Synthesis and antimicrobial activity of novel benzo[f]coumarin compounds

Article abstract of DOI:10.1134/S1068162012040152

The acetyl benzo[f]coumarin condensed with phenyl hydrazine to afford the corresponding phenyl hydrazone which cyclized into the pyrazolyl benzocoumarin under Vilsmeier reaction conditions. The pyrazolylaldehyde was used as starting material for synthesis

Full text of DOI:10.1134/S1068162012040152

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2012, Vol. 38, No. 6, pp. 639–646. © Pleiades Publishing, Ltd., 2012.
Synthesis and Antimicrobial Activity
of Novel Benzo[f]coumarin Compounds1
R. M. Zaki2, Y. A. Elossaily, and A. M. Kamal ElꢀDean
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
eꢀmail: remonch2003@yahoo.com
Received November 17, 2011; in final form, January 18, 2012
Abstract—The acetyl benzo[f]coumarin condensed with phenyl hydrazine to afford the corresponding pheꢀ
nyl hydrazone which cyclized into the pyrazolyl benzocoumarin under Vilsmeier reaction conditions. The
pyrazolylaldehyde was used as starting material for synthesis of other heterocyclic compounds containing
pyrazolylbenzocoumarin moiety. The ethyl benzo[f]coumarin carboxylate were subjected to react with other
reagents to synthesize thiazolidinyl and oxadiazolyl derivatives attached to benzocoumarin system. Some of
novel synthesized compounds showed highly antibacterial and antifungal activities.
Keywords: acetylbenzo[f]coumarin, pyrazolylbenzocoumarin, bromoacetylbenzo[f] chromenone, synthesis, antiꢀ
microbial activity
DOI: 10.1134/S1068162012040152
2 1
INTRODUCTION
the literature procedure was used as a precursor startꢀ
ing material for synthesis other heterocyclic comꢀ
Natural and synthetic coumarins have been found to
exhibit a variety of pharmacological activities like antiꢀ
HIV [1], anticoagulant [2], antibacterial [3], antioxiꢀ
dant [4], and anti inflammatory [5]. Among the diverse
biological activities of coumarin the most intriguing
bioactivity is the effect against breast cancer [6–10].
Figure shows the chemical structures of some potent
antiꢀbreast cancer molecules that contain a coumarin in
their molecular makeup and in this regard it is worth
mentioning that 667 COUMATE is in phasel clinical
trials for the treatment of hormone dependent breast
cancer in postmenopausal women [11]. In continuation
of our work on naphtholaldehyde which was used as
versatile starting materials for synthesis of many heteroꢀ
pounds containing chromene moiety. Compound (I)
condensed with phenyl hydrazine in refluxing ethanol
in the presence of catalytic drops of acetic acid to
afford corresponding phenyl hydrazone (II). When
compound (II) subjected to react with Vilsmeier’s
reagent was cyclized into pyrazolylbenzocoumarin
(
III). Formation of carboxaldehyde (III) was identiꢀ
fied using spectral analyses. IR spectrum showed two
1
bands at 1720, 1680 cm–1 for (2C=O). H NMR
(CDCl3) showed two signals at 8.6, 10.1 for CHꢀpyraꢀ
zole, and CHO. Mass spectrum of aldehydes (III
)
showed a peak at = 366 corresponding to molecuꢀ
m/z
lar ion peak and base peak. When pyrazolylaldehyde
derivative (III) was condensed with thiosemicarbazide
in acetic acid afforded the corresponding thiosemicarꢀ
bazone (IV), IR of compound (IV) showed bands at
3450, 3390, 3350 cm–1 (NH, NH2). Thiosemicarbaꢀ
cyclic compounds containing naphtha[2,1ꢀb]furan
moiety with antiꢀmicrobial activity. Here in we syntheꢀ
sized a series of novel benzocoumarin compounds with
high biological activity [12, 13].
zone (IV) was cyclized with
pounds, namely, ethyl chloroacetate, chloroacetone
or ꢀbromoacetophenone in ethanol in the presence
of sodium acetate to afford thiazolylpyrazolylbenzoꢀ
coumarins ( ) and (VI). Compound ( ) undergoes
α
ꢀhalogenated comꢀ
RESULTS AND DISCUSSION
ω
Coumarins are widely available from the natural
sources [14–16] and exhibit various biological activiꢀ
ties such as anticancer [17], inhibition of platelet
aggregation [18, 19], inhibition of steroid 5aꢀreducꢀ
tase [20] and antiꢀHIV activity [21]. Acetylꢀ
V
I
cycloaddition reaction on arylidene malononitrile in
ethanol in the resence of catalytic amount of piperidine
to afford 2ꢀaminoꢀ6ꢀ(2ꢀoxoꢀbenzo[f]chromenꢀ3ꢀyl)ꢀ4ꢀ
phenylꢀ4Hꢀpyranꢀ3ꢀcarbonitrile (VII) (Scheme 1). The
formation of compound (VII) was supported using eleꢀ
benzo[f]coumarin (I) which synthesized from comꢀ
mercially available starting material and according to
mental and spectral analyses. IR of compound (VIIa
)
showed absorption bands at 1720 cm–1 for one carboꢀ
nyl group in addition to bands at 3480, 3380 cm–1 for
1
The article is published in the original.
Corresponding author: eꢀmail: remonch2003@yahoo.com.
2
639

640
ZAKI et al.
O
O
O
O
O
O
O
S
H2N
O
O
O
O
Et
1st Generation
Neo Tanshinlactone
analogue
667 COUMATE
Neo Tanshinlactone
O
OH
OH
O
N
H
N
OH
O
O
O
O
O
HO
O
O
SP500263
DNHꢀ2
Figure.
NH2 group and at 2220 cm–1 for CN group. 1H NMR 5.7 (1 H, s, H5 pyran, 7–8.7 (m, 12 H, ArꢀH), 8.8
spectrum showed signals at : 4.6 (1 H, s, H4 pyran, (1 H s, CHꢀcoumarin).
δ
H2N
O
NNHPh
O
O
O
CN
PhNHNH
2
Ar–CH=C(CN)
EtOH/AcOH
2
Ar
O
O
O
O
(VII
)
(I
)
(II)
(
(
VIIa), Ar = Ph
VIIb), Ar = C6H4OCH3p
DMF/POCl
3
Ph
Ph
N
N
N
N
H NNHCSNH
2
2
H
AcOH
N
NH2
CHO
O
O
N
O
O
S
(IV)
(III)
ClCH CO Et
2
2
EtOH/AcONa
Ph
Ph
N
N
N
N
H
H
N
N
N
N
O
O
N
O
O
O
N
R
S
S
(
VI)
(V)
(
(
Va), R = Ph
Vb), R = Me
Scheme 1.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
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2012

SYNTHESIS AND ANTIMICROBIAL ACTIVITY
641
When aldehyde (III) allowed to react with hydroxyl 2ꢀaminoꢀ6ꢀmercaptoꢀ4ꢀ[3ꢀ(2ꢀoxoꢀbenzo[f]chromenꢀ
2ꢀyl)ꢀlꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀyl]ꢀpyridineꢀ3,5ꢀdicarꢀ
bonitrile ( ). Structure of compound ( ) was eluciꢀ
dated from elemental and spectral analyses. IR of
ompound ( ) showed appearance of new absorption
bands at 3410, 3310 cm–1 (NH2), and at 2220 cm–1
amine hydrochloride in ethanol in the presence of
sodium acetate, the corresponding oxime (VIII) was
obtained. The produced pyrazolaldehyde oxime
X
X
(
VIII) was dehydrated into corresponding pyrazole
X
carbonitrile derivative (IX) by heating with acetic
anhydride. Compound (III) reacts with cyanothioacetꢀ
amide in ethanol in the presence of piperidine to give (2 CN) group (Scheme 2).
Ph
H NOH, HCl
2
N
N
(III)
EtOH/AcONa
NCCH CSNH
2
EtOH/piperidine
2
O
VIII)
O
N OH
SH
N
(
H2N
CN
Ac2O
Ph
NC
N
N
N
Ph
N
CN
O
(X)
O
O
(IX)
O
Scheme 2.
Bromination of acetylbenzo[f]coumarin (I) using tion in ethanol in the presence of potassium carbonate to
NBS in CHCl3 afforded bromoacetyl derivative (XI), give compound (XIII). Compound (XIII) can be syntheꢀ
which react with mercaptopyridine carbonitrile in ethaꢀ sized directely from (XI) by refluxing with mercaptopyriꢀ
nol in the presence of sodium acetate to afford comꢀ dine carbonitrile in ethanol in the presence of potassium
pound (XII). The latter compound underwent cyclizaꢀ carbonate (Scheme 3).
O
O
O
O
CH2Br
NBS/CHCl3
CN
O
O
)
(
I)
(XI
SH
N
CN
SH
N
NC
O
O
NH2
O
S
EtOH/K2CO3
N
S
O
O
O
(XII)
N
(
XIII
)
Scheme 3.
On the other hand ethyl 2ꢀoxoꢀbenzo[f]coumarinꢀ hydrate in ethanol to afford 2ꢀoxoꢀbenzo[f]coumarinꢀ
3ꢀcarboxylate (XIV) was reacted with hydrazine 3ꢀcarbohydrazide (XV). The latter compound was
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
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642
ZAKI et al.
reacted with carbon disulfide in the mixture of refluxed in different alcohol to give carbamate esters of
dioxan/ammonium hydroxide to produce the correꢀ coumarin (XIV).
sponding ammonium dithiocarbamate (XVI). Dithioꢀ
carbamate salt (XVI) was cyclized using sodium chloꢀ
roacetate solution followed by treatment with dilute
HCl to give thiazolidinone derivative (XVII).
On the other hand carbohydrazide (XV) was
reacted with carbon disulfide in pyridine on steam
bath to give 3ꢀ(5ꢀmercapto[1,3,4]oxadiazolꢀ2ꢀyl)ꢀ
benzo[f]chromenꢀ2ꢀone (XX) in good yield. Comꢀ
Treatment of carbohydrazide (XV) in acetic acid pound (XX) in turn was reacted with phenacyl broꢀ
with sodium nitrite solution at 0–5°C affording the mide in ethanol in the presence of sodium acetate to
coumarin carboazide derivative (XVIII). Carboazide afford 3ꢀ(5ꢀbenzoylmethylmercapto[1,3,4]oxadiazolꢀ
(
XVIII) underwent Curtius rearrangement when 2ꢀyl)ꢀbenzo[f]chromenꢀ2ꢀone (XXI) (Scheme 4).
O
O
O
O
O
H
N
S
S
SNH4
N
1ꢀClCH CO Na/H O
2
N
2
2
N
H
H
2ꢀHCl
S
O
O
(
XVII
)
(XVI)
CS2
Dioxan/NH OH
4
O
O
O
N
N
NH2
SH
O
N
O
NH NH
2
⋅
H O/EtOH
2
CS /pyridine
2
2
H
O
)
O
XV)
O
O
O
(XIV
(
(
XX)
PhCOCH Br/AcONa
2
EtOH
NaNO /AcOH
2
N
N
O
H
N
O
SCH2COPh
O
ROH
R
N3
O
O
)
O
O
O
O
XVIII)
O
(
XXI)
(
(
(
XIX
(
XIXa), R = Et
XIXb), R = •CH(CH3)2
Scheme 4.
Biological activities:
Some of the synthesized compounds in this work
were chosen and screened in vitro for their antimicroꢀ
azole ring in compound (Va ), (Vb), (VI) we noticed
that the activity was increased, when pyrazole ring in
compound (III) replaced with pyran ring in comꢀ
pound (VIIa,b) the activity diminished to zero against
most of fungi species tested. While the maximum inhiꢀ
bition for all species growth was exhibited by pyrazolyꢀ
loxime (VIII) which shows highly antiꢀfungal activity
bial activity against some strains of bacteria and fungi.
The antifungal, antibacterial activities of tested
compounds were evaluated by the reported method
[22] using 2% concentration of selected compounds in
DMSO as a solvent. The inhibition zone (mm) comꢀ
pared with Clotrimazole as a reference. In the case of
antibacterial the concentration of tested compound is
also 2% and the inhibition zone in mm were compared
with chloramphenicol as a reference.
Some tested compounds showed remarkable antiꢀ
bacterial and antifungal activities. In case of antiꢀfunꢀ
gal activity (Table 1) we find that pyrazolylcarboxaldeꢀ
hyde (III), which has no effect against all fungi species
use except Fusarium oxysporum, when the carboxaldeꢀ
against Geotrichum candidum and Candida albicans
,
whereas the aldehydic group in compound (III) was
converted into oxime. Also compound (IX) shows
moderate activity towards all of the tested species.
Replacing the pyrazole ring in compounds (VIII),
(
IX) by oxadiazole ring in compounds (XX), (XXI)
showed no antifungal activity against most of tested
fungi species as in case of pyran compounds (VII a,b).
On the other hand, we noticed that all tested comꢀ
pounds showed remarkable activity against all bacteꢀ
hyde group replaced with thiosemicarbazone group in rial species except in case of phenylthiazole comꢀ
compound (IV), show activity against all tested speꢀ pound (Va ) which showed low activity against Serratia
cies. When thiosemicarbazone group cyclized into thiꢀ marcescens and Bacillus cereus (Table 2). For example,
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
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2012

SYNTHESIS AND ANTIMICROBIAL ACTIVITY
Table 1. Antifungal activity (inhibition zone, mm)
643
Geotrichum
candidum
Candida
albicans
Aspergillus
flavus
Scopulairopsis
brevicaulis
Trichophyton
rubrum
Fusarium
oxysporum
Compd.
(III)
(IV)
(Va)
(Vb)
(VI)
(VIIa)
(VIIb)
(VIII)
(IX)
0
12
16
17
12
0
10
22
20
12
0
0
10
18
10
10
8
0
18
12
14
10
0
0
20
18
16
14
0
0
10
13
8
12
0
8
19
15
17
8
0
0
19
21
0
0
0
0
0
26
18
0
0
26
25
17
14
0
30
26
0
0
42
16
24
0
8
55
(XX)
(XXI)
Clotrimazole
0
28
25
40
Table 2. Antibacterial activity (inhibition zone, mm)
Serratia
marcescens
(Gram negative)
Staphylococcus
aureus
(Gram positive)
Pseudomonas
aeruginosa
(Gram negative)
Escherichia coli
(Gram negative)
Bacillus cereus
(Gram positive)
Compd.
(III)
(IV)
(Va)
(Vb)
(VI)
16
22
18
23
15
10
14
22
18
12
18
34
34
13
0
12
18
8
10
25
24
26
24
36
26
18
0
18
22
0
13
20
8
12
16
12
24
24
18
12
19
44
8
10
24
12
22
30
26
18
16
38
32
14
16
18
22
18
22
32
(VIIa)
(VIIb)
(VIII)
(IX)
(XX)
(XXI)
Chloramphenicol
the pyrazolylcarboxyaldehyde showed moderate activꢀ according to the literature procedure [25], mp 186°C,
110°C
3ꢀ[1ꢀ(Phenylꢀhydrazono)ꢀethyl]ꢀbenzo[f]chromenꢀ
2ꢀone (II). To a mixture of compound ( ) (1.19 g,
.
ity against all the tested bacteria species except against
Escherichia coli which showed high activity. The thioꢀ
semicarbazone (IV) and methyl thiazole (Vb) showed
activity against all tested species. The thiazolone comꢀ
pound (VI) exhibited remarkable activity especially
against Pseudomonas aeruginosa. Replacing pyrazole
ring by pyran ring in compounds (VIIa,b) the activity
decreased, the oxime (VIII) showed high activity
comperable by the carbonitrile (IX). Compounds
I
5 mmol) and phenyl hydrazine (0.54 g, 5 mmol) in
ethanol (20 mL), few drops of acetic acid was added.
The mixture was heated under reflux for 1 h, and then
allowed to cool. The solid product was collected by filꢀ
tration and recrystallized from ethanol as orange crysꢀ
tals in (1.43 g, 87%) yield, mp 218–220°C. Anal.
(
XX), (XXI) showed moderate activity against all the
calcd. for C21H16N2O2 (328.37): C, 76.81; H, 4.91; N,
tested bacterial species.
8.53%. Found: C, 77.02; H, 5.21; N, 8.32%. IR: 3420
1
(NH), 1700 (CO). H NMR (CDCl3): 2.2 (s, 3 H,
CH3), 7.5–8.8 (m, 12 H, ArꢀH), 11.0 (s, 1 H, NH).
EXPERIMENTAL
3ꢀ[1ꢀ(1ꢀPhenylpyrazolꢀ3ꢀylꢀ4ꢀformyl)ꢀethyl]ꢀbenꢀ
Melting points were uncorrected and determined zo[f]chromenꢀ2ꢀone (III): To compound (II) (3.28 g,
using a Kofler melting point apparatus. IR spectra (ν, 0.01 mol) in DMF (10 mL), Vilsmeier reagent
cm–1) were recorded in a Pye Unicam SP 3ꢀ100 specꢀ
DMF/POCl3, 0.03 mol) was added, then the mixture
trometer using KBr Wafer technique. 1H NMR spectra was heated at 70
for 6 h. The reaction mixture was
) were recorded on a Varian EMꢀ390 90 MHz specꢀ allowed to cool, poured into ice/water mixture and
(
°
C
(
δ
trometer in a suitable deuteriated solvent using TMS neutralized with Na2CO3 to pH 7. The solid product
as internal standard. Mass spectra were recrded on a was collected and recrystallized from ethanol as pale
Joel JMS600 mass spectrometer. 1ꢀnaphtholꢀ2ꢀcarꢀ yellow crystals in 65% yield, mp 218–220°C. Anal.
boxaldehyde was prepared according to literature proꢀ calcd. for C23H14N2O3 (366.38): C, 75.40; H, 3.85; N,
cedure [23, 24]. Compound (I), (XIV) was prepared 7.65%. Found: C, 75.64; H, 4.08; N, 7.42%. IR: 1720,
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
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644
ZAKI et al.
1680 (2 C=O). 1H NMR (CDCl3): 7.5–8.2 (m, 11 H,
ArꢀH), 8.4, 8.6 (2 s, 1 H, CH pyrazole, CH couꢀ 4Hꢀpyranꢀ3ꢀcarbonitrile (VIIa–VIIc). General proceꢀ
marin), 9.9 (s, 1 H, CHO). MS: = 366. dure: To a mixture of compound ( ) (1.2 g, 5 mmol)
2ꢀAminoꢀ6ꢀ(3ꢀoxoꢀbenzo[f]chromenꢀ2ꢀyl)ꢀ4ꢀarylꢀ
m
/
z
I
and arylidene malononitrile (5 mmol) in ethanol
(20 mL), few drops of piperidine was added. The mixꢀ
ture was refluxed for 2 h. The solid product, which
formed on hot was collected and recrystallized from
dioxan as yellow crystals.
3ꢀ(2ꢀOxoꢀbenzo[f]chromenꢀ3ꢀyl)ꢀ1ꢀphenylpyrazolꢀ
4ꢀcarboxaldehydeꢀthiosemicarbazone (IV). A mixture
of compound (II) (5 mmol) and thiosemicarbazide in
acetic acid (20 mL) was heated under reflux for 2 h,
then allowed to cool. The solid product was collected
and recrystallized from acetic acid as pale yellow crysꢀ
tals in 88% yield, mp 268–270°C. IR: 3450, 3390,
3350 (NH, NH2). H NMR (DMSOꢀ
(m, 14 H, ArꢀH, CH pyrazole, –CH=N–, CH couꢀ
marin), 9.8 (s, 2 H, NH2), 10.8 (s, 1 H, NH). Anal.
calcd. for C24H17N5O2S (439.50): C, 65.59; H, 3.90;
N, 15.93; S, 7.30%. Found: C, 65.72; H, 4.12; N,
15.70; S, 7.09%.
2ꢀAminoꢀ6ꢀ(2ꢀoxoꢀbenzo[f]chromenꢀ3ꢀyl)ꢀ4ꢀpheꢀ
nylꢀ4Hꢀpyranꢀ3ꢀcarbonitrile (VIIa). Produced in
(1.0 g, 56%) yield, mp > 300°C. IR: 3480, 3380
(NH2), 2220 (CN), 1720 (C=O). 1H NMR
(CF3CO2D): 4.60 (s, 1 H, H4 pyran), 5.70 (s, 1 H, H5
pyran), 7.00–8.70 (m, 12 H, ArꢀH), 8.80 (s, 1 H, couꢀ
marin H). Anal. calcd. for C25H16N2O3 (392.42): C,
76.52; H, 4.11; N, 7.14%. Found: C, 76.74; H, 4.33;
N, 6.94%.
2ꢀAminoꢀ6ꢀ(2ꢀoxoꢀbenzo[f]chromenꢀ3ꢀyl)ꢀ4ꢀpꢀmehoꢀ
xyphenylꢀ4Hꢀpyranꢀ3ꢀcarbonitrile (VIIb). Produced
in (0.076 g, 36%) yield, mp > 300°C. IR: 3480, 3380
(NH2), 2220 (CN), 1720 (C=O). 1H NMR
(CF3CO2D): 3.7 (s, 3 H, CH3), 4.6 (s, 1 H, H4 pyran),
5.8 (s, 1 H, H5 pyran), 7–8.7 (m, 12 H, ArꢀH), 8.9 (s,
1 H, coumarin H). Anal. calcd. for C26H18N2O4
(422.44): C, 73.92; H, 4.29; N, 6.63%. Found: C,
74.15; H, 4.04; N, 6.40%.
1
d6):
δ
7.1–8.6
[3ꢀ(2ꢀOxoꢀbenzo[f]chromenꢀ3ꢀyl)ꢀ1ꢀphenylpyrazolꢀ
4ꢀylidene]ꢀ4ꢀphenyl[1,3]thiazolꢀ2ꢀhydrazone (Va).
A
mixture of compound (IV) (0.44 g, 0.001 mol), phenacyl
bromide (0.2 g, 1 mmol) and sodium acetate (0.01 mol)
in ethanol (20 mL) was heated under reflux for 5 h,
and then allowed to cool. The solid product was colꢀ
lected and recrystallized from ethanol as orange crysꢀ
tals, in 62% yield, mp 168–170°C. IR: 3420 (NH),
1720 (C=O). 1H NMR (DMSOꢀ
d6): 7.1–8.6 (m, 20
δ
H, ArꢀH, CH pyrazole, CH coumarin, CH=N and
CH thiazole), 9.8 (s, 2 H, NH2), 10.8 (s, 1 H,NH).
Anal. calcd. for C32H21N5O2S (539.62): C, 71.23; H,
3.92; N, 12.98; S, 5.94%. Found: C, 71.47; H, 4.12; N,
13.22; S, 6.17%.
3ꢀ(2ꢀOxoꢀbenzo[f]chromenꢀ3ꢀyl)ꢀ1ꢀphenylpyrazolꢀ4ꢀ
carboxaldehydeꢀoxime (VIII). A mixture of compound
III) (1.83 g, 5 mmol), hydroxylamine hydrochloride
(
(0.5 g, 7 mmol) and sodium acetate (0.82 g, 0.01 mol)
in ethanol (20 mL) was refluxed for 4 h, then poured
into cold water (100 mL). The solid precipitate was filꢀ
tered off, dried and recrystallized from ethanol as pale
yellow crystals in (1.6 g, 84%) yield, mp 235°C. IR:
[3ꢀ(2ꢀOxoꢀbenzo[f]chromenꢀ3ꢀyl)ꢀ1ꢀphenylpyrazolꢀ
4ꢀylidene]ꢀ4ꢀmethyl[1,3]thiazolꢀ2ꢀhydrazone (Vb).
A
mixture of compound (IV) (0.44 g, 1 mmol), chloroaceꢀ
tone (0.092 g, 1 mmol) and sodium acetate (0.01 mol) in
ethanol (20 mL) was heated under reflux for 5 h, then
allowed to cool. The solid product was collected and
recrystallized from ethanol as orange crystals, in 68%
yield, mp 154–156°C. Anal. calcd. for C27H19N5O2S
(477.55): C, 67.91; H, 4.01; N, 14.67; S, 6.71%.
Found: C, 68.12; H, 4.23; N, 14.35; S, 6.44%. IR:
3500 (OH), 1700 (C=O). 1H NMR (DMSOꢀ
d6): 7.1–
8.7 (m, 13 H, ArꢀH, CH pyrazole, pyrane H), 11.0 (s,
1 H, OH). Anal. calcd. For C23H15N3O3 (381.39): C,
72.43; H, 3.96; N, 11.02%. Found: C, 72.63; H, 4.21;
N, 10.80%.
3ꢀ(2ꢀOxoꢀbenzo[f]chromenꢀ3ꢀyl)ꢀ1ꢀphenylpyrazoleꢀ
4ꢀcarbonitrile (IX). A sample of compound (VI) (1.9 g,
5 mmol) in acetic anhydride (20 mL) was heated
under reflux for 4 h, then allowed cooling and poured
into cold water (100 mL). The solid product was colꢀ
lected and recrystallized from ethanol as white crysꢀ
tals, in 78% yield, mp 145°C. IR: 2220 (CN), 1720
3450 (NH), 1700 (C=O). 1H NMR (DMSOꢀ
(s, 3 H, H3), 7.1–8.6 (m, 15 H, ArꢀH, CH pyrazole,
CH coumarin, CH=N and CH thiazole), 9.8 (s, 2 H,
NH2), 10.8 (s, 1 H, NH).
d
6): 2.3
δ
2ꢀ{N'ꢀ[3ꢀ(3ꢀOxoꢀ3Hꢀbenzo[f]chromenꢀ2ꢀyl)ꢀ1ꢀpheꢀ
nylꢀ1Hꢀpyrazolꢀ4ꢀylmethylene]ꢀhydrazino}ꢀthiazolꢀ4ꢀ
one (VI). A mixture of compound (IV) (0.44 g,
0.001 mol), ethyl chloroacetate (0.1 mL, 0.12 g,
1 mmol) and sodium acetate (0.01 mol) in ethanol
(20 mL) was heated under reflux for 5 h, and then
(C=O). 1H NMR (DMSOꢀ
d6): 7.1–8.4 (m, 11 H, Arꢀ
H), 8.5, 8.6 (2 s, 2 H, CH pyrazole, pyrane H). Anal.
calcd. for C23H13N3O2 (363.38): C, 76.02; H, 3.61; N,
11.56%. Found: C, 75.80; H, 382; N, 11.71%.
2ꢀAminoꢀ6ꢀmercaptoꢀ4ꢀ[3ꢀ(3ꢀoxoꢀ3
Hꢀbenzo[f]chroꢀ
allowed to cool. The solid product was collected and menꢀ2ꢀyl)ꢀ1ꢀphenylꢀ1
H
ꢀpyrazolꢀ4ꢀyl]ꢀpyridineꢀ3,5ꢀdiꢀ
recrystallized from ethanol as red crystals in (56% carbonitrile (X). To a mixture of compound (III) (1.8 g,
yield), mp 196–198°C. IR: 3450 (NH), 1720, 1700 5 mmol), cyanothioacetamide (0.5 g, 5 mmol), few
1
(2 C=O). H NMR (DMSOꢀ
d
6): 3.9 (s, 2 H, CH2), drops piperidine was added. The mixture was heated
7.0–8.5 (m, 12 H, ArꢀH and CH pyrazole), 8.6, 8.8 under reflux for 4 h, and then was allowed to cool. The
(2s, 2 H, N=CH– proton and CH pyran proton). solid product was collected and recrystallized from
Anal. calcd. for C26H17N5O3S (479.52): C, 65.13; H, ethanol as yellow crystals in (1.1 g, 44%) yield, mp
3.57; N, 14.60; S, 6.69%. Found: C, 64.89; H, 3.35; N, 269–270°C. IR: 3410, 3310 (NH2), 2900–2700 (SH),
14.38; S, 6.85%.
2220 (2 CN), 1720 (C=O). 1H NMR (DMSOꢀ
d6): 3.5
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SYNTHESIS AND ANTIMICROBIAL ACTIVITY
645
(s, 1 H, SH), 5.8 (s, 2 H, NH2), 7.0–8.6 (m, 11 H, Arꢀ chloro acetate solution (prepared from neutralization
H), 8.7, 8.9 (2 s, 2 H, CH pyrazole proton and CH of chloroacetic acid 5 mmol, with NaOH 0.1 N to pH
pyran proton). Anal. calcd. for C29H16N6O2S (512.55): 6 and the complete the neutralization with sodium
C, 67.96; H, 3.15; N, 16.40; S, 6.26%.
3ꢀ(2ꢀBromoꢀacetyl)ꢀbenzo[f]chromenꢀ2ꢀone (XI).
A mixture of compound (I) (2.38 g. 0.01 mol) and
carbonate solution 10% to pH 7) was added. Stirring
continued for 2 h, then heated on water bath for 1 h,
and acidified with (0.1 N HCl) to pH 7. The solid
product was collected and recrystallized from ethanol
N
ꢀbromosuccinimide (2.3 g, 0.01 mol) in chloroform
as yellow crystals (0.96 g, 52%) yield, mp 234–236°C
.
(20 mL) was heated on water bath for 5 h, then the
mixture was evaporated till dryness. The solid residue
was washed with hot water to get ride of any unreacted
Nꢀbromosuccinimide. The solid product was colꢀ
lected and recrystallized from ethanol as yellow crysꢀ
tals, mp 156–58°C. Anal. calcd. for C15H9BrO3
Anal. calcd. for C17H10N2O4S2 (370.41): C, 55.13; H,
2.72; N, 7.56; S, 17.31%. IR: 3410 (NH), 1720, 1690
(2 CO), 1250 (C=S). 1H NMR (CDCl3): 4.6 (s, 2 H,
CH2), 7.3–8.7 (m, 7 H, ArꢀH, CH coumarin), 10.5 (s,
1 H, NH).
1
(317.14): C, 56.81; H, 2.86; Br, 25.20%. H NMR
3ꢀOxoꢀ3Hꢀbenzo[f]chromenꢀ2ꢀcarbonyl
azide
(CDCl3): 4.4 (s, 2 H, CH2), 7.1–8.6 (m, 6 H, ArꢀH),
8.8 (s, 1 H, CH coumarin).
(XVIII). To ice cooled solution of (XV) (1.27 g,
5 mmol) in acetic acid (10 mL), sodium nitrite soluꢀ
tion (0.69 g, 0.01 mol) in H2O (2 mL) was added drop
wise with stirring during 10 minutes. After finishing of
addition, stirring was continued for 1 h., then the reacꢀ
tion mixture was allowed to stand for 4 h, and poured
into cold water (100 mL). The solid product was colꢀ
lected by filtration, dried and used without further
purification. Anal. calcd. for C14H7N3O3 (265.23): C,
63.40; H, 2.66; N, 15.84%. Found: C, 63.65; H, 2.90;
N, 15.69%. IR: 1700, 1720 (2 CO). 1H NMR
(CDCl3): 7.0–8.7 (m, 7 H, ArꢀH, CH coumarin), 9.5
(s, 1 H, NH).
2ꢀ[2ꢀ(4,6ꢀDimethylꢀpyridinꢀ2ꢀylsulfanyl)ꢀacetyl]ꢀ
benzo[f]chromenꢀ3ꢀone (XII). A mixture of comꢀ
pound (XI) (1.1 g, 5 mmol) and 0.82 g, 5 mmol) and
sodium acetate (0.5 g, 6 mmol) in ethanol (20 mL) was
refluxed for 3 h, then allowed to cool. The solid prodꢀ
uct was collected and recrystallized from dioxane as
greenish yellow crystals in (1.3 g, 65% yield, mp.
>300°C. Anal. calcd. for C23H16N2O3S (400.46): C,
68.98; H, 4.03; N, 7.00; S, 8.01%. 1H NMR (DMSOꢀ
d6):
2.5, 2.7 (2 s, 6 H, 2 CH3), 4.05 (s, 2 H, CH2), 7.0 (s, 1
H, CH pyridine), 7.4–8.5 (m, 6 H, ArꢀH), 8.6 (s, 1 H,
CH coumarin).
Alkyl (3ꢀoxoꢀ3Hꢀbenzo[f]chromenꢀ2ꢀyl)ꢀcarbamꢀ
ate (XIX a,b). General Procedure: A sample of carꢀ
boazide (XVIII) (1.32 g, 5 mmol) in appropriate alcoꢀ
hol (10 mL) was heated under refluxed for 2 h. The
reaction mixture was allowed to cool. The solid product
was filtered off, dried and recrystallized from toluene.
3ꢀ(3ꢀAminoꢀ4,6ꢀdimethylꢀthieno[2,3ꢀb]pyridineꢀ
2ꢀcarbonyl)ꢀbenzo[f]chromenꢀ2ꢀone (XIII). To a samꢀ
ple of compound (XII) (2 g, 5 mmol) suspended in
ethanol (20 mL), ethanolic solution sodium ethoxide
(0.34 g in 10 mL ethanol) was added. The mixture was
heated under reflux for 1 h, then allowed to cool and
poured into cold water (100 mL). The solid product
was filtered off and recrystallized from dioxane as yelꢀ
low crystals (0.96 g, 48%) yield, mp > 300°C. Anal.
calcd. for C23H16N2O3S (400.46): C, 68.98; H, 4.03;
(3ꢀOxoꢀ3Hꢀbenzo[f]chromenꢀ2ꢀyl)ꢀcarbamic acid
ethyl ester (XIXa). Produced as grey crystals (0.95 g,
67% yield), mp 137–139°C. Anal. calcd. for
C16H13NO4 (283.29): C, 67.84; H, 4.63; N, 4.94 %.
Found: C, 68.08; H, 4.80; N, 5.17%. IR: 3360 (NH),
N, 7.00; S, 8.01%. Found: C, 69.21; H, 4.25; N, 6.83;
1
1690, 1710, (CO). H NMR (CDCl3): 1.25 (t, 3 H,
1
S, 7.81%. H NMR (DMSCꢀ
d6): 2.6, 2.8 (2 s, 6 H,
CH3 ester), 4.15 (q, 2 H, CH2), 7.0–8.7 (m, 7 H, ArꢀH,
2 CH3), 6.85 (s, 2 H, NH2), 7.0 (s, 1 H, CH pyridine),
7.4–8.7 (m, 7 H, ArꢀH, CH coumarin).
3ꢀOxoꢀ3Hꢀbenzo[f]chromenꢀ2ꢀcarboxylic
CH coumarin), 9.5 (s, 1 H, NH).
(3ꢀOxoꢀ3Hꢀbenzo[f]chromenꢀ2ꢀyl)ꢀcarbamic acid
isopropyl ester (XIXb). Produced as white crystals
(0.86 g, 58% yield), mp 128–130°C. Anal. calcd. for
C17H15NO4 (297.31): C, 68.68; H, 5.09; N, 4.71%. C,
68.46; H, 4.89; N, 4.95%. IR: 3360 (NH), 1690, 1710
(CO). 1H NMR (CDCl3): 1.55 (d, 6 H, 2 CH3), 4.45
(m, 1 H, CH), (7.0–8.7 (m, 7 H, ArꢀH, CH couꢀ
marin), 9.5 (s, 1 H, NH).
acid
hydrazide (XV). A mixture of ester (XIV) (1.34 g,
5 mmol) and 99% hydrazine hydrate (0.26 g, 5 mmol)
in ethanol (20 mL was heated under reflux for 4 h. The
solid product was collected and recrystallized from
dioxane as yellow crystals, (0.88 g, 69%) yield, mp
220°C. Anal. calcd. for C14H10N2O3 (254.25): C,
66.14; H, 3.96; N, 11.02%. IR: 3450, 3370, 3330 (NH,
NH2), 1700, 1670 (2 CO). 1H NMR (CDCl3): 4.5 (s, 2
H, NH2), 7.0–8.7 (m, 7 H, ArꢀH, CH coumarin), 9.7
(s, 1 H, NH).
3ꢀ(5ꢀMercaptoꢀ[1,3,4]oxadiazolꢀ2ꢀyl)ꢀbenzo[f]chroꢀ
menꢀ2ꢀone (XX). A mixture of compound (XV) (1.27 g,
5 mmol), and carbon disulfide (2 mL, 0.33 mol) in
3ꢀOxoꢀ3Hꢀbenzo[f]chromenꢀ2ꢀcarboxylic acid (4ꢀ pyridine (10 mL) was heated on water bath for 10 h,
oxoꢀ2ꢀthioxoꢀthiazolidinꢀ3ꢀyl)ꢀamide (XVII). Ice then allowed to cool. The solid product was collected
cooled stirred solution of compound (XV) (1.27 g, and recrystallized from dioxane as yellow crystals in
5 mmol) in dioxan (10 mL)/ammonium hydroxide (1.06 g, 72%) yield, mp 292–294°C. Anal. calcd. for
solution (5 mL, 30%) mixture, carbon disulfide (2 mL) C15H8N2O3S (296.31): C, 60.80; H, 2.72; N, 9.45; S,
was added. The reaction mixture was stirred for 2 h. To 10.82%. Found: C, 61.02; H, 2.51; N, 9.69; S, 10.61%.
the thiocarbamate salt XVI formed in situ, sodium IR: 2750–2600 (SH), 1700 (CO). 1H NMR (DMSOꢀ
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
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2012

646
ZAKI et al.
8. Gaelle, L.B., Christin, R., Jean, F.P., Jean, D.B.,
d
6): 3.0 (s, 1 H, SH), (7.0–8.7 (m, 7 H, ArꢀH, CH
coumarin).
3ꢀ(5ꢀBenzoylmethylmercaptoꢀ[1,3,4]oxadiazolꢀ2ꢀ
yl)ꢀbenzo[f]chromenꢀ2ꢀone (XXI). A mixture of (XV
Mouad, A., Veronique, M., Barbara, S., and Jack, M. R.,
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9. Brady, H., Desai, S., GayoꢀFung, L.M., Khammuꢀ
ngkhune, S., McKie, J.A., O’Leary, E., Pascasio, L.,
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)
(1.48 g, 5 mmol), phenacyl bromide (1.0 g, 5 mmol)
and sodium acetate (0.82 g, 0.01 mol) in ethanol
(20 mL) was heated under reflux for 3 h, then the reacꢀ
tion mixture was allowed to cool. The solid product
was filtered off, washed several times with water and
recrystallized from ethanol as yellow crystals (1.76 g,
82%) yield, mp 184–186°C. Anal. calcd. for
C23H14N2O4S (414.44): C, 66.66; H, 3.40; N, 6.76; S,
7.74%. Found: C, 66.42; H, 3.18; N, 7.00; S, 7.90%.
11. Stanway, S.J., Purohit, A., Woo, L.W., Sufi, S.,
Vigushin, D., Ward, R., Wilson, R.H., Stanczyk, F.Z.,
Dobbs, N., Kulinskaya, E., Elliott, M., Potter, B.V.,
IR: 1720, 1710 (2CO). 1H NMR (DMSOꢀ
d6): 4.20 (s,
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,
2 H, CH2), (7.0–8.7 (m, 7 H, ArꢀH, CH coumarin).
Procedure of antimicrobial activity. The fungal speꢀ
cies were previously isolated from cases of human derꢀ
matophytosis (Moubasher et al., 1993) [26]. The fungi
were grown in sterilized 9ꢀcm Perti dishes containing
Sabouraud’s.
12. Badr, M.Z.A., Kamal Eldean, A.M., Moustafa, O.S.,
and Zaki, R.M., J. Chem. Res., 2006, vol. 11, pp. 748–
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and Zaki, R.M., J. Chin. Chem. Soc., 2007, vol. 54,
pp. 1045–1052.
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chloramphenicol to suppress bacterial contamination
(AlꢀDoory 1980) [27]. From these cultures, agar discs
(10 mm diam.) containing spores and hyphae were
transferred aseptically to screwꢀtopped vials containing
20 mL sterile distilled water. After thorough shaking,
1ꢀmL samples of the spore suspension were pipetted
into sterile Perti dishes, followed by the addition of
15 mL liquefied SDA medium which was then left to
solidify. The tested compounds and tolnaftate were disꢀ
solved in DMSO to give 2.0% concentration. Antifunꢀ
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using 3ꢀmm diameter filter paper discs (Watmann No. 3)
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and Mukhopadhyay, A.K., J. Indian Chem. Soc., 1998,
vol. 75, pp. 666–671.
loaded with 10 mL of the solution under investigation 19. Cravotto, G., Nano, G.M., Palmisano, G., and
Tagliapietra, S., Tetrahedron: Asymmetry, 2001, vol. 12,
(200 mL/disc, 2.0%). The discs were placed on the surꢀ
face of the fungal cultures which were incubated at
30°C. The diameter of the inhibition zone around each
disc was measured. The previous method was used for
determining antibacterial activity too.
pp. 707–709.
20. Fan, G.J., Mar, W., Park, M.K., Wook, C.E., Kim, K.,
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21. Kashman, Y., Gustafson, K.R., Fuller, R.W., Cardelꢀ
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2012