Synthesis and antibacterial activity of some new 2,3-dimethoxy-3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl)chromanones

Article abstract of DOI:10.1016/j.ejmech.2008.03.028

Seven new 2,3-dimethoxy-3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl)chromanones (5) have been synthesized by the oxidation of 3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl)chromones (4) with iodobenzene diacetate in methanol. The structures of compounds 5 were es

Full text of DOI:10.1016/j.ejmech.2008.03.028

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European Journal of Medicinal Chemistry 44 (2009) 1763e1767
http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and antibacterial activity of some new 2,3-dimethoxy-3-
hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl)chromanones
a
b
Om Prakash a, , Rajesh Kumar , Rakesh Sehrawat
*
a Department of Chemistry, Kurukshetra University, Kurukshetra 136 119, India
b Department of Biotechnology, Kurukshetra University, Kurukshetra 136 119, India
Received 14 December 2007; received in revised form 26 March 2008; accepted 27 March 2008
Available online 4 April 2008
Abstract
Seven new 2,3-dimethoxy-3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl)chromanones (5) have been synthesized by the oxidation of 3-hydroxy-
2-(1-phenyl-3-aryl-4-pyrazolyl)chromones (4) with iodobenzene diacetate in methanol. The structures of compounds 5 were established by the
combined use of 1H NMR, IR and mass spectra. All the seven compounds (5) were tested in vitro for their antibacterial activity against Gram-
positive bacteria namely, Staphylococcus aureus, Staphylococcus epidermidis and Bacillus pumilus and two Gram-negative bacteria namely,
Salmonella typhi and Pseudomonas aeruginosa. Three compounds, 5d, 5f and 5g, have displayed antibacterial activity comparable to the
commercial antibiotics, Linezolid, Cefaclor and Cefuroxime axetial.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Hypervalent iodine; Iodobenzene diacetate; 2,3-Dimethoxy-3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl)chromanones; 3-Hydroxy-2-(1-phenyl-3-aryl-4-
pyrazolyl)chromones; Antibacterial activity
1. Introduction
interesting applications in heterocyclic compounds especially
flavonoids. Among the various such applications, one notewor-
thy example is the oxidation of flavonols with [hydroxy(tosylox-
y)iodo]benzene (HTIB) offering an efficient and convenient
synthesis of 2,3-dimethoxy-3-hydroxyflavanones (Eq. (1)) [22].
Flavonoids are a group of natural products present in a wide
variety of plants. They are found in seeds, citrus fruits, olive oil,
tea and red wine and are commonly consumed with the human
diet [1,2]. Flavonoids exhibit a broad range of biological activ-
ities, including antiviral, antiinflammatory, antioxidant, antial-
lergic, hepatoprotective, antithrombotic and antitumoral
actions [3e5]. Furthermore, these compounds are used in bacte-
riology, pharmacology and medicine due to their bactericidal
activities [6]. On the other hand, substituted pyrazoles also
exhibit a broad spectrum of biological activities such as antidi-
abetic [7], antibacterial [8e10], antimicrobial [11e14] and her-
bicidal [15,16]. The use of hypervalent iodine reagents such as
iodobenzene diacetate (IBD) [17e19], [hydroxy(tosyloxy)-
iodo]benzene (HTIB; Koser’s reagent) [20,21], etc. find
OMe
O
Ar
O
Ar
HTIB
(1)
MeOH
OH
OH
OMe
O
O
A literature survey revealed that the title compounds 2,3-di-
methoxy-3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl)chroma-
nones (5) remain unknown. These observations, coupled with
the diverse biological properties associated with pyrazole and
flavanone derivatives, prompted us to study the scope of the
synthetic route outlined in Eq. (1) on the oxidation of 2-pyra-
zolyl analogues of flavonol (4). There has been a particular
interest in the synthesis of flavonoids with a pyrazole ring at
position C-2 to find new and more potent biological activities
* Corresponding author.
E-mail addresses: dromprakash50@rediffmail.com (O. Prakash),
rajesh_chem12a@rediffmail.com (R. Kumar).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.03.028

1764
O. Prakash et al. / European Journal of Medicinal Chemistry 44 (2009) 1763e1767
Ph
N
[23]. We report herein synthesis of 5ae5g by the oxidation
of 4ae4g using iodobenzene diacetate (IBD) in methanol
with an expectation to find new and more potent antibacterial
agents.
Ph
N
MeOH
..
N
N
O
O
Ar
Ar
Ph
O
I
OH
..
O
OMe
2. Results and discussion
O
4
A
Ph
OMe
I
2.1. Chemistry
OMe
The starting material 2-pyrazolyl analogues of flavonol 4
needed for the synthesis of 5 were prepared by the cyclization
of pyrazolyl analogues of o-hydroxychalcone 3 with hydrogen
peroxide (H2O2) in KOHeMeOH from our previous work
involving Algar Flynn Oymanda (AFO) reaction [23]. The re-
action of 4a was carried out by treatment with 1.1 equiv of
IBD in methanol by stirring at room temperature for 15e
20 min. Usual work-up of the reaction afforded the pure crys-
talline product 5a in 78% yield. Encouraged by the feasibility
of our strategy for 5a, we studied oxidation of a wide range of
substituted 4be4g under similar conditions. This IBD medi-
ated oxidative approach worked nicely to give the desired
products 5be5g in all cases (Scheme 1).
Ph
Ph
N
N
OMe
OMe
O
N
O
N
Ar
O
Ar
OH
OMe
O
O
..
MeOH
5
B
Scheme 2.
2.2. Antibacterial activity
All the seven compounds (5ae5g) were tested in vitro for
their antibacterial activity against three Gram-positive bacteria
namely, Staphylococcus aureus (MTCC 3160), Staphylococcus
epidermidis (MTCC 2639), and Bacillus pumilus (MTCC
1456), and two Gram-negative bacteria namely, Salmonella ty-
phi (MTCC 733) and Pseudomonas aeruginosa (MTCC 3541)
(Tables 1 and 2). Three of these compounds (5d, 5f and 5g) ex-
hibited good antibacterial activity against both Gram-positive
and Gram-negative bacteria. All of the seven compounds
showed activity against Gram-positive bacteria namely S. au-
reus (MTCC 3160). Compound 5g showed maximum antibacte-
rial activity against S. aureus (MIC 2 mg/ml) and S. epidermidis
(MIC 8 mg/ml). It also displayed inhibitory activity against B.
The structures of all new compounds 5ae5g were con-
firmed by their spectral (IR, 1H NMR and mass) and elemental
analytical data. The IR spectra of compounds 5ae5g exhibited
characteristic absorption band at 1690e1700 cmꢀ1 and 3410e
3420 cmꢀ1 due to carbonyl and hydroxyl functional groups,
1
respectively. The H NMR spectra of all the products 5ae5g
showed two characteristic singlets due to C(2) and C(3)
methoxy group protons at d 3.00 and d 3.15 present. The
C(3)eOH proton appeared as broad singlet at d 4.6e
4.8 ppm and C(5)eH in pyrazole ring appeared as singlet at
d 8.30. Other protons appeared in the aromatic regions.
The conversion of 4 / 5 probably proceeds accordingly to
Scheme 2 which is analogous to earlier reports [24].
Ph
Ph
OH
OH
N
N
N
KOH-MeOH
THF
+
N
CH3
Ar
CHO
O
Ar
O
1
2
3
H2O2
Ph
Ph
N
N
N
OMe
O
N
O
IBD
Ar
MeOH
OH
Ar
OH
OMe
O
O
5
4
Ar = a, C6H5; b, 4-CH3C6H4; c, 4-OCH3C6H4, d, 4-ClC6H4;
e, 4-BrC6H4; f, 4-FC6H4; g, 4-NO2C6H4
Scheme 1.

O. Prakash et al. / European Journal of Medicinal Chemistry 44 (2009) 1763e1767
1765
Table 1
In vitro antibacterial activity of 5ae5g by using agar diffusion assay technique
4. Experimental
Compound
Diameter of zone of growth inhibitiona (mm)
Melting points were determined in open capillaries with
electrical melting point apparatus and are uncorrected. The
IR spectra were obtained with a Buck Scientific IR M-500
Sa
Se
Bp
St
Pa
5a
5b
18.15
16.10
17.96
20.35
10.26
22.99
25.98
8.11
e
e
e
e
1
spectrophotometer. The H NMR spectra were recorded on
12.64
e
16.69
e
e
e
e
5c
5d
e
e
e
e
e
14.67
e
a Bruker (300 MHz) spectrometer using tetramethylsilane as
an internal standard. All the new compounds gave satisfactory
analytical results (within 0.4 of the theoretical values). The
starting material 2-pyrazolyl analogues of flavanol were avail-
able from our previous work involving AFO reaction of pyra-
zolyl analogues of o-hydroxychalcone [23].
5e
e
e
5f
5g
12.11
18.52
7.17
10.11
15.77
7.07
18.16
20.58
7.78
22.16
16.59
7.23
DMSO
e No activity.
a
Mean of three replicates. Sa, S. aureus (MTCC 3160); Se, S. epidermidis
(MTCC 2639); Bp, B. pumilus (MTCC 1456); St, S. typhi (MTCC 733); Pa,
P. aeruginosa (MTCC 3541).
4.1. 2,3-Dimethoxy-3-hydroxy-2-(1-phenyl-3-aryl-
4-pyrazolyl)chromanones (5ae5g)
General procedure. To a suspension of 4 (1.0 mmol) in meth-
anol (20 ml) was added iodobenzene diacetate (1.1 mmol) and
the mixture was stirred at room temperature for 15e20 min.
All the reactants dissolved and a colorless crystalline product
separated out. The solid product was filtered and washing
with cold methanol (5e10 ml) gave almost pure products 5.
The products 5 were recrystallized with methanol.
The physical, analytical and spectral data of 3-hydroxy-2-
(1-phenyl-3-aryl-4-pyrazolyl)chromanones 5ae5g are given
below.
pumilus (MIC 32 mg/ml), S. typhi (MIC 8 mg/ml) and P. aerugi-
nosa (MIC 8 mg/ml). Compound 5f was found to be effective
against S. aureus (MIC 4 mg/ml). It also inhibited the growth
of S. typhi and P. aeruginosa at MIC 8 mg/ml. Compound 5d
inhibited the growth of S. aureus at 8 mg/ml, S. epidermidis at
16 mg/ml and P. aeruginosa at 32 mg/ml. The antibacterial activ-
ity of these compounds was also compared with three commer-
cial antibiotics namely Linezolid, Cefaclor and Cefuroxime
axetial. Three compounds (5d, 5g and 5f) showed comparable
activity as displayed in Tables 1 and 2.
4.1.1. 2,3-Dimethoxy-3-hydroxy-2-(1,3-diphenyl-4-
pyrazolyl)chromanone (5a)
Yield: 78%; mp 146e148 ꢁC; IR (nmax, in KBr): 3418 cmꢀ1
(eOH str.), 1697 cmꢀ1 (C]O str.); 1H NMR (CDCl3,
300 MHz, d): 3.15 (s, 3H, OCH3), 3.00 (s, 3H, OCH3), 4.89 (s,
1H, OH), 8.32 (s, 1H), 7.86e7.96 (m, 5H), 7.33e7.41 (m,
7H), 7.13e7.16 (m, 1H), 6.80 (d, 1H, J ¼ 7.8 Hz). Anal. Calcu-
lated for C26H22N2O5: C 70.59, H 4.98, N 6.33. Found: C 70.95,
H 4.69, N 6.55; MS: m/z, Mþ 442.
3. Conclusion
We described herein an efficient and convenient synthesis
of new compounds 5ae5g, thereby emphasizing the increas-
ing utility of organoiodine(III) mediated methods. The results
on the antibacterial activity are also encouraging as out of
seven compounds tested, three compounds (5d, 5f and 5g)
showed good antibacterial activity as displayed in Tables 1
and 2. A comparison of antibacterial activity of these com-
pounds with that of three commercial antibiotics namely Line-
zolid, Cefaclor and Cefuroxime axetil indicated that
compound 5g show very good activity.
4.1.2. 2,3-Dimethoxy-3-hydroxy-2-(1-phenyl-3-( p-tolyl)-
4-pyrazolyl)chromanone (5b)
Yield: 75%; mp 184e186 ꢁC; IR (nmax, in KBr): 3413 cmꢀ1
(eOH str.), 1697 cmꢀ1 (C]O str.);1H NMR (CDCl3, 300 MHz,
d): 2.41 (s, 3H, CH3), 3.14 (s, 3H, OCH3), 3.00 (s, 3H, OCH3),
4.50 (s, 1H, OH), 8.32 (s, 1H), 7.21 (d, 2H, J ¼ 8.1 Hz), 7.59
(d, 2H, J ¼ 8.1 Hz), 7.84e7.91 (m, 5H), 7.32e7.37 (m, 3H),
6.87 (d, 1H, J ¼ 8.4 Hz). Anal. Calculated for C27H24N2O5: C
71.05, H 5.26, N 6.14. Found: C 70.82, H 5.32, N 6.04; MS:
m/z, Mþ 456.
Table 2
MIC of 5ae5g against test bacteria by using agar dilution assay
Compound
MICa (mg/ml)
Sa
Se
Bp
St
Pa
5a
5b
16
32
16
8
>64
64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
8
>64
>64
>64
32
4.1.3. 2,3-Dimethoxy-3-hydroxy-2-(1-phenyl-3-( p-anisyl)-
4-pyrazolyl)chromanone (5c)
5c
5d
>64
16
Yield: 72%; mp 151e153 ꢁC; IR (nmax, in KBr): 3420 cmꢀ1
(eOH str.), 1699 cmꢀ1 (C]O str.); 1H NMR (CDCl3,
300 MHz, d): 3.78 (s, 3H, OCH3), 3.05 (s, 3H, OCH3), 2.90 (s,
3H, OCH3), 4.82 (s, 1H, OH), 8.29 (s, 1H), 8.4 (d, 3H,
J ¼ 8.7 Hz), 7.75 (d, 2H, J ¼ 8.1 Hz), 6.79 (d, 2H, J ¼
8.1 Hz), 6.85 (d, 1H, J ¼ 9.0 Hz), 7.37e7.48 (m, 3H), 7.20e
7.25 (m, 1H), 7.02e7.06 (m, 1H). Anal. Calculated for
5e
64
4
>64
64
>64
8
5f
5g
2
8
32
4
8
16
Linezolid
Cefaclor
Cefuroxime axetial
4
<16
2
8
<16
<16
>16
2
8
>16
8
8
8
8
a
Mean of three replicates.

1766
O. Prakash et al. / European Journal of Medicinal Chemistry 44 (2009) 1763e1767
C27H24N2O6: C 68.64, H 5.08, N 5.93. Found: C 68.70, H 4.97,
N 6.02; MS: m/z, Mþ 472.
and distilled water 1000 ml, adjusted to pH 7.3), were used for
the biological assays.
4.1.4. 2,3-Dimethoxy-3-hydroxy-2-(1-phenyl-3-( p-chloro-
phenyl)-4-pyrazolyl)chromanone (5d)
5.2. Test microorganisms
Yield: 78%; mp 159e160 ꢁC; IR (nmax, in KBr): 3406 cmꢀ1
(eOH str.), 1697 cmꢀ1 (C]O str.); 1H NMR (CDCl3,
300 MHz, d): 3.13 (s, 3H, OCH3), 3.00 (s, 3H, OCH3), 4.91
(s, 1H, OH), 8.30 (s, 1H), 7.92e7.96 (m, 3H), 7.84 (d, 2H,
J ¼ 8.1 Hz), 7.49 (d, 2H, J ¼ 8.1 Hz), 7.31e7.38 (m, 4H),
7.12e7.17 (m, 1H), 6.85 (d, 1H, J ¼ 8.4 Hz). Anal. Calculated
for C26H21N2O5Cl: C 65.55, H 4.41, N 5.88. Found: C 65.37,
H 4.32, N 5.98; MS: m/z, Mþ 476.
Three Gram-positive bacteria S. aureus (MTCC 3160), S.
epidermidis (MTCC 2639), and B. pumilus (MTCC 1456),
and two Gram-negative bacteria S. typhi (MTCC 733) and P.
aeruginosa (MTCC 3541) were used for the biological assays.
5.3. Primary screening
Primary screening of seven compounds (5ae5g) was done
by the agar diffusion assay technique. Twenty-four-hour-old
bacterial cultures of all test microorganisms were used as in-
oculum, which was adjusted to 0.5 McFarland Standard, that
is, 1.5 ꢂ 108 CFU/ml [25]. The stock solutions of all the test
compounds (1 mg/ml) were prepared by dissolving 1 mg of
the test compound in DMSO (1 ml). Linezolid, Cefaclor, Ce-
furoxime axetil, and DMSO were used as positive and negative
controls, respectively.
Twenty milliliters of molten and cooled MHA and 500 ml of
each test bacterial culture were mixed (separate flasks were
used for each bacterial culture) and poured in sterilized and
labeled Petri plates. The wells of 6 mm were punched in the
solidified Petri plates aseptically. Fifty microliters from stock
solutions of all the compounds as well as controls was added
to each well of labeled Petri plates and incubated at 35 ꢁC for
24 h. The diameter of the zone of growth inhibition around
each well was measured after incubation using a Vernier
Caliper.
4.1.5. 2,3-Dimethoxy-3-hydroxy-2-(1-phenyl-3-( p-bromo-
phenyl)-4-pyrazolyl)chromanone (5e)
Yield: 76%; mp 179e180 ꢁC; IR (nmax, in KBr): 3412 cmꢀ1
(eOH str.), 1693 cmꢀ1 (C]O str.); 1H NMR (CDCl3,
300 MHz, d): 3.04 (s, 3H, OCH3), 2.92 (s, 3H, OCH3), 4.82
(s, 1H, OH), 8.21 (s, 1H), 7.76e7.86 (m, 5H), 7.39e7.44
(m, 3H), 7.52 (d, 2H, J ¼ 8.1 Hz), 7.27 (d, 2H, J ¼ 8.1 Hz),
6.77 (d, 1H, J ¼ 8.4 Hz). Anal. Calculated for C26H21N2O5Br:
C 60.0, H 4.03, N 5.38. Found: C 60.21, H 3.98, N 5.52; MS:
m/z, Mþ 520.
4.1.6. 2,3-Dimethoxy-3-hydroxy-2-(1-phenyl-3-( p-fluoro-
phenyl)-4-pyrazolyl)chromanone (5f)
Yield: 80%; mp 162e164 ꢁC; IR (nmax, in KBr): 3412 cmꢀ1
(eOH str.), 1693 cmꢀ1 (C]O str.); 1H NMR (CDCl3,
300 MHz, d): 3.12 (s, 3H, OCH3), 3.01 (s, 3H, OCH3), 4.92
(s, 1H, OH), 8.31 (s, 1H), 7.90e7.99 (m, 3H), 7.85 (d, 2H,
J ¼ 8.1 Hz), 7.56 (d, 2H, J ¼ 8.1 Hz), 7.34e7.42 (m, 4H),
7.10e7.17 (m, 1H), 6.81 (d, 1H, J ¼ 8.4 Hz). Anal. Calculated
for C26H21N2O5F: C 67.82, H 4.56, N 6.09. Found: C 67.68, H
4.49, N 6.18; MS: m/z, Mþ 460.
5.4. Minimum inhibitory concentration
The minimum inhibitory concentration (MIC) is the lowest
concentration of the antimicrobial agent that prevents the de-
velopment of visible growth after overnight incubation [26].
MIC of compounds against Gram-positive and Gram-negative
test bacteria was determined by the method of NCCLS [27].
All the test cultures were streaked on SCDA and incubated
overnight at 37 ꢁC. Turbidity of all the bacterial cultures was
adjusted to 0.5 McFarland Standard by preparing bacterial sus-
pension of 3e5-well isolated colonies of the same morpholog-
ical type selected from an agar plate culture. The cultures were
further diluted 10-fold to get an inoculum size of 1.2 ꢂ 107
CFU/ml. Stock solution of 4 mg/ml of each compound was
prepared in DMSO and was appropriately diluted to get a final
concentration of 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, and 0.12 mg/
ml. Standard antibiotics (Linezolid, Manufacturer e Alembic,
Batch no. 6893002; Cefaclor, Manufacturer e Galaxo, Batch
no. 1305911; Cefuroxime axetial, Manufacturer e Galaxo,
Batch no. HD-313) were also diluted in the same manner.
Three hundred and twenty microliters of each dilution was
added to 20 ml molten and cooled MHA (separate flasks
were taken for each dilution). After thorough mixing, the me-
dium was poured in sterilized Petri plates. The test bacterial
cultures were spotted in a predefined pattern by ascetically
4.1.7. 2,3-Dimethoxy-3-hydroxy-2-(1-phenyl-3-( p-nitro-
phenyl)-4-pyrazolyl)chromanone (5g)
Yield: 72%; mp 189e191 ꢁC; IR (nmax, in KBr): 3412 cmꢀ1
(eOH str.), 1693 cmꢀ1 (C]O str.); 1H NMR (CDCl3,
300 MHz, d): 3.12 (s, 3H, OCH3), 2.92 (s, 3H, OCH3), 4.82
(s, 1H, OH), 8.32 (s, 1H), 8.33 (d, 2H, J ¼ 8.1 Hz), 8.10 (d,
2H, J ¼ 8.1 Hz), 7.75e7.69 (m, 6H), 7.21e7.29 (m, 2H);
6.89 (d, 1H, J ¼ 8.4 Hz). Anal. Calculated for C26H21N3O7:
C 64.07, H 4.31, N 8.62. Found: C 63.95, H 4.45, N 8.47;
MS: m/z, Mþ 487.
5. In vitro biological assay
5.1. Medium
Two solid media, namely MullereHinton agar (MHA; beef
infusion 300 g/L, casein acid hydrolysate 17.5 g/L, starch
1.5 g/L, agareagar 17 g/L, and distilled water 1000 ml, adjusted
to pH 7.4) and soyabean casein digest agar (SCDA; casein enzy-
matic hydrolysate 17.0 g/L, papain digest of soyabean 3.0 g/L,
NaCl 5.0 g/L, dipotassium phosphate 2.5 g/L, dextrose 2.5 g/L,

O. Prakash et al. / European Journal of Medicinal Chemistry 44 (2009) 1763e1767
1767
[9] V. Kumar, R. Aggarwal, P. Tyagi, S.P. Singh, Eur. J. Med. Chem. 40
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transferring 5 ml of each bacterial culture on the surface of
solidified agar plates and incubated at 35 ꢁC for 24 h.
[10] J.L. Kane, B.H. Hirth, O. Laing, B.B. Gourlie, S. Nahill, G. Barsomiam,
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We are thankful to CSIR, New Delhi for the award of Se-
nior Research Fellowship to Rajesh Kumar. Thanks are also
due to RSIC, Lucknow, India, for providing mass and elemen-
tal analyses.
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