a–h), depending on the pH and
position of the dissociated hydroxyl hydrogen atoms, many
possible b-diketones glucosides (DKG) conformations can
be described for the neutral (N) forms. These relevant
structures are sketched in Figs. 2 and 3.
In past, for example, in structure of curcumin deriva-
tives, attention was mainly devoted to the diketo form.
However, from a chemical point of view, all other forms
(tautomers and their conformers) are possible.
H
H
H
H
H
O
O
H
O
H
O
O
O
O
R
6'
3'
O
H
O
1'
2'
5'
4'
H
O
R
O
O
Aryl
3
1
O
Aryl
2
O
O
O
O
O
H
H
H
Fig. 2 General tautomerism process in series of compounds (3a–h)
Fig. 3 Different (O–Hd? d-O)
–
hexa-membered antibacterial
pharmacophore sites (red half
circle) present in a, b, and
c tautomers. The opened
δ
δ
δ+
δ+
δ+
δ
δ
(Od- d-O) four-membered
–
δ+
δ+
antifungal pharmacophore site
(green half circle) present only
in a tautomerm (Color figure
online)
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Med Chem Res (2013) 22:964–975
969
diversity, biochemical specificity, and other molecular
properties that make them favorable as lead and standard
reference (SR) structures for drug discovery, and which serve
to differentiate them from libraries of synthetic and combi-
natorial compounds.
mass spectrometer using m-nitrobenzyl alcohol (NBA)
matrix.
General procedure for the synthesis of O-b-D-
glucosides of b-diketones (3a–h)
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 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
ampicillin and fluconazole (3a–h).
General procedure for the synthesis of (2a–h)
To a solution of 1-(20,40-dihydroxy-50-substituted phenyl)-
3-heteroaryl-propane-1,3-diones (1a–h) (0.01 mol in 25
mL of 2.5 % methanolic KOH) under nitrogen atmosphere,
was added drop wise TAGBr (4 g in 30 mL dry acetone).
The resulting mixture was stirred at 0–3 °C for 8 h. The
reaction mixture was stirred continuously for 10 h. The
progress of the reaction was monitored by TLC. The sol-
vent was removed under reduced pressure. The resulting
brown syrup was dissolved in methanol: chloroform (5:15)
and chromatographed on 60–120 mesh silica gel eluting
with 10 % methanol in chloroform to obtain the brown
syrupy compound (2a).
Conclusion
The water-soluble O,O,O-functionalized compounds 1-(40-
O-b-D-glucopyranosyloxy-20-hydroxy-50-substituted phe-
nyl)-3-heteroaryl-propane-1,3-diones (3a–h) have been
synthesized by glucosylation of 1-(20,40-dihydroxy-50-
substituted phenyl)-3-heteroaryl-propane-1,3-diones with
glucosyl donor in good yield. All the compounds (3a–
h) were screened for the antimicrobial and antioxidant
activity. The compounds (3c), (3e), (3f), and (3g) were
found to be potent antibacterial and antifungal agents but
less active than ampicillin and fluconazole. The newly
synthesized (3a–h) were also shown to posses promising
antioxidant activity. In contrast to glucosyl moiety which
increases aqueous solubility, the tautomerism decreases
bioactivity of series. It is predicted that the most of these
compounds could be used without great risk of toxicity in
diverse antibacterial activity. Thus, the POM calculations
and actual experimental verification in one handy value not
only proves the compounds’ overall potential to qualify for
a drug but also potentially interesting for further optimi-
zation and exploration of b-diketo functionality.
1-[20-Hydroxy-40-(2000,3000,4000,6000-tetra-O-acetyl-O-b-D-gluco
pyranosyloxy)phenyl]-3-furyl-propane-1,3-dione (2a) Yield
73 %; [a]2D5 = -5.1 (c 0.1, CH3OH); IR (KBr): 3403 (–OH),
2844 (glucosidic CH), 1763 (C=O of O-acetyl groups of
glycone moiety), 1741 (C=O), 1599 (aromatic C=C), 1148
1
(C–O); H NMR (DMSO-d6, d, 300 MHz): 15.89 (s, 1H,
enolic OH), 11.81 (s, 1H, 20-OH), 8.39 (s, 1H, –CH=),
6.41–7.49 (m, 6H, Ar–H), 2.03, 2.04, 1.98, 2.03 (s, 3H, OAc),
3.47–4.98 (m, 6H, b-D-glucopyranosyl ring), 4.81 (d, 1000-H,
anomeric proton, J1,2 = 7.8 Hz); 13C NMR (DMSO-d6, d,
300 MHz): 189.9 (s, C-1, C=O), 185.1 (s, C-3), 94.2 (s, C-2,
–CH=), 115.6 (s, C-10), 163.7 (s, C-20), 104.6 (s, C-30), 164.8
(s, C-40), 159.1 (s, C-50), 131.7 (s, C-60), 136.9 (s, C-100),
125.6 (s, C-200), 119.1 (s, C-300), 148.1 (s, C-400), 21.3 (s,
C-atom, CH3 of acetyl group), 170.9 (s, C=O, acetyl group),
102.4 (s, C-1000, anomeric C-atom), 72.8 (s, C-2000), 71.0 (s,
C-3000), 71.9 (s, C-4000), 75.1 (s, C-5000), 65.7 (s, C-6000). Anal.
Calcd. for C27H28O14 (M?): (576): C, 56.25; H, 4.90. Found:
C, 56.27; H, 4.91.
Experimental
1-[20-Hydroxy-40-(2000,3000,4000,6000-tetra-O-acetyl-O-b-D-
glucopyranosyloxy)phenyl]-3-thienyl-propane-1,3-dione
(2b) Yield 71 %; [a]2D5 = -8.1 (c 0.1, CH3OH); IR
(KBr): 3400 (–OH), 2849 (glucosidic CH), 1765 (C=O of
O-acetyl groups of glycone moiety), 1743 (C=O), 1601
(aromatic C=C), 1141 (C–O); 1H NMR (DMSO-d6, d,
300 MHz): 15.92 (s, 1H, enolic OH), 11.89 (s, 1H, 20-OH),
8.44 (s, 1H, –CH=), 6.46–7.39 (m, 6H, Ar–H), 2.06, 2.01,
1.91, 2.03 (s, 3H, OAc), 3.48–4.94 (m, 6H, b-D-glucopyr-
anosyl ring), 4.86 (d, 1000-H, anomeric proton, J1,
Materials and methods
Melting points were determined in open glass capillaries
and are uncorrected. Elemental analyses were determined
using the Perkin Elmer 2400 CHN analyzer. FT-IR spectra
were recorded using (KBr) disk on Perkin Elmer spectrum
Rx-I spectrometer. H and 13C NMR were recorded on
1
Bruker AC-300 F (300 MHz) NMR spectrometer by using
DMSO-d6 and CDCl3 as solvent and tetramethylsilane as
an internal standard. Mass spectra were recorded on 70-S
= 7.8 Hz); 13C NMR (DMSO-d6, d, 300 MHz): 189.5 (s,
2
C-1, C=O), 184.8 (s, C-3), 93.9 (s, C-2, –CH=), 115.5 (s,
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Med Chem Res (2013) 22:964–975
C-10), 163.8 (s, C-20), 104.3 (s, C-30), 164.2 (s, C-40), 159.5
(s, C-50), 131.9 (s, C-60), 137.1 (s, C-100), 124.2 (s, C-200),
118.8 (s, C-300), 148.9 (s, C-400), 21.9 (s, C-atom, CH3 of
acetyl group), 171.3 (s, C=O, acetyl group), 102.8 (s, C-1000,
anomeric C-atom), 72.9 (s, C-2000), 71.6 (s, C-3000), 72.4 (s,
C-4000), 75.3 (s, C-5000), 65.5 (s, C-6000). Anal. Calcd. for
C27H28O13S (M?): (592): C, 54.73; H, 4.76. Found: C,
54.75; H, 4.77.
anomeric proton, J1, 2 = 8.2 Hz), 2.5 (s, 4H, glucosidic OH),
8.55 (s, 1H, –CH=), 6.55–7.71 (m, 6H, Ar–H); 13C NMR
(DMSO-d6, d, 300 MHz) 190.4 (s, C-1, C=O), 184.7 (s, C-3),
93.8 (s, C-2, –CH=), 115.4 (s, C-10), 164.8 (s, C-20), 105.1 (s,
C-30), 162.5 (s, C-40), 109.3 (s, C-50),010 31.6 (s, C-60), 130.7 (s,
C-100),010021.6 (s, C-200), 122.5 (s, C-3 ), 128.9 (s, C-400), 64.4
(s, C-6 ), 73.5 (s, C-4000), 75.2 (s, C-2000), 77.7 (s, C-3000), 82.4
(s, C-5000), 106.4 (s, C-1000, anomeric C-atom); Anal. Calcd.
for C19H20O10 (M?): (408) C, 55.88; H, 4.94. Found: C,
55.87; H, 4.95 %.
1-[20-Hydroxy-40-(2000,3000,4000,6000-tetra-O-acetyl-O-b-D-gluco
pyranosyloxy)phenyl]-3-(2-pyridyl)-propane-1,3-dione (2c)
Yield 75 %; [a]2D5 = -4.1 (c 0.1, CH3OH); IR (KBr): 3409
(–OH), 2853 (glucosidic CH), 1761 (C=O of O-acetyl groups
of glycone moiety), 1739 (C=O), 1598 (aromatic C=C), 1141
1-(40-O-b-D-glucopyranosyloxy-20-hydroxyphenyl)-3-thienyl-
propane-1,3-dione (3b) Yield 68 %; [a]2D5 = -11.2 (c 0.1,
CH3OH); FT-IR (KBr): 3408 (br, OH peak of carbohydrate
residue), 3426 (OH), 1735 (C=O), 2844 (glucosidic CH),
1591 (aromatic C=C), 1146 (C–O); 1H NMR (DMSO-d6, d,
300 MHz) 16.01 (s, 1H, enolic OH), 12.20 (s, 1H, 20-OH),
3.45–4.88 (m, 6H, b-D-glucopyranosyl ring), 5.97 (d, 1000-H,
anomeric proton, J1, 2 = 8.2 Hz), 2.8 (s, 4H, glucosidic OH),
8.51 (s, 1H, –CH=), 6.45–7.69 (m, 6H, Ar–H); 13C NMR
(DMSO-d6, d, 300 MHz) 190.1 (s, C-1, C=O), 184.3 (s, C-3),
93.2 (s, C-2, –CH=), 115.5 (s, C-10), 165.6 (s, C-20), 105.3 (s,
C-30), 162.8 (s, C-40), 109.1 (s, C-50),010 32.1 (s, C-60), 130.2 (s,
C-100),010021.0 (s, C-200), 122.7 (s, C-3 ), 127.5 (s, C-400), 65.6
(s, C-6 ), 73.7 (s, C-4000), 75.5 (s, C-2000), 77.8 (s, C-3000), 82.5
(s, C-5000), 106.8 (s, C-1000, anomeric C-atom); Anal. Calcd.
for C19H20O9S (M?): (424) C, 53.77; H, 4.75. Found: C,
53.78; H, 4.76 %.
1
(C–O); H NMR (DMSO-d6, d, 300 MHz) 15.91 (s, 1H,
enolic OH), 12.04 (s, 1H, 20-OH), 8.51 (s, 1H, –CH=),
6.55–7.71 (m, 7H, Ar–H), 2.04, 2.05, 1.97, 2.03 (s, 3H, OAc),
3.43–4.94 (m, 6H, b-D-glucopyranosyl ring), 4.83 (d, 1000-H,
anomeric proton, J1, 2 = 7.9 Hz); 13C NMR (DMSO-d6, d,
300 MHz): 189.4 (s, C-1, C=O), 186.6 (s, C-3), 92.2 (s, C-2,
–CH=), 114.2 (s, C-10), 163.9 (s, C-20), 103.7 (s, C-30), 164.1
(s, C-40), 108.6 (s, C-50), 132.6 (s, C-60), 130.8 (s, C-100),
121.5 (s, C-200), 132.2 (s, C-300), 128.1 (s, C-400), 129.3 (s,
C-500), 21.5 (s, C-atom, CH3 of acetyl group), 170.4 (s, C=O,
acetyl group), 103.6 (s, C-1000, anomeric C-atom), 71.4 (s,
C-2000), 71.2 (s, C-3000), 71.6 (s, C-4000), 73.5 (s, C-5000), 67.0 (s,
C-6000). Anal. Calcd. for C28H29NO13 (M?): (587) C, 57.24;
H, 4.98. Found: C, 57.26; H, 4.99.
General procedure for the synthesis of 1-(40-O-b-D-gluco
pyranosyloxy-20-hydroxy-50-substituted phenyl)-3-
heteroaryl-propane-1,3-diones (3a–h)
1-(40-O-b-D-glucopyranosyloxy-20-hydroxyphenyl)-3-(2-pyr-
idyl)-propane-1,3-dione (3c) Yield 71 %; [a]2D5 = -14.3
(c 0.1, CH3OH); FT-IR (KBr): 3410 (br, OH peak of car-
bohydrate residue), 3435 (OH), 1742 (C=O), 2861 (gluco-
1
A freshly prepared sodium methoxide (3 mL, 0.1 mol) was
added to a solution of 1-[20-hydroxy-40-(2000,3000,4000,6000-tetra-
O-acetyl-O-b-D-glucopyranosyloxy)-50-substituted phenyl]-
3-heteroaryl-propane-1,3-dione (2) (0.005 mol) in dry
methanol (20 mL) and stirred at room temperature under
nitrogen atmosphere for 10 h. The reaction mixture was
neutralized with ion-exchange resin (Amberlite IR-120,
SD Fine H? form), filtered and concentrated in vaccuo to
afford viscous 1-(40-O-b-D-glucopyranosyloxy-20-hydroxy-
50-substituted phenyl)-3-heteroaryl-propane-1,3-dione (3) as
solid yield. The compounds were found to be optically
active.
sidic CH), 1603 (aromatic C=C), 1145 (C–O); H NMR
(DMSO-d6, d, 300 MHz): 15.96 (s, 1H, enolic OH), 12.03 (s,
1H, 20-OH), 3.35–4.97 (m, 6H, b-D-glucopyranosyl ring),
5.78 (d, 1000-H, anomeric proton, J1, 2 = 7.9 Hz), 2.9 (s, 4H,
glucosidic OH), 8.58 (s, 1H, –CH=), 6.57–7.41 (m, 7H, Ar–
H); 13C NMR (DMSO-d6, d, 300 MHz): 190.4 (s, C-1, C=O),
184.5 (s, C-3), 93.6 (s, C-2, –CH=), 115.7 (s, C-10), 164.4 (s,
C-20), 104.9 (s, C-30), 164.5 (s, C-40), 109.6 (s, C-50), 132.9 (s,
C-60), 131.5 (s, C-100), 126.4 (s, C-200), 123.4 (s, C-300), 129.7
(s, C-400), 131.3 (s, C-500), 64.5 (s, C-6000), 72.6 (s, C-4000), 76.8
(s, C-2000), 77.9 (s, C-3000), 82.3 (s, C-5000), 106.2 (s, C-1000,
anomeric C-atom); Anal. Calcd. for C20H21NO9 (M?): (419)
C, 57.28; H, 5.05. Found: C, 57.30; H, 5.06 %.
1-(40-O-b-D-glucopyranosyloxy-20-hydroxyphenyl)-3-furyl-
propane-1,3-dione (3a) Yield 71 %; [a]2D5 = -13.8 (c 0.1,
CH3OH); FT-IR (KBr): 3401 (br, OH peak of carbohydrate
residue), 3422 (OH), 1735 (C=O), 2857 (glucosidic CH),
1599 (aromatic C=C), 1146 (C–O); 1H NMR (DMSO- d6, d,
300 MHz) 15.91 (s, 1H, enolic OH), 12.22 (s, 1H, 20-OH),
3.44–4.86 (m, 6H, b-D-glucopyranosyl ring), 5.91 (d, 1000-H,
1-(40-O-b-D-glucopyranosyloxy-20-hydroxyphenyl)-3-(3-
pyridyl)-propane-1,3-dione (3d) Yield 69 %; [a]D25
-16.1 (c 0.1, CH3OH); IR (KBr): 3413 (br, OH peak of
carbohydrate residue), 3429 (OH), 1734 (C=O), 2825
=
1
(glucosidic CH), 1603 (aromatic C=C), 1151 (C–O); H
NMR (DMSO-d6, d, 300 MHz): 15.98 (s, 1H, enolic OH),
123

Med Chem Res (2013) 22:964–975
971
1
(glucosidic CH), 1601 (aromatic C=C), 1142 (C–O); H
12.13 (s, 1H, 20-OH), 3.43–4.97 (m, 6H, b-D-glucopyran-
osyl ring), 5.72 (d, 1000-H, anomeric proton, J1, 2 = 7.8 Hz),
2.2 (s, 4H, glucosidic OH), 8.50 (s, 1H, –CH=), 6.47–7.49
(m, 7H, Ar–H), 13C NMR (DMSO-d6, d, 300 MHz): 191.4
(s, C-1, C=O), 184.3 (s, C-3), 94.5 (s, C-2, –CH=), 115.4 (s,
C-10), 164.2 (s, C-20), 111.9 (s, C-30), 164.5 (s, C-40), 109.7
(s, C-50), 132.9 (s, C-60), 125.9 (s, C-100), 126.8 (s, C-200),
128.9 (s, C-300), 133.5 (s, C-400), 132.5 (s, C-500), 64.0 (s,
C-6000), 72.9 (s, C-4000), 75.4 (s, C-2000), 77.5 (s, C-3000), 82.7
(s, C-5000), 106.4 (s, C-1000, anomeric C-atom); Anal. Calcd.
for C20H21NO9 (M?): (419) C, 57.28; H, 5.05. Found: C,
57.29; H, 5.04 %.
NMR (DMSO-d6, d, 300 MHz): 15.99 (s, 1H, enolic OH),
12.13 (s, 1H, 20-OH), 3.41–4.99 (m, 6H, b-D-glucopyranosyl
ring), 5.81 (d, 1000-H, anomeric proton, J1, 2 = 7.9 Hz), 2.8
(s, 4H, glucosidic OH), 8.54 (s, 1H, –CH=), 6.55–7.45 (m,
6H, Ar–H); 13C NMR (DMSO-d6, d, 300 MHz): 190.3 (s,
C-1, C=O), 184.9 (s, C-3), 94.9 (s, C-2, –CH=), 117.8 (s,
C-10), 164.6 (s, C-20), 104.9 (s, C-30), 164.5 (s, C-40), 109.6 (s,
C-50), 131.6 (s, C-60), 132.9 (s, C-100), 126.7 (s, C-200), 123.8
(s, C-300), 128.6 (s, C-400), 132.7 (s, C-500), 65.2 (s, C-6000),
72.8 (s, C-4000), 76.5 (s, C-2000), 77.8 (s, C-3000), 82.8 (s, C-5000),
106.7 (s, C-1000, anomeric C-atom); Anal. Calcd. for
C20H20ClNO9 (M?): (453) C, 52.93; H, 4.44. Found: C,
52.94; H, 4.46 %.
1-(50-Chloro-40-O-b-D-glucopyranosyloxy-20-hydroxyphenyl)-
3-furyl-propane-1,3-dione (3e) Yield 73 %; [a]2D5 = -13.1
(c 0.1, CH3OH); FT-IR (KBr): 3410 (br, OH peak of car-
bohydrate residue), 3431 (OH), 1732 (C=O), 2851 (gluco-
1-(50-Chloro-40-O-b-D-glucopyranosyloxy-20-hydroxyphenyl)-
3-(3-pyridyl)-propane-1,3-dione (3h) Yield 63 %; [a]D25
-15.6 (c 0.1, CH3OH); IR (KBr): 3417 (br, OH peak of
carbohydrate residue), 3437 (OH), 1734 (C=O), 2831
=
1
sidic CH), 1601 (aromatic C=C), 1141 (C–O); H NMR
(DMSO- d6, d, 300 MHz) 15.94 (s, 1H, enolic OH), 12.09 (s,
1H, 20-OH), 3.47–4.89 (m, 6H, b-D-glucopyranosyl ring),
5.99 (d, 1000-H, anomeric proton, J1, 2 = 8.2 Hz), 2.6 (s, 4H,
glucosidic OH), 8.59 (s, 1H, –CH=), 6.45–7.74 (m, 5H, Ar–
H); 13C NMR (DMSO-d6, d, 300 MHz) 190.0 (s, C-1, C=O),
184.1 (s, C-3), 93.6 (s, C-2, –CH=), 115.9 (s, C-10), 164.1 (s,
C-20), 105.8 (s, C-30), 162.7 (s, C-40), 114.2 (s, C-50), 131.1 (s,
C-60), 130.7 (s, C-100), 120.9 (s, C-200), 122.7 (s, C-300), 129.6
(s, C-400), 64.8 (s, C-6000), 72.3 (s, C-4000), 75.5 (s, C-2000), 77.9
(s, C-3000), 82.2 (s, C-5000), 106.4 (s, C-1000, anomeric C-atom);
Anal. Calcd. for C19H19ClO10 (M?): (442) C, 51.54; H, 4.32.
Found: C, 51.56; H, 4.34 %.
1
(glucosidic CH), 1607 (aromatic C=C), 1155 (C–O); H
NMR (DMSO-d6, d, 300 MHz): 16.11 (s, 1H, enolic OH),
12.10 (s, 1H, 20-OH), 3.51–4.98 (m, 6H, b-D-glucopyran-
osyl ring), 5.79 (d, 1000-H, anomeric proton, J1, 2 = 7.8 Hz),
2.5 (s, 4H, glucosidic OH), 8.54 (s, 1H, –CH=), 6.51–7.63
(m, 6H, Ar–H), 13C NMR (DMSO-d6, d, 300 MHz): 192.1
(s, C-1, C=O), 185.3 (s, C-3), 94.0 (s, C-2, –CH=), 116.6 (s,
C-10), 164.7 (s, C-20), 111.6 (s, C-30), 164.6 (s, C-40), 109.9
(s, C-50), 131.8 (s, C-60), 123.9 (s, C-100), 122.7 (s, C-200),
128.7 (s, C-300), 133.9 (s, C-400), 137.4 (s, C-500), 64.6 (s,
C-6000), 72.7 (s, C-4000), 75.5 (s, C-2000), 77.8 (s, C-3000), 82.1
(s, C-5000), 105.5 (s, C-1000, anomeric C-atom); Anal. Calcd.
for C20H20ClNO9 (M?): (453) C, 52.93; H, 4.44. Found:
C, 52.95; H, 4.42 %.
1-(50-Chloro-40-O-b-D-glucopyranosyloxy-20-hydroxyphenyl)-
3-thienyl-propane-1,3-dione (3f) Yield 65 %; [a]D25
-15.6 (c 0.1, CH3OH); FT-IR (KBr): 3404 (br, OH peak of
carbohydrate residue), 3429 (OH), 17356 (C=O), 2859
=
Antimicrobial screenings of compounds (3a–h)
1
(glucosidic CH), 1597 (aromatic C=C), 1144 (C–O); H
NMR (DMSO-d6, d, 300 MHz) 16.11 (s, 1H, enolic OH),
12.07 (s, 1H, 20-OH), 3.51–4.98 (m, 6H, b-D-glucopyranosyl
ring), 5.99 (d, 1000-H, anomeric proton, J1, 2 = 8.2 Hz), 2.7
(s, 4H, glucosidic OH), 8.61 (s, 1H, –CH=), 6.49–7.76 (m,
5H, Ar–H); 13C NMR (DMSO-d6, d, 300 MHz) 190.5 (s,
C-1, C=O), 184.8 (s, C-3), 93.7 (s, C-2, –CH=), 115.8 (s,
C-10), 164.6 (s, C-20), 105.6 (s, C-30), 161.4 (s, C-40), 111.4 (s,
C-50), 133.1 (s, C-60), 130.4 (s, C-100), 121.5 (s, C-200), 121.4
(s, C-300), 126.6 (s, C-400), 65.3 (s, C-6000), 73.1 (s, C-4000), 75.0
(s, C-2000), 77.5 (s, C-3000), 82.2 (s, C-5000), 106.4 (s, C-1000,
anomeric C-atom); Anal. Calcd. for C19H19ClO9S (M?):
(458) C, 49.73; H, 4.17. Found: C, 49.72; H, 4.16 %.
Antibacterial activity (in vitro)
Two gram-positive (Staphylococcus aureus ATCC 25923
and Bacillus subtilis ATCC 6633) and two gram-negative
(Escherichia coli ATCC 25922 and Pseudomonas aeru-
ginosa ATCC 27853) bacteria were used as quality control
strains. For determining anti-yeast activities of the com-
pounds, the following reference strains were tested: Can-
dida albicans ATCC 10231 and Candida glabrata ATCC
36583. Ampicillin trihydrate and fluconazole were used as
standard antibacterial and antifungal agents, respectively.
Solutions of the test compounds and reference drugs were
dissolved in DMSO at a concentration of 20 mg/mL. The
twofold dilution of the compounds and reference drug were
prepared (20, 10, 5.0, 2.5, 1.25, 0.625, 0.31, 0.15, 0.07,
0.03, 0.019, 0.01, 0.005[) mg/mL. Antibacterial activities
of the bacterial strains were carried out in Muller–Hinton
1-(50-Chloro-40-O-b-D-glucopyranosyloxy-20-hydroxyphenyl)-
3-(2-pyridyl)-propane-1,3-dione (3g) Yield 75 %; [a]D25
-15.6 (c 0.1, CH3OH); FT-IR (KBr): 3413 (br, OH peak
of carbohydrate residue), 3431 (OH), 1742 (C=O), 2860
=
123

972
Med Chem Res (2013) 22:964–975
broth (Difco) medium, at pH 6.9, with an inoculum of
(1–2) 9 103 cells mL-1 by the spectrophotometric method
and an aliquot of 100 lL was added to each tube of the
serial dilution. The chemical compounds-broth medium
serial tube dilutions inoculated with each bacterium were
incubated on a rotary shaker at 37 °C for 24 h at 150 rpm.
Molecular properties calculations
Molinspiration calculations (Parvez, et al., 2010;
Sheikh et al., 2011)
clog P (octanol/water partition coefficient) is calculated by
the methodology developed by molinspiration as a sum of
fragment-based contributions and correction factors. The
method is very robust and is able to process practically all
organic and the most organometallic molecules. Molecular
polar surface area (PSA) TPSA is calculated based on the
methodology published by Ertl et al. as a sum of fragment
contributions. O- and N-centered polar fragments are con-
sidered. PSA has been shown to be a very good descriptor
characterizing drug absorption, including intestinal absorp-
tion, bioavailability, Caco-2 permeability and blood–brain
barrier penetration. Predicted results of compounds and
molecular properties (TPSA, GPCR ligand, and ICM) are
valued (Tables 4, 5). Lipophilicity (log P value) and PSA
values are two important predictors of per oral bioavail-
ability of drug molecules (Chang et al., 2004; Clark, 1999).
Therefore, we calculated log P and PSA values for com-
pounds (3a–h) using molinspiration software programs and
compared them to the values obtained for standard market
available drugs. For all compounds the calculated log
P values were lower than 5, which is the upper limit for drugs
to be able to penetrate through biomembranes according to
Lipinski’s rules. The PSA is calculated from the surface
areas that are occupied by oxygen and nitrogen atoms and by
hydrogen atoms attached to them. Thus, the PSA is closely
related to the hydrogen bonding potential of a compound
Antifungal activity (in vitro)
All fungi were cultivated in Sabouraud dextrose agar
(Merck). The fungi inoculums were prepared in Sabouraud
liquid medium (Oxoid) which had been kept at 36 °C
overnight and was diluted with RPMI-1640 medium with
L-glutamine buffered with 3-[N-morpholino]-propanesul-
fonic acid (MOPS) at pH 7 to give a final concentration of
2.5 9 103 cfu/mL. The microplates were incubated at
36 °C and read visually after 24 h, except for Candida
species when it was at 48 h. The incubation chamber was
kept humid. At the end of the incubation period, MIC
values were recorded as the lowest concentrations of the
substances that gave no visible turbidity. The DMSO dil-
uents at a maximum final concentration of 12.5 % had no
effect on the microorganism’s growth.
Minimum inhibitory concentration
The MICs of the chemical compounds assays were carried
out as described by Clause (1989) with minor modifica-
tions. The MICs of the chemical compounds were recorded
as the lowest concentration of each chemical compounds in
the tubes with no growth (i.e., no turbidity) of inoculated
bacteria.
˚
(Clark, 1999). Molecules with PSAs of 140 A or more are
expected to exhibit poor intestinal absorption (Clark, 1999).
Table 4 shows that all the compounds are not within this
limit with all compounds is having minimum non compa-
rable values of log P and PSA to reference drugs. This is also
supported by the antibacterial screening data of compounds
in terms of maximum zone of inhibitions. It has to be kept in
mind that log P and PSA values are only two important,
although not sufficient criteria for predicting oral absorption
of a drug. To support this contention, note that all the com-
pounds have zero violations of the rule of five. The rule of
five is a set of parameters devised to aid the screening of
potential drug hits identified through processes such as high
throughput screening (Lipinski et al., 2001). The criteria of
Lipinski et al. (2001) are as follows: (i) not more than five
hydrogen bond donors; (ii) not more than ten hydrogen bond
acceptors; (iii) formula weight \500; and (iv) log P \ 5.
Two or more violations of the rule of five suggest the
probability of problems in bioavailability (Lipinski et al.,
2001). All the compounds have zero–one violations of the
rule of five. Drug-likeness of compounds (3a–h) is tabulated
Antioxidant assay
In vitro free radical scavenging activities of (3a–h) were
evaluated by DPPH assay method. This method is based on
the reduction of a methanolic solution of the colored DPPH
radical. To a set of test tubes containing 3 mL of methanol,
50 lL of DPPH reagent (2 mg/mL) was added. The initial
absorbance was measured. To this test tube, methanolic
solution of different test solutions (1 mg/mL) were added
(10–50 lL). Ascorbic acid (0.5 mg/mL) was added in the
range of 10–25 lL. After 20 min, absorbance was recorded
at 521 nm. The experiment was performed in triplicate.
The percentage reduction in absorbance was calculated
from the initial and final absorbance of each solution.
Percentage scavenging of DPPH radical was calculated
using the formula:
% Scavenging of DPPH ¼ ½ðcontrol ꢁ test=controlÞꢂ ꢃ 100:
123

Med Chem Res (2013) 22:964–975
973
Table 4 Molinspiration calculations of molecular properties and drug-likeness of compounds (3a–h)
Compounds
MW
Molinspiration calculations
Drug-likeness
GPCRL
cLog P
TPSA
OHNI
N viol.
Vol.
ICM
KI
NRL
3a
Taut1-3a
Taut2-3a
3b
408
408
-0.21
167
170
5
6
0
1
339
339
-0.81
-0.82
-1.02
-1.01
-1.02
-1.07
-1.33
-1.30
0.98
Taut1-3b
Taut2-3b
3c
424
424
0.43
1.62
154
157
5
6
0
1
349
348
-0.90
-0.91
-0.86
-1.03
-0.99
-1.04
-1.04
-0.96
Taut1-3c
Taut2-3c
3d
419
419
-0.64
167
170
5
6
0
1
354
353
-0.63
-0.67
-0.79
-0.80
-0.75
-0.82
-0.78
-0.76
0.55
Taut1-3d
Taut2-3d
3e
419
419
-0.71
167
170
5
6
0
1
354
353
-0.62
-0.76
-0.71
-0.83
-0.67
-0.84
-0.74
-0.79
0.48
Taut1-3e
Taut2-3e
3f
443
443
0.39
1.58
167
170
5
6
0
1
353
353
-0.81
-0.83
-1.00
-0.99
-0.97
-1.01
-1.37
-1.34
Taut1-3f
Taut2-3f
3g
459
459
1.03
2.22
154
157
5
6
0
1
362
362
-0.90
-0.91
-0.84
-1.01
-0.94
-0.98
-1.08
-1.01
Taut1-3g
Taut2-3g
3h
454
454
-0.04
167
170
5
6
0
1
367
367
-0.65
-0.68
-0.78
-0.79
-0.71
-0.78
-0.83
-0.82
1.15
Taut1-3h
Taut2-3h
454
454
-0.10
167
170
5
6
0
1
367
367
-0.63
-0.77
-0.71
-0.82
-0.64
-0.81
-0.79
-0.84
1.09
Osiris calculations (Parvez et al., 2010; Sheikh et al.,
2011)
in Table 4. Drug-likeness may be defined as a complex
balance of various molecular properties and structure fea-
tures which determine whether particular molecule is similar
to the known drugs. These properties, mainly hydropho-
bicity, electronic distribution, hydrogen bonding character-
istics, molecule size, and flexibility and presence of various
pharmacophores features influence the behavior of molecule
in a living organism, including bioavailability, transport
properties, affinity to proteins, reactivity, toxicity, metabolic
stability, and many others. Activity of all eight compounds
and standard drugs were rigorously analyzed under four
criteria of known successful drug activity in the areas of
GPCR ligand activity, ion channel modulation, kinase
inhibition activity, and nuclear receptor ligand activity.
Results are shown for all compounds in Tables 4 and 5 by
means of numerical assignment. Likewise all compounds
have consistent negative values in all categories and
numerical values conforming and comparable to that of
standard drugs used for comparison. Therefore, it is readily
seen that all the analogs are expected to have near similar
activity to standard drugs used based upon these four rig-
orous criteria (GPCR ligand, ion channel modulator, kinase
inhibitor, and nuclear receptor ligand).
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. With
our recent publication of the drug design combination of
various pharmacophore sites by using heterocyclic structure,
it is now possible to predict activity and/or inhibition with
increasing success in two targets (bacteria and HIV virus).
This is done using a combined electronic/structure docking
procedures and an example is given here. The remarkably
well behaved mutagenicity of divers synthetic molecules
classified in data base of Celeron Company of Switzerland
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. Toxicity risks (mutagenicity, tumori-
genicity, irritation, and reproduction) and physico-chemical
properties (clog P, solubility, drug-likeness, and drug score
123

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Med Chem Res (2013) 22:964–975
at low risk comparable with standard drugs used. The log
P value of a compound, which is the logarithm of its
partition coefficient between n-octanol and water, is a well-
established measure of the compound’s hydrophilicity.
Low hydrophilicity and therefore high log P values may
cause poor absorption or permeation. It has been shown for
compounds to have a reasonable probability of being well
absorb their log P value must not be[5.0. On this basis, all
the series is having log P values under the acceptable cri-
teria. Along with this, compounds (3e) and (3g) which have
shown good antibacterial screening results is having low
log P values as compared to other compounds in the series.
The aqueous solubility of a compound significantly affects
its absorption and distribution characteristics. Typically, a
low solubility goes along with a bad absorption and
therefore the general aim is to avoid poorly soluble com-
pounds. Our estimated log S value is a unit stripped loga-
rithm (base 10) of a compound’s solubility measured in
mol/L. There are more than 80 % of the drugs on the
market have an (estimated) log S [ -4. In case of com-
pounds (3e) and (3g), values of log S are low as compared
to others in the series. Further, the Table 4 shows drug-
likeness of compounds (3a–h) which is in the comparable
zone with that of standard drugs used. We have calculated
overall DS for the compounds (3a–h) and compared with
that of standard drugs ampicillin used as shown in Tables 4
and 5. The DS combines drug-likeness, clog P, log S,
molecular weight and toxicity risks in one handy value may
be used to judge the compound’s overall potential to qualify
for a drug. The reported compounds (3a–h) shown moder-
ate to good DS as compared with standard drugs used.
Table 5 Osiris calculations of compounds (3a–h) (Color table
online)
Compounds Toxicity risks
MUT TUMO IRRI REP
Osiris calculations
MW cLogP
S
DL D–S
3a
408 −0.71 −2.86 −8.5
0.41
Taut1-3a
Taut2-3a
3b
408 −0.82 −2.35 −2.62 0.22
424 0.03
−3.19 −7.94 0.4
Taut1-3b
424 −0.08 −2.68 −1.84 0.37
Taut2-3b
3c
419 −0.79 −2.41 −7.38 0.42
Taut1-3c
419 −0.89 −1.9
−2.23 0.37
Taut2-3c
3d
419 −0.89 −2.39 −7.33 0.33
419 −1.00 −1.87 −1.87 0.38
Taut1-3d
Taut2-3d
3e
442 −0.10 −3.60 −9.88 0.37
442 −0.20 −3.09 −3.99 0.19
Taut1-3e
Taut2-3e
3f
458 0.64
458 0.54
−3.93 −9.32 0.35
−3.41 −3.21 0.31
Taut1-3f
Taut2-3f
3g
Acknowledgments The authors are sincerely thankful to the Head,
Department of Chemistry, R.T.M. Nagpur University, Nagpur, for
providing necessary laboratory facilities and Director, SAIF, Chan-
digarh, for providing spectral data of the compounds.
453 −0.17 −3.15 −8.75 0.38
453 −0.28 −2.63 −3.60 0.32
Taut1-3g
Taut2-3g
3h
453 −0.28 −3.12 −8.7
0.31
Taut1-3h
453 −0.28 −2.63 −3.60 0.32
Taut2-3h
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