ORIGINAL RESEARCH

Antimicrobial/antioxidant activity and POM analyses of novel7-O-b-D-glucopyranosyloxy-3-(4,5-disubstitutedimidazol-2-yl)-4H-chromen-4-ones

Kishor Hatzade • Javed Sheikh • Vijay Taile •

Ajay Ghatole • Vishwas Ingle • Murat Genc •

Siham Lahsasni • Taibi Ben Hadda

Received: 5 August 2014 / Accepted: 17 January 2015

� Springer Science+Business Media New York 2015

Abstract A series of 7-O-b-D-glucopyranosyloxy-3-(4,5-

disubstituted imidazol-2-yl)-4H-chromen-4-ones 4 were

synthesized and tested for in vitro antibacterial/antifungal

and antioxidant activity. The synthesized compounds O-b-

D-glucoside of 7-hydroxyl-3-imidazolyl-4H-chromen-4-

ones showed good antibacterial/antifungal activity as well

as antioxidant activity. The results suggest that aglycone as

well as their O-glucosides could be promising candidates

for new combined antifungal/antibacterial as well as anti-

oxidant agents (3 in 1). Experimental data and Petra/Osiris/

Molinspiration (POM) analyses, respectively, show high

bioactivity against various microorganisms at a very low

concentration without any side effect, suggesting that series

2–4 is a potential antimicrobial inhibitor and further it

deserves to be validated for in vivo studies.

Graphical Abstract

7-Hydroxy-3-(4,5-disubstituted imidazol-2-yl)-4H-chro-

men-4-ones and their O-b-D-glucosides were synthesized

and evaluated for in vitro antimicrobial and antioxidant

activity. The compounds were also subjected to high-

throughput POM bioinformatics to study the bioavailability.

Keywords

7-Hydroxyl-3-imidazolyl-4H-chromen-4-ones �O-b-D-glucosides � Antifungal/antibacterial activity �POM bioinformatics

Introduction

Carbohydrates are being considered as extremely useful

stereochemical building blocks for complex organic syn-

thesis (Nicolaou and Mitchell, 2001). Apart from being an

energy source in leaving systems, carbohydrates increas-

ingly are being recognized as playing important roles in a

Electronic supplementary material The online version of thisarticle (doi:10.1007/s00044-015-1326-8) contains supplementarymaterial, which is available to authorized users.

K. Hatzade � V. Taile � V. Ingle

Organic Research Lab-1, Department of Chemistry, Rashtrasant

Tukdoji Maharaj Nagpur University, Nagpur 440033, India

K. Hatzade (&) � J. Sheikh � A. Ghatole

Department of Chemistry, Dhote Bandhu Science College,

Gondia 441614, India

e-mail: kishorhatzade@gmail.com

M. Genc

Department of Chemistry, FSA, Adiyaman University,

Adiyaman 02040, Turkey

S. Lahsasni

Department of Chemistry, Science College, King Saud

University, Riyadh, Kingdom of Saudi Arabia

T. Ben Hadda

Laboratoire Chimie Materiaux, FSO, Universite Mohammed

1ER, Oujda 60000, Morocco

123

Med Chem Res

DOI 10.1007/s00044-015-1326-8

MEDICINALCHEMISTRYRESEARCH

variety of biological processes, such as signaling, cell–cell

communications, molecular and cellular targeting (Sears

and Wong, 1999). O-b-D-glucosides possess higher degree

of biological activities such as cell growth regulation, cell

differentiation, immunological response, antitumour, anti-

parasitic, antifungal activities (Gagneux and Varki, 1999;

Giannis, 1994; Hart, 1992; Rademacher et al., 1988; Varki,

1993; Varki and Cummings, 1999). Several flavonoids

have been reported to possess therapeutically interesting

biological activities such as anticancer (Atassi et al., 1985;

Birt et al., 2001; Gobbi et al., 2003; Lopez-Lazaro, 2002;

Pouget et al., 2001; Zheng et al., 2003), anti-HIV (Hu

et al., 1994; Ungwitayatorn et al. 2004; Yu et al., 2004),

and antioxidant properties (Burda and Oleszek, 2001;

Rackova et al., 2005; Soobrattee et al., 2005). Similarly,

imidazoles show antimalarial, antifungal, anticonvulsant,

anticancer, anorectic, antituberculosis, antihypertensive,

hypoglysacemic, and antiprotozoal activities (Elks and

Ganellin, 1990). In continuation to earlier work (Hatzade

et al., 2008, 2009, 2010; Ingle et al., 2007; Sheikh et al.,

2014; Taile et al., 2009, 2010a, b, c, 2011) and keeping

close watch on the various biological activities of chromen-

4-ones, imidazoles and importance of glucose moiety.

Herein, we report the synthesis of new substituted flavo-

noids 7-hydroxy-3-(imidazol-2-yl)-4H-chromen-4-ones 2.

These compounds were subjected to glucosylation with a-

acetobromoglucose yielding 7-O-b-D-glucopyranosyloxy-3-

(imidazol-2-yl)-4H-chromen-4-ones 4. Elemental analysis,

IR, 1H NMR, 13C NMR, EI-MS spectral data were obtained

to determine the structure of the newly synthesized com-

pounds. Moreover, newly synthesized compounds were

tested against different bacterial/fungal strains. These

compounds were also evaluated for their in vitro free

radical scavenging activity (antioxidant activity). The

structures of the standard drugs used and synthesized

compounds are shown in Fig. 1.

Results and discussion

Chemistry

The 7-hydroxy-3-formyl-4H-chromen-4-one 1 was prepared

by Vilsmeier–Haack reaction (Nohara et al., 1974) from res-

acetophenone. The condensation of 1 with various 1,2-dicar-

bonyl compounds afforded 7-hydroxy-3-(4,5-disubstituted

imidazol-2-yl)-4H-chromen-4-ones 2 (Table 1) (Grimmett,

1997). The potassium salts of 2 were prepared by the action of

anhydrous K2CO3 in the presence of 18-crown-6 as a catalyst.

An interaction between the potassium salt and a-acetob-

romoglucose under argon atmosphere in acetonitrile gave

2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyloxy-3-(4,5-disubstituted

imidazol-2-yl)-4H-chromen-4-ones 3 (Table 2). Finally, 3

were deacetylated in the presence of anhydrous zinc acetate

(Wang et al., 2001), yielding corresponding O-b-D-glucosides

4 (Table 3). The synthetic pathway is outlined below in

Scheme 1.

All the structures were confirmed on the basis of spectral

analysis (IR, NMR, and mass spectra), elemental analysis,

and chemical analysis. The IR spectrum of 2c showed a

broad peak at 3,400.3 cm-1 due to the –OH stretch; the peak

at 3,064 cm-1 was appeared due to –NH stretch; a strong

absorption at 1,621.9 cm-1 was assigned to C=O stretch; the

peaks at 1,454.7 and 1,171 cm-1 were due to C=N and C–

O–C stretches, respectively. The 1H NMR data of 2a–

f showed the singlet signal at d 11.9–13.1 for the presence of

N–H proton. The d value of C-2 proton of chromen-4-one

ring varies from 7.26 to 7.56, while hydroxyl group exhibits

a singlet at d 4.93–5.12. The absence of IR band in 3c at

3,400.3 cm-1 (due to –OH stretch) is indicating the forma-

tion of product. Further, the peaks at 3,055.9 and

2,924.2 cm-1 were due to the C–H and N–H stretches,

respectively. The C=O stretch peak was found to be shifted

to 1,728.6 cm-1. A strong absorption at 1,757.5 cm-1 was

assigned to C=O stretch of O-acetyl groups of glucose

moiety. The peaks at 1,621 and 1,037 cm-1 were attributed

to the C=N and C–O–C stretches, respectively. A sharp peak

at 2,853.5 cm-1 was assigned to glucosidic C–H stretch.

The 1H NMR data of 4a–f show the presence of carbohy-

drate moiety. The chemical shifts of the anomeric proton

show O-b-D-linkage at d 5.54–5.85 (C–H), indicating the

linkage of carbohydrate unit to C-7 position of the aglycone

and also the absence of hydroxyl proton. The NMR multi-

plicity signals at d 3.41–4.05 (6H) due to the presence of b-

D-glucopyranosyl ring were observed for all O-glucosides.

The 1H NMR spectrum showed the singlet signal at d11.8–13.2 for NH in addition to the aromatic protons at d6.37–7.08. The 13C NMR spectrum revealed the presence of

the signals at d 130.9–136.6 and 127.8–132.1 corresponding

to imidazole C-20 and C-40 and 50, respectively. The 13C

NMR spectrum 4a–f showed the anomeric C-atom (C-100) at

d 105–106.2. The imidazole substituted C-atom (C-3), and

O-b-D-linkage (C-7) of chromen-4-one ring gives the peak at

d 117.8–119.4 and 163.5–165.1. The compounds gave sat-

isfactory CHN analysis, and EI-MS data of these compounds

were found in agreement with the assigned structure.

Pharmacology

Biological activity

Antimicrobial activities of the prepared compounds were

tested against bacterial strain such as Escherichia coli,

Klebisilla aerogens, Staphyllococcus aureus, Bacillus

Med Chem Res

123

substilis, and antifungal activity against Aspergillus niger

and Candida albicans using cup-plate diffusion method.

Ciprofloxacin (SD-1), sulphacetamide (SD-2) for bacteria

and gentamycin (SD-3), clotrimazole (SD-4) for fungi were

used as reference drugs. The results of tested compounds

against bacteria and fungi are shown in Table 4.

As shown in Table 4, the aglycone compounds showed

weak activity, whereas the glycosides had showed the

highest antimicrobial activity against gram-positive, gram-

negative bacteria and fungi. The results of antibacterial

activities indicated that slight difference between the

activities of all the glucosides against tested bacteria except

4d. The compounds 4a–c and 4e–f showed highest anti-

bacterial activity against all the bacterium. Compound 4d

showed poor activity against all the bacteria. Similarly, the

results of antifungal activity revealed that the glycosides

had promising antifungal activities against two yeast

strains (C. albicans and A. niger) except 4d which showed

highest activity against C. albicans but poor activity

against A. niger. These results suggested that glycosides

had effective and selective antimicrobial activities against

both bacteria and fungi.

The free radical scavenging activity using DPPH assay

method is summarized in Table 4. According these results,

the newly synthesized glucosides had more promising

antioxidant activities than that of aglycone compounds.

Structure–activity relationship

Structure–activity relationships, a powerful stencil used for

tailoring effective lead molecules, were studied. Here, all

the synthesized aglycone and their O-glucoside derivatives

were screen for antimicrobial and antioxidant properties. It

is observed that all the derivatives are active, but by

competing aglycone and their O-glucoside derivatives the

O-glucoside derivatives show good to moderate activity

compare to standard drugs. The observation in Table 4

shows that the activity of compounds (4a–f) enhances and

N N

NH

O

O H

O

F N H2

SO

O

NH CH3

O

Ciprofloxacin Sulphacetamide Gentamycin

N

N

Cl

O

O H

O

OH

OH

OHO

O

R"

O

NH

N

R

R'

Clotrimazole Ascorbic Acid 2a-f & 4a-f

Fig. 1 Structures of standard

drugs and POM analyzed

2a–f and 4a–f compounds

Table 1 Characterization data of 7-hydroxy-3-(4,5-disubstituted imidazol-2-yl)-4H-chromen-4-ones 2a–f

Comp. R R0 M.P. (�C) Crystallization solvent Mol. wt. C H N

found (calcd) %

Yield (%)

2a H H 290 Ethanol 228.20 63.10 3.51 12.21

(63.16 3.53 12.28)

81

2b CH3 CH3 295 Chloroform?dioxane 256.26 65.58 4.72 10.89

(65.62 4.72 10.93)

76

2c C6H5 H 282 Ethanol 304.30 71.01 3.93 9.20

(71.05 3.97 9.21)

78

2d C6H5 C6H5 220 Chloroform?dioxane 380.40 75.75 4.21 7.35

(75.78 4.24 7.36)

90

2e C6H5 4-OCH3C6H4 284 Chloroform?dioxane 410.43 73.11 4.39 6.80

(73.16 4.42 6.83)

89

2f 2-ClC6H4 2-ClC6H4 231 Ethanol 449.29 64.12 3.11 6.22

(64.16 3.14 6.24)

78

Med Chem Res

123

is affected by certain amount due to the introduction of

glycoside ring to the compound 2a–f.

Our hybrid molecule may be considered as a template

scaffold, in which one can insert substituents at different

positions to enhance the specificity toward microorgan-

isms, thereby manifesting antimicrobial and antioxidant

activities. These molecules possess (Fig. 2) ring A as

substituted chromen-4-one ring in imidazole skeleton at

C-3 and glycoside group at C-7 position. Ring B consti-

tuted the substitute imidazole subunit, and ring C was

derived by glycosylation on hydroxyl group at position C-7

of the chromen-4-one ring A.

The compound 4a displayed maximum antibacterial

activity against gram-positive S. aureus and B. substilis as

well as comparably good antioxidant activity due to un-

substituted imidazole ring B and glucoside group, i.e., ring

C, while compound 4b showed good antibacterial activity

against gram-negative E. coli and K. aerogens due to two

methyl group substitution on imidazole ring at position C-4

and C-5 with glycol molecule which attach as ring C to

chromen-4-one ring A at position C-7.

It is also interesting to note that the compound 4c

exhibits significant antifungal activity against C. albicans

and A. niger revealing that phenyl group substitution on

imidazole ring at position C-4. The presence of the electron

withdrawing group like -Cl as substituent on the imidazole

ring B is not showing relative effect compared to the

electron giving group to imidazole ring.

POM virtual screening of 2a–f and 4a–f

Tautomerism/conformerism/mesomerism is the important

and under-appreciated phenomenon in the drug design

process (Ben Hadda et al., 2013a, b, c; Chohan et al., 2010;

Table 2 Characterization data of 2,3,4,6-tetra-O-acetyl-7-O-b-D-glucopyranosyloxy-3-(4,5-disubstituted imidazol-2-yl)-4H-chromen-4-ones 3a–f

Comp R R0 [a]D25 (�) Mol. wt. C H N

found (calcd) %

Yield (%)

3a H H -3.1 558.49 55.89 4.66 5.00

(55.91 4.69 5.02)

86

3b CH3 CH3 -5.1 586.54 57.31 5.16 4.75

(57.34 5.16 4.78)

76

3c C6H5 H -1.5 634.59 60.54 4.76 4.36

(60.57 4.77 4.41)

88

3d C6H5 C6H5 -1.9 710.68 64.19 4.80 3.90

(64.22 4.82 3.94)

80

3e C6H5 4-OCH3C6H4 -1.5 740.71 63.21 4.89 3.77

(63.24 4.90 3.78)

89

3f 2-ClC6H4 2-ClC6H4 -2.4 779.57 58.54 4.10 3.55

(58.55 4.14 3.59)

75

Table 3 Characterization data of 7-O-b-D-glucopyranosyloxy-3-(4,5-disubstituted imidazol-2-yl)-4H-chromene-4-ones 4a–f

Comp R R0 [a]D25 (�) Mol. wt. Molecular Formula C H N

found (calcd) %

Yield (%)

4a H H -9.1 390 C18H18N2O8 55.35 4.66 7.16

(55.39 4.65 7.18)

90

4b CH3 CH3 -10.1 418 C20H22N2O8 57.37 5.27 6.67

(57.41 5.30 6.70)

91

4c C6H5 H -15.5 466 C24H22N2O8 61.78 4.76 5.99

(61.80 4.75 6.01)

96

4d C6H5 C6H5 -11.9 542 C30H26N2O8 66.38 4.80 5.14

(66.41 4.83 5.16)

92

4e C6H5 4-OCH3C6H4 -9.8 572 C31H28N2O9 65.01 4.94 4.88

(65.03 4.93 4.89)

89

4f 2-ClC6H4 2-ClC6H4 -12.4 611 C30H24Cl2N2O8 58.90 3.95 4.55

(58.93 3.96 4.58)

85

Med Chem Res

123

Jarrahpour et al., 2010, 2012; Parvez et al., 2010a, b; Sheikh

et al., 2011, 2014; Sheikh and Ben Hadda, 2013). Therefore,

the purpose of this study is important and has a potential to

improve how the descriptor-based Petra/Osiris/Molinspira-

tion (POM) analyses are performed. Our study is unique, as

we have to choose a simplistic approach to the problem.

Tautomers/conformers/mesomers equilibria in homologous

structures depend on structure and the fractions of indi-

vidual tautomer/conformer/mesomer in the equilibrium

mixture. It will vary from compound to compound in the

set. These fractions are a key component in the correct

bioactivity attribution. So, we suggest that the study is

reworked with the multi-species formalism (Fig. 3).

As it is shown in Fig. 3, it becomes theoretically evident

that only Conformer II, which represents good relative

stability because of an intramolecular interaction and a

(NH–OC) pharmacophore site, is the most favorable iso-

mer representing the major factors in determining the

antibacterial activity.

On the other hand, experimental antimicrobial screening

of all series of compounds shows a good antifungal activity

(Table 4), although there is no favorable and evident anti-

fungal pharmacophore site. This conflicting situation

between experimental and theoretical arguments led us to get

a more detailed look on the possibility of biotransformation/

metabolism of some compounds containing similar 1,3-

pyrazol and 4H-chromen-4-one, and we got the reason for all

queries (Fig. 1).

Molecular properties calculations For the development

of binding approaches for 2a–f and 4a–f in the biological

environment, the identification of the active 2–4 structures

present is important. Neither experimental nor theoretical

data are available for the identification of water-solvated

2a–f and 4a–f species. The objective of this study is to

investigate the potential pharmacophore sites of 2a–f and

4a–f species using antibacterial and antifungal screenings

depending on pH and comparison with the calculated

molecular properties. To verify these structures, further

POM analyses were carried out, for example, calculation of

net atomic charges, bond polarity, atomic valence, electron

delocalization, and lipophilicity.

Pi-charge calculations The series 2a–f and 4a–f have

been subjected to delocalised-charge calculations using

Petra method of the non-hydrogen common atoms (Fig. 3),

obtained from the partial pi-charge of the heteroatoms, and

have been used to model the bioactivity against bacteria

and fungi.

It is found that the negative charges of the nitrogen of

1,3-pyrazolic ring and carbonyl group of 4H-chromen-4-

one contribute positively in favor of generation of various

OHO

O

N

N

R

R'

OK+O-

O

N

N

R

R'

O

O

N

N

R

R'

O

H

AcO

H

AcO

H

HOAcH

O

OAc

O

H

HO

H

HO

H

HOHH

OH

OO

O

N

N

R

R'

2

3

4

H

H

OHO

O

CHO

1

H

H

O

O

R

R'

R R'a) H Hb) CH3 CH3c) C6H5 Hd) C6H5 C6H5e) C6H5 4-OCH3C6H4f) 2-ClC6H4 2-ClC6H4

+(i)

(ii)

(iii)

(iv)

Scheme 1 (i) CH3COONH4,

CH3COOH (ii) K2CO3, CH3CN,

Ar atm. (iii) a-acetobromoglucose,

18-crown-6 (iv) Zn(CH3COO)2,

MeOH (Hatzade et al., 2013)

Med Chem Res

123

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(0.4

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(0.4

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(0.5

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(0.5

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(0.8

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(0.7

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64

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(0.3

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(0.3

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(0.5

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(0.4

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87

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(0.8

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(0.9

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(0.7

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(0.8

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(0.7

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(0.8

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(0.8

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(0.8

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(1.6

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(1.4

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(0.8

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(0.8

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79

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(0.5

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(0.6

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(0.6

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(0.6

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20

(0.5

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(0.6

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13

(0.5

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(0.6

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(0.9

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(0.8

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(0.5

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(0.7

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(0.8

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19

(0.6

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25

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(0.8

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19

(0.8

6)c

(0.9

0)d

29

(1.3

8)c

(1.2

6)d

17

(0.6

8)c

(0.7

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75

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(0.7

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21

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24

(0.8

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(0.9

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24

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17

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22

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Med Chem Res

123

conformer forms (Conformers I and II), and this is in good

agreement with the mode of biological action of the

compounds bearing (Xd-–Yd?) pharmacophore site. It was

hypothesized that difference in charges between two het-

eroatoms of the same dipolar pharmacophore site (COd-–

NHd?) may facilitate the drug/bacterial target interaction,

more than viruses and fungi (Ben Hadda et al., 2013a, b, c;

Chohan et al., 2010; Jarrahpour et al., 2010, 2012; Parvez

et al., 2010a, b; Sheikh et al., 2011, 2014; Sheikh and Ben

Hadda, 2013).

Osiris calculations With our recent publications on drug

design combination of various pharmacophore sites (Ben

Hadda et al., 2013a, b, c; Chohan et al., 2010; Jarrahpour

et al., 2010, 2012; Parvez et al., 2010a, b; Sheikh et al.,

2011, 2014; Sheikh and Ben Hadda, 2013), it becomes now

easier for us to predict the type of bioactivity of candidate

drugs. This is done using a combined electronic/structure

docking procedure, and an example will be given here

(Table 5). The remarkably well-behaved mutagenicity of

divers’ synthetic molecules classified in the 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.

From the data evaluated, Table 5 indicates that all

structures are supposed to be non-mutagenic when run

through the mutagenicity assessment system and as far as

irritating and reproductive effects are concerned, and all

the compounds are at low risk compared with standard

drugs used (except 2e and 4e).

The clogP 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 hydrophilic-

ity. Low hydrophilicity and therefore high clogP values

may cause poor absorption or permeation. It has been

shown for compounds to have a reasonable probability of

being well absorb, their clogP value must not be [5.0.

On this basis, all the series of compounds 2a–f and 4a–

f having clogP values under the acceptable criteria should

be active. The geometrical parameter and the aqueous

solubility of a compound significantly affect its absorption,

distribution characteristics, and bioactivity.

Typically, a low solubility goes along with a bad

absorption, and therefore, the general aim is to avoid

poorly soluble compounds.

Our estimated logS value is a unit stripped logarithm

(base 10) of a compound’s solubility measured in mol/L.

More than 80 % of the drugs on the market have an

(estimated) logS value [4. In the case of compounds 2a–f

and 4a–f, values of logS are negative, and majority is under

acceptable criteria. Furthermore, Table 5 shows the drug

likenesses of compounds 2a–f and 4a–f which are in a

comparable zone with that of standard drugs. We have

calculated overall drug score (DS) for the compounds 2a–f

and 4a–f. The drug score combines drug likeness, clogP,

logS, molecular weight, and toxicity risks in one handy

value that may then be used to judge the compound’s

overall potential to qualify a drug. This value is calculated

by multiplying contributions of the individual properties

with Eq. 1.

DS ¼Y 1

2þ 1

2Si

� �Yti ð1Þ

Definition of drug score (DS), where S = 1/1 ? eap ? b,

DS is the drug score, Si is the contribution calculated

directly from of clogP, logS, 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 clogP, logS, molecular weight, and drug

likeness, respectively. ti is the contribution 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 2a–f and 4a–f showed moderate to

good drug scores as compared to the standard drugs.

We have calculated overall drug-score (DS) for the

compounds 2a–f and 4a–f and compared with that of

standard drugs used SD 1–5 as shown in Table 5. The DS

Fig. 3 Identification of dual antibacterial/antifungal pharmacophore

sites of compounds 2a–f and 4a–f

Fig. 2 7-o-b-D-glucopyranosyloxy-3-(4, 5-disubstituted imidazol-2-yl)-

4H-chromen-4-ones

Med Chem Res

123

combines drug likeness, clogP, logS, molecular weight,

and toxicity risks in one handy value that may be used to

judge the compound’s overall potential to qualify for a

drug. The reported compounds 2a–f and 4a–f showed good

DS (DS = 0.18–0.70). That indicates that majority of

parameters in drug design have been realized (Table 5).

Molinspiration calculations

The method is very robust and is able to process practically

all organic and most organometallic molecules. Total polar

surface area (TPSA) is calculated based on the methodol-

ogy published by Ertl et al. (2000) as a sum of fragment-

based contributions. O- and N-centered polar fragments are

considered. PSA has been shown to be a very good

descriptor characterizing drug absorption, including intes-

tinal absorption, bioavailability, and blood–brain barrier

penetration (Ertl et al., 2000). Prediction results of com-

pounds 2a–f and 4a–f for molecular properties (TPSA,

GPCR ligand, and ICM) are valued (Table 6).

Lipophilicity (clogP value) and polar surface area (PSA)

values are two important predictors of oral bioavailability

of drug molecules (Lipinski et al., 2001). Therefore, we

calculated clogP and PSA values for compounds 2a–f and

4a–f using Molinspiration software programs and com-

pared them to the values obtained for standard market

available drugs. For all the compounds, the calculated

clogP values were lower than five, which is the upper limit

for drugs to be able to penetrate through biomembranes

according to Lipinski’s rules. 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 (Clark, 1999).

Molecules with PSAs of 140 A or more are expected to

exhibit poor intestinal absorption (Clark, 1999). Table 6

shows that all the compounds are within this limit with

compounds 2a–f (except 2f), and 4a–f is having minimum

comparable values of clogP and TPSA. This is also sup-

ported by the biological screening data of compounds in

terms of maximum of dual bacteria and fungus inhibition.

It has to be kept in mind that clogP and TPSA values are

only two important, although not sufficient, criteria for

predicting oral absorption of a drug. To support this con-

tention, note that all the compounds have one violation of

the Rule of 5. The Rule of 5 is a set of parameters devised

Table 5 Drug-score calculations of compounds 2a–f and 4a–f

Compd. Toxicity risksa Drug scoreb

MUT TUMO IRRI REP CLP S DL DS

2a ??? ??? ??? ??? 0.37 -1.42 -0.21 0.70

2b ??? ??? ??? ??? 1.16 -2.15 -1.26 0.57

2c ??? ??? ??? ??? 2.12 -3.20 0.41 0.69

2d ??? ??? ??? ??? 3.87 -4.97 0.80 0.51

2e ??? – ??? – 3.80 -4.99 1.58 0.19

2f ??? ??? ??? ??? 5.08 -6.45 1.03 0.32

4a ??? ??? ??? ??? -1.62 -1.30 -3.40 0.46

4b ??? ??? ??? ??? 0.83 -2.04 -4.67 0.43

4c ??? ??? – ??? 0.13 -3.08 -2.80 0.39

4d ??? ??? ??? ??? 1.88 -4.86 -2.45 0.28

4e ??? – ??? – 1.81 -4.88 -1.64 0.10

4f ??? ??? ??? ??? 3.09 -6.33 -2.29 0.19

SD-1 ??? ??? ??? ??? -1.53 -3.32 -2.07 0.82

SD-2 – ??? ??? – 0.16 -1.53 5.46 0.35

SD-3 ??? ??? ??? ??? -4.03 -1.18 4.88 0.77

SD-4 ??? ??? ??? ??? 5.37 -7.72 0.92 0.30

SD-5 ??? ??? ??? ??? -2.46 -0.35 0.02 0.74

For antibacterial activity, SD-1 = ciprofloxacin and SD-2 = sulphacetamide; for antifungal activity, SD-3 = gentamycin and SD-4 = clo-

trimazole. For antioxidant activity, SD-5 = ascorbic acid

(???), not toxic; (?), slightly toxic; (–), highly toxica MUT mutagenic, TUMO tumorigenic, IRRI irritant, REP reproductive effectiveb CLP clogP, S solubility, DL drug likeness

Med Chem Res

123

to aid the screening of potential drug ‘‘hits’’ identified

through processes such as high-throughput screening (Li-

pinski et al., 2001). Application of Rule of 5 increases the

probability of potential chemotherapeutic to have favorable

bioavailability. The criteria are as follows: (1) not more than

five hydrogen bond donors; (2) not more than ten hydrogen

bond acceptors; (3) formula weight\500; and (4) clogP\5.

Two or more violations of the Rule of 5 suggest the prob-

ability of problems in bioavailability (Lipinski et al., 2001).

Most of the compounds have zero or one violations of the

Rule of 5. Drug likeness of compounds 2a–f and 4a–f is

tabulated in Table 6. Drug likeness may be defined as a

complex balance of various molecular properties and

structure features, which determine whether particular

molecule is similar to the known drugs. These properties,

mainly hydrophobicity, electronic distribution, hydrogen

bonding characteristics, molecule size, flexibility, and the

presence of various pharmacophores features influence the

behavior of molecule in a living organism, including bio-

availability, transport properties, affinity to proteins, reac-

tivity, toxicity, metabolic stability, and many others.

Activity of all twelve compounds and standard drugs were

rigorously analyzed under three criteria of known successful

drug activity in the areas of ion channel modulation, kinase

inhibition (KI) activity, and nuclear receptor ligand activity.

Results are shown in Table 6 for all the compounds.

Likewise, 8/12 of all compounds have consistent positive

values in KI category. Therefore, it is readily seen that most

of the compounds are expected to have near similar or better

wide dual activity to standard drugs used based upon these

three rigorous criteria (ion channel modulator, kinase

inhibitor, and nuclear receptor ligand).

Conclusions

The synthesized glucosides of 7-hydroxy-3-(4,5-disubsti-

tuted imidazol-2-yl)-4H-chromen-4-ones have been evalu-

ated for in vitro antimicrobial and antioxidant activity. The

in vitro results indicated that new glucosides of 7-hydroxy-

3-imidazolyl-4H-chromen-4-ones had greater pharmaco-

logical significance than that of aglycone. Particularly, we

suggested that the compounds 4a–c and 4e–f could be

promising candidates for new antibacterial as well as

antioxidant agents.

In our computational findings, we have observed that

most of the tested compounds of series 2a–f and 4a–

f showed moderate to high activity against bacteria and

fungus. The results of this virtual screening investigation

support the suggested models for antibacterial/antifungal

activity; we developed in the past 20 years in collaboration

with NCI and TAACF of USA.

Table 6 Drug-likeness calculations of compounds 2a–f and 4a–f

Compd. MW (g/mol) Physicochemical propertiesa Drug likenessb

TPSA O/NH VIOL ROTB VOL ICM KI NRL PI EN

2a 228 79 2 0 1 189 -0.38 0.00 -0.24 -0.82 0.19

2b 256 79 2 0 1 222 -0.44 -0.05 -0.12 -0.75 0.07

2c 304 79 2 0 2 260 -0.23 0.28 0.02 -0.53 0.21

2d 580 79 2 0 3 332 -0.33 0.21 0.00 -0.60 0.13

2e 410 88 2 0 4 357 -0.36 0.17 -0.02 -0.60 0.09

2f 449 79 2 1 3 359 -0.31 0.20 0.00 -0.57 0.08

4a 390 158 5 0 4 321 -0.21 0.10 -0.02 -0.19 0.41

4b 354 158 5 0 4 354 -0.27 -0.01 -0.03 -0.26 0.29

4c 466 158 5 0 5 392 -0.15 0.13 -0.04 -0.27 0.34

4d 542 158 5 1 6 464 -0.46 0.05 -0.11 -0.38 0.20

4e 572 168 5 2 7 489 -0.63 -0.07 -0.24 -0.39 0.07

4f 611 158 5 1 6 491 -0.61 -0.04 -0.20 -0.38 0.06

SD-1 331 75 2 0 3 285 -0.04 -0.07 -0.19 -0.21 0.28

SD-2 214 89 3 0 2 175 -0.48 -0.70 -1.28 -0.36 -0.12

SD-3 476 205.5 12 2 2 453 -0.24 -0.76 -1.05 -0.46 0.18

SD-4 345 18 0 1 4 310 0.30 0.14 -0.21 -0.13 0.42

SD-5 176 107 4 0 2 140 -0.24 -1.09 -1.01 -0.81 0.20

For antibacterial activity, SD-1 = ciprofloxacin and SD-2 = sulphacetamide; for antifungal activity, SD-3 = gentamycin and SD-4 = clo-

trimazole. For antioxidant activity, SD-5 = ascorbic acida TPSA total polar surface area, O/NH O–HN interaction, VIOL number of violation, VOL volumeb ICM ion channel modulator, KI kinase inhibitor, NRL nuclear receptor ligand, PI protease inhibitor, EI enzyme inhibitor

Med Chem Res

123

Experimental protocols

Chemistry

General procedures

All the reagents and chemicals were purchased from Sigma-

Aldrich. Melting points measured in open capillary tube

were uncorrected. FT-IR spectra were recorded on Perkin-

Elmer spectrum Rx-I spectrophotometer. 1H and 13C NMR

spectra were recorded on a Bruker II-400 NMR spectro-

photometer (1H, 400 MHz and 13C, 100 MHz), using TMS

as an internal standard in DMSO and CDCl3; chemical shifts

(d) were measured in ppm. Multiplicity was simplified such

as s = singlet, d = doublet, t = triplet, and m = multiplet.

Mass spectra were determined on Hitachi Perkin-Elmer

RMU 6D mass spectrometer. Elemental analyses were

determined using the Perkin-Elmer 2400 CHN analyzer.

Various 1,2-dicarbonyl compounds were prepared using

methods described in the literature (Furniss et al., 1989).

General procedure for the preparation of compound 1

In three-necked flask, dry DMF (121 mL) and POCl3(75 mL, 0.49 mol) were added slowly with vigorous stir-

ring at 50 �C. Heating and stirring were continued for 2 h

at 45–55 �C. The solution of resacetophenone (18.24 g,

0.12 mol) in DMF (25 mL) was then slowly added with

stirring at 50 �C, and the stirring was continued for 2 h.

After cooling, the mixture was kept overnight at room

temperature and diluted slowly by adding ice-cold water

(500 mL) and stirred again for 6 h. The red crystalline

product obtained was filtered off and recrystallised from

alcohol, m.p. 269 �C, yield 45 g (78 %). Its alcoholic

solution gives violet coloration with neutral FeCl3. IR

(KBr): 3,428.8 (phenolic OH), 3,087.3, 2,363.0 (Ar –CH

str), 2,773.9 (–CH str in aldehydic gp), 1,685.6 (C=O str),

1,614.1 (C=C str) and 1,093.8 (due to C–O–C ether link-

age). 1H-NMR (400 MHz, DMSO-d6): d 9.59 (s, 1H,

CHO), 8.05 (s, 2-H, CH), 6.35–7.05 (m, 3H, Ar–H), 4.95

(s, 1H, –OH). 13C NMR (100 MHz, DMSO-d6): 188.1 (s,

CHO of C-3), 174.9 (s, C-4, C=O), 171.0 (s, C-2), 161.2 (s,

C-7), 157.9 (s, C-9), 131.4 (s, C-5), 121.7 (s, C-3, C–CHO),

114.0 (s, C-10), 109.4 (s, C-6), 104.8 (s, C-8).

General procedure for the preparation of compounds 2

A mixture of 7-hydroxy-3-formyl-4H-chromen-4-one

(0.95 g, 5 mmol), 1,2-dicarbonyl compound (0.662 g,

5 mmol), ammonium acetate (0.77 g, 10 mmol) and glacial

acetic acid (50 mL) was refluxed for 2 h. It was poured on

to cold water (200 mL). The solid product obtained was

filtered, washed with water, and crystallized from solvents.

7-Hydroxy-3-(1H-imidazol-2-yl)-4H-chromen-4-one: 2a Yield

81 %, m.p. 290–292 �C. IR (KBr): 3,451.3 (br, OH str),

2,958.4 (NH– str), 1,615.9 (C=O str), 1,455.5 (C=N str)

and 1,150.4 (due to C–O–C ether linkage). 1H-NMR

(400 MHz, DMSO-d6): d 12.9 (s, 10-H, N–H), 7.26 (s, 2-H,

CH), 7.05 (d, 40-H, 50-H) (CH), 6.49–7.00 (m, 3H, Ar–H),

5.12 (s, 1H, –OH). 13C NMR (100 MHz, DMSO-d6): 174.9

(s, C-4, C=O), 163.9 (s, C-7), 159.8 (s, C-2), 159.0 (s, C-9),

135.9 (s, C-20), 131.9 (s, C-5), 128.0 (s, C-40,C-50), 118.2

(s, C-3), 115.8 (s, C-10), 111.0 (s, C-6), 104.6 (s, C-8). EI-

MS: m/z (%) 229 (M?, 100), 136 (18), 91 (30). Anal. Calcd

for C12H8N2O3: C, 63.16; H, 3.53; N, 12.28. Found: C,

63.10; H, 3.51; N, 12.21(%).

3-(4,5-Dimethyl-1H-imidazol-2-yl)-7-hydroxy-4H-chromen-

4-one: 2b Yield 76 %, m.p. 295–297 �C. IR (KBr):

3,412.5 (br, OH str), 3,012.9 (NH– str), 1,608.6 (C=O str),

1,452.4 (C=N str) and 1,165.7 (due to C–O–C ether link-

age). 1H-NMR (400 MHz, DMSO-d6): d 13.1 (s, 10-H, N–

H), 7.52 (s, 2-H, CH), 6.45–7.00 (m, 3H, Ar–H), 4.99 (s,

1H, –OH), 2.31 (s, 40-H, CH3), 2.20 (s, 50-H, CH3). 13C

NMR (100 MHz, DMSO-d6): 176.1 (s, C-4, C=O), 164.5

(s, C-7), 158.9 (s, C-2), 157.8 (s, C-9), 135.7 (s, C-20),132.1 (s, C-40, C-50), 131.4 (s, C-5), 119.0 (s, C-3), 116.8

(s, C-10), 110.1 (s, C-6), 105.5 (s, C-8), 12.2 (s, CH3 of

C-40, C-50). EI-MS: m/z (%) 257 (M?, 100), 136 (15),

91(19). Anal. Calcd for C14H12N2O3: C, 65.62; H, 4.72; N,

10.93. Found: C, 65.58; H, 4.72; N, 10.89(%).

7-Hydroxy-3-(4-phenyl-1H-imidazol-2-yl)-4H-chromen-4-

one: 2c Yield 78 %, m.p. 282–284 �C. IR (KBr): 3,400.3

(br, OH str), 3,064 (NH– str), 1,621.9 (C=O str), 1,454.7

(C=N str) and 1,171.0 (due to C–O–C ether linkage). 1H-

NMR (400 MHz, DMSO-d6): d 12.7 (s, 10-H, N–H), 7.56

(s, 2-H, CH), 7.05 (s, 50-H, CH), 6.41–7.02 (m, 8H, Ar–H),

5.02 (s, 1H, –OH). 13C NMR (100 MHz, DMSO-d6): 174.8

(s, C-4, C = O), 165.1 (s, C-7), 160.0 (s, C-2), 157.5 (s,

C-9), 135.5 (s, C-20), 132.0 (s, C-5), 130.2 (s, C-40),125–133.5 (aromatic 6C-atom), 121.0 (s, C-50), 117.6 (s,

C-3), 115.9 (s, C-10), 110.1 (s, C-6), 104.8 (s, C-8),. EI-

MS: m/z (%) 305 (M?, 100), 136 (10), 91(21). Anal. Calcd

for C18H12N2O3: C, 71.05; H, 3.97; N, 9.21. Found: C,

71.01; H, 3.93; N, 9.21(%).

3-(4,5-Diphenyl-1H-imidazol-2-yl)-7-hydroxy-4H-chromen-

4-one: 2d Yield 90 %, m.p. 220–223 �C. IR (KBr):

3,412.3 (br, OH str), 3,065.1 (NH– str), 1,631.4 (C=O str),

1,455.6 (C=N str) and 1,159.7 (due to C–O–C ether link-

age). 1H-NMR (400 MHz, DMSO-d6): d 12.9 (s, 10-H, N–

H), 7.57 (s, 2-H, CH), 6.43–7.01 (m, 13H, Ar–H), 4.94 (s,

1H, –OH). 13C NMR (100 MHz, DMSO-d6): 175.2 (s, C-4,

C=O), 164.9 (s, C-7), 159.4 (s, C-2), 157.9 (s, C-9), 135.6

(s, C-20), 133.1 (s, C-5), 129.0 (s, C-40, C-50), 127-133

(aromatic 12C-atom), 117.9 (s, C-3), 117.0 (s, C-10), 109.8

Med Chem Res

123

(s, C-6), 106.1 (s, C-8). EI-MS: m/z (%) 380 (M?, 100),

136 (15), 91 (34). Anal. Calcd for C24H16N2O3: C, 75.78;

H, 4.24; N, 7.36. Found: C, 75.75; H, 4.21; N, 7.35(%).

7-Hydroxy-3-[5-(4-methoxyphenyl)-4-phenyl-1H-imidazol-

2-yl]-4H-chromen-4-one: 2e Yield 89 %, m.p. 284 �C.

IR (KBr): 3,446.9 (br, OH str), 2,994.4 (NH– str), 1,620.4

(C=O str), 1,457.1 (C=N str) and 1,154.2 (due to C–O–C

ether linkage). 1H-NMR (400 MHz, DMSO-d6): d 12.6 (s,

10-H, N–H), 7.52 (s, 2-H, CH), 6.38-7.09 (m, 12H, Ar–H),

4.93 (s, 1H, –OH), 3.69 (s, 3H, OCH3). 13C NMR

(100 MHz, DMSO-d6): 176.1 (s, C-4, C=O), 165.2 (s, C-7),

159.0 (s, C-9), 158.9 (s, C-2), 136.1 (s, C-20), 131.6 (s,

C-5), 128.7 (s, C-40, C-50), 119.2 (s, C-3), 117.1 (s, C-10),

109.8 (s, C-6), 106.1 (s, C-8), 115–165 (aromatic 12C-

atom), 54.8 (s, C-atom of OCH3). EI-MS: m/z (%) 411

(M?, 100), 136 (17), 91 (10). Anal. Calcd for C18H12N2O3:

C, 73.16; H, 4.42; N, 6.83. Found: C, 73.11; H, 4.39; N,

6.80(%).

3-[4,5-Bis(2-chlorophenyl)-1H-imidazol-2-yl]-7-hydroxy-4H-

chromen-4-one: 2f Yield 78 %, m.p. 231–233 �C. IR

(KBr): 3,442.8(br, OH str), 3,057.0 (NH– str), 1,623.5

(C=O str), 1,451.8 (C=N str) and 1,165.8 (due to C–O–C

ether linkage). 1H-NMR (400 MHz, DMSO-d6): d 11.9 (s,

10-H, N–H), 7.52 (s, 2-H, CH), 6.41–7.05 (m, 11H, Ar–H),

4.96 (s, 1H, –OH). 13C NMR (100 MHz, DMSO-d6): 176.1

(s, C-4, C=O), 164.7 (s, C-7), 159.9 (s, C-2), 159.1 (s, C-9),

136.7 (s, C-20), 132.0 (s, C-5), 129.9 (s, C-40,C-50), 118.1

(s, C-3), 117.2 (s, C-10), 109.9 (s, C-6), 104.6 (s, C-8),

125-135 (aromatic 12C-atom). EI-MS: m/z (%) 450 (M?,

100), 136 (25), 91(26). Anal. Calcd for C24H16N2O3: C,

64.16; H, 3.14; N, 6.24. Found: C, 64.12; H, 3.11; N,

6.22(%).

General procedure for the preparation of compounds 3

A mixture of 7-hydroxy-3-(4,5-disubstituted imidazol-2-

yl)-4H-chromen-4-one (0.1,186 g, 0.39 mmol), K2CO3

(0.042 g, 0.43 mmol), and acetonitrile (50 mL) was stirred

at room temperature under argon atmosphere. 18-Crown-6

(10 mg, 0.04 mmol) was added followed by a-acetob-

romoglucose (0.245 g, 0.58 mmol). After 5 h, it was

poured into ice-cold water and neutralized with H2SO4

(1 mol/L). The product was extracted in ethyl acetate

(50 mL 9 4). Removal of the volatiles under reduced

pressure afforded a brown colored semisolid.

3a Yield 86 %. [a]D25 = -3.1 (c 0.1, CH3OH). IR (KBr):

3,042.1 (–CH= str), 2,954.0 (NH– str), 2,854.3 (glucosidic

C–H str), 1,760.8 (C=O of O-acetyl gps of glycone moiety),

1,721.7 (C = O str), 1,645.5 (C = N str), 1,051.8 (C–O–C,

ether linkage). 1H-NMR (400 MHz, DMSO-d6): d 12.5 (s,

10-H, N–H), 7.46 (s, 2-H, CH), 7.15 (d, 40-H, 50-H) (CH),

6.40–6.59 (m, 3H, Ar–H), 4.87–5.00 (m, 3H, 200,300,400-H),

4.76 (d, 1H, 100-H, anomeric proton), 4.39 (dd, 1H, 500-H),

3.86–4.24 (m, 2H, 600-H), 2.05, 2.01, 1.99, 1.95 (s, 3H,

OAc). 13C NMR (100 MHz, DMSO-d6): 174.9 (s, C-4,

C=O), 171.0 (s, C-atoms of Acetyl C=O), 164.2 (s, C-7),

159.1 (s, C-2), 158.1 (s, C-9), 135.9 (s, C-20), 130.9 (s,

C-5), 128.0 (s, C-40,C-50), 117.6 (s, C-3), 116.2 (s, C-10),

110.1 (s, C-6), 103.4 (s, C-8), 101.9 (s, C-100, anomeric

C-atom), 74.9 (s, C-500), 72.8 (s, C-200), 71.5 (s, C-400), 71.1

(s, C-300), 66.1 (s, C-600), 21.8 (s, C-atom, CH3 of acetyl

group). EI-MS: m/z (%) 559 (M?, 17), 228 (100), 136 (12),

91(25). Anal. Calcd for C26H28O12N2: C, 55.91; H, 4.69;

N, 5.02. Found: C, 55.89; H, 4.66; N, 5.00(%).

3b Yield 76 %. [a]D25 = -5.1 (c 0.1, CH3OH). IR (KBr):

3,057.5 (–CH= str), 2,935.1 (NH– str), 2,882.0 (glucosidic

C–H str), 1,758.3 (C=O of O-acetyl gps of glycone moiety),

1,727.4 (C=O str), 1,623.8 (C=N str), 1,054.9 (C–O–C,

ether linkage). 1H-NMR (400 MHz, DMSO-d6): d 12.9 (s,

10-H, N–H), 7.48 (s, 2-H, CH), 6.49–7.00 (m, 3H, Ar–H),

4.85–5.04 (3H, m, 200,300,400-H), 4.71 (1H, d, 100-H, ano-

meric proton), 4.40 (1H, dd, 500-H), 3.90–4.21 (2H, m, 600-H), 2.34 (s, 40-H, CH3), 2.24 (s, 50-H, CH3), 2.04, 2.02,

1.98,1.96 (s, 3H, OAc). 13C NMR (100 MHz, DMSO-d6):

176.0 (s, C-4, C=O), 170.5 (s, C-atoms of Acetyl C=O),

164.7 (s, C-7), 159.0 (s, C-2), 158.0 (s, C-9), 135.7 (s,

C-20), 132.1 (s, C-40,C-50), 130.8 (s, C-5), 117.8(s, C-3),

115.1 (s, C-10), 108.1 (s, C-6), 104.1 (s, C-8), 102.8 (s,

C-100, anomeric C-atom), 75.5 (s, C-500), 72.2 (s, C-200), 71.5

(s, C-300), 71.0 (s, C-400), 66.0 (s, C-600), 20.9 (s, C-atom,

CH3 of acetyl group), 11.4 (s, CH3 of C-40,C-50). EI-MS:

m/z (%) 587 (M?, 11), 256 (100), 136 (21), 91 (25). Anal.

Calcd for C28H32N2O12: C, 57.34; H, 5.16; N, 4.78. Found:

C, 57.31; H, 5.16; N, 4.75(%).

3c Yield 88 %. [a]D25 = -1.5 (c 0.1, CH3OH). IR (KBr):

3,055.9 (–CH = str), 2,924.2 (NH– str), 2,853.5 (gluco-

sidic C–H str), 1,757.5 (C=O of O-acetyl gps of glycone

moiety), 1,728.6 (C=O str), 1,621 (C=N str), 1,037 (C–O–

C, ether linkage) and 688.9 (benzene monosubstituted). 1H-

NMR (400 MHz, DMSO-d6): d 12.5 (s, 10-H, NH), 7.50 (s,

2-H, CH), 7.09 (s, 50-H, CH), 6.41-7.05 (m, 8H, Ar–H),

4.84–4.99 (3H, m, 200,300,400-H), 4.79 (1H, d, 100-H, ano-

meric proton), 4.45 (1H, dd, 500-H), 3.81–4.25 (2H, m, 600-H), 1.94, 1.96, 2.01, 2.02 (s, 3H) (COCH3). 13C NMR

(100 MHz, DMSO-d6): 176.2 (s, C-4, C=O), 169.9 (s,

C-atoms of Acetyl C=O), 163.8 (s, C-7), 158.9 (s, C-2),

158.0 (s, C-9), 135.5 (s, C-20), 130.0 (s, C-40), 127.5-133.5

(aromatic 6C-atom), 131.5 (s, C-5), 119.9 (C-50), 117.8 (s,

C-3), 114.8 (s, C-10), 109.4 (s, C-6), 104.1 (s, C-8), 101.9

(s, C-100, anomeric C-atom), 75.4 (s, C-500), 72.1 (s, C-200),71.7 (s, C-300), 71.5 (s, C-400), 66.1 (s, C-600), 22.0 (s,

C-atom, CH3 of acetyl group). EI-MS: m/z (%) 634 (M?,

20), 304 (100), 136 (16), 91 (29). Anal. Calcd for

C32H32O12N2: C, 60.57; H, 4.77; N, 4.41. Found: C, 60.54;

H, 4.76; N, 4.36(%).

Med Chem Res

123

3d Yield 80 %. [a]D25 = -1.9 (c 0.1, CH3OH). IR (KBr):

3,021.6 (–CH= str), 2,945.4 (NH– str), 2,854.9 (glucosidic

C–H str), 1,754.2 (C=O of O-acetyl gps of glycone moiety),

1,721.7 (C=O str), 1,645.7 (C=N str), 1,055.3 (C–O–C,

ether linkage) and 689.1 (benzene monosubstituted). 1H-

NMR (400 MHz, DMSO-d6): d 12.8 (s, 10-H, N–H), 7.61

(s, 2-H, CH), 6.38–7.05 (m, 13H, Ar–H), 4.86-5.02 (3H, m,

200,300,400-H), 4.79 (1H, d, 100-H, anomeric proton), 4.41 (1H,

dd, 500-H), 3.89–4.29 (2H, m, 600-H), 2.02, 2.00, 1.99, 1.91

(s, 3H, OAc). 13C NMR (100 MHz, DMSO-d6): 175.8 (s,

C-4, C=O), 171.0 (s, C-atoms of Acetyl C=O), 164.1 (s,

C-7), 160.2 (s, C-2), 157.1 (s, C-9), 135.9 (s, C-20), 131.6

(s, C-5), 129.5 (s, C-40, C-50), 128–133 (aromatic 12C-

atom), 118.6 (s, C-3), 116.0 (s, C-10), 109.9 (s, C-6), 104.3

(s, C-8), 102.9 (s, C-100, anomeric C-atom), 75.4 (s, C-500),72.1 (s, C-200), 71.3 (s, C-400), 71.2 (s, C-300), 66.1 (s, C-600),20.7 (s, C-atom, CH3 of acetyl group). EI-MS: m/z (%) 711

(M?, 14), 379 (100), 136 (11), 91 (29). Anal. Calcd for

C38H36N2O12: C, 64.22; H, 4.82; N, 3.94. Found: C, 64.19;

H, 4.80; N, 3.90(%).

3e Yield 89 %. [a]D25 = -1.5 (c 0.1, CH3OH). IR (KBr):

3,045.8 (–CH= str), 2,957.1 (NH– str), 2,857.2 (glucosidic

C–H str), 1,775.6 (C=O of O-acetyl gps of glycone moiety),

1,718.2 (C=O str), 1,645.2 (C=N str), 1,091.0 (C–O–C,

ether linkage). 1H-NMR (400 MHz, DMSO-d6): d 12.7 (s,

10-H, N–H), 7.49 (s, 2-H, CH), 6.37–7.01 (m, 12H, Ar–H),

4.84–5.05 (m, 3H, 200,300,400-H), 4.78 (d, 1H, 100-H, ano-

meric proton), 4.41 (dd, 1H, 500-H), 3.87–4.29 (m, 2H, 600-H), 3.71 (s, 3H, OCH3), 2.01, 2.01, 2.00, 1.97 (s, 3H, OAc).13C NMR (100 MHz, DMSO-d6): 174.8 (s, C-4, C=O),

170.0 (s, C-atoms of Acetyl C = O), 164.1 (s, C-7), 158.7

(s, C-2), 157.5 (s, C-9), 135.4 (s, C-20), 131.0 (s, C-5),

128.9 (s, C-40,C-50), 118.9 (s, C-3), 115.9 (s, C-10), 109.7

(s, C-6), 103.1 (s, C-8), 101.9 (s, C-100, anomeric C-atom),

114.5–164.5 (aromatic 12C-atom), 75.1 (s, C-500), 71.9 (s,

C-200), 71.3 (s, C-300), 71.1 (s, C-400), 66.1 (s, C-600), 56.1 (s,

C-atom of OCH3), 21.4 (s, C-atom, CH3 of acetyl group).

EI-MS: m/z (%) 741 (M?, 21), 410 (100), 136 (11), 91 (29).

Anal. Calcd for C39H38N2O13: C, 63.24; H, 4.90; N, 3.78.

Found: C, 63.21; H, 4.89; N, 3.77(%).

3f Yield 75 %. [a]D25 = -2.4 (c 0.1, CH3OH). IR (KBr):

3,045.9 (–CH= str), 2,934.9 (NH– str), 2,858.6 (glucosidic

C–H str), 1,767.6 (C=O of O-acetyl gps of glycone moiety),

1,717.0 (C=O str), 1,631.2 (C=N str), 1,074.5 (C–O–C,

ether linkage). 1H-NMR (400 MHz, DMSO-d6): d 12.1 (s,

10-H, N–H), 7.49 (s, 2-H, CH), 6.44–7.01 (m, 11H, Ar–H),

4.81–4.99 (3H, m, 200,300,400-H), 4.77 (d, 1H, 100-H, ano-

meric proton), 4.41 (dd, 1H, 500-H), 3.84–4.20 (m, 2H, 600-H), 2.04, 2.01, 2.00, 1.98 (s, 3H, OAc). 13C NMR

(100 MHz, DMSO-d6): 175.1 (s, C-4, C=O), 171.0 (s,

C-atoms of Acetyl C=O), 163.7 (s, C-7), 159.0 (s, C-2),

158.2 (s, C-9), 135.8 (s, C-20), 131.6 (s, C-5), 128.9 (s,

C-40,C-50), 119.0 (s, C-3), 115.8 (s, C-10), 109.8 (s, C-6),

103.4 (s, C-8), 101.7 (s, C-100, anomeric C-atom), 125–135

(aromatic 12C-atom), 74.9 (s, C-500), 73.1 (s, C-200), 71.4 (s,

C-300), 71.1 (s, C-400), 66.0 (s, C-600), 21.4 (s, C-atom, CH3

of acetyl group). EI-MS: m/z (%) 780 (M?, 18), 449 (100),

136 (27), 91 (19). Anal. Calcd for C38H34N2O12Cl2: C,

58.55; H, 4.14; N, 3.59. Found: C, 58.54; H, 4.10; N,

3.55(%).

General procedure for the preparation of compounds 4

The mixture of 2,3,4,6-tetra-O-acetyl-7-O-b-D-glucopyr-

anosyloxy-3-(4,5-disubstituted imidazol-2-yl)-4H-chromen-

4-one (69 mg, 0.109 mmol), dry methanol (2 mL), and

anhydrous zinc acetate (23 mg, 0.126 mmol) was refluxed

for 7 h. After cooling at room temperature, it was filtered

through cation-exchanged resin; the solvent was removed

under vacuum. The residue was purified by silica gel

chromatography (CHCl3, MeOH, 12:1 v/v) to get titled

compound.

4a Yield 90 %. [a]D25 = -9.1 (c 0.1, CH3OH). IR (KBr):

3,412.0 (br, OH peak of carbohydrate residue), 2,928.6

(NH– str), 2,852.9 (glucosidic C–H str), 1,599.4 (C=O str),

1,445.2 (C=N str), 1,089.5 (C–O–C, ether linkage). 1H

NMR (400 MHz, DMSO-d6): d 12.7 (s, 10-H, N–H), 7.51

(s, 2-H, CH), 7.06 (d, 40-H, 50-H) (CH), 6.37-6.55 (m, 3H,

Ar–H), 5.74 (d, 100-H, anomeric proton), 3.44–4.02 (m, 6H,

b-D-glucopyranosyl ring). 13C NMR (100 MHz, DMSO-

d6): 174.7 (s, C-4, C=O), 163.8 (s, C-7), 159.6 (s, C-2),

158.1 (s, C-9), 136.1 (s, C-20), 130.8 (s, C-5), 127.8 (s,

C-40,C-50), 118.2 (s, C-3), 116.2 (s, C-10), 109.9 (s, C-6),

106.0 (s, C-100, anomeric C-atom), 104.0 (s, C-8), 82.1 (s,

C-500), 77.6 (s, C-300), 74.9 (s, C-200), 73.1 (s, C-400), 64.0 (s,

C-600). EI-MS: m/z (%) 391 [(M ? 1)?, 10], 228 (100), 136

(15), 91 (25). Anal. Calcd for C18H16N2O8: C, 55.39; H,

4.65; N, 7.18. Found: C, 55.35; H, 4.66; N, 7.16(%).

4b Yield 91 %. [a]D25 = -10.1 (c 0.1, CH3OH). IR

(KBr): 3,445.8 (br, OH peak of carbohydrate residue),

2,957.6 (NH– str), 2,855.6 (glucosidic C–H str), 1,597.5

(C=O str), 1,414.2 (C=N str), 1,091.5 (C–O–C, ether

linkage). 1H NMR (400 MHz, DMSO-d6): d 13.2 (s, 10-H,

N–H), 7.56 (s, 2-H, CH), 6.41-6.49 (m, 3H, Ar–H), 5.69 (d,

100-H, anomeric proton), 3.45–4.05 (m, 6H, b-D-glucopyr-

anosyl ring), 2.34 (s, 40-H, CH3), 2.19 (s, 50-H, CH3). 13C

NMR (100 MHz, DMSO-d6): 176.0 (s, C-4, C=O), 163.5

(s, C-7), 159.6 (s, C-2), 158.1 (s, C-9), 135.6 (s, C-20),132.1 (s, C-40,C-50), 131.1 (s, C-5), 118.0 (s, C-3), 115.1 (s,

C-10), 109.3 (s, C-6), 105.0 (s, C-100, anomeric C-atom),

103.5 (s, C-8), 81.1 (s, C-500), 77.7 (s, C-300), 75.9 (s, C-200),73.0 (s, C-400), 65.8 (s, C-600), 11.9 (s, CH3 of C-40,C-50).EI-MS: m/z (%) 419 [(M ? 1)?, 7], 256 (100), 163 (18),

136 (28), 91 (16). Anal. Calcd for C20H20N2O8: C, 57.41;

H, 5.30; N, 6.70. Found: C, 57.37; H, 5.27; N, 6.67(%).

Med Chem Res

123

4c Yield 96 %. [a]D25 = –15.5 (c 0.1, DMSO). IR (KBr):

3,400.3 (br, OH peak of carbohydrate residue), 2,925.1

(NH– str), 2,854.1 (glucosidic C–H str), 1,591.9 (C=O str),

1,404.2 (C=N str), 1,070.9 (C–O–C, ether linkage) and

688.5 (benzene monosubstituted); 1H NMR (400 MHz,

DMSO-d6): d 12.7 (s, 10-H, NH), 7.48 (s, 2-H, CH), 7.11 (s,

50-H, CH), 6.43-6.99 (m, 8H, Ar–H), 5.85 (d, 100-H, ano-

meric proton), 3.41–4.00 (m, 6H, b-D-glucopyranosyl ring).13C NMR (100 MHz, DMSO-d6): 176.2 (s, C-4, C=O),

164.7 (s, C-7), 159.1 (s, C-2), 157.7(s, C-9), 136.4 (s, C-20),131.0 (s, C-5), 129.2 (s, C-40), 127.0–133.5 (aromatic 6C-

atom), 121.4 (C-50), 119.4 (s, C-3), 114.9 (s, C-10), 109.1

(s, C-6), 105.4 (s, C-100, anomeric C-atom), 103.1 (s, C-8),

81.2 (s, C-500), 77.0 (s, C-300), 75.1 (s, C-200), 73.9 (s, C-400),65.7 (s, C-600). EI-MS: m/z (%) 467 [(M ? 1)?, 4], 304

(100), 227 (20), 163 (21), 136 (18), 91 (30), 77 (18). Anal.

Calcd for C24H20N2O8: C, 60.57; H, 4.77; N, 4.41. Found:

C, 60.54; H, 4.76; N, 4.36(%).

4d Yield 92 %. [a]D25 = -11.9 (c 0.1, DMSO). IR

(KBr): 3,428.2 (br, OH peak of carbohydrate residue),

2,929.1 (NH– str), 2,857.9 (glucosidic C–H str), 1,597.0

(C=O str), 1,428.7 (C=N str), 1,100.4 (C–O–C, ether

linkage). 1H NMR (400 MHz, DMSO-d6): d 11.8 (s, 10-H,

N–H), 7.59 (s, 2-H, CH), 6.50–7.05 (m, 13H, Ar–H), 5.80

(d, 100-H, anomeric proton), 3.43–4.08 (m, 6H, b-D-gluco-

pyranosyl ring). 13C NMR (100 MHz, DMSO-d6): 176.1 (s,

C-4, C = O), 164.5 (s, C-7), 160.2 (s, C-2), 157.1 (s, C-9),

136.5 (s, C-20), 130.9 (s, C-5), 129.6 (s, C-40, C-50), 127.4-

133.9 (aromatic 12C-atom), 118.9 (s, C-3), 115.1 (s, C-10),

109.5 (s, C-6), 106.2 (s, C-100, anomeric C-atom), 104.1 (s,

C-8), 81.4 (s, C-500), 77.2 (s, C-300), 75.2 (s, C-200), 73.9 (s,

C-400), 64.9 (s, C-600). EI-MS: m/z (%) 542 (M?, 9), 379

(100), 227 (11), 163 (41), 136 (19), 91 (21), 77 (20). Anal.

Calcd for C30H24N2O8: C, 64.22; H, 4.82; N, 3.94. Found:

C, 64.19; H, 4.80; N, 3.90(%).

4e Yield 89 %. [a]D25 = -9.8 (c 0.1, DMSO). IR (KBr):

3,410.8 (br, OH peak of carbohydrate residue), 2,943.9

(NH– str), 2,855.5 (glucosidic C–H str), 1,593.4 (C=O

str), 1,415.2 (C=N str), 1,098.6 (C–O–C, ether linkage).1H NMR (400 MHz, DMSO-d6): d 12.9 (s, 10-H, N–H),

7.51 (s, 2-H, CH), 6.39–7.08 (m, 12H, Ar–H), 5.54 (d, 100-H, anomeric proton), 3.45–4.08 (m, 6H, b-D-glucopyran-

osyl ring), 3.70 (s, 3H, OCH3). 13C NMR (100 MHz,

DMSO-d6): 176.1 (s, C-4, C=O) 163.8 (s, C-7), 158.8 (s,

C-2), 157.4 (s, C-9), 136.1 (s, C-20), 131.4 (s, C-5), 129.1

(s, C-40,C-50), 118.1 (s, C-3), 115.3 (s, C-10), 115-164

(aromatic 12C-atom), 110.1 (s, C-6), 106.1 (s, C-100,anomeric C-atom), 103.5(s, C-8), 81.1 (s, C-500), 78.1 (s,

C-300), 74.7 (s, C-200), 73.1 (s, C-400), 64.6 (s, C-600), 56.0

(s, C-atom of OCH3). EI-MS: m/z (%) 573 [(M ? 1)?,

11], 410 (100), 163 (29), 91 (19). Anal. Calcd for

C31H26N2O8: C, 63.03; H, 4.93; N, 4.89. Found: C, 65.01;

H, 4.94; N, 4.88(%).

4f Yield 85 %. [a]D25 = -12.4 (c 0.1, DMSO). IR (KBr):

3,454.0 (br, OH peak of carbohydrate residue), 2,927.9

(NH– str), 2,851.7 (glucosidic C–H str), 1,590.6 (C=O str),

1,419.9 (C=N str), 1,094.6 (C–O–C, ether linkage). 1H

NMR (400 MHz, DMSO-d6): d 12.6 (s, 10-H, N–H), 7.55

(s, 2-H, CH), 6.40–7.01 (m, 11H, Ar–H), 5.68 (d, 100-H,

anomeric proton), 3.41–4.04 (m, 6H, b-D-glucopyranosyl

ring). 13C NMR (100 MHz, DMSO-d6): 176.1 (s, C-4,

C=O), 165.1 (s, C-7), 159.0 (s, C-2), 158.2 (s, C-9), 135.6

(s, C-20), 130.9 (s, C-5), 129.0 (s, C-40,C-50) 126.5–134.5

(aromatic 12C-atom), 117.8 (s, C-3), 115.1 (s, C-10), 109.9

(s, C-6), 106.2 (s, C-100, anomeric C-atom), 104.3 (s, C-8),

82.4 (s, C-500), 77.2 (s, C-300), 75.8 (s, C-200), 73.1 (s, C-400),64.1 (s, C-600). EI-MS: m/z (%) 612 [(M ? 1)?, 9], 449

(100), 163 (19), 91 (23). Anal. Calcd for C30H22N2O8Cl2:

C, 58.93; H, 3.96; N, 4.58. Found: C, 58.90; H, 3.95; N,

4.55(%).

Biological assays

Antibacterial assay

The synthesized compounds 4a–f were screened for their

in vitro antibacterial activity against E. coli, K. aerogens, S.

aureus, and B. substilis by the cup-plate diffusion method.

The test compounds were dissolved in methanol at a con-

centration of 100 lg/mL by using standard ciprofloxacin

and sulphacetamide (100 lg/mL) for bacteria. The zone of

inhibition after 24 h of incubation at 37 �C was compared

with standard drugs.

Antifungal activity

Compounds 4a–f was also screened at 100 lg/mL concen-

tration in methanol against A. niger and C. albicans for its

antifungal activity by the cup-plate diffusion method. The

zone of inhibition after 7 days at 20 �C was compared with

standard drugs gentamycin and clotrimazole (100 lg/mL).

Minimum inhibitory concentration (MIC lg/mL)

The MICs of the chemical compounds assays were carried

out as described by Clause (1989). The minimum inhibi-

tory concentrations 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.

Antioxidant activity

In vitro free radical scavenging activities of 4a–f were

evaluated by DPPH assay method. This method is based on

Med Chem Res

123

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 these test tubes, methanolic

solution of different test solutions (1 mg/mL) was 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 516 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 Control� Testð Þ=Control½ �� 100:

The results of antimicrobial (antibacterial and antifungal)

activity and antioxidant activity are shown in Table 4.

Acknowledgments The authors are thankful to the Director, SAIF,

Chandigarh, and the Head, Department of Chemistry, IIT-Pawai,

Mumbai, for providing necessary spectral analysis, and the Head,

Department of Chemistry, R. T. M. Nagpur University, Nagpur, for

providing necessary laboratory facilities. Prof. Siham Lahsasni would

like to extend his sincere appreciation to the Deanship of Scientific at

King Saud University for its funding of this computational research

through the Research Group Project No. RGP-VPP-222.

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