Synthesis and antimicrobial activity of bischalcone derivatives

Article abstract of DOI:10.1007/s00044-012-0137-4

Several bischalcones (2a-h and 5a-e) and flavones (3a-f) were synthesized and evaluated for their antimicrobial actions. Bischalcones were prepared by condensing 1,1′-(4,6-dimethyl-1,3-phenylene)diethanone (1) or 1-(5-acetyl-2,4-dimethoxyphenyl)-1-ethanone (4) with arylaldehydes. Bischalcones were cyclized in presence of iodine to give corresponding flavones (3a-f). An alternative route to synthesize the flavones consisted in preparing the diester derivatives (6a-f) of (1) with different aromatic acids, which could be converted to β-diketones followed by cyclization to give the corresponding flavones. However, all the attempts in this direction were unsuccessful and it could not be possible to proceed beyond diester stage; six diester derivatives (6a-f) were synthesized. The structures of the synthesized compounds were assigned on the basis of ¹H NMR, mass spectral data and microanalyses results. The antimicrobial screening was performed at a concentration of 100 μg/mL by cup plate method; the compounds inhibiting growth of one or more of the microorganisms were further tested for their minimum inhibitory concentration (MIC) by turbidity method. Preliminary antimicrobial results revealed that the compounds 2a-h and 3a-f were significant in their antibacterial and antifungal activities. MICs results showed that the compound 2f exhibited very good activity against E. coli, P. aeruginosa, and C. albicans with MIC-12.5 μg/mL. Similar type of activity was shown the compound 3a against S. aureus and C. albicans with MIC-12.5 μg/mL. Another compound, 3f, was active against P. aeruginosa and C. albicans with MIC-12.5 μg/mL. Methylation of the two chelated hydroxyls (5a-e) significantly reduced the activity. However, oxidative cyclization of bischalcones resulted in compounds (3a-f) which were found to be considerably active. Diesters (6a-f) were insignificant in their antimicrobial activities.

Full text of DOI:10.1007/s00044-012-0137-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0137-4
ORIGINAL RESEARCH
Synthesis and antimicrobial activity of bischalcone derivatives
•
Asif Husain Aftab Ahmad Ibraheem Ahmed I. Mkhalid
•
•
•
Ravinesh Mishra Mohd Rashid
Received: 21 November 2011 / Accepted: 31 May 2012
ꢀ Springer Science+Business Media, LLC 2012
Abstract Several bischalcones (2a–h and 5a–e) and
flavones (3a–f) were synthesized and evaluated for their
antimicrobial actions. Bischalcones were prepared by
condensing 1,10-(4,6-dimethyl-1,3-phenylene)diethanone
(1) or 1-(5-acetyl-2,4-dimethoxyphenyl)-1-ethanone (4)
with arylaldehydes. Bischalcones were cyclized in pres-
ence of iodine to give corresponding flavones (3a–f). An
alternative route to synthesize the flavones consisted in
preparing the diester derivatives (6a–f) of (1) with different
aromatic acids, which could be converted to b-diketones
followed by cyclization to give the corresponding flavones.
However, all the attempts in this direction were unsuc-
cessful and it could not be possible to proceed beyond
diester stage; six diester derivatives (6a–f) were synthe-
sized. The structures of the synthesized compounds were
and antifungal activities. MICs results showed that the
compound 2f exhibited very good activity against E. coli,
P. aeruginosa, and C. albicans with MIC-12.5 lg/mL.
Similar type of activity was shown the compound 3a
against S. aureus and C. albicans with MIC-12.5 lg/mL.
Another compound, 3f, was active against P. aeruginosa
and C. albicans with MIC-12.5 lg/mL. Methylation of the
two chelated hydroxyls (5a–e) significantly reduced the
activity. However, oxidative cyclization of bischalcones
resulted in compounds (3a–f) which were found to be
considerably active. Diesters (6a–f) were insignificant in
their antimicrobial activities.
Keywords Bischalcones ꢀ Flavone ꢀ Antibacterial ꢀ
Antifungal
1
assigned on the basis of H NMR, mass spectral data and
microanalyses results. The antimicrobial screening was
performed at a concentration of 100 lg/mL by cup plate
method; the compounds inhibiting growth of one or more
of the microorganisms were further tested for their mini-
mum inhibitory concentration (MIC) by turbidity method.
Preliminary antimicrobial results revealed that the com-
pounds 2a–h and 3a–f were significant in their antibacterial
Introduction
Over the past decades, the incidence of systemic bacterial
and fungal infections has been increasing dramatically due
to an increase in the number of immuno-compromised
hosts (Davies, 1996). Immunosuppression due to malig-
nancy, immunosuppressive therapies, HIV-infection,
broad-spectrum antimicrobial treatment and age, as well as
invasive procedures and mucosal barriers places patients at
risk for microbial infections. The increasing incidence of
resistance to a large number of antibacterial agents is
becoming a major concern (Chu et al., 1996). Currently, a
small number of antifungal agents are available, and all
have some drawbacks regarding their spectrum, toxicity,
tissue distribution, and high cost (Dupont et al., 2002;
Baddley and Moser, 2004).
A. Husain (&) ꢀ R. Mishra ꢀ M. Rashid
Department of Pharmaceutical Chemistry,
Faculty of Pharmacy, Jamia Hamdard (Hamdard University),
New Delhi 110 062, India
e-mail: drasifhusain@yahoo.com; ahusain@jamiahamdard.ac.in
A. Ahmad
KAU-Community College, King Abdul Aziz University,
Jeddah 21589, Kingdom of Saudi Arabia
I. A. I. Mkhalid
Chemistry Department, Faculty of Science, King Abdul Aziz
University, Jeddah 21589, Kingdom of Saudi Arabia
These observations place new emphasis on the need of
as well as search for alternative new and more effective
123

Med Chem Res
Synthesis of the compounds
antimicrobial agents with
a broad-spectrum activity
(Alvarez et al., 2008). Among a wide variety of compounds
that have been explored for developing pharmaceutically
important antimicrobial agents, Flavonoidal derivatives—
chalcones and bischalcones, flavanones and flavones have
played an important role (Cushnie and Lamb, 2005;
Nowakowska, 2007; Lin et al., 2002; Batovska and
Todorova, 2010; Sharma et al., 2009; Oganesyan et al.,
1988). Flavonoids have attracted considerable attention due
to their marked physiological activity and distinct func-
tions. Flavonoids form a large group of naturally occurring
organic compounds and possess wide range of pharmaco-
logical actions including antimicrobial action (Casano
et al., 2010; Liu et al., 2010; Mojzis et al., 2008; Alvim
et al., 2010; Boumendiel et al., 2009; Alcaraz et al., 2000,
pp. 5–15). Moreover, flavonoidal derivatives acquire a
special place in natural chemistry and in heterocyclic
chemistry because this system is a frequently encountered
structural motif in many pharmacologically relevant com-
pounds (Gatto et al., 2002; Sherif et al., 2008; Ashok and
Sarma, 1987, pp. 15–19).
Synthesis of 1-(5-acetyl-2,4-dimethoxyphenyl)-1-ethanone
(4)
mixture of 1,10-(4,6-dimethyl-1,3-phenylene)-
A
diethanone (1). (2.5 mmol), dimethylsulphate (5 mmol)
and anhydrous potassium carbonate (11.25 g) in dry ace-
tone (100 mL) was refluxed for 6 h. The contents were
then filtered, concentrated to a small volume and poured
onto crushed ice. A solid mass separated out which was
filtered, washed with water, dried and then crystallized
from methanol: dichloromethane mixture to give shiny
1
needles of 4. Yield 74 %; m.p. 164–166 ꢁC; Rf 0.76; H
NMR (CDCl3) d ppm: 2.61 (s, 6H, 29 –COCH3), 3.93 (s,
6H, 29 –OCH3), 6.34 (s, 1H, H-2), 8.37 (s, 1H, H-5); MS:
m/z 222 (M?), 207, 177, 175, 149; C12H14O4; Calc. C
64.85, H 6.35; Found C 64.71, H, 6.22.
Synthesis of Bischalcones (2a–i and 5a–e) (Dhar, 1981)
general procedure A mixture of 1/4 (5 mmol) in ethanol
(20 mL), aromatic aldehyde (10 mmol) and a solution of
potassium hydroxide (3 g) in distilled water (5 mL) was
stirred for 2 h at room temperature and then left overnight.
It was poured into cold water and acidified with HCl, a
solid mass separated out which was filtered, washed with
water, sodium bicarbonate solution (2 % w/v in water) and
again with water. It was crystallized from methanol to give
2a–i (it gave a violet colour with alcoholic ferric chloride
solution and a red colour with conc. sulphuric acid) and
5a–e (It gave a red colour with conc. sulphuric acid and no
colour with alcoholic ferric chloride solution).
Resorcinol is a simple and important aromatic chemical
(1,3-benzenediol) that has been chemically incorporated
into various compounds to enhance their pharmacological
profile (Soliman et al., 2005; Khan et al., 2002, 2010). In
view of these points it was considered worthwhile to study
some flavonoidal derivatives for their antimicrobial
actions.
3-(4-Chlorophenyl)-1-{5-[3-(4-chlorophenyl)-2-prope-
noyl]-2,4-dihydroxyphenyl}-2-propen-1-one (2a): Yield
61 %; m.p. 210–212 ꢁC; Rf 0.72; 1H NMR (CDCl3)
d ppm: 6.62 (s, 1H, H-30), 7.08 (d, 4H, J = 8.1 Hz, 29
H-3,5), 7.39 (d, 2H, J = 15.6 Hz, 29 H-a), 7.71 (d, 4H,
J = 8.1 Hz, 29 H-2,6), 8.04 (d, 2H, J = 15.6 Hz, 29
H-b), 8.66 (s, 1H, H-60), 13.53 (s, 2H, OH); MS: m/z 439
(M?), 327, 163, 137; C24H16Cl2O4; Calc. C 65.62, H 3.67;
Found: C 65.44, H 3.72.
Materials and methods
Chemistry
All the solvents were of LR grade and were obtained from
Merck (Mumbai, India), S.D. fine (Mumbai, India) and
CDH (New Delhi, India). Melting points are uncorrected
and were recorded in liquid paraffin bath using open end
capillaries. 1H NMR spectra were recorded on Bruker
spectropsin DPX-300 MHz in CDCl3; chemical shift (d)
values are reported in parts per million (ppm). The splitting
pattern abbreviations are as follows: s, singlet; d, doublet;
dd, double doublet; m, multiplet. Mass spectroscopic
analyses for compounds were performed on a JEOL JMS-D
300 instrument. Elemental analyses were performed on a
Perkin-Elmer 240 analyzer and were in range of 0.4 %
for each element analyzed (C, H, N). Thin-layer chroma-
tography (TLC) was carried out to monitor the reactions
using silica gel G (Merck) as stationary phase in the solvent
system-Toluene: Ethyl acetate: Formic acid (5:4:1, v/v/v);
iodine chamber, and UV lamp were used for visualization
of TLC spots.
3-(3-Chlorophenyl)-1-{5-[3-(3-chlorophenyl)-2-prope-
noyl]-2,4-dihydroxyphenyl}-2-propen-1-one (2b): Yield
58 %; m.p. 184–186 ꢁC; Rf 0.70; 1H NMR (CDCl3)
d ppm: 6.57 (s, 1H, H-30), 7.21–7.84 (m, 8H, 29 H-2,
4,5,6), 7.96 (d, 2H, J = 15.6 Hz, 29 H-a), 8.35 (d, 2H,
J = 15.6 Hz, 29 H-b), 8.61 (s, 1H, H-60), 13.58 (s, 2H,
OH); MS: m/z 439 (M?), 163, 137, 77; C24H16Cl2O4;
Calc. C 65.62, H 3.67; Found C 65.41, H 3.73.
1-{2,4-Dihydroxy-5-[3-(3,4,5-trimethoxyphenyl)-2-prope-
noyl]phenyl}-3-(3,4,5-trimethoxyphenyl) -2-propen-1-one
(2c): Yield 64 %; m.p. 190–192 ꢁC; Rf 0.73; 1H NMR
(CDCl3) d ppm: 3.97–4.01(broad s, 18H, 69 –OCH3), 6.21
(s, 2H, OH), 6.54 (s, 1H, H-30), 7.66–7.71 (m, 4H, 29
H-2,6), 7.83 (d, 2H, J = 15.3 Hz, 29 H-a), 8.27 (d, 2H,
123

Med Chem Res
J = 15.6 Hz, 29 H-b), 8.56 (s, 1H, H-60), 13.64 (s, 2H,
OH); MS: m/z 550 (M?), 326, 164, 77; C2H1Cl2O4; Calc.
C 65.45, H 5.49; Found C 65.37; H 5.41.
J = 15.3 Hz, 29 H-a), 8.05 (d, 2H, J = 15.3 Hz, 29 H-b),
8.19 (s, 1H, H-60); MS: m/z 458 (M?), 327, 161, 121;
C28H26O6; C 73.35, H 5.72; Found C 73.23, H 5.81.
1-{2,4-Dimethoxy-5-[3-(3,4-dimethoxyphenyl)-2-prope-
noyl]phenyl}-3-(3,4-dimethoxyphenyl)-2-propen-1-one (5b):
1-{2,4-Dihydroxy-5-[3-(2-methylphenyl)-2-propenoyl]
phenyl}-3-(2-methylphenyl)-2-propen-1-one (2d): Yield
60 %; m.p. 209–211 ꢁC; Rf 0.71; 1H NMR (CDCl3)
d ppm: 2.44 (s, 6H, 29 –CH3), 6.31 (s, 2H, OH), 6.51
(s, 1H, H-30), 7.08 (m, 4H, 29 H-3,5), 7.54 (m, 4H, 29
H-4,6), 7.76 (d, 2H, J = 15.3 Hz, 29 H-a), 8.23 (d, 2H,
J = 15.3 Hz, 29 H-b), 8.57 (s, 1H, H-60), 13.61 (s, 2H,
OH); MS: m/z 398 (M?), 307, 280, 118; C26H22O4;
C 78.37, H 5.56; Found C 78.26; H 5.38.
1
Yield 65 %; m.p. 208–210 ꢁC; Rf 0.66; H NMR (CDCl3)
d ppm: 3.79 (s, 6H, 29 –OCH3), 4.16 (broad s, 12H, 49
–OCH3), 6.55 (s, 1H, H-30), 6.82 (d, 2H, J = 7.6 Hz, 29
H-5), 7.14–7.22 (m, 4H, 29 H-2,6), 7.26 (d, 2H, J =
15.6 Hz, 29 H-a), 7.71 (d, 2H, J = 15.6 Hz, 29 H-b),
8.08 (s, 1H, H-60); MS: m/z 518 (M?), 357, 162, 77;
C30H30O8; C 69.49, H 5.83; Found C 69.43, H 5.75.
3-(2-Furyl)-1-{5-[3-(2-furyl)-2-propenoyl]-2,4-dime-
thoxyphenyl}-2-propen-1-one (5c): Yield 70 %; m.p.
216–218 ꢁC; Rf 0.64; 1H NMR (CDCl3) d ppm: 3.95
(s, 6H, 29 –OCH3), 6.33 (s, 1H, H-30), 6.86–7.59
(m, 8H, 2 9 furyl hydrogens ? 2H-a), 7.78 (d, 2H,
J = 15.3 Hz, 29 H-b), 8.12 (s, 1H, H-60); MS: m/z 378
(M?), 301, 137; C22H18O6; C 69.84, H 4.79; Found C
69.56, H 4.75.
1-{2,4-Dihydroxy-5-[3-(3-methoxyphenyl)-2-propenoyl]
phenyl}-3-(3-methoxyphenyl)-2-propen-1-one (2e): Yield
63 %; m.p. 192–194 ꢁC; Rf 0.73; 1H NMR (CDCl3) d ppm:
3.92 (s, 6H each, 49 –OCH3), 6.53 (s, 1H, H-30), 7.32–7.78
(m, 8H, 29 H-2,4,5,6), 7.80 (d, 2H, J = 15.3 Hz, 29 H-a),
8.07 (dd, 2H, J = 8.1 Hz, 1.8 Hz, 29 H-6), 8.23 (d, 2H,
J = 15.3 Hz, 29 H-b), 8.31 (s, 1H, H-60), 13.59 (s, 2H,
OH); MS: m/z 430 (M?), 296, 163, 134, 104; C26H22O6;
Calc. C 72.55, H 5.15; Found C 72.40, H 5.21.
1-{2,4-Dimethoxy-5-[3-(3,4,5-trimethoxyphenyl)-2-prope-
noyl]phenyl}-3-(3,4,5-trimethoxyphenyl)-2-propen-1-one (5d):
3-(2-Furyl)-1-{5-[3-(2-furyl)-2-propenoyl]-2,4-dihydroxy-
phenyl}-2-propen-1-one (2f): Yield 61 %; m.p. 224 ꢁC;
1
Yield 62 %; m.p. 196–198 ꢁC; Rf 0.67; H NMR (CDCl3)
1
Rf 0.69; H NMR (CDCl3) d ppm: 6.51 (s, 1H, H-30),
d ppm: 3.89 (s, 6H, 29 –OCH3), 4.08 (broad s, 18H, 6 9
–OCH3), 6.51 (s, 1H, H-30), 7.24–7.78 (m, 8H, 29
H-2,6 ? 2H-a ? 2H-b), 8.12 (s, 1H, H-60); MS: m/z 578
(M?), 191, 146, 134; C32H34O10; C 66.43, H 5.92; Found C
66.50, H 4.78.
7.24–7.67 (m, 6H, 29 furyl H), 7.65 (d, 2H, J = 15.3 Hz,
29 H-a), 8.22 (d, 2H, J = 15.3 Hz, 29 H-b), 8.38 (s, 1H,
H-60), 13.51 (s, 2H, OH); MS: m/z 350 (M?), 272, 163, 102,
91; C20H14O6; Calc. C 68.57, H 4.03; Found C 68.52, H
4.15.
3-(4-Diethylaminophenyl)-1-{5-[3-(4-diethylaminophe-
nyl)-2-propenoyl]-2,4-dimethoxyphenyl}-2-propen-1-one
(5e): Yield 64 %; m.p. 218–220 ꢁC; Rf 0.66; 1H NMR
(CDCl3) d ppm: 1.52-1.58 (m, 12H, 49 –CH3), 3.87 (s, 6H,
29 –OCH3), 4.04-4.11 (m, 8H, 49 –CH2–), 6.38 (s, 1H,
H-30), 6.62 (d, 4H, J = 7.8 Hz, 29 H-3,5), 7.26 (d, 2H,
J = 15.3 Hz, 29 H-a), 7.44 (d, 4H, J = 7.6 Hz, 29
H-2,6), 7.68 (d, 2H, J = 15.6 Hz, 29 H-b), 8.19 (s, 1H,
H-60); MS: m/z 540 (M?), 338, 174, 134; C34H40O8; C
75.53, H 7.46, N 5.18; Found C 75.45, H 7.28, N 5.30.
3-(4-Dimethylaminophenyl)-1-{5-[3-(4-dimethylaminophe-
nyl)-2-propenoyl]-2,4-dihydroxyphenyl}-2-propen-1-one (2g):
1
Yield 52 %; m.p. 232-234 ꢁC; Rf 0.71; H NMR (CDCl3) d
ppm: 2.42 (broad s, 12H, 49 –CH3), 6.64 (s, 1H, H-30), 7.26
(d, 4H, J = 7.8 Hz, 29 H-3,5), 7.39 (d, 2H, J = 15.3 Hz, 29
H-a), 7.57 (d, 4H, J = 7.6 Hz, 29 H-2,6), 7.98 (d, 2H,
J = 15.6 Hz, 29 H-b), 8.56 (s, 1H, H-60), 13.57 (s, 2H, OH);
MS: m/z 456 (M?), 310, 146, 134, 91; C28H28N2O4; Calc.
C 73.66, H 6.18, N 6.14; Found C 73.58, H 5.96, N 6.21.
3-(4-Diethylaminophenyl)-1-{5-[3-(4-diethylaminophenyl)-
2-propenoyl]-2,4-dihydroxyphenyl}-2-propen-1-one
(2h):
Synthesis of flavones (3a–c) (Doshi et al., 1986) General
procedure To a solution of compound 2a (200 mg) in
dimethylsulphoxide (5 mL), 2 crystals of iodine were
added. The contents were refluxed for 30 min, cooled to
room temperature and poured into ice cold water. A solid
mass separated out which was filtered, washed with water,
sodium thiosulphate solution (2 %w/v in water) and again
with water. After drying it was crystallized from metha-
nol:dichloromethane mixture to give TLC pure 3a–c (It did
not give colour with ethanolic ferric chloride solution).
2,8-Bis(4-Chlorophenyl)-4H,6H-pyrano[3,2-g]chromene-4,
6-dione (3a): Yield 36 %, m.p. 226–228 ꢁC; Rf 0.56; 1H NMR
(CDCl3) d ppm: 6.97 (s, 2H, 29 H-3), 7.39 (s, 1H, H-8), 7.52-
7.76 (m, 8H, p-chlorophenyl), 9.37 (s, 1H, H-5); MS: m/z 435
1
Yield 50 %; m.p. 220-222 ꢁC; Rf 0.68; H NMR (CDCl3) d
ppm: 1.56-1.61 (m, 12H, 49 –CH3), 4.08-4.13 (m, 8H, 49
–CH2–), 6.57 (s, 1H, H-30), 7.23 (d, 4H, J = 7.8 Hz, 29
H-3,5), 7.37 (d, 2H, J = 15.3 Hz, 29 H-a), 7.61 (d, 4H,
J = 7.6 Hz, 29 H-2,6), 7.88 (d, 2H, J = 15.6 Hz, 29 H-b),
8.48 (s, 1H, H-60), 13.55 (s, 2H, OH); MS: m/z 512 (M?), 338,
174, 163; C32H36N2O4; Calc. C 74.97, H 7.08, N 5.46; Found
C 75.11, H 6.95, N 5.65.
1-{2,4-Dimethoxy-5-[3-(3-methoxyphenyl)-2-propenoyl]
phenyl}-3-(3-methoxyphenyl)-2-propen-1-one (5a): Yield
62 %; m.p. 210–212 ꢁC; Rf 0.67; 1H NMR (CDCl3)
d ppm: 3.86 & 4.02 (s each, 12H, 49 –OCH3), 6.58 (s, 1H,
H-30), 6.92–7.48 (m, 8H, 29 H-2,4,5,6), 7.54 (d, 2H,
123

Med Chem Res
(M?), 298, 207, 136; C24H12Cl2O4; C 66.23, H 2.78; Found
C 66.05, H 2.74.
(CDCl3) d ppm: 2.63 (s, 6H, 29 –COCH3), 7.21 (s, 1H,
H-2), 7.44–7.56 (m, 6H, 29 H-30,40,50), 7.92–8.08 (m, 2H,
29 H-60), 8.21 (s, 1H, H-5); MS: m/z 492 (M?), 344, 104,
77; C24H16N2O10; C 58.54, H 3.28, N 5.69; Found C 58.47,
H 3.16, N 5.81.
2,8-Bis(3-chlorophenyl)-4H,6H-pyrano[3,2-g]chromene-
1
4,6-dione (3b): Yield 32 %, m.p. 220–222 ꢁC; Rf 0.54; H
NMR (CDCl3) d ppm: 7.03 (s, 2H, 29 H-3), 7.48 (s, 1H,
H-8), 7.46-7.82 (m, 8H, 29 m-chlorophenyl), 9.46 (s, 1H,
H-5); MS: m/z 435 (M?), 298, 235, 136; C24H12Cl2O4;
C 66.23, H 2.78; Found C 66.18, H 2.66.
4,6-Diacetyl-1,3-di(3-nitrophenyl carbonyloxy)benzene
1
(6b): Yield 68 %; m.p. 148–150 ꢁC; Rf 0.77; H NMR
(CDCl3) d ppm: 2.61 (s, 6H, 29 –COCH3), 7.18 (s, 1H,
H-2), 7.21–7.38 (m, 6H, 29 H-40,50,60), 7.49–7.62 (m, 2H,
29 H-20), 8.45 (s, 1H, H-5); MS: m/z 492 (M?), 150, 104,
77; C24H16N2O10; C 58.54, H 3.28, N 5.69; Found C 58.50,
H 3.21, N 5.63.
2,8-Bis(3,4,5-Trimethoxylphenyl)-4H,6H-pyrano[3,2-g]
chromene-4,6-dione (3c): Yield 41 %; m.p. 236–238 ꢁC;
Rf 0.58; 1H NMR (CDCl3) d ppm: 3.91 (broad s, 18H, 69
–OCH3), 6.94 (s, 2H, 2 9H-3), 7.46 (s, 1H, H-8), 7.33–7.78
(m, 4H, 29 trimethoxyphenyl), 9.39 (s, 1H, H-5); MS:
m/z 546 (M?), 326, 267, 135, 91, 77; C30H26O10; C 65.93,
H 4.80; Found C 65.68, H 4.92.
4,6-Diacetyl-1,3-di(2-methoxyphenyl carbonyloxy)ben-
1
zene (6c) Yield 72 %; m.p. 132-134 ꢁC; Rf 0.74; H NMR
(CDCl3) d ppm: 2.60 (s, 6H, 29 –COCH3), 3.87 (s, 6H, 29
–OCH3), 7.24 (s, 1H, H-2), 7.32–7.67 (m, 8H, 29
H-30,40,50,60), 8.18 (s, 1H, H-5); MS: m/z 462 (M?), 328,
135, 105; C26H22O8; C 67.53, H 4.79; Found C 67.45, H
5.06.
2,8-Bis(2-Methylphenyl)-4H,6H-pyrano[3,2-g]chromene-4,
1
6-dione (3d): Yield 62 %; m.p. 212–214 ꢁC; Rf 0.53; H
NMR (CDCl3) d ppm: 2.42 (s, 6H, 29 –CH3), 6.83 (s, 2H, 29
H-3), 7.32 (s, 1H, H-8), 7.38–7.81 (m, 8H, 29 o-tolyl), 9.19
(s, 1H, H-5); MS: m/z 394 (M?), 236, 208, 91; C26H18O4;
C 79.17, H 4.60; Found C 78.94, H 4.78.
4,6-Diacetyl-1,3-di(3-chlorophenyl carbonyloxy)benzene
(6d): Yield 66 %; m.p. 143–145 ꢁC; Rf 0.75; 1H NMR
(CDCl3) d ppm: 2.44 (s, 6H, 29 –COCH3), 7.13 (d, 2H,
J = 7.6 Hz, 29 H-50), 7.21 (s, 1H, H-2), 7.29–7.53 (m, 8H,
29 H-20,40,50,60), 8.41 (s, 1H, H-5); MS: m/z 471 (M?), 332,
139, 111; C24H16Cl2O6; C 61.16, H 3.42; Found C 60.91, H
3.63.
2,8-Bis(3-Methoxylphenyl)-4H,6H-pyrano[3,2-g]chro-
mene-4,6-dione (3e): Yield 47 %; m.p. 226–228 ꢁC;
Rf 0.55; 1H NMR (CDCl3) d ppm: 3.87 (s, 6H, 29
–OCH3), 6.85 (s, 2H, 29 H-3), 7.38 (s, 1H, H-8), 7.41–
7.84 (m, 8H, 29 m-methoxyphenyl), 9.37 (s, 1H, H-5);
MS: m/z 426 (M?), 296, 134, 77; C26H18O6; C 73.23,
H 4.25; Found C 73.05, H 4.14.
4,6-Diacetyl-1,3-di(4-chlorophenyl carbonyloxy)benzene
(6e): Yield 70 %; m.p. 138–140 ꢁC; Rf 0.76; 1H NMR
(CDCl3) d ppm: 2.29 (s, 6H, 29 –COCH3), 6.96 (s, 1H,
H-2), 7.28 (d, 4H, J = 7.6 Hz, 29 H-30,50), 7.82 (d, 4H,
J = 7.8 Hz, 29 H-20,60), 8.19 (s, 1H, H-5); MS: m/z 471
(M?), 139, 111; C24H16Cl2O6; C 61.16, H 3.42; Found C
61.04, H 3.58.
2,8-Bis(2-furyl)-4H,6H-pyrano[3,2-g]chromene-4,6-dione
(3f): Yield 47 %; m.p. 242-244 ꢁC; Rf 0.52; 1H NMR
(CDCl3) d ppm: 6.88 (s, 2H, 29 H-3), 7.34 (s, 1H, H-8),
7.36-7.71 (m, 6H, 29 furyl H), 9.39 (s, 1H, H-5); MS:
m/z 346 (M?), 98, 35, 16; C20H10O6; C, 69.37; H, 2.91;
Found C 69.12, H 2.76.
4,6-Diacetyl-1,3-di(2-methylphenyl carbonyloxy)benzene
(6f): Yield 74 %; m.p. 115–117 ꢁC; Rf 0.72; 1H NMR
(CDCl3) d ppm: 2.51 (s, 6H, 29 –CH3), 2.67 (s, 6H, 29
–COCH3), 7.19 (s, 1H, H-2), 7.24–7.43 (m, 6H, 29
H-30,40,50), 7.76–7.82 (m, 2H, 29 H-60), 8.21 (s, 1H, H-5);
MS: m/z 430 (M?), 119, 91, 77; C26H22O6; C 72.55, H 5.15;
Found C 72.38, H 5.23.
Attempted synthesis of (3a–c) via Baker–Venkataraman
rearrangement (Jain et al., 1982). This route of synthesis
involved three steps namely—(i) synthesis of diester (ii)
synthesis of b-diketone from diester and (iii) cyclization of
the b-diketone to the corresponding flavone.
Synthesis of diesters (6a–f) General procedure To a
solution of 1 (2 mmol) in dry pyridine (5 mL) was added a
solution of aromatic acid (4 mmol) in dry pyridine (5 mL).
The contents were stirred for 5 min and POCl3 (0.3 mL)
was added dropwise into it. Stirring was continued for
another 2 h and then reaction mixture poured into ice cold
water containing HCl. A solid mass separated out which
was filtered, washed with water and dried. It was crystal-
lized from methanol:dichloromethane mixture to give TLC
pure 6a–f (it did not give colour with ethanolic ferric
chloride solution).
Attempted synthesis of b-diketones It gave back the
starting material (1).
Microbiology
The synthesized compounds were evaluated for their anti-
microbial activity (Colle et al., 1989; Varma, 1998) against
three bacterial strains and three fungal strains at a con-
centration of 100 lg/mL by cup plate method. Compounds
inhibiting growth of one or more of the test microorgan-
isms were further tested for their minimum inhibitory
concentration (MIC).
4,6-Diacetyl-1,3-di(2-nitrophenyl carbonyloxy)benzene
(6a): Yield 70 %; m.p. 138–140 ꢁC; Rf 0.76; 1H NMR
123

Med Chem Res
Antibacterial activity
compounds and standard drug (Griseofulvin) solutions
(100 lg/mL) were made in DMSO and added in each well
separately and petridishes kept aseptically for 1 h for dif-
fusion of the sample. After the completion of diffusion, all
the petridishes were kept for incubation at 37 ꢁC for
3–4 days and then diameter of the zone of inhibition was
measured in mm (Table 2). Compounds inhibiting growth
of one or more of the fungal strains were further tested for
their MIC. A solution of the compounds (100 lg/mL) was
prepared in DMSO and a series of doubling dilutions
prepared with sterile pipettes. To each of a series of sterile
test tubes a standard volume of nutrient broth medium was
added. A control tube containing no antimicrobial agent
was included. The tubes were inoculated with
*1.6 9 104–6 9 104 c.f.u. mL-1 and incubated for 48 h
at 37 ꢁC and examined for growth. The lowest concentra-
tion (highest dilution) required to arrest the growth of
fungus was regarded as MIC.
The compounds were screened for their antibacterial
activity against Staphylococcus aureus (ATCC-25923),
Escherichia coli (ATCC-25922), and Pseudomonas aeru-
ginosa (ATCC-27853) bacterial strains at a concentration
of 100 lg/mL by cup plate method (Colle et al., 1989).
Ciprofloxacin was used as standard drug for comparison.
Freshly prepared liquid agar medium (20 mL/petridish)
was poured into each petridishes and the plates were dried
by placing in an incubator at 37 ꢁC for 1 h. Then stan-
dardized culture of microorganism was spread on each
petridishes by L-shaped spreader. Wells (6 mm) were
made using an agar punch and, each well was labeled
accordingly. A control (solvent) was also included in the
test. The test compound and standard drug solutions
(100 lg/mL) were made in dimethylsulfoxide (DMSO) and
added in each well separately and petridishes kept asepti-
cally for 1 h for diffusion of the sample. After the com-
pletion of diffusion, all the petridishes were kept for
incubation at 37 ꢁC for 24 h and then diameter of the zone
of inhibition was measured in mm (Table 2).
Results and discussion
Compounds inhibiting growth of one or more of the test
microorganisms were further tested for their MIC by
broth dilution technique. A solution of the compounds
(100 lg/mL) was prepared in DMSO and a series of dou-
bling dilutions prepared with sterile pipettes. To each of a
series of sterile test tubes a standard volume of nutrient
broth medium was added. A control tube containing no
antimicrobial agent was included. The inoculum consisting
of an overnight broth culture of microorganisms was added
to separate tubes. The tubes were incubated at 37ꢁ for 24 h
and examined for turbidity. The highest dilution (lowest
concentration) required to stop the growth of bacteria was
regarded as MIC.
Synthesis
The protocol for synthesis of title compounds is presented
in Scheme 1. The starting material, 1,10-(4,6-dimethyl-1,3-
phenylene)diethanone (1), was condensed with different
arylaldehydes in presence of potassium hydroxide follow-
ing Claisen-Schmidt reaction conditions (Dhar, 1981) to
give 8 bischalcones (2a–h). Bischalcones were cyclized in
presence of traces of iodine in dimethylsulphoxide to give
6 flavones (3a–f) (Doshi et al., 1986). An alternative route
to synthesize the flavones consisted in preparing the diester
derivatives of (1) with different aryl acids in presence of
phosphorous oxychloride, which could be converted to
b-diketones through Baker–Venkataraman rearrangement
(Jain et al., 1982) followed by cyclization to give the
corresponding flavones. However, this route of flavone
synthesis was unsuccessful and it was not possible to go
beyond diester stage; 6 diester derivatives (6a–f) were
prepared. The dimethyl ether derivative (4) was synthe-
sized by reacting compound (1) with dimethylsulphate in
the presence of potassium carbonate. This compound (4)
was condensed with different arylaldehydes to give 5 bis-
chalcones (5a–e). The structures were established on the
Antifungal activity
Antifungal activity of the synthesized compounds was
determined against Candida albicans (ATCC-10231),
Aspergillus niger (ATCC-16404) and Rhizopus oryza
(MTCC-262) by agar diffusion method (Varma, 1998).
Sabourands agar media was prepared by dissolving peptone
(1 g), D-glucose (4 g) and agar (2 g) in distilled water
(100 mL) and adjusting pH to 5.7. Normal saline was used
to make a suspension of spore of fungal strain for lawning.
A loopful of particular fungal strain was transferred to
3 mL saline to get a suspension of corresponding species.
Agar media (20 mL) was poured into each petridish and
the plates were dried by placing in an incubator at 37 ꢁC
for 1 h. Wells were made using an agar punch and, each
well was labeled accordingly. A control was also prepared
in triplicate and maintained at 37 ꢁC for 3–4 days. The test
1
basis of H NMR, Mass spectral data and elemental anal-
ysis results.
In general, the 1H NMR spectra of bischalcones
(2a–h and 5a–e) explained the presence of two –CH=CH–
groups from the presence of two doublets at d 7.5 and d 8.2
as two doublets integrating for two CH-a and two CH-b
protons, respectively. Chalcone ring protons H-30 & H-60
appeared as singlet at d 6.6 and d 8.1, respectively. Other
123

Med Chem Res
Ar
OH
HO
Ar
O
O
HO
OH
O
O
Ar-CHO
KOH
I2
Ar
Ar
DMSO
O
O
Ac2O
ZnCl2
3a-f
2a-h
H3CO
OCH3
H3CO
OCH3
Dimethyl
sulphate
HO
O
OH
Ar
Ar
Ar-CHO
KOH
Dry acetone
O
O
O
O
4
5a-e
O
1
POCl3
O
O
O
O
COOH
R
R
R
O
O
6a-f
x
HO
O
OH
O
R
R
O
O
Scheme 1 Protocol for synthesis of title compounds
signals were observed at appropriate d values integrating
for the protons of two phenyl rings. In addition to these
peaks, one more peak was observed as a singlet at d 3.8 in
the case of chalcones 5a–e integrating for two methoxy
groups. They (5a–e) did not show the presence of hydroxyl
group as evident from the negative ferric chloride test,
while chalcones 2a–h gave positive ferric chloride test
showing the presence of hydroxyl group. Mass spectral of
bischalcones showed the presence of molecular ion peaks
in reasonable intensities. Cyclization of bischalcones 2 into
flavones 3a–f was carried out using DMSO/I2 reagent. The
formation of flavones was supported by spectral data and
elemental analysis. A negative ferric chloride test also
indicated the absence of hydroxyl group. In 1H NMR
spectra of flavones 3a–f, there located three singlet at d 6.9,
d 7.4, and d 9.3 integrating for 29 H-3, H-8 and H-5 of
flavones ring, respectively. The spectral data together with
negative ferric chloride test confirmed the cyclization of
bischalcones to flavones. Another route was tried for syn-
thesis of flavones 3 via Baker–Venkataraman rearrange-
ment. For this, first diesters 6a–f were synthesized in order
to prepare b-diketones, which in turn would be cyclized to
get the desired flavones. However, diesters could not be
converted into b-diketones and this route found unsuc-
cessful. In 1H NMR spectral data, presence of a singlet at d
2.6 integrating for 29 COCH3 protons together with
negative ferric chloride test indicated the formation of
diesters. Mass spectral data of diesters 3a–f showed the
presence of molecular ion peaks in reasonable intensities.
In case of compounds having phenyl rings with chloro-
substituents (2a, 2b, 3a, 3b, 6d and 6e), the molecular ion
peak or their fragments having chloro-group appeared as
cluster of peaks.
Antibacterial and antifungal activity
The newly prepared compounds were screened for their
antibacterial activity against S. aureus (ATCC-25923),
E. coli (ATCC-25922) and P. aeruginosa (ATCC-27853)
bacterial species, and antifungal activity against Candida
albicans (ATCC-10231), Aspergillus niger (ATCC-16404)
and Rhizopus oryza (MTCC-262). The initial test was
performed at a concentration of 100 lg/mL and the com-
pounds found active were further tested for their MIC. The
preliminary antimicrobial results (Table 2) indicated that
the compounds 2a–h and 3a–f showed significant anti-
bacterial and antifungal activities. The MIC data showed
that compound 2f exhibited very good activity against
E. coli, P. aeruginosa, and C. albicans with MIC-12.5
lg/mL. Similar type of activity was shown the compound
3a against S. aureus and C. albicans with MIC-12.5
lg/mL. Another compound, compound 3f was active
123

Med Chem Res
Table 1 Antibacterial and antifungal activities (MIC, lg/mL) of the title compounds
Ar
Ar
OH
O
HO
O
H3CO
OCH3
O
O
O
O
Ar
Ar
Ar
Ar
Ar
Ar
O
O
O
O
O
O
2a-h
O
O
3a-f
5a-e
6a-f
Compounds
Ar
Antibacterial activity
Antifungal activity
S. aureus
E. coli
P. aeruginosa
C. albicans
A. niger
R. oryza
2a
4-Chlorophenyl
3-Chlorophenyl
50
50
–
25
50
50
50
[100
50
50
50
50
–
2b
[100
50
50
2c
3,4,5-Trimethoxyphenyl
2-Methylphenyl
3-Methoxyphenyl
2-Furyl
50
–
[100
[100
50
25
2d
[100
50
[100
25
–
2e
50
12.5
25
50
25
50
50
50
25
50
50
[100
25
50
50
[100
25
[100
–
2f
25
12.5
50
12.5
50
25
2g
4-Dimethylaminophenyl
4-Diethylaminophenyl
4-Chlorophenyl
3-Chlorophenyl
3,4,5-Trimethoxyphenyl
2-Methylphenyl
3-Methoxyphenyl
2-Furyl
50
[100
[100
50
2h
50
[100
25
50
3a
12.5
25
12.5
50
3b
25
25
3c
[100
50
[100
50
50
50
3d
[100
[100
25
50
[100
25
3e
50
50
25
3f
25
12.5
–
12.5
[100
[100
50
50
5a
3-Methoxyphenyl
3,4-Dimethoxyphenyl
2-Furyl
–
[100
50
–
5b
[100
50
–
[100
50
–
5c
–
–
[100
–
5d
3,4,5-Trimethoxyphenyl
4-Diethylaminophenyl
2-Nitrophenyl
[100
–
50
[100
[100
–
[100
–
–
5e
–
[100
–
–
6a
50
[100
–
–
–
6b
3-Nitrophenyl
[100
–
–
[100
–
–
–
6c
2-Methoxyphenyl
3-Chlorophenyl
4-Chlorophenyl
2-Methylphenyl
–
[100
–
[100
–
–
6d
[100
[100
–
–
–
–
6e
[100
–
–
[100
–
–
[100
–
6f
–
–
Standard-1a
Standard-2a
Standard-3b
6.25
nt
6.25
nt
6.25
nt
nt
nt
nt
6.25
[100
6.25
nt
6.25
nt
[100
[100
nt
nt not tested; MIC minimum inhibitory concentration
a
b
–, Insignificant activity; Standard-1 = Ciprofloxacin, Standard-2 Griseofulvin; Standard-3 = Quercetin (a natural antimicrobial flavonoid,
data from literature; Gatto et al., 2002)
against P. aeruginosa and C. albicans with MIC-12.5
lg/mL. Compound 3e showed significant activity against
C. albicans, A. niger and R. oryza at 25 lg/mL concen-
tration. Compound 3b also exhibited significant activity
against S. aureus, P. aeruginosa and A. niger with 25
lg/mL concentration. Compound 2e was significant in its
action against C. albicans and R. oryza at 25 lg/mL con-
centration. Results are presented in Table 1.
An analysis of results revealed that the compounds
2a–h and 3a–f showed a good antibacterial and anti-
fungal activity. Methylation of the two chelated hydroxyls
(5a–e) was done in order to see the change in antimicro-
bial action of bischalcones, and this resulted in signifi-
cant decrease in antimicrobial activity. However, oxidative
cyclization of bischalcones resulted in flavones (3a–f) which
were found to be considerably active. Bischalcones were
123

Med Chem Res
Table 2 Preliminary antibacterial and antifungal activities of the title compounds
Compounds
Antibacterial activitya
Antifungal activitya
S. aureus
E. coli
P. aeruginosa
C. albicans
A. niger
R. oryza
2a
??
?
??
–
???
??
?
??
??
???
?
??
?
??
??
??
–
2b
2c
??
?
??
–
??
–
2d
?
2e
??
???
??
??
???
???
?
??
???
???
??
???
??
??
?
??
???
??
?
???
???
??
??
???
??
??
??
???
???
?
??
???
?
???
??
??
?
2f
2g
2h
?
3a
???
???
?
??
???
??
?
???
??
??
?
3b
3c
3d
??
??
???
–
??
??
???
–
3e
?
???
??
–
???
?
3f
???
?
5a
–
5b
?
??
–
–
?
?
–
5c
??
?
–
??
?
??
–
?
5d
??
–
?
–
5e
–
?
–
?
–
6a
??
?
?
–
–
–
–
6b
–
–
?
–
–
6c
–
–
?
–
?
–
6d
?
–
–
–
–
–
6e
?
?
–
?
–
?
6f
–
–
–
–
–
–
Standard-1b
Standard-2b
????
nt
????
nt
????
nt
nt
nt
nt
????
????
????
nt not tested
a
Zone of inhibition: –,\5 mm (insignificant or no activity); ?, 5–9 mm (weak activity); ??, 10–14 mm (moderate activity); ???, 15–20 mm
(strong activity); ????, [20 mm
b
Standard-1, Ciprofloxacin; Standard-2, Griseofulvin
(5a–e). In other words, methylation of the two
hydroxyls (5a–e) resulted in decreased antimicrobial
activity.
almost having equal antibacterial and antifungal actions.
Flavones were slightly more active as antibacterial than
as antifungal. Diesters (6a–f) were insignificant in their
antimicrobial activities.
•
•
•
The antimicrobial activity was found improved due to
presence of electron withdrawing groups like chloro on
ortho, meta or para position(s) of the two aryl rings.
para-Substituted derivatives were more active than
meta or ortho substituted derivatives.
Structure activity relationship (SAR)
The following points could be drawn after analyzing the
antimicrobial results:
On the other hand the electron releasing groups like
methyl, methoxy, hydroxyl group attached with the two
phenyl rings decreased the antimicrobial activity. meta-
Substituted derivatives were more active than para or
ortho substituted derivatives.
•
•
Flavones (3a–f) were found to have better antimicrobial
activity than those of Bischalcones (2a–h and 5a–e).
Among Bischalcones (2a–h and 5a–e), the com-
pounds having free hydroxyls (2a–h) were more active
than those of the compounds having methoxy groups
Diesters (6a–f) were least active among all the
synthesized compounds
123

Med Chem Res
Chu DTW, Plattner JJ, Katz L (1996) New directions in antibacterial
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Dhar DN (1981) The chemistry of chalcones and related compounds.
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Doshi AG, Soni PA, Ghiya BJ (1986) Oxidation of 20-hydroxychal-
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Gatto MT, Falcocchio S, Grippa E, Mazzanti G, Battinelli L, Nicolosi
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Two series of bischalcones (2a–h and 5a–e) and a series of
flavones (3a–f) were synthesized successfully. Two routes
were applied for the synthesis of flavones; first route of
synthesis of flavones via oxidative cyclization of bischal-
cones gave six flavones (3a–f), the other route for prepara-
tion of flavones via Baker–Venkataraman was unsuccessful.
Among the synthesized compounds, three compounds, 3-(2-
furyl)-1-{5-[3-(2-furyl)-2-propenoyl]-2,4-dihydroxyphenyl}-
2-propen-1-one 2f, 2,8-bis(4-chlorophenyl)-4H,6H-pyrano
[3,2-g]chromene-4,6-dione 3a and 2,8-bis(2-furyl)-4H,6H-
pyrano[3,2-g]chromene-4,6-dione 3f emerged as lead com-
pounds. These compounds showed good antibacterial and
antifungal activities with MIC 12.5 lg/mL. After analyzing
the results, it is conceivable that the derivatives showing
significant antimicrobial activity can be further modified to
exhibit better potency than the standard drugs.
Acknowledgments The authors are thankful to CDRI-Lucknow,
and IIT-Delhi for spectral studies. Help provided by Prof. P. K. Pillai,
Department of Microbiology, Majeedia Hospital, New Delhi, is
gratefully acknowledged.
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