5-phenyl-1-benzofuran-2-yl derivatives: Synthesis, antimicrobial, and antioxidant activity

Article abstract of DOI:10.1007/s00044-012-0017-y

Previously unknown biphenyl containing 5-phenyl-1-benzofuran-2-yl derivatives; methanones (2a-i), tertiary alcohols (3a-l), and carbinols (4a-f) were synthesized and evaluated for their antimicrobial and antioxidant activities to study the effect of funct

Full text of DOI:10.1007/s00044-012-0017-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:78–87
DOI 10.1007/s00044-012-0017-y
ORIGINAL RESEARCH
5-phenyl-1-benzofuran-2-yl derivatives: synthesis, antimicrobial,
and antioxidant activity
•
Chandrashekar Aswathanarayanappa Eswarappa Bheemappa
•
•
Yadav D. Bodke Venkatesh K. Bhovi Raghu Ningegowda
•
•
•
M. C. Shivakumar S. K. Peethambar Sandeep Telkar
•
Received: 28 January 2012 / Accepted: 29 February 2012 / Published online: 13 March 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Previously unknown biphenyl containing
5-phenyl-1-benzofuran-2-yl derivatives; methanones (2a–i),
tertiary alcohols (3a–l), and carbinols (4a–f) were synthe-
sized and evaluated for their antimicrobial and antioxidant
activities to study the effect of functionalization at the
carbonyl carbon and substitution at biphenyl ring on these
activities. The introduction of hydroxyl group at carbonyl
carbon enhanced the antioxidant property (3a, 3g, 3h, 4a,
and 4b), while antimicrobial activity decreased; the carbi-
nol and tertiary alcohols corresponding to methanone 2a
and 2b showed no antimicrobial activity. Biphenyl meth-
anones 1, 2a, 2f, and 2g exhibited antimicrobial activity
with minimal inhibitory concentration ranging between
0.001 and 0.500 mg/mL, tertiary alcohols 3a, 3g, and 3h
and carbinols 4a and 4b exhibited the promising antioxi-
dant property. The mode of action of these active
compounds was carried out by docking of receptor GlcN6P
synthase with newly synthesized candidate ligands 1, 2a,
2e, 2f, 2g, 2h, 3a, 3g, 3h, 4c, and 4d.
Keywords Benzofuran ꢀ Antimicrobial ꢀ Antioxidant ꢀ
Toxicity ꢀ Biphenylmethanone ꢀ Carbinols
Introduction
Life threatening infectious disease caused by multi-
drug-resistant pathogenic bacteria (Gram-positive/Gram-
negative) increased an alarming level around the world.
Owing to this increased microbial resistance, new classes
of antimicrobial agents with novel mechanisms are today’s
need to fight against the multidrug-resistant infections.
Heterocyclic compounds play an important role in an
untiring effort aimed at developing new antimicrobial
agents with new mechanism of action. These heterocyclic
compounds are well known to possess diverse pharmaco-
logical properties, viz. anti-inflammatory, anticancer,
anticonvulsant, antimalarial etc. Benzofurans are very
interesting heterocycles, which are ubiquitous in nature and
show a wide range of biological activities. Substituted phe-
nyl-benzofuran in various positions have been shown to
display different biological activity, 2-substituted benzofu-
rans (Khan and co workers, 2005; Gundogdu and co workers,
2006) as antimicrobials; 3-amino-1-benzofurans and
3-methyl-1-benzofurans as analgesics (Radl and co workers,
2000); benzofurany-lacryloylpiperazines as antidepressants
(Dauzonne et al., 1995); (4-hydroxy-3-methyl-6-phenyl-
benzofuran-2-yl)phenylmethanone as potent anti-tumor
agent (Hayakawa and co workers, 2004). Cloridarol, a
2-substituted benzofuran is used in for treatment of lipidemia
and as an anticoagulant and racemates of 2-benzofuranyl
C. Aswathanarayanappa ꢀ R. Ningegowda ꢀ M. C. Shivakumar
Biocon Ltd., 20th KM, Hosur Road, Electronic City,
Bangalore 560100, Karnataka, India
C. Aswathanarayanappa (&) ꢀ Y. D. Bodke ꢀ V. K. Bhovi
Department of Industrial Chemistry, Jnanasahyadri, Kuvempu
University, Shankaraghatta, Shimoga 577451, Karnataka, India
e-mail: chandrashekar.ashwath@gmail.com
E. Bheemappa
Sir M.V. Government Science College, Bhadravathi 577301,
Karnataka, India
S. K. Peethambar
Department of Biochemistry, Jnanasahyadri, Kuvempu
University, Shankaraghatta, Shimoga 577451, Karnataka, India
S. Telkar
Department of Biotechnology and Bioinformatics,
Jnanasahyadri, Kuvempu University, Shankaraghatta,
Shimoga 577451, Karnataka, India
123

Med Chem Res (2013) 22:78–87
79
carbinols have been shown to display antifungal and aro-
matase inhibiting activities (Ghelardoni and co workers,
1981). Recently, synthesis of aryl 2-benzofuranyl deriva-
tives with high enantiomeric purity has been reported
(Messina and co workers, 1999). Amiodarone, a benzofuran
derivative was shown to have antiarrhythmic property and
belong to a new class of antiarrhythmic and anti-ischemia
drugs (Singh and Vaughan 1970).
carbonyl compound and substitution at biphenyl ring on the
antimicrobial and antioxidant property and to obtain the
active compounds with enhanced activity.
Materials and methods
Chemistry
In this communication we report the synthesis and
characterization of hitherto unknown 5-phenyl-1-benzofu-
ran-2-yl derivatives containing benzofuran pharmacophore;
methanones (2a–i), carbinols (3a–l) and tertiary alcohols
(4a–f), three different series of compounds containing
different substitutions at biphenyl ring and functionaliza-
tion at carbonyl carbon. Further, it comprises the investi-
gation of in vitro antimicrobial activity against Escherichia
coli (NCTC 12923), Staphylococcus aureus (NCTC
10788), Bacillus subtilis (NCTC 10400), and Candida
albicans (NCPF 3179) and antioxidant activity by DPPH
method. Based on the promising in vitro antimicrobial
results and by considering GlcN6P synthase as the target
receptor it was thought worthy to perform molecular
docking studies and screening for supportive coordination
between in silico studies with in vitro results. Comparative
and automated docking studies with newly synthesized
compounds were performed to determine the best in silico
conformation. The present contribution also describes our
efforts to understand the influence of structural variation at
(5-bromo-1-benzofuran-2-yl)(4-bromophenyl)methanone 1
was synthesized from the reaction of 2-bromo-1-(4-bromo-
phenyl)ethanone and 5-bromo-2-hydroxybenzaldehyde with
aqueous Na2CO3 and 4-dimethylaminopyridine (DMAP) at
80 °C (Shang and co workers, 2010). The target com-
pounds 2a–i were obtained by Suzuki coupling reaction
(Miyaura et al., 1981) of dibromo compound 1 catalyzed
by Tetrakis(triphenylphosphine)palladium [Pd(PPh3)4]
with suitable boronic acids. Compounds 2a–c were reacted
with suitable Grignard reagents to obtain corresponding
tertiary alcohols, 3a–l. Compounds 2a–f were converted to
their corresponding racemic carbinols 4a–f using sodium
borohydride (Scheme 1). All these compounds were char-
acterized by using spectroscopic methods. 1H and 13C
NMR spectra were recorded with a Brucker Avance
DPX400 spectrometer operating at 400 MHz, with Me4Si
as internal standard. The chemical shifts are expressed as d
values in parts per million (ppm) and the coupling con-
stants (J) are given in hertz (Hz). Mass spectra were
Scheme 1 Synthesis of
substituted 5-phenyl-1-
R
R1MgX
d
Br
O
R
O
benzofuran-2-yl derivatives.
Reagents and conditions
a DMAP, Na2CO3, H2O, 80 °C,
5 h b Pd(PPh3)4, EtOH,
Na2CO3(aq), toluene, 110 °C,
5 h, then H2O2, RT, 1 h
c NaBH4, dioxane, 2–6 h
d Grignard reagent, THF, RT,
5–6 h
Br
Br
CHO
OH
O
a
b
R
+
O
RB(OH)2
HO
R1
R
Br
3a-l
Br
O
R
O
2a-i
1
R
c
O
R
R
S
R
4a
HO
2a
4a-f
2f
4b
4c
4d
O
O
R
R1
2b
(CH3)2CH-
(CH2)3CH-
2g
2h
3a-d
3e-h
F
2c
2d
CH3CH2-
O
C6H5CH2-
NO2
O
3i-l
Cl
F
O
4e
4f
2i
2e
S
O
O
CN
NO2
O
123

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Med Chem Res (2013) 22:78–87
Biphenyl-4-yl(5-phenyl-1-benzofuran-2-yl)methanone (2a)
determined with Agilent LC/MS instrument. Flash column
chromatography was performed with silica gel (230–400
mesh) (Merck), TLC was carried out on precoated silica
plates (kiesel gel 60 F254, BDH). Melting points were
determined in open capillaries on Buchi melting point
apparatus and are uncorrected. All reagents involved in the
experiments are commercially available and used without
further purification. The yields are of purified compounds
and are not optimized.
Pale yellow solid (78 %), m.p.: 162–168 °C. 1H NMR
(DMSO-d6, d ppm); 7.89 (s, 1H), 7.26–7.34 (m, 5H),
7.13–7.22 (m, 6H), 6.97–7.06 (m, 5H), 6.97 (s, 1H); Anal.
calcd. for C27H18O2: C, 86.53; H, 4.80; O, 8.54 %; found:
C, 86.50; H, 4.76; O, 8.50 %. MW: 374.43; [m/z]?: 375.33.
(40-Ethyl-biphenyl-4-yl)-[5-(4-ethyl-phenyl)-benzofuran-2-
yl]methanone (2b)
General
1
Pale yellow solid (69 %), m.p.: 136.5-139 °C. H NMR
Synthesis of (5-bromo-1-benzofuran-2-yl)
(4-bromophenyl)methanone (1)
(DMSO-d6, d ppm); 9.1 (s, 1H), 8.01 (d, J = 8.2 Hz, 2H),
7.67 (d, J = 8.39 Hz, 2H), 7.64 (dd, J1 = 1.74 Hz,
J2 = 10.4 Hz, 4H), 7.22–7.44 (m, 3H), 6.9 (d, J = 2.9 Hz,
2H), 6.63 (d, J = 2.8 Hz, 2H), 2.60 (q, J = 7.6 Hz, 4H),
1.1 (t, J = 7.1 Hz, 6H); Anal. calcd. for C31H26O2: C,
86.40; H, 6.03; O, 7.43 %; found: C, 86.37; H, 6.00; O,
7.41 %. MW: 430.53; [m/z]?: 431.41.
To DMAP (10 % mmol) and Na2CO3 (1.5 mmol) in
water, 2-bromo-1-(4-bromophenyl)ethanone (1 mmol) and
5-bromo-2-hydroxybenzaldehyde (1 mmol) were added.
The resulting mixture was stirred at 80 °C for 5 h. The
mixture was extracted with CH2Cl2 (30 mL), washed with
water. The organic layers were combined washed with
saturated sodium chloride solution, dried over anhydrous
Na2SO4, and evaporated in vacuum. The residue was
purified by column chromatography on silica gel (230–400
mesh) (ethyl acetate/petroleum ether = 20/80, v/v) to give
(20-Ethoxy-biphenyl-4-yl)-[5-(2-ethoxy-phenyl)-
benzofuran-2-yl]methanone (2c)
Pale yellow solid (84 %), m.p.: 125–128 °C. 1H NMR
1
the pure product 1 (89 %). H NMR (CDCl3, d ppm): 8.1
(DMSO-d6,
d ppm); 7.60–7.67 (m, 4H), 7.45 (d,
(s, 1H), 7.9 (d, J = 7.8 Hz, 2H), 7.7 (d, J = 7.7 Hz, 2H),
7.65–7.68 (m, 1H), 7.6 (s, 1H), 7.5–7.58 (m, 2H). m.p.:
125.5–128.5 °C. MW: 380.06; [m/z]?: 381.0.
J = 8.2 Hz, 1H), 7.38 (dd, J1 = 1.78 Hz, J2 = 10 Hz,
1H), 7.26–7.28 (m, 5H), 6.96–7.15 (m, 4H), 6.90 (s, 1H),
3.98 (q, J = 6.76 Hz, 4H), 1.26 (t, J = 7.60 Hz, 6H);
Anal. calcd. for C31H26O4: C, 80.50; H, 5.67; O, 13.84 %;
found: C, 80.35; H, 5.65; O, 13.8 %. MW: 462.5; [m/z]?:
463.4.
General method for the preparation of the biphenyl
methanones 2a–i
Two molar aqueous Na2CO3 (11.65 mL) was added to a
solution of (5-bromo-1-benzofuran-2-yl)(4-bromophe-
nyl)methanone 1 (1.0 g, 3.32 mmol) in toluene (20 mL).
The mixture was bubbled with nitrogen for one minute and
then Pd(PPh3)4 (0.20 g, 0.166 mmol) was added to the
mixture. Phenyl or substituted phenyl boronic acid
(6.64 mmol) in ethanol (5 mL) was added to the above
mixture and the reaction was refluxed at 110 °C for 5 h.
After the reaction was complete, the residual borane was
oxidized by the addition of H2O2 (30 %, 2.5 mL) at room
temperature for 1 h. The solvent was removed under the
vacuum. The crude product was extracted with CH2Cl2
(100 mL) and washed with water (2 9 100 mL) and sat-
urated sodium chloride solution (100 mL). The organic
layer was dried over anhydrous Na2SO4, filtered and con-
centrated under the vacuum to result light yellow oily
residue. Purification by flash column chromatography
(ethyl acetate/petroleum ether = 30/70, v/v) gave the cor-
responding biphenyl methanone 2a–i.
(20-Fluoro-biphenyl-4-yl)-[5-(2-fluoro-phenyl)-benzofuran-
2-yl]methanone (2d)
Pale yellow solid (68 %), m.p.: 120–124 °C. 1H NMR
(DMSO-d6, d ppm); 8.01 (d, J = 8 Hz, 2H), 7.90 (s, 1H),
7.46–7.87 (m, 5H), 7.30–7.41 (m, 8H); Anal. calcd. for
C27H16F2O2: C, 78.94; H, 3.89; O, 7.79 %; found: C, 78.9;
H, 3.84; O, 7.75 %. MW: 410.4; [m/z] ?: 411.43.
(30-Nitro-biphenyl-4-yl)-[5-(3-nitro-phenyl)-benzofuran-2-
yl]methanone (2e)
Pale yellow solid (80 %), m.p.: 165–169 °C. 1H NMR
(DMSO-d6, d ppm); 8.01 (d, J = 8 Hz, 2H), 7.92 (s, 1H),
7.43–7.85 (m, 5H), 7.28–7.39 (m, 8H); Anal. calcd. for
C27H16N2O6: C, 69.76; H, 3.44; N, 6.02; O, 20.67 %;
found: C, 69.72; H, 3.40; N, 5.98; O, 20.61 %; MW:
464.42; [m/z] ?: 465.41.
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Med Chem Res (2013) 22:78–87
81
(30-Methanesulfonyl-biphenyl-4-yl)-[5-(3-methanesulfonyl-
phenyl)-benzofuran-2-yl]methanone (2f)
Grignard reagent was quenched by the addition of aqueous
hydrochloric acid (1.5 N, 20 mL) and stirred at room
temperature for 30 min. The solvent was concentrated
under reduced pressure and water (10 mL) was added to
the residue. The product was extracted with ethyl acetate
(2 9 50 mL) and washed with saturated sodium chloride
solution (25 mL), the organic layers were combined and
dried over anhydrous Na2SO4 and the solvent concentrated
under reduced pressure to obtain crude compounds. Puri-
fication by flash column chromatography (ethyl acetate/
petroleum ether = 40/60, v/v) gave the corresponding
tertiary alcohols 3a–l.
Brown solid (69 %), m.p.: 123–135 °C. 1H NMR (DMSO-
d6, d ppm); 8.26 (s, 2H), 8.01–8.15 (m, 6H), 7.75–7.81 (m,
4H), 7.70 (t, J = 8 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 3.02
(s, 6H); Anal. calcd. for C29H22O6S2: C, 65.58; H, 4.14; O,
18.09; S, 12.09 %; found: C, 65.54; H, 4.12; O, 18.05; S,
12.07 %. MW: 530.6; [m/z]?: 531.5.
(40-Vinyl-biphenyl-4-yl)-[5-(4-vinyl-phenyl)-benzofuran-2-
yl]methanone (2g)
1-Biphenyl-4-yl-2-methyl-1-(5-phenyl-benzofuran-2-
yl)propan-1-ol (3a)
Yellow solid (72 %), m.p.: 126–129 °C. 1H NMR (DMSO-
d6, d ppm); 7.6–7.7 (m, 4H), 7.48 (d, J = 8.4 Hz, 1H), 7.44
(dd, J1 = 1.7 Hz, J2 = 10.2 Hz, 1H), 7.34–7.38 (m, 5H),
7.24–7.32 (m, 4H), 7.20 (s, 1H), 7.19 (t, J = 1.82 Hz, 2H),
5.99 (d, J = 17.64 Hz, 1H); Anal. calcd. for C31H22O2: C,
87.22; H, 5.15; O, 7.5 %; found: C, 87.18; H, 5.11; O, 7.46
%. MW: 426.5; [m/z]?: 427.4.
Brown syrup (53 %), 1H NMR (DMSO-d6, d ppm); 7.79 (s,
1H), 7.26–7.33 (m, 5H), 7.12–7.20 (m, 6H), 6.98–7.07 (m,
5H), 6.90 (s, 1H), 5.87 (s, 1H), 4.08–4.21 (m, 1H), 1.25 (d,
J = 3.6 Hz, 6H); Anal. calcd. for C30H26O2 C, 86.01; H,
6.21; O, 7.64 %; found: C, 85.97; H, 6.18; O, 7.60 %. MW:
418.52; [m/z]?: 419.5.
1-{3-[2-(30-Acetyl-biphenyl-4-carbonyl)-benzofuran-5-yl]-
phenyl}ethanone (2h)
1-Biphenyl-4-yl-2,2-dimethyl-1-(5-phenyl-benzofuran-2-
yl)propan-1-ol (3b)
Yellow solid (63 %), m.p.: 109.5–114.0 °C. 1H NMR
Yellow solid (65 %), m.p.: 105–108 °C. 1H NMR (DMSO-
d6, d ppm); 7.89 (s, 1H), 7.26–7.35 (m, 5H), 7.14–7.24
(m, 6H), 6.98–7.07 (m, 5H), 6.97 (s, 1H), 6.07 (s, 1H), 1.05
(s, 9H); Anal. calcd. for C31H28O2 C, 86.08; H, 6.47; O,
7.39 %; found: C, 86.02; H, 6.42; O, 7.35 %. MW: 432.55;
[m/z]?: 433.44.
(DMSO-d6,
d ppm); 7.6–7.68 (m, 4H), 7.40 (d,
J = 8.16 Hz, 1H), 7.35 (dd, J1 = 1.7 Hz, J2 = 10.2 Hz,
1H), 7.23–7.26 (m, 5H), 6.99–7.14 (m, 4H), 6.97 (s, 1H),
2.5 (s, 6H); Anal. calcd. for C31H22O4 C, 81.21; H, 4.84; O,
13.96 %; found: C, 81.10; H, 4.82; O, 13.92 %. MW:
458.5; [m/z]?: 459.4.
1-Biphenyl-4-yl-1-(5-phenyl-benzofuran-2-yl)propan-1-ol
(3c)
6-Chloro-40-[5-(2-chloro-5-cyano-phenyl)benzofuran-2-
carbonyl]biphenyl-3-carbonitrile (2i)
Yellow solid (58 %), m.p.: 132–137 °C. 1H NMR (DMSO-
d6, d ppm); 7.84 (s, 1H), 7.24–7.31 (m, 5H), 7.10–7.25 (m,
6H), 6.98–7.10 (m, 5H), 6.90 (s, 1H), 5.98 (s, 1H), 2.58 (q,
J = 7.6 Hz, 2H), 1.10 (t, J = 7.55 Hz, 3H); Anal. calcd.
for C29H24O2 C, 86.03; H, 5.93; O, 7.91 %; found: C,
86.01; H, 5.89; O, 7.87 %. MW: 404.49; [m/z]?: 405.4.
Pale yellow solid (75 %), m.p.: 182–188 °C. 1H NMR
(DMSO-d6, d ppm); 7.54 (s, 1H), 7.50 (d, J = 7.29 Hz,
1H), 7.24–7.29 (m, 5H), 7.12–7.23 (m, 6H), 6.98 (s, 1H);
Anal. calcd. for C29H14Cl2N2O2 C, 70.54; H, 2.83; N, 5.67;
O, 6.48 %; found: C, 70.50; H, 2.79; N, 5.63; O, 6.44 %.
MW: 493.33; [m/z]?: 494.31.
1-Biphenyl-4-yl-2-phenyl-1-(5-phenyl-benzofuran-2-
yl)ethanol (3d)
General method for the preparation of the tertiary
alcohols 3a–l
Brown syrup (76 %), 1H NMR (DMSO-d6, d ppm); 7.82 (s,
1H), 7.40–7.81 (m, 7H), 7.28–7.33 (m, 3H), 7.14–7.23 (m,
6H), 6.98–7.06 (m, 5H), 6.82 (s, 1H), 6.15 (s, 1H), 5.10 (d,
J = 4 Hz, 2H); Anal. calcd. for C34H26O2 C, 87.44; H,
5.57; O, 6.85 %; found: C, 87.41; H, 5.52; O, 6.81 %. MW:
466.56; [m/z]?: 467.62.
To a cooled (0 °C) solution of biphenyl methanone
(1 mmol) in anhydrous THF (25 mL) was added Grignard
reagent (6 mmol) under nitrogen and then the mixture was
allowed to stir at room temperature under nitrogen for
5–6 h. After the reaction was complete, the residual
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Med Chem Res (2013) 22:78–87
1-(40-Ethyl-biphenyl-4-yl)-1-[5-(4-ethyl-phenyl)-
benzofuran-2-yl]-2-methyl-propan-1-ol (3e)
1.25 (d, J = 3.6 Hz, 6H); Anal. calcd. for C34H34O4 C,
80.53; H, 6.71; O, 12.63 %; found: C, 80.50; H, 6.65; O,
12.61 %. MW: 506.63; [m/z]?: 507.5.
Brown syrup (60 %), 1H NMR (DMSO-d6, d ppm); 7.78 (s,
1H), 7.45–7.60 (m, 7H), 7.25–7.35 (m, 5H), 6.95 (d,
J = 8.45 Hz, 2H), 6.85 (s, 1H), 5.85 (s, 1H), 2.80 (m, 1H),
2.58 (q, J = 7.79 Hz, 4H), 1.25 (d, J = 3.5 Hz, 6H); 1.07
(t, J = 7.45 Hz), 6H); Anal. calcd. for C34H34O2 C, 85.96;
H, 7.16; O, 6.74 %; found: C, 85.92; H, 7.12; O, 6.70 %.
MW: 474.63; [m/z]?: 475.52.
1-(20-Ethoxy-biphenyl-4-yl)-1-[5-(2-ethoxy-phenyl)-
benzofuran-2-yl]-2,2-dimethyl-propan-1-ol (3j)
Yellow solid (60 %), m.p.: 105–109 °C. 1H NMR (DMSO-
d6, d ppm); 7.61–7.67 (m, 4H), 7.45 (d, J = 8.4 Hz, 1H),
7.35 (dd, J1 = 1.6 Hz, J2 = 10 Hz, 1H), 7.25–7.28 (m,
5H), 6.95–7.08 (m, 4H), 6.90 (s, 1H), 6.01 (s, 1H), 4.01 (q,
J = 1.6 Hz, 4H), 1.22 (t, J = 7.6 Hz, 6H), 1.02 (s, 9H);
Anal. calcd. for C35H36O4 C, 80.66; H, 6.91; O, 12.29 %;
found: C, 80.61; H, 6.86; O, 12.21 %. MW: 520.65; [m/
z]?: 521.6.
1-(40-Ethyl-biphenyl-4-yl)-1-[5-(4-ethyl-phenyl)-
benzofuran-2-yl]-2,2-dimethyl-propan-1-ol (3f)
Brown syrup (52 %), 1H NMR (DMSO-d6, d ppm);
7.61–7.70 (m, 4H), 7.44 (d, J = 8.41 Hz, 1H), 7.34 (dd,
J1 = 1.7 Hz, J2 = 10.1 Hz, 1H), 7.25–7.29 (m, 5H),
6.95–7.10 (m, 4H), 6.90 (s, 1H), 6.01 (s, 1H), 2.59 (q,
J = 7.55 Hz, 4H), 1.09 (t, J = 7.7 Hz, 6H); 1.03 (s,9H);
Anal. calcd. for C35H36O2 C, 85.95; H, 7.36; O, 6.54 %;
found: C, 85.91; H, 7.32; O, 6.51 %. MW: 488.65; [m/z]?:
489.6.
1-(20-Ethoxy-biphenyl-4-yl)-1-[5-(2-ethoxy-phenyl)-
benzofuran-2-yl]propan-1-ol (3k)
Yellow solid (61 %), m.p.: 165–167 °C. 1H NMR (DMSO-
d6, d ppm); 7.66 (s, 1H), 7.45–7.49 (m, 5H), 7.26–7.34 (m,
5H), 7.06 (t, J = 2.8 Hz, 2H), 6.97 (q, J = 7.2 Hz, 2H),
6.83 (s, 1H), 5.92 (s, 1H), 4.01 (q, J = 1.6 Hz, 6H), 1.23 (t,
J = 7.6 Hz, 9H); Anal. calcd. for C33H32O4 C, 80.37; H,
6.49; O, 12.99 %; found: C, 80.32; H, 6.47; O, 12.91 %.
MW: 492.6; [m/z]?: 493.5.
1-(40-Ethyl-biphenyl-4-yl)-1-[5-(4-ethyl-phenyl)-
benzofuran-2-yl]propan-1-ol (3g)
1
Brown solid (85 %), m.p.: 139-141 °C. H NMR (DMSO-
d6, d ppm); 7.80 (s, 1H), 7.45–7.59 (m, 7H), 7.24–7.30 (m,
5H), 6.95 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 6.62 (d,
J = 8.4 Hz, 1H), 5.95 (s, 1H), 2.58 (q, J = 7.6 Hz, 6H),
1.08 (t, J = 7.6 Hz, 9H); Anal. calcd. for C33H32O2 C,
85.97; H, 6.94; O, 6.94 %; found: C, 85.91; H, 6.91; O,
6.92 %. MW: 460.6; [m/z]?: 461.57.
1-(20-Ethoxy-biphenyl-4-yl)-1-[5-(2-ethoxy-phenyl)-
benzofuran-2-yl]-2-phenyl-ethanol (3l)
Brown syrup (76 %), 1H NMR (DMSO-d6, d ppm); 7.63 (s,
1H), 7.28–7.55 (m, 4H), 7.19–7.24 (m, 5H), 6.98–7.06 (m,
10H), 6.84 (s, 1H), 6.15 (s, 1H), 4.46 (d, J = 5.6 Hz, 2H),
4.02 (q, J = 1.65 Hz, 4H), 1.23 (t, J = 7.6 Hz, 6H); Anal.
calcd. for C38H34O4 C, 82.2; H, 6.12; O, 11.5 %; found: C,
82.01; H, 6.08; O, 11.3 %. MW: 554.67; [m/z]?: 555.6.
1-(40-Ethyl-biphenyl-4-yl)-1-[5-(4-ethyl-phenyl)-
benzofuran-2-yl]-2-phenyl-ethanol (3h)
Yellow solid (92 %), m.p.: 146–148 °C. 1H NMR (DMSO-
d6, d ppm); 7.78 (s, 1H), 7.27–7.54 (m, 4H), 7.19–7.24 (m,
5H), 6.98–7.09 (m, 10H), 6.80 (s, 1H), 6.20 (s, 1H), 4.46
(d, J = 5.5 Hz, 2H), 2.57 (q, J = 7.76 Hz, 4H), 1.07 (t,
J = 7.7 Hz, 6H); Anal. calcd. for C38H34O2 C, 87.24; H,
6.50; O, 6.12 %; found: C, 87.20; H, 6.46; O, 6.09 %. MW:
522.67; [m/z]?: 523.6.
General method for the preparation of the carbinols
4a–f
To a cooled (0 °C) solution of biphenyl methanone
(5 mmol) in anhydrous 1,4-dioxan (15 mL) was added
sodium borohydride (10 mmol) and then the mixture was
allowed to stir at room temperature under nitrogen for
2–6 h. The solvent was concentrated under reduced
pressure and aqueous hydrochloric acid (1.5 N, 10 mL)
was added to the residue. The oil formed was extracted
with diethyl ether (2 9 50 mL) and washed with water
(2 9 25 mL), the organic layers were combined and
dried over the anhydrous Na2SO4 and the solvent con-
centrated under reduced pressure to obtain the title
compounds 4a–f.
1-(20-Ethoxy-biphenyl-4-yl)-1-[5-(2-ethoxy-phenyl)-
benzofuran-2-yl]-2-methyl-propan-1-ol (3i)
1
White solid (50 %), m.p.: 123–128 °C. H NMR (DMSO-
d6, d ppm); 7.61–7.68 (m, 4H), 7.5 (d, J = 8.3 Hz, 1H),
7.36 (dd, J1 = 1.7 Hz, J2 = 10.5 Hz, 1H), 7.27–7.29 (m,
5H), 6.96–7.10 (m, 4H), 6.90 (s, 1H), 5.81 (s, 1H), 4.08 (m,
1H), 3.99 (q, J = 6.8 Hz, 4H), 1.27 (t, J = 7.6 Hz, 6H),
123

Med Chem Res (2013) 22:78–87
83
Biphenyl-4-yl-(5-phenyl-benzofuran-2-yl)methanol (4a)
(20-Ethoxy-biphenyl-4-yl)[5-(2-ethoxy-phenyl)benzofuran-
2-yl]methanol (4f)
1
Pale yellow solid (90 %), m.p.: 148–153.5 °C. H NMR
(DMSO-d6, d ppm); 9.06 (s, 1H), 7.45–7.81 (m, 10H), 7.28
(d, J = 7.1 Hz, 4H), 7.24 (d, J = 6.8 Hz, 2H), 6.75 (s,
1H), 6.28 (d, J = 5.2 Hz, 1H), 5.84 (d, J = 4.8 Hz, 1H);
Anal. calcd. for C27H20O2 C, 86.06; H, 5.31; O, 8.50 %;
found: C, 86.02; H, 5.27; O, 8.46 %. MW: 376.44; [m/z]?:
377.5.
Brown solid (82 %), m.p.: 152.5–157 °C. 1H NMR
(DMSO-d6, d ppm); 7.7 (s, 1H), 7.4–7.52 (m, 6H),
7.24–7.34 (m, 8H), 6.97 (s, 1H), 6.29 (d, J = 4.6 Hz, 1H),
5.94 (d, J = 4.75 Hz, 1H), 3.94 (q, J = 6.66 Hz, 4H), 1.24
(t, J = 7.54 Hz, 6H); Anal. calcd. for C31H28O4 C, 80.07;
H, 6.02; O, 13.77 %; found: C, 80.03; H, 6.00; O, 13.73 %.
MW: 464.55; [m/z]?: 465.45.
(40-Ethyl-biphenyl-4-yl)-[5-(4-ethyl-phenyl)-benzofuran-2-
yl]methanol (4b)
Pharmacology
The newly synthesized compounds were screened for their
antimicrobial and antioxidant properties to study the effect
of functionalization at the carbonyl carbon and substitution
at biphenyl ring on these activities.
1
White solid (88 %), m.p.: 131–135 °C. H NMR (DMSO-
d6, d ppm); 9.06 (s, 1H), 7.46–7.80 (m, 10H), 7.26 (d,
J = 6.8 Hz, 4H), 6.75 (s, 1H), 6.28 (d, J = 5.2 Hz, 1H),
5.8 (d, J = 4.8 Hz, 1H), 2.61 (q, J = 7.6 Hz, 4H), 1.08 (t,
J = 7.2 Hz, 6H); Anal. calcd. for C31H28O2 C, 86.0; H,
6.47; O, 7.39 %; found: C, 85.97; H, 6.43; O, 7.35 %. MW:
432.5; [m/z]?: 433.4.
Antimicrobial activity
The antimicrobial activities of the synthesized compounds
against E. coli, S. aureus, B. subtilis,, and C. albicans were
examined qualitatively and quantitatively by the presence
or absence of inhibition zones and zone diameter. Each vial
with one bead was inoculated into 10 mL Tryptone soya
broth (TSB) in 50 mL conical flask, and were incubated at
37 °C for bacteria and 30 °C for fungi till they showed
good growth. From the well grown flask 100 lL of the
inoculum was spread uniformly on the pre-set media plates
(Tryptone soya agar (TSA) and malt extract agar (MEA)
respectively for bacteria and fungi). Sterile filter paper
disks (5 mm diameter) were placed on the spread plates,
from the stock solutions of the compounds 5 lL (250 lg)
of the sample was loaded aseptically. Dimethyl sulfoxide
(DMSO) was used as negative control and ampicillin (for
bacteria) and nystatin (for fungi) as positive controls. TSA
plates were incubated at 37 °C for 24 h and MEA plates
were incubated at 30 °C for 3 days. The plates were
checked for zone of inhibition, the compounds which
showed good zone inhibition, were studied for minimum
inhibitory concentration (MIC). MIC was performed at
different concentrations 1, 10, 25, and 50 mg/mL. 100 lL
of the inoculum was uniformly spread onto preset plates
placed sterile filter paper disks (5 mm diameter) on the
spread plates and 5 lL of the sample was loaded asepti-
cally. TSA plates were incubated at 37 °C for 24 h and
MEA plates were incubated at 37 °C for 3 days. The
results given in Table 1 shows that compounds 1, 2a, 2f,
and 2g exhibited antimicrobial activity with MIC ranging
between 0.001 mg/mL to 0.500 mg/mL. Moreover com-
pounds 2e, 2h, 4c, and 4d shows activity against B. subtilis
and 4d against S. aureus with MIC ranging between
0.050 mg/mL to 0.500 mg/mL.
(20-Fluoro-biphenyl-4-yl)-[5-(2-fluoro-phenyl)-benzofuran-
2-yl]methanol (4c)
Pale yellow solid (92 %), m.p.: 102–106 °C. 1H NMR
(DMSO-d6, d ppm); 7.74 (s, 1H), 7.49–7.59 (m, 6H),
7.26–7.29 (m, 8H), 6.79 (s, 1H), 6.35 (d, J = 4.8 Hz, 1H),
5.91 (d, J = 4.8 Hz, 1H); Anal. calcd. for C27H18F2O2 C,
78.5; H, 4.36; O, 7.75 %; found: C, 78.1; H, 4.32; O, 7.72
%. MW: 412.42; [m/z]?: 413.4.
(30-Nitro-biphenyl-4-yl)-[5-(3-nitro-phenyl)-benzofuran-2-
yl]methanol (4d)
Pale yellow solid (86 %), m.p.: 115–119 °C. 1H NMR
(DMSO-d6, d ppm); 7.75 (s, 1H), 7.49–7.60 (m, 6H),
7.29–7.34 (m, 8H), 6.97 (s, 1H), 6.35 (d, J = 4.7 Hz, 1H),
5.97 (d, J = 4.9 Hz, 1H); Anal. calcd. for C27H18N2O6 C,
69.46; H, 3.85; N, 6.00; O, 20.58 %; found: C, 69.42; H,
3.82; N, 5.98; O, 20.54 %. MW: 466.44; [m/z]?: 467.3.
(30-Methanesulfonyl-biphenyl-4-yl)[5-(3-
methanesulfonylphenyl)benzofuran-2-yl]methanol (4e)
1
White solid (96 %), m.p.: 125–128 °C. H NMR (DMSO-
d6, d ppm); 7.7 (s, 1H), 7.45–7.55 (m, 6H), 7.24–7.32 (m,
8H), 6.98 (s, 1H), 6.30 (d, J = 4.65 Hz, 1H), 5.91 (d,
J = 4.75 Hz, 1H); 3.04 (s, 6H); Anal. calcd. for
C29H24O6S2 C, 65.33; H, 4.50; O, 18.02; S, 12.01 %;
found: C, 65.30; H, 4.46; O, 18.00; S, 11.97 %. MW:
532.62; [m/z]?: 533.6.
123

84
Med Chem Res (2013) 22:78–87
Table 1 Zone of inhibition and MIC of 5-phenyl-1-benzofuran-2-yl derivatives
Zone of inhibition in mm (50 mg/mL concentration)
Minimum inhibitory concentration (MIC mg/mL)
Compounds
S. aureus
B. subtilis
E. coli
C. albicans
S. aureus
B. subtilis
E. coli
C. albicans
1
23
15
0
24
22
7
17
0
15
10
0
0.050
0.001
–
0.050
0.010
0.050
0.500
0.050
0.100
0.050
0.500
0.050
0.050
0.010
–
2a
–
–
–
–
–
–
–
2e
0
2f
0
16
16
10
6
0
6
–
0.500
0.500
–
2g
10
8
0
6
0.250
0.100
–
2h
0
0
4c
0
0
0
–
4d
6
6
0
0
0.500
–
Ampicillin
Nystatin
16
0
15
0
20
0
0
6
Table 2 DPPH assay in % of 5-phenyl-1-benzofuran-2-yl derivatives
Antioxidant studies
Compounds DPPH assay in % Compounds DPPH assay in %
The target compounds were tested for 2,2-diphenyl-1-
picryhydrazyl (DPPH) radical scavenging activity with
butylated hydroxytoluene (BHT) as standard according to
the previously reported procedure (Braca and co workers,
2001). This method is based on the reduction of free radical
DPPH by free radical scavengers. The procedure involves
the measurement of decrease in absorbance of DPPH at
517 nm, which is proportional to the activity of free radical
scavenger added to DPPH reagent solution. A stock solu-
tion of test compounds (1 mg/mL) and DPPH (0.004 %)
was prepared in 95:5 methanol:water. To 3 mL of freshly
prepared DPPH solution in test tube, was added stock
solution of test compound (100 lg) and reacted for 15 min
and the absorbance was measured at 517 nm using UV–
Visible spectrophotometer (Shimadzu UV-1800, Japan).
BHT was used as a reference standard and dissolved in
distilled water to make the stock solution with the same
concentration (1 mg/mL). Ascorbic acid was used as con-
trol sample and 95 % methanol served as blank. % scav-
enging of the DPPH free radical was measured by using the
following equation:
1
11.7
7.3
3f
24.2
55.2
60.3
11.4
21.2
5.5
2a
2b
2c
2d
2e
2f
3g
3h
3i
17.3
16.1
18.7
19.5
12.3
33.7
19.0
15.8
52.3
18.8
12.9
30.5
34.7
3j
3k
3l
16.4
79.5
55.7
21.3
19.9
39.8
19.3
90.42
–
2g
2h
2i
4a
4b
4c
4d
4e
4f
3a
3b
3c
3d
3e
BHT
–
connection error in bond order. OSIRIS, an ADMET based
Java library layer that provides reusable cheminformatics
functionality which is an entirely in-house developed drug
discovery informatics system was used to predict the total
drug score via in silico (Thomas and co workers, 2009).
Energy of the molecules was minimized using Dundee
PRODRG2 server (Alexander et al., 2004). The energy
minimized compounds were then read as input for Auto-
Dock 4.2, in order to carry out the docking simulation
(Morris and co workers, 1998). All the heteroatoms were
removed from the2VF5.pdb, to make complex receptor
free of any ligand before docking. The Graphical User
Interface program ‘‘AutoDock Tools’’ was used to prepare,
run, and analyze the docking simulations. Kollman united
atom charges, solvation parameters and polar hydrogen’s
were added to the receptor for the preparation of protein in
docking simulation. Since ligands are not peptides,
% Scavenging activity
¼ ðabsorbance of the control
ꢁabsorbance of the test sampleÞ=
absorbance of the control ꢂ 100:
The results are tabulated in Table 2, compounds 3a, 3g,
3h, 4a, and 4b show comparable activity with the standard.
In silico molecular docking studies
The ligands were drawn in ChemDraw Ultra 6.0 (Chem
Office package) assigned with proper 2D orientation
and the structure of each compound was analyzed for
123

Med Chem Res (2013) 22:78–87
85
Gasteiger charge was assigned and then non-polar hydro-
gens were merged. AutoDock requires pre-calculated grid
maps, one for each atom type; present in the ligand being
docked and it stores the potential energy arising from the
interaction with macromolecule. This grid must surround
the region of interest (active site) in the macromolecule.
In the present study, the binding site was selected based on
the amino acid residues, which are involved in binding
with glucosamine-6-phosphate (D-fructose-6-P phosphate)
of GlcN-6-P synthases obtained from PDB with ID 2VF5
which would be considered as the best accurate active
region as it is solved by experimental crystallographic data
(Wallace and co workers, 1995). The region of D-fructose-
6-P phosphate bound within GlcN-6-P synthases was
considered to be active site as the enzyme exhibits absolute
specificity for L-glutamine as an amino donor and for
D-fructose-6-P phosphate as an acceptor substrate. GlcN-
6-P synthase catalyses a practically irreversible reaction,
catalyzing the first committed step in an important branch
of the glycolytic pathway, this amidotransferase is an
obvious point of metabolic control and hence the target
(Chmara et al., 1986; Badet et al., 1988). Therefore, the
grid was centered at the region including all the 12 amino
acid residues (Ala602, Val399, Ala400, Gly301, Thr302,
Ser303, Cys300, Gln348, Ser349, Thr352, Ser347, and
Lys603) that surround active site. The grid box size was set
residues in the considered active pocket. Docking software
AutoDock 4.2 Program supplied with AutoGrid 4.0 and
AutoDock 4.0 was used to produce grid maps. The spacing
between grid points was 0.375 angstroms. The Lamarckian
Genetic Algorithm (LGA) was chosen to search for the best
conformers. During the docking process, a maximum of 10
conformers was considered for each compound. All the
AutoDock docking runs were performed in Intel Centrino
Core2Duo CPU @ 2.20 GHz of IBM system origin, with
2 GB DDR2 RAM. AutoDock 4.0 was compiled and run
under Windows XP operating system.
Results and discussion
The newly synthesized compounds were screened for their
antimicrobial and antioxidant properties to study the effect
of functionalization at the carbonyl carbon and substitution
at biphenyl ring on these activities. The introduction of
hydroxyl group at carbonyl carbon enhanced the antioxi-
dant property (3a, 3g, 3h, 4a, and 4b), while antimicrobial
activity decreased; biphenyl methanone 1, 2a, 2f, and 2g
exhibited antimicrobial activity with minimal inhibitory
concentration (MIC) ranging between 0.001 mg/mL to
0.500 mg/mL (Table 1), tertiary alcohols 3a, 3g, and 3h
and carbinols 4a and 4b exhibited the promising antioxi-
dant property (Table 2). Biphenyl methanone 2a when
converted to corresponding carbinol (4a) and tertiary
alcohols (3a–d); 3a and 4a have not shown antimicrobial
˚
at 70, 64, and 56 A for x, y, and z, respectively, and the grid
center was set to 30.59, 15.822, and -3.497 for x, y, and
z respectively, which covered all the 12 amino acid
Fig. 1 Ligands 2a, 2g,
ampicillin, and nystatin docked
in best of its conformation in
image a, b, c, and
d respectively. (In all the
images the ligands are
represented in green color and
the target protein GlcN-6-P in
secondary structure and
secondary colorization) (Color
figure online)
123

86
Med Chem Res (2013) 22:78–87
activity, but antioxidant property correspondingly
increased. The carbinol 4b of 4-ehtyl biphenyl methanone
(2b) and its tertiary alcohols 3e–h have not shown anti-
microbial activity, but antioxidant property correspond-
ingly increased. 2-ethoxy-biphenyl derivatives (2c, 3i–
l and 4f) were not active for these studies. The dibromo
compound 1 with MIC of 0.05 mg/mL against antibacterial
and antifungal strains (S. aureus, B. subtilis, E. Coli, and
C. albicans, when bromo group was displaced with its
bipheyl substituents, the derivatives (2a–i, 3a–l, and 4a–
f) were inactive against E.Coli. The biphenyl compound 2a
(without substitution on biphenyl ring) and 4-vinyl (2g)
were active against S.aureus, B.subtilis, and C.albicans;
3-methylsulphonyl (2f) derivative was active against
B.subtilis and C.albicans; 2-acetyl derivative (2h) was
active against S.aureus and B.subtilis; 3-nitro methanone
derivative 2e and its carbinol 4d were active against
B.subtilis, and S.aureus and B.subtilis respectively; 3-nitro
methanone derivative 2e and 2-fluoro carbinol 4c were
equally active against B.subtilis. Other methanone deriva-
tives, 2-ethoxy (2c), 2-flouro (2d) and their carbinols
(4f and 4c respectively) and 2-chloro-5-cyano methanone
derivative (2i) have not shown activity on any of the strains
tested. Biphenyl methanones (2a–i) have displayed poor
antioxidant activity but carbinol of 2a and 2b (4a and 4b,
respectively) and tertiary alcohols (3a, 3g and 3h) good
activity against the standard used. The antimicrobial
activity of biphenyl methanone (2a–i) shows that the
activity has bettered with decreasing order of electron
withdrawing nature (NO2 [ CN [ CH3CO; 2e, 2f, and 2h,
respectively) or electron donating nature (vinyl [ phenyl;
2g and 2a, respectively), but have not shown promising
antioxidant activity. The functionalization (decrease in the
electron withdrawing effect) at carbonyl carbon of biphe-
nyl methanone reduced antimicrobial activity, but the
antioxidant activity has bettered; the carbinols 4c and 4d
have shown antimicrobial activity and tertiary alcohols
(3a–i) have not shown antimicrobial activity, and carbinols
Table 3 Binding energy (kJ mol-1), inhibition constant, and total
internal energy (kJ mol-1
)
Compound Binding energy (kJ mol-1
)
Inhibition constant (lM)
1
-6.58
-10.16
-7.37
-6.14
-8.22
-7.32
-7.47
-7.56
15.02
08.09
03.96
03.55
07.10
01.31
03.36
02.28
05.44
03.14
2a
2e
2f
2g
2h
4c
4d
Ampicillin -7.66
Nystatin -2.72
Fig. 2 The crevice of the
portion of the target protein
GlcN-6-P and ligand 2a docked
in best of its conformation.
a Ligand molecule being shown
in ball and stick in green color
and the target protein molecule
in molecular surface view
colored by residue. b 2D
LIGPLOT view of ligand
molecule being shown in ball
and stick and the surrounded
amino acid residues of the
active pocket crevice after
docking (Color figure online)
123

Med Chem Res (2013) 22:78–87
87
agents possessing different structure–activity relationships. Bio-
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(3a, 3g, and 3h) and tertiary alcohols (4a and 4b) have
exhibited antioxidant activity. The effect of increase in
antioxidant activity of carbinols and tertiary alcohols could
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`
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to satisfy the purpose. The docking of receptor GlcN-6-P
with newly synthesized candidate ligands exhibited well
established bonds with one or more amino acids in the
receptor active pocket. The active pocket consisted of 12
amino acid residues as Ala602, Val399, Ala400, Gly301,
Thr302, Ser303, Cys300, Gln348, Ser349, Thr352, Ser347,
and Lys603 using LIGPLOT. The synthesized ligand mol-
ecules having 2D structure were converted to energy mini-
mized 3D structures and were further used for in silico
protein–ligand docking. The ligands 1, 2a, 2e, 2f, 2g, 2h, 4c,
and 4d and ampicillin and nystatin were considered
for this study. The molecules 2a (binding energy of
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-10.16 kJ mol-1)and2g (binding energy of -8.22 kJ mol-1
)
have showed considerably good binding energy, Fig. 1
shows the docked images. Table 3 shows the binding energy
and inhibition constant of the compounds and the standards
tested. Figure 2 shows the critical image view using LIG-
PLOT of molecule 2a which promises to be the best among
all the synthesized series.
Conclusion
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program to generate schematic diagrams of protein-ligand
interactions. Protein Eng 8:127–134
In conclusion, the synthesized compounds 1, 2a, 2f, and 2g
showed antimicrobial activity and 3a, 3g, 3h, 4a exhibited
promising antioxidant activity. The most active compound
2a possessed MIC of 0.001 mg/mL against S.aureus and
0.01 mg/mL against B.subtilis and C.albicans and com-
pound 1 with MIC of 0.05 mg/mL against each of S.aur-
eus, B.subtilis, E.Coli, and C.albicans and 4a showed
promising antioxidant activity by DPPH method.
Acknowledgments The authors thank M/s. Biocon Ltd., Bangalore,
India for providing laboratory facility for necessary laboratory works,
analytical support and antimicrobial activity. We also gratefully
acknowledge Dr. P. V. Srinivas for his continued advice.
Miyaura N, Suzuki A, Yanagi T (1981) The palladium-catalyzed
cross-coupling reaction of phenylboronic acid with haloarenes in
the presence of bases. Synth Commun 11:513–519
Singh BN, Vaughan WEM (1970) The effect of amiodarone, a new
anti-anginal drug, on cardiac muscle. Br J Pharmacol 39:
657–667
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