Synthesis, biopharmaceutical characterization, antimicrobial and antioxidant activities of 1-(4′-O-β-d-glucopyranosyloxy-2′- hydroxyphenyl)-3-aryl-propane-1,3-diones

Article abstract of DOI:10.1016/j.ejmech.2011.01.068

This research communication is toward the investigation of the antibacterial, antifungal and antioxidant activities of the synthesized compounds 1-(4′-O-β-d-glucopyranosyloxy-2′-hydroxyphenyl)-3- aryl-propane-1,3-diones (5a)-(5h). These compounds have bee

Full text of DOI:10.1016/j.ejmech.2011.01.068

European Journal of Medicinal Chemistry 46 (2011) 1390e1399
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, biopharmaceutical characterization, antimicrobial and antioxidant
activities of 1-(40-O-
b-
D
-glucopyranosyloxy-20-hydroxyphenyl)-3-aryl-propane-
1,3-diones
,
b
,
b
b
b
c
d
Javed Sheikh a , Ali Parvez , Harjeet Juneja , Vishwas Ingle , Zahid Chohan , Moulay Youssoufi ,
*
Taibi Ben Hadda d
a National Environmental Engineering Research Institute, Nehru Marg, Nagpur 440020, India
b Department of Chemistry, RTM Nagpur University, Nagpur 440033, India
c Department of Chemistry, Bahauddin Zakariya University, Multan 60800, Pakistan
d Laboratoire Chimie des Matériaux, Faculté des Sciences, 60000 Oujda, Université Mohammed Premier, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
This research communication is toward the investigation of the antibacterial, antifungal and antioxidant
activities of the synthesized compounds 1-(40-O- -glucopyranosyloxy-20-hydroxyphenyl)-3-aryl-
b-D
Received 8 August 2010
Received in revised form
27 January 2011
Accepted 28 January 2011
Available online 19 February 2011
propane-1,3-diones (5a)e(5h). These compounds have been obtained by the interaction of
bromoglucose with 1-(20,40-dihydroxyphenyl)-3-aryl-propane-1,3-diones (3a)e(3h) under anhydrous
condition and at lower temperature. The structures of these newly synthesized O- -glucopyranosides
a-aceto-
b-D
were established on the basis of chemical, elemental, and spectral analyses. Further, the compounds (5b),
(5c), (5d) and (5g) showed potent antibacterial and antifungal activity. A good correlation was obtained
between the theoretical predictions of bioavailability using Lipinski’s rule-of-five and experimental
verification.
Keywords:
b
-Diketones
Glucosylation
O- -glucosides
Ó 2011 Elsevier Masson SAS. All rights reserved.
b-D
Antibacterial
Antifungal
Antioxidant activity
1. Introduction
b-diketones and carbohydrate have broad spectrum of medicinal
values. -diketones shown to have anecdotal extent of pharmaco-
b
The clinical relevance of bacterial and fungal diseases has
increased over the past 30 years due to an increasing population of
immunocompromised patients who have cancer, AIDS or have
received transplants. Actually the problems of multi-drug resistant
microorganism have reached on alarming level in many countries
around the world. A numbers of recent clinical reports describe the
increasing occurrence of penicillin-resistant Staphylococcus aureus
and other antibiotic-resistant human pathogenic microorganisms
in United States of America and European countries. Infections
caused by those microorganisms pose a serious challenge to the
medical community and need for an effective therapy has led to
a search for novel more selective and efficient antimicrobial agents.
In this work, we report the synthesis, antimicrobial and anti-
logical activities like antibacterial [1], antiviral [2], insecticidal [3],
antioxidant [4] and potential prophylactic antitumor activity [5,6].
It has also been used as an anti-sunscreen agent [7]. In liquid
solutions [8] as well as in the solid state [9] beta-diketones exists
almost exclusively as the enol tautomer, which is stabilized by the
intramolecular hydrogen bonding. Recently it is reported that
b-ketoenols are important pharmacophores of HIV-1 integrase (IN)
inhibitors [10].
The rational design of new HIV-1 Integrase (H-I) inhibitors, one
validated target for chemotherapeutic intervention [11], is funda-
mentally based on intermolecular coordination between H-I/
chemical inhibitor/metals (Mg2þ and Mn2þ, co-factors of the
enzyme), leading in the formation of bimetallic complexes [12,13].
Thereby, several bimetallic metal complexes, in many cases
exploring the well-known polydentate ligands, appear in this
scenario as the most promising concept to employ in either enzyme/
drug interaction or electron transfer process, in the last case
involving the biological oxygen transfer [14e16]. Another exciting
oxidant activity of O-b-D-glucoside derivatives of b-diketones. The
* Corresponding author. Department of Chemistry, RTM Nagpur University,
Nagpur 440033, India. Tel.: þ91 9975840141; fax: þ91 712 2249892.
E-mail addresses: javedchemie@gmail.com (J. Sheikh), taibi.ben.hadda@gmail.
com (T. Ben Hadda).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.01.068

J. Sheikh et al. / European Journal of Medicinal Chemistry 46 (2011) 1390e1399
1391
example of application for such polydentate ligand involves the
synergic water activation, which occurs via the so-called “remote
metallic atoms”. Such organometallic compounds are structurally
deemed to promote or block the H-I activity [17]. These explanations
above detailed clearly demonstrate that polydentate ligands are of
special interest in the bioorganometallic chemistry field [18].
Looking for the design of new bimetallic coordinating ligands to
further explore in the building of intermolecular system involving
H-I/inhibitor/metal complexation, we have targeted to study the
synthesis and structural biology of diketo O,O,O-ligands (5a)e(5h).
Correspondingly, carbohydrates play important structural and
functional roles in numerous physiological processes, including
various disease states [19,20]. The relatively recent recognition 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 [21]. For example, cancer cell metas-
tasis [22] and cellecell adhesion in the inflammatory response [23]
are dependent on cell surface presentation of specific glycans.
Synthetic carbohydrates-based cancer vaccines [24] and small
molecules selective inhibitors [25] 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 [26].
The enormous significance of
b
-diketones and carbohydrate-
-glucosyl
-diketones and to study their pharmacological
based drugs caught our attention for the synthesis of O-
b-D
derivatives of
b
2'
6'
3'
5'
2"
3"
O
R
4'
O
R
4"
HO
OH
O
O
C
R
3
6
1"
1'
4
C
O
O
C
2
POCl3/Pyridine
+
HO
10
9
CH3
1
5"
6"
7 CH3
5
8
(2 equivalent)
HO
O
(1)
(2a)-(2h)
3"
3'
HO 4'
2' OH
OH
4"
2"
NaOH/DMSO
R
5"
2
R
1'
5'
1
3
1"
6"
6'
O
OH
O
O
(3a)-(3h)
OAc
H
H
O
i) Methanolic KOH
ii) TAGBr
AcO
AcO
O
OH
H
H
OAc
H
(3a)-(3h)
R
N2 Atmosphere
O
O
(4a)-(4h)
OH
H
H
O
HO
HO
CH3ONa, CH3OH
O
OH
(4a)-(4h)
H
H
OH
N2 Atmosphere
R
H
O
O
(5a)-(5h)
R=
OH
H
(a) H
H
O
HO
HO
3'
4'
3"
(b) 2-Cl
O
2' OH
2"
1"
4"
H
OH
R
(c) 3-Cl
2
H
H
1'
5'
1
3
5"
(d) 4-Cl
6"
6'
O
OH
(e) 3-OCH3
(f) 4-OCH3
(g) 3-CH3
(h) 4-CH3
Scheme 1. Synthesis of 1-(40-O- -D-glucopyranosyloxy-20-hydroxyphenyl)-3-arylpropane-1,3-diones (5a)e(5h).
b

1392
J. Sheikh et al. / European Journal of Medicinal Chemistry 46 (2011) 1390e1399
activities viz., antibacterial, antifungal and antioxidant in first stage
and then against HIV and various virus.
C. albicans in vitro antifungal activity comparable to slightly
lower than the Fluconazole and against S. aureus indicated in
vitro antibacterial activity comparable to slightly lower than the
Ampicillin respectively. The presence of electron-withdrawing
group on the aromatic ring in general increases the antimicro-
bial activities of the tested compounds compared to compounds
having electron-donating groups. Based upon the results it will
also be necessary to optimize the lead compound by substitu-
tion in the C2, C3 and C4 position in both the phenyl ring by
chloro and polar group seems to be very important for anti-
bacterial effect, as well as the presence of glucosidic moiety in
the aromatic ring seems to be very important for antibacterial
effect and cellecell recognition.
2. Chemistry
In this study eight new O-b-D
-glucosides of 1-(20,40-dihydrox-
yphenyl)-3-aryl-propane-1,3-diones have been synthesized and
their antibacterial, antifungal and antioxidant activities were
evaluated.
At the first stage, 1-(20,40-dihydroxyphenyl)-3-aryl-propane-1,3-
diones (3a)e(3h) were prepared from 2,4-diaroyloxyacetophenones
(2a)e(2h) employing Baker-Venkataraman transformation. The
functionalized
tion were then coupled with
used for glucosylation) under nitrogen atmosphere to give 1-[20-
hydroxy-40-(2000,3000,4000,6000-tetra-O-acetyl-O-
-glucopyranosyloxy)
phenyl]-3-aryl-propane-1,3-diones (4a)e(4h). In the final stage,
tetra-O-acetyl-O- -glucosides (4a)e(4h) were deacetylated in dry
methanol with sodium methoxide solution under nitrogen
atmosphere to afford 1-(40-O- -glucopyranosyloxy-20-hydrox-
b-diketones (3a)e(3h) in 2.5% methanolic KOH solu-
These results suggested that O-b-D-glucosides had effective
a-acetobromoglucose (glucosyl donor
improvement of bioavailability and the electro-acceptor or electro-
donor nature of substituent (R) had effective and direct impact on
selective antimicrobial activities against both bacteria and fungi.
Table 2 also summarizes free radical scavenging activity (antioxi-
dant activity) using the DPPH assay method. According to these
b-D
b-D
results, the newly synthesized O-b-D-glucosides had more prom-
ising antioxidant activity.
b-D
yphenyl)-3-aryl-propane-1,3-diones (5a)e(5h). The structures of the
synthesized compounds were confirmed by spectral methods (FT IR,
1H NMR, 13C NMR, Mass) and elemental analysis. The detailed
synthetic strategy is outlined in the Scheme 1.
4. Results and discussion
4.1. Spectroscopic characterizations of compounds
3. In vitro antimicrobial and antioxidant activity
4.1.1. IR spectra
The present paper is focused on the synthesis of novel O-
b
-
D
-
The IR spectra of (3a) showed a stretching frequency at
glucosides of 1-(20,40-dihydroxyphenyl)-3-aryl-propane-1,3-dio-
nes as possible antibacterial, antifungal and antioxidant agent.
The minimal inhibitory concentrations (MICs, mg mLꢀ1) of tested
compounds against certain bacteria and fungi are shown in
Tables 1 and 2. A series of novel compounds (5a)e(5h) were
prepared and tested for their in vitro antimicrobial activity
against the four strains of bacteria (gram þve, gram ꢀve), and
two strains of fungi (Candida albicans and Candida glabrata). Four
compounds of the obtained series showed high in vitro antimi-
3420 cmꢀ1 and 1743 cmꢀ1 corresponds to OH and C]O respec-
tively. The O-b-D b-D
-glucoside 1-(40-O- -glucopyranosyloxy-20-
hydroxyphenyl)-3-phenyl-propane-1,3-dione (5a) posses the
characteristic bands at 3400 cmꢀ1 (OH peak of carbohydrate
residue) and 2854 cmꢀ1 (glucosidic CH) indicating the formation of
O-b-D
-glucoside. This was also confirmed by its 1H NMR, 13C NMR,
and Mass spectral data.
4.1.2. 1H and 13C NMR spectra
crobial
activity.
1-(40-O-
b
-
D
-Glucopyranosyloxy-20-hydrox-
The 1H NMR spectrum of (3a) exhibited a singlet at
d 15.72 ppm
yphenyl)-3-(200-chlorophenyl)-propane-1,3-dione (5b) showed
excellent activity against Escherichia coli and Pseudomonas aeru-
due to enolic proton (since enol form in
a singlet at 12.02 ppm due to phenolic proton adjacent to the
carbonyl group and a singlet at 4.76 ppm corresponds to the
phenolic proton away from carbonyl group. 13C NMR spectra gives
a singlet at 192.1 ppm due to ketonic carbon C-1 and at
178.4 ppm due to enolic carbon C-3 confirming the keto-enol
b-diketone is more stable),
d
ginosa, 1-(40-O-
b
-
D
-glucopyranosyloxy-20-hydroxyphenyl)-3-(300-
d
chlorophenyl)-propane-1,3-dione (5c) showed excellent activity
against E. coli indicated in vitro antibacterial activity comparable to
d
slightly lower than the Ampicillin. 1-(40-O-
b
-
D
-Glucopyranosyloxy-
20-hydroxyphenyl)-3-(400-chlorophenyl)-propane-1,3-dione (5d) and
1-(40-O- -glucopyranosyloxy-20-hydroxyphenyl)-3-(300-methyl-
d
tautomerism in b
-diketone (3a). The presence of characteristic 1H
b-D
NMR peaks and 13C NMR peaks are consistent with the structure of
phenyl)-propane-1,3-dione (5g) showed excellent activity against
1-(20,40-dihydroxyphenyl)-3-phenyl-propane-1,3-dione (3a). The
Table 1
Table 2
Antibacterial activity of compounds (5a)e(5h). Minimum inhibitory concentrations
Antifungal and antioxidant activity of compounds (5a)e(5h). Minimum inhibitory
(MICs, mg/mL).
concentration (MICs, mg/mL).
Compound
R
Antibacterial Activitya
S. aureus B. subtilis
Compound
R
Antifungal Activitya
C. albicans C. glabrata
Antioxidant Activity
DPPH % Inhibition
E. coli
P. aeruginosa
ATCC 25923 ATCC 6633 ATCC 27853 ATCC 27853
ATCC 10231 ATCC 36583 antioxidant
5a
5b
5c
5d
5e
5f
5g
5h
H
0.3
0.15
1.25
0.625
0.3
0.15
2.5
2.5
2.5
0.005
1.25
0.02
0.02
0.07
2.5
5
5.0
5.0
0.01
0.15
0.02
1.25
0.02
5.0
0.03
10
5.0
0.005
5a
5b
5c
5d
5e
5f
5g
5h
H
2.5
5.0
10
0.15
2.5
5.0
10
5.0
5.0
2.5
10
5.0
0.01
e
81.15
89.11
83.52
84.34
77.34
73.45
79.49
81.98
e
2-Cl
3-Cl
4-Cl
3-OCH3 0.625
4-OCH3 2.5
3-CH3
4-CH3
e
0.15
0.15
0.15
2-Cl
3-Cl
4-Cl
3-OCH3 10
4-OCH3
3-CH3
4-CH3
e
1.25
2.5
5.0
0.01
0.02
0.625
0.019
Ampicillin
Fluconazole
Ascorbic acid
e
e
98.03
a
Antibacterial activity: In present protocol 1.25 mg mLꢀ1 is considered as
moderate activity, 0.07 mg mLꢀ1 is considered as good activity and 0.019 mg mLꢀ1 is
considered as excellent activity compared to the standard drug Ampicillin.
a
Antifungal activity: In present protocol 0.15 mg mLꢀ1 is considered as excellent
activity compared to the standard drug Fluconazole.

J. Sheikh et al. / European Journal of Medicinal Chemistry 46 (2011) 1390e1399
1393
Mass spectrum showed a molecular ion peak at 256 (Mþ), confirms
the molecular formula C15H12O4 of (3a). The 1H and 13C NMR data
show the presence of carbohydrate moiety. The chemical shifts of
which determine whether particular molecule is similar to the
known drugs. These properties, mainly hydrophobicity, electronic
distribution, hydrogen bonding characteristics, molecule size and
flexibility and presence of various pharmacophore features influ-
ence 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 Table 4 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
compounds are expected to have near similar activity to standard
drugs used based upon these four rigorous criteria (GPCR ligand,
ion channel modulator, kinase inhibitor, and nuclear receptor
ligand).
the anomeric proton show
b
-linkage at
d
5.89 (J1, ¼ 8.2 Hz),
2
indicating the linkage of the carbohydrate unit to the C-400 position
of the aglycone moiety. Compound (5a) exhibited
d 7.43 (d, 2H,
J2 e6 ¼ 8.8 Hz, 200-H, 600-H), 6.54e7.73 (m, 5H, AreH), and the
00
00
characteristic pyranosyl ring protons at
d 3.41e4.80, all are in
agreement with the structure of 1-(40-O- -glucopyranosyloxy-20-
b-D
hydroxyphenyl)-3-phenyl-propane-1,3-dione (5a). Further the
structure of 5a was confirmed by its molecular ion peak at 418.
5. Virtual screenings and molecular properties calculations
5.1. Molinspiration calculations [27,33]
MiLogP (octanol/water partition coefficient) is calculated by the
methodology developed by Molinspiration as a sum of fragment-
based contributions and correction factors (Tables 3 and 4). The
method is very robust and is able to process practically all organic
and most organometallic molecules. Molecular Polar Surface Area
TPSA is calculated based on the methodology published by Ertl et al.
as a sum of fragment contributions [27,32]. O- and N- centered polar
fragments are considered. PSA has been shown to be a very good
descriptor characterizing drug absorption, including intestinal
absorption, bioavailability, Caco-2 permeability and bloodebrain
barrier penetration. Prediction results of compounds (5a)e(5h)
molecular properties (TPSA, GPCR ligand and ICM) are valued in
Tables 3 and 4 (Supplementary information). Oral bioavailability is
a desirable property of compounds under investigation in the drug
discovery process. Lipinski’s rule-of-five is a simple model to forecast
the absorption and intestinal permeability of a compound. In the
rule-of-five model, compounds are considered likely to be well
absorbed when they possess these attributes-molecular
weight < 500, cLogP < 5, number of H-bond donors < 5, number
H-bond acceptors < 10, and number of rotatable bonds < 10. Lip-
ophilicity (log P value) and polar surface area (PSA) values are two
important properties for the prediction of oral bioavailability of drug
molecules [28,29]. Therefore we have calculated log P and PSA values
for compounds (5a)e(5h) using molinspiration software programs
and compared them with the values obtained for standard drugs
Ampicillin and Fluconazole. For all the compounds, without excep-
tion, the calculated clogP values were around 0.5e2.5 (<5), which is
the upper limit for the drugs to be able to penetrate through bio-
membranes according to Lipinski’s rules. So all of these compounds
present good oral bioavailability.
The lowest degree of lipophilicity among all the compounds was
exhibited by compounds (5a)e(5h), which are an indication for
good water solubility. The polar surface area (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
[29]. Molecules with PSA values around of 160 Å or more are
expected to exhibit poor intestinal absorption [29]. Table 4 shows
that all the compounds are within this limit. 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 [30].
To support this contention, note that all the compounds have only
one violation of the Rule-of-five. Two or more violations of the rule-
of-five suggest the probability of problems in bioavailability [31].
All B and C Tautomeric forms of the compounds (5a)e(5h) have
only one violation of the rule-of-five with Tautomeric form A is
having zero violation. Drug likeness of compounds (5a)e(5h) is
tabulated in Table 4. Drug likeness may be defined as a complex
balance of various molecular properties and structure features
5.2. Osiris calculations [27,34]
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 produc-
tion of unwanted metabolites can result in many adverse drug
reactions. With our recent work on the drug design by 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) [27,35]. This was done
using a combined electronic/structure docking procedure and an
example will be given here. The remarkably well behaved muta-
genicity of divers synthetic molecules classified in data base of
CELERON Company of Swiss can be used to quantify the role played
by various organic groups in promoting or interfering with the way
a drug can associate with DNA. The Osiris calculations are tabulated
in Tables 3 and 4 (Supplementary information). Toxicity risks
(mutagenicity, tumorogenicity, irritation, reproduction) and phys-
icochemical properties (miLogP, solubility, drug likeness and drug-
score) of compounds (5a)e(5h) are 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 Table 4 indicates that, all structures are supposed to be
non-mutagenic, non-irritating with no reproductive effects when
run through the mutagenicity assessment system 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 hydrophilicities 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 greater than 5.0. On this basis, all the
compounds (5a)e(5h) are having log P values in the acceptable
criteria. Along with this, compound (5g), which have shown good
antibacterial screening results against S. aureus ATCC 25923
(MIC ¼ 0.019), is having same log P value as compared to other
compounds in the series.
5.2.1. The aqueous solubility of compounds
The aqueous solubility of a compound significantly affects its
absorption and distribution characteristics. Typically, a low solu-
bility goes along with a bad absorption and therefore the general

1394
J. Sheikh et al. / European Journal of Medicinal Chemistry 46 (2011) 1390e1399
aim is to avoid poorly soluble compounds. Our estimated log S value
is a unit stripped logarithm (base 10) of a compound’s solubility
measured in mol/liter. There are more than 80% of the drugs on the
market have an (estimated) log S value greater than ꢀ4. In case of
compounds (5a)e(5h), values of log S are around ꢀ4. Further, Table
4 shows drug likeness of compounds (5a)e(5h) which is in the
comparable zone with that of standard drugs used for comparison.
We have calculated overall drug score (DS) for the compounds
(5a)e(5h) and compared with that of standard drugs Ampicillin
and Fluconazole used as shown in Table 4. The drug score combines
drug likeness, miLogP, log S, molecular weight and toxicity risks
in one handy value than may be used to judge the compound’s
overall potential to qualify for a drug. This value is calculated by
multiplying contributions of the individual properties with the
equation (1):
(MICs ¼ 0.03e5 mg/mL). In case of compound (5a), there is no
substitution on the terminal phenyl ring. Accordingly, an effort
was initiated to establish a pharmacophore hypothesis to delin-
eate the requirements of the active site via a comprehensive
program of analog synthesis and evaluation of the effects of
structural modification(s) on antibacterial activity of (5a). We
then set out to determine the resultant in vitro effects of
chemical alterations in this region. The modulating antibacterial
effect(s) of substituent having different electronegative proper-
ties, located at the ortho, meta and para-positions of phenyl ring
sites were ascertained next. A combination of the intact diketo-2-
hydroxyl-phenyl-sugar skeleton and substituted eCl at position-
2 on the phenyl ring (5b), at position-3 (in case of 5c) and at
position-4 (in case of 5d) generated higher antibacterial activity
with respect to remaining series in both the Gram-positive and
Gram-negative inhibition tests. We postulate that the strong
tendency to form a (OHdþ/Odꢀ) dipolar pharmacophore site in
the predominant form is likely to be responsible for the rise of
ꢀ
ꢁ
Y
Y
1
2
1
2
DS ¼
þ
Si
ti
(1)
biological activity observed with these semi
p-conjugated
where; S ¼ 1/1 þ eap þ b.
derivatives. If this hypothesis is correct, by modifying parent
molecule (5a), we may be able not only to modulate the degree of
interaction of the compound with various bacteria but to orient
the nature (antibacterial or antiviral) of bioactivity.
DS is the drug score. Si is the contributions calculated directly
from of miLogP; log S, molecular weight and drug likeness (pi) via
the second equation, which describes a spline curve. Parameters
a and b are (1, ꢀ5), (1, 5), (0.012, ꢀ6) and (1, 0) for miLogP, log S,
molecular weight and drug likeness, respectively. ti is the contri-
butions taken from the four toxicity risk types. The ti values are 1.0,
0.8 and 0.6 for no risk, medium risk and high risk, respectively. The
reported compounds (5a)e(5h) showed moderate to good drug
score as compared with standard drugs used.
6. Conclusion
The O,O-functionalized beta-diketo-sugar [1-(40-O-
b-D-gluco-
pyranosyloxy-20-hydroxyphenyl)-3-aryl-propane-1,3-diones]
molecules have been synthesized by glucosylation of 1-(20,40-
dihydroxyphenyl)-3-aryl-propane-1,3-diones with glucosyl donor
5.3. Petra calculations [27,34]
in good yield. All the synthesized O-b-D-glucosides (5a)e(5h) were
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.
characterized by spectral and elemental analyses. The synthesized
compounds were studied theoretically for prediction of bioactivity
and verified experimentally. All the compounds (5a)e(5h) were
screened for the antimicrobial and antioxidant activity. The
compounds (5b), (5c), (5d) and (5g) were found to be potent
antibacterial and antifungal agents comparable with Ampicillin
and Fluconazole. The newly synthesized (5a)e(5h) were also
shown to have the promising antioxidant activity. Both, the
theoretical predictions and experimental verification found to
have a good correlation. Thus, it is concluded that the compounds
were found to possess a broad range of hydrophilic and lipophilic
character, revealed by their Log S and Log P values respectively. All
the B and C tautomeric forms of the compounds (5a)e(5h) have
only one violation of the rule-of-five whereas tautomeric form A is
having zero violation, hence an indication of favorable bioavail-
ability based on drug likeness. The presence of glucosyl moiety in
the compounds increased its significant hydrophilic nature (sup-
ported by its Log S values around ꢀ4). The considerable number of
hydrogen donor/acceptor atoms incurred significant hydrophilic
character into the majority of these drugs (supported by Log
P values less than 5). Comparing relative activity scores of Ampi-
cillin and Fluconazole utilizing four drug classes (GPCR ligand, ion
channel modulator, kinase inhibitor, and nuclear receptor ligand)
showed all compounds are very highly correlated with expected
similar bioactivity. On the basis of hypothesis based on Petra, it is
found that, these compounds could form the highly interesting
combined two or more pharmacophore sites in one molecule
typically. It is predicted that most of these compounds could be
used without great risk of toxicity in diverse antibacterial activity.
Thus, the drug score combines drug likeness, miLogP, log
S, molecular weight and toxicity risks in one handy value not only
proves the compound’s overall potential to qualify for a drug but
also potentially interesting for further optimization.
The following chemical effects can be quantified: heats of
formation, bond dissociation energies, sigma charge distribution,
p
-charge distribution, inductive effect, resonance effect, delo-
calization energies and polarizability effect. The series of
compounds (5a)e(5h) have been subjected to delocalized-charge
calculations using Petra method of the non-hydrogen common
atoms, obtained from the partial pi-charge of the heteroatoms,
have been used to model the bioactivity against bacteria. It is
found that the negative charges of the oxygen atoms and the
partial pi positive charges of oxygen atoms contribute positively
in favor of an antibacterial activity, more, and this is in good
agreement with the mode of antibacterial action of the
compounds bearing (Xdꢀ/Ydþ) pharmacophore(s) site(s). It was
hypothesized that difference in charges between two hetero-
atoms of the same pharmacophore site (Xdꢀ/Ydþ) may facilitate
the inhibition of bacteria, more than viruses. This hypothesis was
rationalized as follows [27,34].
The structure of synthesized beta-diketo-sugar derivatives
(5a)e(5h) for ease of analysis can be divided into three parts,
Viz., central diketo skeleton, substituted-phenyl ring and another
phenyl ring as side chain attached to glucosyl moiety. We have
fixed the former diketo skeleton part and varied the latter two by
substituting with several functional groups such as 2-Cl, 3-Cl, 4-
Cl, 3-OCH3, 4-OCH3, 3-CH3, 4-CH3 and substituting the H-2 of
second phenyl ring by 2-hydroxyl one in case of all compound
(5a)e(5h). Compound (5f) is among the least active substances to
have been evaluated as antibacterial agents in this series having
average zone of inhibition ranging from 5 mm to 10 mm

J. Sheikh et al. / European Journal of Medicinal Chemistry 46 (2011) 1390e1399
1395
7. Experimental protocols
7.2.1.4. 2,4-Bis(4-chlorobenzoyloxy)acetophenone (2d). Yield 68%;
mp 105 ꢁC; FT-IR (KBr): 1762 (ester C]O), 1689 (C]O), 1602
7.1. Materials and methods
(aromatic C]C), 1139 (C-O); 1H NMR (DMSO-d6,
d, 300 MHz): 2.61
(s, 3H, CH3), 8.06 (d, 2H, J2’e6’ ¼ 8.4 Hz, 20-H, 60-H), 7.47 (d, 2H,
J3 e5 ¼ 8.4 Hz, 30-H, 50-H), 8.08 (d, 2H, J2 e6 ¼ 8.4 Hz, 200-H, 600-H),
0
0
00
00
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) disc on PerkineElmer spectrum Rx-I spectrometer. 1H NMR
and 13C NMR were recorded on Bruker AC-300 F (300 MHz) NMR
spectrometer by using DMSO-d6 and CDCl3 as solvent and tetra-
methylsilane as an internal standard. Mass spectra were recorded
on 70-S Mass spectrometer using m-nitrobenzyl alcohol (NBA)
matrix.
7.49 (d, 2H, J3 e5 ¼ 8.4 Hz, 300-H, 500-H), 6.69e7.74 (m, 2H, AreH),
00
00
6.71 (s, 3-H, AreH); 13C NMR (DMSO-d6,
d, 300 MHz) 199.5 (s, C-7,
C]O), 154.7 (s, C-2, CeO), 154.5 (s, C-4, CeO), 165.4 (s, C-9, C-10,
C]O), 129.4 (s, C-10), 130.8 (s, C-20, C-60), 128.7 (s, C-30, C-50), 138.3
(s, C-40), 129.5 (s, C-100), 130.7 (s, C-200, C-600), 128.9 (s, C-300, C-500),
138.5 (s, C-400), 29.8 (s, CH3 of C-8), 120.1 (s, C-1), 109.5 (s, C-3), 112.7
(s, C-5), 130.2 (s, C-6). C22H14Cl2O5 (Mþ): (429) C, 61.56; H, 3.29.
Found: C, 61.61; 3.31.
7.2.1.5. 2,4-Bis(3-methoxybenzoyloxy)acetophenone (2e). Yield 75%;
mp 90 ꢁC; FT-IR (KBr): 1760 (ester C]O), 1681 (C]O), 1600
7.2. General procedure for the synthesis of compounds (2)e(5)
(aromatic C]C), 1143 (CeO); 1H NMR (DMSO-d6,
d
, 300 MHz) 2.53
(s, 3H, CH3), 7.02e8.05 (m, 10H, AreH), 6.63 (s, 3-H, AreH), 3.70 (s,
6H, 30-OCH3, 300-OCH3); 13C NMR (DMSO-d6,
, 300 MHz) 199.0 (s,
7.2.1. General procedure for the preparation of 2,4-diaroyloxy-
acetophenones (2)
d
Resacetophenone (1) (0.01 mol) and aromatic carboxylic acids
(0.02 mol) were dissolved in 5 mL of redistilled pyridine and cooled,
to that POCl3 1 mL was added drop wise with constant stirring
maintaining the temperature below 20 ꢁC. The reaction mixture
was kept overnight at room temperature and poured with stirring
on ice cold dil HCl (1 mol in 50 mL). A white granulated solid
compound (2) separated out which was washed with cold water, dil
NaHCO3 solution and again with cold water. The product was
filtered off, dried and recrystallized from alcohol. The completion of
the reaction was monitor by TLC.
C-7, C]O), 155.9 (s, C-2, C-O), 156.0 (s, C-4, CeO), 166.8 (s, C-9, C-10,
C]O), 131.1 (s, C-10), 114.2 (s, C-20), 160.6 (s, C-30), 119.2 (s, C-40),
129.7 (s, C-50), 122.9 (s, C-60), 131.2 (s, C-100), 114.4 (s, C-200), 160.7 (s,
C-300), 119.3 (s, C-400), 129.9 (s, C-500), 123.1 (s, C-600), 29.4 (s, CH3 of C-
8), 119.3 (s, C-1), 109.8 (s, C-3), 112.7 (s, C-5), 130.2 (s, C-6), 56.2 (s,
OCH3 of C-70 & OCH3 of C-700). Anal. Calcd. for C24H20O7 (Mþ): (420)
C, 68.57; H, 4.80. Found: C, 68.59; H, 4.82.
7.2.1.6. 2,4-Bis(4-methoxybenzoyloxy)acetophenone (2f). Yield 71%;
mp 102 ꢁC; FT-IR (KBr): 1766 (ester C]O), 1685 (C]O), 1603
(aromatic C]C), 1144 (CeO); 1H NMR (DMSO-d6,
d, 300 MHz) 2.59
7.2.1.1. 2,4-Dibenzoyloxyacetophenone (2a). Yield 78%; mp 78 ꢁC;
FT-IR (KBr): 1765 (ester C]O), 1690 (C]O), 1601 (aromatic C]C),
(s, 3H, CH3), 8.03 (d, 2H, J2 e4 ¼ 8.1 Hz, 20-H, 40-H), 6.99 (d, 2H,
0
0
J3 e5 ¼ 8.1 Hz, 30-H, 50-H), 8.04 (d, 2H, J2 e4 ¼ 8.1 Hz, 200-H, 400-H),
0
0
00
00
1145 (C-O); 1H NMR (DMSO-d6,
d, 300 MHz) 2.53 (s, 3H, CH3), 8.02
6.98 (d, 2H, J3 e5 ¼ 8.1 Hz, 300-H, 500-H), 6.68e7.76 (m, 2H, AreH),
00
00
(d, 2H, J2 e6 ¼ 7.8 Hz, 20-H, 60-H), 8.07 (d, 2H, J2 e6 ¼ 7.8 Hz, 200-H,
6.79 (s, 3-H, AreH), 3.68 (s, 6H, 40-OCH3, 400-OCH3); 13C NMR
0
0
00
00
600-H), 6.73e7.91 (m, 8H, AreH), 6.73 (s, 3-H, AreH); 13C NMR
(DMSO-d6, d, 300 MHz) 199.7 (s, C-7, C]O), 155.7 (s, C-2, CeO),
(DMSO-d6,
d
, 300 MHz) 199.5 (s, C-7, C]O), 153.7 (s, C-2, CeO),
155.9 (s, C-4, CeO), 164.4 (s, C-9, C-10, C]O), 122.4 (s, C-10), 131.8 (s,
C-20, C-60), 114.7 (s, C-30, C-50), 165.3 (s, C-40), 122.5 (s, C-10), 131.9 (s,
C-20, C-60), 114.9 (s, C-30, C-50), 165.5 (s, C-40), 29.1 (s, CH3 of C-8),
120.4 (s, C-1), 108.7 (s, C-3), 112.1 (s, C-5), 130.9 (s, C-6), 56.1 (s,
OCH3 of C-70 & OCH3 of C-700). Anal. Calcd. for C24H20O7 (Mþ): (420)
C, 68.57; H, 4.80. Found: C, 68.56; H, 4.85.
156.4 (s,0C-4, CeO), 165.1 (s, C-9, C-10, C]O), 130.1 (s, C-10), 129.7 (s,
C-20, C-6 ),128.2 (s, C-30, C-50),133.1 (s, C-40),130.2 (s, C-100),129.5 (s,
C-200, C-600), 128.3 (s, C-300, C-500), 133.3 (s, C-400), 28.8 (s, CH3 of C-8),
120.3 (s, C-1), 108.5 (s, C-3), 113.7 (s, C-5), 131 (s, C-6). Anal. Calcd.
for C22H16O5 (Mþ): (360) C, 73.33; H, 4.48. Found: C, 73.35; H, 4.49.
7.2.1.2. 2,4-Bis(2-chlorobenzoyloxy)acetophenone (2b). Yield 69%;
mp 99 ꢁC; FT-IR (KBr): 1763 (ester C]O), 1685 (C]O), 1602
7.2.1.7. 2,4-Bis(3-methylbenzoyloxy)acetophenone (2g). Yield 76%;
mp 109 ꢁC; FT-IR (KBr): 1767 (ester C]O), 1689 (C]O), 1603
(aromatic C]C), 1131 (CeO); 1H NMR (DMSO-d6,
d
, 300 MHz) 2.49
(s, 3H, CH3), 6.74e8.40 (m, 10H, AreH), 6.69 (s, 3-H, AreH); 13C
NMR (DMSO-d6, , 300 MHz) 199.1 (s, C-7, C]O), 155.7 (s, C-2,
(aromatic C]C), 1146 (CeO); 1H NMR (DMSO-d6,
d
, 300 MHz) 2.58
(s, 3H, CH3), 6.79e8.10 (m, 10H, AreH), 6.75 (s, 3-H, AreH), 2.39 (s,
6H, 30-CH3, 300-CH3); 13C NMR (DMSO-d6,
, 300 MHz) 199.6 (s, C-7,
d
d
CeO), 156.6 (s, C-4, CeO), 165.1 (s, C-9, C-10, C]O), 130.5 (s, C-10),
134.7 (s, C-20), 128.6 (s, C-30), 135.1 (s, C-40), 127 (s, C-50), 131.1 (s, C-
60), 130.4 (s, C-100), 134.4 (s, C-200), 128.8 (s, C-300), 135.6 (s, C-400),
127.3 (s, C-500), 131.4 (s, C-600), 29.2 (s, CH3 of C-8), 119 (s, C-1), 108.9
(s, C-3), 113.2 (s, C-5), 130.9 (s, C-6). Anal. Calcd. for C22H14Cl2O5
(Mþ): (429) C, 61.56; H, 3.29. Found: C, 61.60; 3.36.
C]O), 154.9 (s, C-2, CeO), 155.0 (s, C-4, CeO), 166.2 (s, C-9, C-10,
C]O), 130.1 (s, C-10), 130.2 (s, C-20), 138.6 (s, C-30), 134.2 (s, C-40),
128.7 (s, C-50), 127.9 (s, C-60), 130.2 (s, C-100), 130.4 (s, C-200), 138.7 (s,
C-300), 134.3 (s, C-400), 128.9 (s, C-500), 128.0 (s, C-600), 29.1 (s, CH3 of C-
8), 120.3 (s, C-1), 109.6 (s, C-3), 112.9 (s, C-5), 130.8 (s, C-6), 24.8 (s,
CH3 of C-70 & CH3 of C-700). Anal. Calcd. for C24H20O5 (Mþ): (388) C,
74.21; H, 5.19. Found: C, 74.23; H, 5.22.
7.2.1.3. 2,4-Bis(3-chlorobenzoyloxy)acetophenone (2c). Yield 76%;
mp 101 ꢁC, FT-IR (KBr): 1763 (ester C]O), 1680 (C]O), 1599
7.2.1.8. 2,4-Bis(4-methylbenzoyloxy)acetophenone (2h). Yield 72%;
mp 116 ꢁC; FT-IR (KBr): 1767 (ester C]O), 1680 (C]O), 1601
(aromatic C]C), 1140 (CeO); 1H NMR (DMSO-d6,
d
, 300 MHz) 2.57
(s, 3H, CH3), 6.73e8.19 (m, 10H, AreH), 6.68 (s, 3-H, AreH); 13C
NMR (DMSO-d6, , 300 MHz) 199.7 (s, C-7, C]O), 154.9 (s, C-2,
(aromatic C]C), 1141 (CeO); 1H NMR (DMSO-d6,
d, 300 MHz): 2.52
(s, 3H, CH3), 8.01 (d, 2H, J2 e4 ¼ 8.6 Hz, 20-H, 40-H), 7.19 (d, 2H,
0
0
d
CeO), 153.4 (s, C-4, CeO), 166.3 (s, C-9, C-10, C]O), 130.9 (s, C-10),
134.2 (s, C-20), 130.6 (s, C-30), 135.2 (s, C-40), 128.0 (s, C-50), 130.9 (s,
C-60), 130.7 (s, C-100), 134.4 (s, C-200), 130.7 (s, C-300), 135.3 (s, C-40),
128.2 (s, C-500), 131.1 (s, C-600), 28.8 (s, CH3 of C-8), 118.3 (s, C-1),
109.2 (s, C-3), 113.7 (s, C-5), 131.2 (s, C-6). Anal. Calcd. for
C22H14Cl2O5 (Mþ): (429) C, 61.56; H, 3.29. Found: C, 61.62; 3.33.
J3 e5 ¼ 8.6 Hz, 30-H, 50-H), 8.03 (d, 2H, J2 e4 ¼ 8.6 Hz, 200-H, 400-H),
0
0
00
00
7.20 (d, 2H, J3 e5 ¼ 8.6 Hz, 300-H, 500-H), 6.79e7.73 (m, 2H, AreH),
00
00
6.71 (s, 3-H, AreH), 2.43 (s, 6H, 40-CH3, 400-CH3); 13C NMR (DMSO-
d6, d, 300 MHz) 199.1 (s, C-7, C]O), 155.2 (s, C-2, CeO), 155.4 (s, C-4,
CeO), 166.4 (s, C-9, C-10, C]O), 122.3 (s, C-10), 130.4 (s, C-20, C-60),
129.7 (s, C-30, C-50), 143.3 (s, C-40), 122.4 (s, C-100), 130.6 (s, C-200, C-

1396
J. Sheikh et al. / European Journal of Medicinal Chemistry 46 (2011) 1390e1399
600), 129.9 (s, C-300, C-500), 143.4 (s, C-400), 29.5 (s, CH3 of C-8), 120.2 (s,
C-1), 108.8 (s, C-3), 113.1 (s, C-5), 131.9 (s, C-6), 24.1 (s, CH3 of C-70 &
CH3 of C-700). C24H20O5 (Mþ): (388) C, 74.21; H, 5.19. Found: C, 74.24;
H, 5.20.
O), 1601 (aromatic C]C), 1145 (CeO); 1H NMR (DMSO-d6,
d,
300 MHz) 16.01 (s, 1H, enolic OH), 12.05 (s, 1H, 20-OH), 4.89 (s, 1H,
40-OH), 8.42 (s, 1H, eCH]), 6.43e7.49 (m, 6H, AreH), 6.39 (s, 30-H,
AreH), 3.76 (s, 3H, 300-OCH3); 13C NMR (DMSO-d6,
d, 300 MHz):
189.7 (s, C-1, C]O), 184.9 (s, C-3), 93.4 (s, C-2, eCH]), 115.6 (s, C-
10), 163.7 (s, C-20), 104.1 (s, C-30), 164.2 (s, C-40), 109.8 (s, C-50), 132.7
(s, C-60), 131.4 (s, C-100), 110.2 (s, C-200), 160.4 (s, C-300), 113.4 (s, C-400),
129.8 (s, C-500), 118.4 (s, C-600), 55.9 (s, OCH3 of C-700). Anal. Calcd. for
C16H14O5 (Mþ): (286) C, 67.13; H, 4.93. Found: C, 67.11; H, 4.89.
7.2.2. General procedure for the preparation of 1-(20,40-dihydroxy-
phenyl)-3-aryl-propane-1,3-diones (3)
The product (2) (0.005 mol) was dissolved in 4 mL of DMSO. To
that solution powdered NaOH (1 g) was added with vigorous stir-
ring for about 5 min. The stirring was continued for about 5 min
further. The reaction mixture was then cooled and poured on cold
water. The pale yellow solid product (3) obtained was washed with
water and filtered off. It was crystallized from alcohol. The progress
of the reaction was monitored by TLC.
7.2.2.6. 1-(20,40-Dihydroxyphenyl)-3-(400-methoxyphenyl)-propane-
1,3-dione (3f). Yield 64%; mp 164 ꢁC; FT-IR (KBr): 3419 (OH), 1713
(C]O), 1600 (aromatic C]C), 1139 (CeO); 1H NMR (DMSO-d6,
d,
300 MHz): 15.99 (s, 1H, enolic OH), 12.29 (s, 1H, 20-OH), 4.68 (s, 1H,
00
00
40-OH), 8.41 (s, 1H, eCH]), 7.20 (d, 2H, J2 e4 ¼ 8.1 Hz, 2 -H, 4 -H),
00
00
7.2.2.1. 1-(20,40-Dihydroxyphenyl)-3-phenyl-propane-1,3-dione (3a).
Yield 67%; mp 158 ꢁC; FT-IR (KBr): 3420 (OH), 1743 (C]O), 1598
7.19 (d, 2H, J3 e5 ¼ 8.1 Hz, 300-H, 500-H), 6.49e7.41 (m, 2H, AreH),
00
00
6.37 (s, 30-H, AreH), 3.65 (s, 3H, 400-OCH3); 13C NMR (DMSO-d6,
d,
(aromatic C]C), 1142 (CeO); 1H NMR (DMSO-d6,
d
, 300 MHz) 15.72
300 MHz) 189.3 (s, C-1, C]O), 184.9 (s, C-3), 94 (s, C-2, eCH]),
116.3 (s, C-10), 163.9 (s, C-20), 104.5 (s, C-30), 165.7 (s, C-40), 110.4 (s,
C-50), 131.2 (s, C-60), 122.4 (s, C-100), 127.8 (s, C-200, C-600), 114.8 (s, C-
300, C-500), 159.5 (s, C-400), 56 (s, OCH3 of C-700). Anal. Calcd. for
C16H14O5 (Mþ): (286) C, 67.13; H, 4.93. Found: C, 67.21; H, 4.95.
(s, 1H, enolic OH), 12.02 (s, 1H, 20-OH), 4.76 (s, 1H, 40-OH), 8.41 (s, 1H,
eCH]), 7.39 (d, 2H, J2 e6 ¼ 8.4 Hz, 200-H, 600-H), 6.48e7.47 (m, 5H,
00
00
AreH), 6.39 (s, 30-H, AreH); 13C NMR (DMSO-d6,
d, 300 MHz) 189.8
(s, C-1, C]O),184.9 (s, C-3), 94 (s, C-2, eCH]),115.4 (s, C-10), 163.2 (s,
C-20), 104.5 (s, C-30), 165.7 (s, C-40), 109 (s, C-50), 132.7 (s, C-60), 130.4
(s, C-100), 126.4 (s, C-200, C-600), 128.7 (s, C-300, C-500), 128 (s, C-400). Anal.
Calcd. for C15H12O4 (Mþ): (256) C, 70.31; H, 4.72. Found: C, 70.55;
4.91.
7.2.2.7. 1-(20,40-Dihydroxyphenyl)-3-(300-methylphenyl)-propane-
1,3-dione (3g). Yield 74%; mp 136 ꢁC; IR (KBr): 3439 (OH), 1744 (C]
O), 1600 (aromatic C]C), 1148 (CeO); 1H NMR (DMSO-d6,
d,
300 MHz): 16.03 (s, 1H, enolic OH), 12.01 (s, 1H, 20-OH), 4.78 (s, 1H,
7.2.2.2. 1-(20,40-Dihydroxyphenyl)-3-(200-chlorophenyl)-propane-1,3-
40-OH), 8.49 (s, 1H, eCH]), 6.46e7.47 (m, 6H, AreH), 6.39 (s, 30-H,
dione (3b). Yield 70%; mp 151 ꢁC; FT-IR (KBr): 3417 (OH), 1738 (C]
AreH), 2.46 (s, 3H, 300-CH3); 13C NMR (DMSO-d6,
d, 300 MHz) 189.9
O), 1599 (aromatic C]C), 1144 (CeO); 1H NMR (DMSO-d6,
d
,
(s, C-1, C]O), 184.7 (s, C-3), 93.8 (s, C-2, eCH]), 115.9 (s, C-10),
164.7 (s, C-20), 104.1 (s, C-30), 164 (s, C-40), 109.2 (s, C-50), 131.9 (s, C-
60), 130.4 (s, C-100), 126.2 (s, C-200), 138.4 (s, C-300), 128.4 (s, C-400),
128.8 (s, C-500), 123.4 (s, C-600), 24.8 (s, CH3 of C-700). Anal. Calcd. for
C16H14O4 (Mþ): (270) C, 71.10; H, 5.22. Found: C, 71.19; H, 5.32.
300 MHz) 15.79 (s, 1H, enolic OH), 12.00 (s, 1H, 20-OH), 4.79 (s, 1H,
40-OH), 8.49 (s, 1H, eCH]), 6.41e7.39 (m, 6H, AreH), 6.33 (s, 30-H,
AreH); 13C NMR (DMSO-d6,
d, 300 MHz) 189.7 (s, C-1, C]O), 185.9
(s, C-3), 93 (s, C-2, eCH]), 115.3 (s, C-10), 163.4 (s, C-20), 104.1 (s, C-
30), 165.2 (s, C-40), 109.4 (s, C-50), 133.1 (s, C-60), 131.7 (s, C-100), 131.2
(s, C-200), 128.8 (s, C-300), 129.4 (s, C-400), 126.8 (s, C-500), 130.2 (s, C-
600). Anal. Calcd. for C15H11ClO4 (Mþ): (290) C, 61.98; H, 3.81. Found:
C, 62.09; 3.97.
7.2.2.8. 1-(20,40-Dihydroxyphenyl)-3-(400-methylphenyl)-propane-1,
3-dione (3h). Yield 72%; mp: 170 ꢁC; FT-IR (KBr): 3425 (OH), 1723
(C]O), 1602 (aromatic C]C), 1140 (CeO); 1H NMR (DMSO-d6,
d,
300 MHz) 15.97 (s, 1H, enolic OH), 12.12 (s, 1H, 20-OH), 4.78 (s, 1H,
00
00
7.2.2.3. 1-(20,40-Dihydroxyphenyl)-3-(300-chlorophenyl)-propane-1,3-
40-OH), 8.43 (s, 1H, eCH]), 7.19 (d, 020 H, J2 e4 ¼ 8.6 Hz, 2 -H, 4 -H),
00
00
dione (3c). Yield 71%; mp 124 ꢁC; FT-IR (KBr): 3423 (OH), 1739 (C]
7.11(d, 2H, J3 e5 ¼ 8.6 Hz, 300-H, 5 -H), 6.42e7.39 (m, 2H, AreH),
00
00
O), 1600 (aromatic C]C), 1143 (CeO); 1H NMR (DMSO-d6,
d
,
6.41 (s, 30-H, AreH); 2.45 (s, 3H, 400-CH3); 13C NMR (DMSO-d6,
d,
300 MHz) 15.89 (s, 1H, enolic OH), 12.01 (s, 1H, 20-OH), 4.86 (s, 1H,
300 MHz) 189.6 (s, C-1, C]O), 184.5 (s, C-3), 94.2 (s, C-2, eCH]),
116.3 (s, C-10), 164.3 (s, C-20), 104.6 (s, C-30), 1650.07 (s, C-40), 109.6 (s,
C-50), 131.6 (s, C-60), 127.4 (s, C-100), 126.8 (s, C-2 , C-600), 129.2 (s, C-
300, C-500), 137.5 (s, C-400), 24.4 (s, CH3 of C-700). Anal. Calcd. for
C16H14O4 (Mþ): (270) C, 71.10; H, 5.22. Found: C, 71.21; H, 5.33.
40-OH), 8.42 (s, 1H, eCH]), 6.47e7.23 (m, 6H, AreH), 6.33 (s, 30-H,
AreH); 13C NMR (DMSO-d6,
d, 300 MHz) 190.1 (s, C-1, C]O), 185.2
(s, C-3), 93.4 (s, C-2, eCH]), 115.9 (s, C-10), 163.2 (s, C-20), 104.3 (s,
C-30), 164.2 (s, C-40), 109 (s, C-50), 132.7 (s, C-60), 131.8 (s, C-100), 126.2
(s, C-200), 134.4 (s, C-300), 128.4 (s, C-400), 130.8 (s, C-500), 124.4 (s, C-
600). Anal. Calcd. for C15H11ClO4 (Mþ): (290) C, 61.98; H, 3.81. Found:
C, 61.97; H, 3.92.
7.2.3. General procedure for the synthesis of 1-[20-hydroxy-40-
(2000,3000,4000,6000-tetra-O-acetyl-O-
b-D-glucopyranosyloxy)phenyl]-3-
aryl-propane-1,3-diones (4)
7.2.2.4. 1-(20,40-Dihydroxyphenyl)-3-(400-chlorophenyl)-propane-1,3-
To a solution of 1-(20,40-dihydroxyphenyl)-3-aryl-propane-1,3-
diones (3) (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 0e3 ꢁC for 8 h. The
reaction mixture was stirred continuously for 10 h. The progress of
the reaction was monitored by TLC. The solvent was removed under
reduced pressure. The resulting brown syrup was dissolved in
methanol: chloroform (5:15) and chromatographed on 60e120
mesh silica gel eluting with 10% methanol in chloroform to obtain
the brown syrupy compound (4).
dione (3d). Yield 69%; mp 210 ꢁC; IR (KBr): 3422 (OH), 1733 (C]O),
1600 (aromatic C]C), 1143 (CeO); 1H NMR (DMSO-d6,
d, 300 MHz)
15.89 (s, 1H, enolic OH), 12.09 (s, 1H, 20-OH), 4.72 (s, 1H, 40-OH), 8.51
(s, 1H, eCH]), 7.30 (d, 2H, J2 e4 ¼ 7.9 Hz, 200-H, 400-H), 7.12 (d, 2H,
00
00
J3 e5 ¼ 7.9 Hz, 300-H, 500-H), 6.46e7.40 (m, 2H, AreH), 6.37 (s, 30-H,
00
00
AreH); 13C NMR (DMSO-d6,
d, 300 MHz) 189.7 (s, C-1, C]O), 185.3
(s, C-3), 94.5 (s, C-2, eCH]), 116.4 (s, C-10), 163.6 (s, C-20), 104.5 (s,
C-30), 164.7 (s, C-40), 109.5 (s, C-50), 132.1 (s, C-60), 128.4 (s, C-100),
127.4 (s, C-200, C-600), 128.8 (s, C-300, C-500), 133.5 (s, C-400). Anal. Calcd.
for C15H11ClO4 (Mþ): (290) C, 61.98; H, 3.81. Found: C, 62.15; H, 4.01.
7.2.3.1. 1-[20-Hydroxy-40-(2000,3000,4000,6000-tetra-O-acetyl-O-
pyranosyloxy)phenyl]-3-phenyl-propane-1,3-dione (4a). Yield 76%;
a 2D5
½ ꢂ ¼ ꢀ4.3 (c 0.1, CH3OH); IR (KBr): 3401 (eOH), 2842 (glucosidic
b-D-gluco-
7.2.2.5. 1-(20,40-Dihydroxyphenyl)-3-(300-methoxyphenyl)-propane-
1,3-dione (3e). Yield 73%; mp 189 ꢁC; IR (KBr): 3428 (OH), 1743 (C]

J. Sheikh et al. / European Journal of Medicinal Chemistry 46 (2011) 1390e1399
1397
CH), 1766 (C]O of O-acetyl groups of glycone moiety), 1743 (C]O),
1598 (aromatic C]C),1142 (CeO); 1H NMR (DMSO-d6,
, 300 MHz):
7.2.4.1. 1-(40-O- -glucopyranosyloxy-20-hydroxyphenyl)-3-phenyl-
b-D
d
propane-1,3-dione (5a). Yield 69%; ½a D25
¼ ꢀ14.6 (c 0.1, CH3OH); FT-
ꢂ
15.49 (s, 1H, enolic OH), 11.87 (s, 1H, 20-OH), 8.32 (s, 1H, eCH]),
IR (KBr): 3400 (br, OH peak of carbohydrate residue), 3420 (OH),
7.42 (d, 2H, J2 e6 ¼ 8.3 Hz, 200-H, 600-H), 6.38e7.26 (m, 5H, AreH),
1738 (C]O), 2854 (glucosidic CH), 1597 (aromatic C]C), 1143
00
00
6.39 (s, 30-H, AreH), 2.06, 2.02, 1.99, 2.01 (s, 3H, OAc), 3.43e4.92 (m,
(CeO); 1H NMR (DMSO-d6,
d, 300 MHz) 15.85 (s, 1H, enolic OH),
6H,
b
-
D
-glucopyranosyl ring), 4.79 (d, 1000-H, anomeric proton, J1,
12.56 (s, 1H, 20-OH), 3.41e4.80 (m, 6H,
b-D-glucopyranosyl ring),
¼ 7.9 Hz); 13C NMR (DMSO-d6,
d, 300 MHz): 189.8 (s, C-1, C]O),
5.89 (d, 1000-H, anomeric proton, J1, 2 ¼ 8.2 Hz), 2.3 (s, 4H, glucosidic
2
184.9 (s, C-3), 94 (s, C-2, eCH]), 115.4 (s, C-10), 163.2 (s, C-20), 104.5
(s, C-30), 164.5 (s, C-40), 109 (s, C-50), 132.7 (s, C-60), 130.4 (s, C-100),
126.4 (s, C-200, C-600), 128.7 (s, C-300, C-500), 128 (s, C-400), 21.1 (s, C-
atom, CH3 of acetyl group), 170.8 (s, C]O, acetyl group), 102.1 (s, C-
1000, anomeric C-atom), 72.6 (s, C-2000), 71.2 (s, C-3000), 71.6 (s, C-4000),
74.9 (s, C-5000), 65.8 (s, C-6000). Anal. Calcd. for C29H30O13 (Mþ): (586):
C, 59.38; H, 5.16. Found: C, 59.22; H, 5.10.
OH), 8.49 (s, 1H, eCH]), 7.43 (d, 2H, J2 e6 ¼ 8.8 Hz, 200-H, 600-H),
00
00
6.54e7.73 (m, 5H, AreH), 6.39 (s, 30-H, AreH); 13C NMR (DMSO-d6,
d, 300 MHz) 190.1 (s, C-1, C]O), 184.3 (s, C-3), 93.6 (s, C-2, eCH]),
115.5 (s, C-10), 164.0 (s, C-20), 104.9 (s, C-30), 162.1 (s, C-40), 109.8 (s,
C-50), 132.3 (s, C-60), 130.4 (s, C-100), 127.6 (s, C-200, C-600), 128.5 (s, C-
300, C-500), 128.9 (s, C-400), 64.2 (s, C-6000), 73.1 (s, C-4000), 74.9 (s, C-2000),
77.6 (s, C-3000), 82.1 (s, C-5000), 106.3 (s, C-1000, anomeric C-atom); Anal.
Calcd. for C21H22O9 (Mþ): (418) C, 60.28; H, 5.30. Found: C, 60.50; H,
5.42%.
7.2.3.2. 1-[20-Hydroxy-40-(2000,3000,4000,6000-tetra-O-acetyl-O-
b-D-gluco-
pyranosyloxy)phenyl]-3-(200-chloro phenyl)-propane-1,3-dione (4b).
Yield 70%; ½a 2D5
ꢂ
¼ ꢀ7.5 (c 0.1, CH3OH); IR (KBr): 3400 (eOH), 2841
7.2.4.2. 1-(40-O- -glucopyranosyloxy-20-hydroxyphenyl)-3-(200-
b-D
(glucosidic CH), 1763 (C]O of O-acetyl groups of glycone moiety),
1740 (C]O), 1599 (aromatic C]C), 1145 (CeO); 1H NMR (DMSO-d6,
chlorophenyl)-propane-1,3-dione (5b). Yield 73%; ½a D25
¼ ꢀ16.1
ꢂ
(c 0.1, CH3OH); FT-IR (KBr): 3404 (br, OH peak of carbohydrate
residue), 3419 (OH), 1732 (C]O), 2850 (glucosidic CH), 1600
d
, 300 MHz) 15.70 (s, 1H, enolic OH), 12.10 (s, 1H, 20-OH), 8.43 (s, 1H,
eCH]), 6.23e7.45 (m, 6H, AreH), 6.30 (s, 30-H, AreH), 2.03, 2.00,
(aromatic C]C), 1149 (CeO); 1H NMR (DMSO-d6,
d, 300 MHz):
1.95, 2.05 (s, 3H, OAc), 3.33e4.90 (m, 6H,
b
-
D
-glucopyranosyl ring),
15.90 (s, 1H, enolic OH), 12.09 (s, 1H, 20-OH), 3.49e4.92 (m, 6H,
b-D-
4.85 (d, 1000-H, anomeric proton, J1, 2 ¼ 8.0 Hz); 13C NMR (DMSO-d6,
glucopyranosyl ring), 5.74 (d, 1000-H, anomeric proton, J1, 2 ¼ 8.0 Hz),
2.1 (s, 4H, glucosidic OH), 8.40 (s, 1H, eCH]), 6.49e7.40 (m, 6H,
d, 300 MHz): 188.9 (s, C-1, C]O), 184.9 (s, C-3), 93.1 (s, C-2, eCH]),
114.5 (s, C-10), 163.9 (s, C-20), 102.6 (s, C-30), 167.2 (s, C-40), 108.4 (s,
C-50), 132.6 (s, C-60), 131.3 (s, C-100), 132.4 (s, C-200), 128.8 (s, C-300),
129.6 (s, C-400), 126.8 (s, C-500), 127.2 (s, C-600), 21.2 (s, C-atom, CH3 of
acetyl group), 170.2 (s, C]O, acetyl group), 102.9 (s, C-1000, anomeric
C-atom), 73.2 (s, C-2000), 71.4 (s, C-3000), 70.1 (s, C-4000), 74.6 (s, C-5000),
66.4 (s, C-6000). Anal. Calcd. for C29H29ClO13 (Mþ): (620) C, 56.09; H,
4.71. Found: C, 56.00; H, 4.81.
AreH), 6.39 (s, 30-H, AreH); 13C NMR (DMSO-d6,
d, 300 MHz): 189.9
(s, C-1, C]O), 185.0 (s, C-3), 93.5 (s, C-2, eCH]), 116.3 (s, C-10),
164.4 (s, C-20), 104.5 (s, C-30), 165.6 (s, C-40), 109.1 (s, C-50), 133.3 (s,
C-60), 131.0 (s, C-100), 131.5 (s, C-200), 128.9 (s, C-300), 129.7 (s, C-400),
125.8 (s, C-500), 132.2 (s, C-600), 64.9 (s, C-6000), 73.6 (s, C-4000), 75.6 (s,
C-2000), 78.3 (s, C-3000), 83.4 (s, C-5000), 106.5 (s, C-1000, anomeric C-
atom); Anal. Calcd. for C21H21ClO9 (Mþ): (452) C, 55.70; H, 4.67.
Found: C, 55.69; H, 4.70%.
7.2.3.3. 1-[20-Hydroxy-40-(2000,3000,4000,6000-tetra-O-acetyl-O-
b-D-gluco-
pyranosyloxy)phenyl]-3-(300-chlorophenyl)-propane-1,3-dione (4c).
7.2.4.3. 1-(40-O- -glucopyranosyloxy-20-hydroxyphenyl)-3-(300-
b-D
Yield 72%; ½a 2D5
ꢂ
¼ ꢀ3.9 (c 0.1, CH3OH); IR (KBr): 3410 (eOH), 2849
chlorophenyl)-propane-1,3-dione (5c). Yield 73%; ½a D25
¼ ꢀ15.5
ꢂ
(glucosidic CH), 1769 (C]O of O-acetyl groups of glycone
moiety), 1744 (C]O), 1601 (aromatic C]C), 1148 (CeO); 1H NMR
(c 0.1, CH3OH); FT-IR (KBr): 3409 (br, OH peak of carbohydrate
residue), 3429 (OH), 1742 (C]O), 2859 (glucosidic CH), 1605
(DMSO-d6,
OH), 8.42 (s, 1H, eCH]), 6.53e7.65 (m, 6H, AreH), 6.39 (s, 30-H,
AreH), 2.05, 2.03, 1.99, 2.00 (s, 3H, OAc), 3.44e4.99 (m, 6H,
d
, 300 MHz) 15.80 (s, 1H, enolic OH), 12.05 (s, 1H, 20-
(aromatic C]C), 1147 (CeO); 1H NMR (DMSO-d6,
d, 300 MHz):
15.99 (s, 1H, enolic OH), 12.08 (s, 1H, 20-OH), 3.31e4.90 (m, 6H,
b-D-
b
-
D
-
glucopyranosyl ring), 5.70 (d, 1000-H, anomeric proton, J1, 2 ¼ 7.9 Hz),
2.4 (s, 4H, glucosidic OH), 8.49 (s, 1H, eCH]), 6.50e7.21 (m, 6H,
glucopyranosyl ring), 4.89 (d, 1000-H, anomeric proton, J1,
¼ 7.9 Hz); 13C NMR (DMSO-d6,
d
, 300 MHz): 189.2 (s, C-1, C]O),
AreH), 6.41 (s, 30-H, AreH); 13C NMR (DMSO-d6,
d, 300 MHz): 190.9
2
186.8 (s, C-3), 92.7 (s, C-2, eCH]), 114.6 (s, C-10), 163.6 (s, C-20),
102.9 (s, C-30), 167.0 (s, C-40), 109.5 (s, C-50), 132.4 (s, C-60), 131.6
(s, C-100), 126.9 (s, C-200), 132.4 (s, C-300), 128.3 (s, C-400), 130.1 (s, C-
500), 127.4 (s, C-600), 21.3 (s, C-atom, CH3 of acetyl group), 170.9 (s,
C]O, acetyl group), 102.5 (s, C-1000, anomeric C-atom), 71.2 (s, C-
2000), 71.5 (s, C-3000), 71.1 (s, C-4000), 73.6 (s, C-5000), 66.9 (s, C-6000).
Anal. Calcd. for C29H29ClO13 (Mþ): (620) C, 56.09; H, 4.71. Found:
C, 56.00; H, 4.81.
(s, C-1, C]O), 184.9 (s, C-3), 93.9 (s, C-2, eCH]), 115.8 (s, C-10),
163.1 (s, C-20), 104.5 (s, C-30), 164.5 (s, C-40), 109.1 (s, C-50), 132.2 (s,
C-60), 132.6 (s, C-100), 126.6 (s, C-200), 135.4 (s, C-300), 128.7 (s, C-400),
131.3 (s, C-500), 125.6 (s, C-600); 64.4 (s, C-6000), 72.4 (s, C-4000), 76.3 (s,
C-2000), 77.2 (s, C-3000), 82.4 (s, C-5000), 106.0 (s, C-1000, anomeric C-
atom); Anal. Calcd. for C21H21ClO9 (Mþ): (452) C, 55.70; H, 4.67.
Found: C, 55.77; H, 4.81%.
7.2.4.4. 1-(40-O- -glucopyranosyloxy-20-hydroxyphenyl)-3-(400-
b-D
7.2.4. General procedure for the synthesis of 1-(40-O-
b
-
D
-
chlorophenyl)-propane-1,3-dione (5d). Yield 68%; ½a D25
¼ ꢀ18.1
ꢂ
glucopyranosyloxy-20-hydroxyphenyl)-3-aryl-propane-1,3-diones
(c 0.1, CH3OH); IR (KBr): 3410 (br, OH peak of carbohydrate residue),
3431 (OH),1731 (C]O), 2823 (glucosidic CH),1604 (aromatic C]C),
(5)
A freshly prepared sodium methoxide (3 mL, 0.1 mol) was added
1149 (CeO); 1H NMR (DMSO-d6,
d, 300 MHz): 15.99 (s, 1H, enolic
to a solution of 1-[20-hydroxy-40-(2000,3000,4000,6000-tetra-O-acetyl-O-
b
-
OH), 12.12 (s, 1H, 20-OH), 3.44e4.99 (m, 6H,
b-D-glucopyranosyl
D-glucopyranosyloxy)phenyl]-3-aryl-propane-1,3-dione (4) (0.005
ring), 5.79 (d, 1000-H, anomeric proton, J1, ¼ 7.8 Hz), 2.2 (s,004H,
2
00
00
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 Hþ
form), filtered and concentrated in vaccuo to afford viscous 1-(40-O-
glucosidic OH), 8.52 (s,1H, eCH]), 7.39 (d, 2H, J2 e4 ¼ 7.9 Hz, 2 -H,
400-H), 7.22 (d, 2H, J3 e5 ¼ 7.9 Hz, 300-H, 500-H), 6.47e7.49 (m, 3H,
00
00
AreH), 6.39 (s, 30-H, AreH); 13C NMR (DMSO-d6,
d, 300 MHz): 191.1
(s, C-1, C]O), 184.3 (s, C-3), 94.9 (s, C-2, eCH]), 115.4 (s, C-10),
164.9 (s, C-20), 103.9 (s, C-30), 164.8 (s, C-40), 109.7 (s, C-50), 132.9 (s,
C-60), 128.9 (s, C-100), 127.8 (s, C-200, C-600), 128.9 (s, C-300, C-500), 133.5
(s, C-400), 64.0 (s, C-6000), 72.9 (s, C-4000), 75.4 (s, C-2000), 77.5 (s, C-3000),
b-D
-glucopyranosyloxy-20-hydroxyphenyl)-3-aryl-propane-1,3-
dione (5) as solid yield. The compounds were found to be optically
active.

1398
J. Sheikh et al. / European Journal of Medicinal Chemistry 46 (2011) 1390e1399
82.7 (s, C-5000), 106.4 (s, C-1000, anomeric C-atom); Anal. Calcd. for
C21H21ClO9 (Mþ): (452) C, 55.70; H, 4.67. Found: C, 55.73; H, 4.71%.
6.50e7.24 (m, 3H, AreH), 6.43 (s, 30-H, AreH); 2.67 (s, 3H, 400-CH3);
13C NMR (DMSO-d6, 300 MHz)
: 189.9 (s, C-1, C]O), 184.6 (s, C-3),
d
94.7 (s, C-2, eCH]), 116.8 (s, C-10), 164.5 (s, C-20), 105.6 (s, C-30),
164.7 (s, C-40), 109.8 (s, C-50), 133.6 (s, C-60), 127.7 (s, C-100), 127.8 (s,
C-200, C-600), 129.8 (s, C-300, C-500), 138.5 (s, C-400), 24.9 (s, CH3 of C-700),
65.4 (s, C-6000), 72.0 (s, C-4000), 75.1 (s, C-2000), 76.9 (s, C-3000), 82.4 (s, C-
5000), 105.6 (s, C-1000, anomeric C-atom); Anal. Calcd. for C22H24O9
(Mþ): (432) C, 61.11; H, 5.59. Found: C, 61.13; H, 5.64%.
7.2.4.5. 1-(40-O- -glucopyranosyloxy-20-hydroxyphenyl)-3-(300-
b-D
methoxyphenyl)-propane-1,3-dione (5e). Yield 73%; ½a D25
¼ ꢀ17.3
ꢂ
(c 0.1, CH3OH); IR (KBr): 3400 (br, OH peak of carbohydrate residue),
3422 (OH), 1733 (C]O), 2825 (glucosidic CH), 1600 (aromatic C]
C), 1143 (CeO); 1H NMR (DMSO-d6,
d, 300 MHz): 16.00 (s, 1H, enolic
OH), 12.01 (s, 1H, 20-OH), 3.49e4.91 (m, 6H,
b-D-glucopyranosyl
ring), 5.73 (d, 1000-H, anomeric proton, J1, ¼ 7.9 Hz), 2.0 (s, 4H,
8. Biological properties
2
glucosidic OH), 8.49 (s, 1H, eCH]), 6.39e7.40 (m, 6H, AreH), 6.32
(s, 30-H, AreH), 3.79 (s, 3H, 300-OCH3); 13C NMR (DMSO-d6,
d
,
8.1. Antibacterial activity (in vitro)
300 MHz): 189.1 (s, C-1, C]O), 184.4 (s, C-3), 93.0 (s, C-2, eCH]),
116.6 (s, C-10), 163.9 (s, C-20), 105.1 (s, C-30), 164.9 (s, C-40), 108.9 0(0s,
C-50), 133.7 (s, C-60), 132.4 (s, C-100), 110.8 (s, C-200), 160.7 (s, C-3 ),
111.4 (s, C-400), 129.7 (s, C-500), 118.9 (s, C-600), 56.0 (s, OCH3 of C-700),
64.4 (s, C-6000), 72.5 (s, C-4000), 75.2 (s, C-2000), 77.3 (s, C-3000), 81.7 (s, C-
5000), 105.3 (s, C-1000, anomeric C-atom); MS (EI, 70 eV): m/z (%) 286
(Mþ, 100), 224 (32), 105 (49), 51 (13). Anal. Calcd. for C22H24O10
(Mþ): (448) C, 58.93; H, 5.39. Found: C, 58.89; H, 5.45%.
Two Gram-positive (S. aureus ATCC 25923 and Bacillus subtilis
ATCC 6633) and two Gram-negative (E. coli ATCC 25922 and
P. aeruginosa ATCC 27853) bacteria were used as quality control
strains. For determining anti-yeast activities of the compounds, the
following reference strains were tested: C. albicans ATCC 10231 and
C. 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 dis-
solved in DMSO at a concentration of 20 mg mLꢀ1. 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 mLꢀ1. Antibacterial activities of the bacterial strains were
carried out in MullereHinton broth (Difco) medium, at pH 6.9, with
an inoculum of (1e2) ꢃ 103 cells mLꢀ1 by the spectrophotometric
7.2.4.6. 1-(40-O- -glucopyranosyloxy-20-hydroxyphenyl)-3-(400-
b-D
methoxyphenyl)-propane-1,3-dione (5f). Yield 66%; ½a D25
¼ ꢀ13.6
ꢂ
(c 0.1, CH3OH); FT-IR (KBr): 3405 (br, OH peak of carbohydrate
residue), 3413 (OH), 1723 (C]O), 2828 (glucosidic CH), 1603
(aromatic C]C), 1142 (CeO); 1H NMR (DMSO-d6,
d, 300 MHz):
15.91 (s, 1H, enolic OH), 12.02 (s, 1H, 20-OH), 3.53e4.79 (m, 6H,
b-D-
glucopyranosyl ring), 5.81 (d, 1000-H, anomeric proton, J1, 2 ¼ 8.0 Hz),
2.5 (s, 4H, glucosidic OH), 8.49 (s, 1H, eCH]), 7.28 (d,00 2H,
method and an aliquot of 100 mL 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.
00
J2 e4 ¼ 8.1 Hz, 200-H, 400-H), 7.11 (d, 2H, J3 e5 ¼ 8.1 Hz, 3 -H, 5 -H),
00
00
00
00
6.39e7.31 (m, 3H, AreH), 6.41 (s, 30-H, AreH), 3.71 (s, 3H, 400-OCH3);
13C NMR (300 MHz, DMSO-d6):
d 190.3 (s, C-1, C]O), 185.9 (s, C-3),
93.8 (s, C-2, eCH]), 116.9 (s, C-10), 164.9 (s, C-20), 105.5 (s, C-30),
165.3 (s, C-40), 110.0 (s, C-50), 133.2 (s, C-60), 122.9 (s, C-100), 128.8 (s,
C-200, C-600), 117.8 (s, C-300, C-500), 160.5 (s, C-400), 56.7 (s, OCH3 of C-
700), 64.9 (s, C-6000), 72.1 (s, C-4000), 75.7 (s, C-2000), 77.6 (s, C-3000), 81.8
(s, C-5000), 105.5 (s, C-1000, anomeric C-atom); Anal. Calcd. for
C22H24O10 (Mþ): (448) C, 58.93; H, 5.39. Found: C, 58.99; H, 5.41%.
8.2. 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]-propanesulfonic acid (MOPS) at pH 7 to give a final
concentration of 2.5 ꢃ 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 diluents at a maximum final concentration of
12.5% had no effect on the microorganism’s growth.
7.2.4.7. 1-(40-O- -glucopyranosyloxy-20-hydroxyphenyl)-3-(300-
b-D
methylphenyl)-propane-1,3-dione (5g). Yield 75%; ½a D25
¼ ꢀ19.2
ꢂ
(c 0.1, CH3OH); IR (KBr): 3409 (br, OH peak of carbohydrate residue),
3430 (OH),1749 (C]O), 2834 (glucosidic CH),1605 (aromatic C]C),
1129 (CeO); 1H NMR (DMSO-d6,
d, 300 MHz): 16.09 (s, 1H, enolic
OH), 11.88 (s, 1H, 20-OH), 3.40e4.81 (m, 6H,
b-D-glucopyranosyl
ring), 5.65 (d, 1000-H, anomeric proton, J1, ¼ 7.8 Hz), 2.3 (s, 4H,
2
glucosidic OH), 8.51 (s, 1H, eCH]), 6.43e7.43 (m, 6H, AreH), 6.41
(s, 30-H, AreH), 2.51 (s, 3H, 300-CH3); 13C NMR (DMSO-d6, 300 MHz)
8.3. Minimum inhibitory concentration (MIC)
d: 191.2 (s, C-1, C]O), 183.7 (s, C-3), 92.8 (s, C-2, eCH]), 116.4 (s, C-
10), 164.6 (s, C-20), 104.8 (s, C-30), 164.7 (s, C-40), 109.2 (s, C-50), 132.9
(s, C-60), 130.4 (s, C-100), 126.9 (s, C-200), 137.4 (s, C-300), 128.4 (s, C-400),
128.8 (s, C-500), 123.4 (s, C-600), 26.8 (s, CH3 of C-700), 65.0 (s, C-6000),
72.9 (s, C-4000), 75.9 (s, C-2000), 77.9 (s, C-3000), 81.4 (s, C-5000),105.8 (s, C-
1000, anomeric C-atom); Anal. Calcd. for C22H24O9 (Mþ): (432) C,
61.11; H, 5.59. Found: C, 61.13; H, 5.64%.
The MICs of the chemical compounds assays were carried out as
described by Clause [36] with minor modifications. The minimum
inhibitory concentrations of the chemical compounds were recor-
ded as the lowest concentration of each chemical compounds in the
tubes with no growth (i.e. no turbidity) of inoculated bacteria.
8.4. Antioxidant assay
7.2.4.8. 1-(40-O- -glucopyranosyloxy-20-hydroxyphenyl)-3-(400-
b-D
methylphenyl)-propane-1,3-dione (5h). Yield 70%; ½a D25
ꢂ
¼ ꢀ16.6
In vitro free radical scavenging activities of (5a)e(5h) 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 mL of DPPH
reagent (2 mg/mL) was added. The initial absorbance was
measured. To this test tube, methanolic solution of different test
(c 0.1, CH3OH); FT-IR (KBr): 3413 (br, OH peak of carbohydrate
residue), 3435 (OH), 1733 (C]O), 2839 (glucosidic CH), 1600
(aromatic C]C), 1149 (CeO); 1H NMR (DMSO-d6,
d
, 300 MHz):
15.94 (s, 1H, enolic OH), 12.19 (s, 1H, 20-OH), 3.53e4.71 (m, 6H,
b
-D
-
glucopyranosyl ring), 5.74 (d, 1000-H, anomeric proton, J1, 2 ¼ 7.8 Hz),
2.5 (s, 4H, glucosidic OH), 8.43 (s, 1H, eCH]), 7.23 (d,00 2H,
solutions (1 mg/mL) was added (10e50
mL) was added in the range of 10e25 L. After 20 min, absorbance
mL). Ascorbic acid (0.5 mg/
00
00
00
00
00
00
00
J2 e4 ¼ 8.5 Hz, 2 -H, 4 -H), 7.34 (d, 2H, J3 e5 ¼ 8.4 Hz, 3 -H, 5 -H),
m

J. Sheikh et al. / European Journal of Medicinal Chemistry 46 (2011) 1390e1399
1399
[14] M. Sechi, F. Carta, L. Sannia, R. Dallocchio, A. Dessì, R.I. Al-Safi, N. Neamati,
was recorded at 516 nm. The experiment was performed in tripli-
cate. The percentage reduction in absorbance was calculated from
the initial and final absorbance of each solution. Percentage scav-
enging of DPPH radical was calculated using the formula:
Design, synthesis, molecular modeling, and anti-HIV-1 integrase activity of
a
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% Scavenging of DPPH ¼ ½ðControl ꢀ TestÞ=ðControlÞꢂ ꢃ 100
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