Synthesis and antimicrobial of new anthraquinone derivatives incorporating pyrazole moiety

Article abstract of DOI:10.1016/j.ejmech.2010.01.021

Treatment of 2-cyano-N-(9,10-dioxo-9,10-dihydro-anthracen-2-yl)-acetamide (1) with phenyl isothiocyanate/dimethylsulphate afforded the corresponding ketene N,S-acetal 2 which upon treatment with hydrazine hydrate and 4-aminoantipyrine afforded the pyrazolo derivatives 3 and 4, respectively. 3-aminopyrazole derivative 3 was utilized as key intermediate for the synthesis of pyrazolo[3,4-d]pyrimidine 5, pentaaza-as-indacene 6, triaza-cyclopenta[c]phenanthrene 7, pyrazolo[1,5-a]pyrimidine 8, 9 and (dimethyl-pyrrol-1-yl)pyrazole 10 derivatives. Furthermore, treatment of 1 with DMF/DMA gave the corresponding acrylamide derivative 11 which upon treatment with hydrazine hydrate afforded the corresponding 3-aminopyrazole derivative 12. Moreover, coupling of 1 with 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-diazonium chloride gave the hydrazone derivative 13 which upon cyclization with acetic acid afforded the corresponding pentaaza-fluorene derivative 14. Representative compounds of the synthesized products were evaluated as antimicrobial agents. Some of these compounds exhibited promising activities.

Full text of DOI:10.1016/j.ejmech.2010.01.021

European Journal of Medicinal Chemistry 45 (2010) 1843–1848
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antimicrobial of new anthraquinone derivatives incorporating
pyrazole moiety
*
M.A. Gouda , M.A. Berghot, A.I. Shoeib, A.M. Khalil
Chemistry Department, Faculty of Science, Mansoura University, El-Gomhoria Street, Mansoura 35516, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of 2-cyano-N-(9,10-dioxo-9,10-dihydro-anthracen-2-yl)-acetamide (1) with phenyl iso-
thiocyanate/dimethylsulphate afforded the corresponding ketene N,S-acetal 2 which upon treatment
with hydrazine hydrate and 4-aminoantipyrine afforded the pyrazolo derivatives 3 and 4, respectively. 3-
Received 9 July 2009
Received in revised form
5 January 2010
Accepted 11 January 2010
Available online 20 January 2010
aminopyrazole derivative
3 was utilized as key intermediate for the synthesis of pyrazolo[3,4-
d]pyrimidine 5, pentaaza-as-indacene 6, triaza-cyclopenta[c]phenanthrene 7, pyrazolo[1,5-a]pyrimidine
8, 9 and (dimethyl-pyrrol-1-yl)pyrazole 10 derivatives. Furthermore, treatment of 1 with DMF/DMA gave
the corresponding acrylamide derivative 11 which upon treatment with hydrazine hydrate afforded the
corresponding 3-aminopyrazole derivative 12. Moreover, coupling of 1 with 4,6-dimethyl-1H-pyr-
azolo[3,4-b]pyridin-3-diazonium chloride gave the hydrazone derivative 13 which upon cyclization with
acetic acid afforded the corresponding pentaaza-fluorene derivative 14. Representative compounds of
the synthesized products were evaluated as antimicrobial agents. Some of these compounds exhibited
promising activities.
Keywords:
Anthraquinone
Ketene N,S-acetal
Aminopyrazole
Phenanthrene
Pyrimidine
Antimicrobial agent
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
Numerous 4-aminobenzopyrans and their derivatives have drawn
considerable attention in the last decade as the modulators of
Aminoanthraquinones [1] have attracted considerable attention
from both synthetic and medicinal chemists due to their biological
activities covering a wide range of applications anthracenedione
moiety [1].
potassium channels influencing cardiac activity of the heart and
blood pressure [11]. Pyrazole nucleus has pronounced pharmaco-
logical applications as anti-anxiety and antipyretic [12], analgesic
and anti-inflammatory drugs [13–15], and certain alkyl pyrazoles
show significant bacteriostatic, bactericidal and fungicidal activi-
ties [16].
These biological data prompted us to synthesize some new
pyrazole derivatives incorporating 2-amino-9,10-anthraquinone
moiety, starting from 2-cyano-N-(9,10-dioxo-9,10-dihydro-anthra-
cen-2-yl)acetamide in order to investigate their antimicrobial
activity [17].
In recent years, the problem of multidrug resistance (MDR)
towards numerous antitumor compounds has also become
important and much effort has been directed towards incorpora-
tion of a five- or six-membered heterocyclic ring in the several
aminoanthraquinone derivatives were identified as DNA inter-
calating agents [2] and the antitumor antibiotics, daunomycin, and
adriamycin [3] are examples of derivatives. Anthraquinone deriv-
atives have been utilized for the activation of human telomerase
reverse transcriptase expression [4]. Annulated arene heterocycles
and carbocycles such as chromanones [5] chromans [6] quinolines
[7] and tetrahydroquinolines [8] are present as important core
structures in many biologically active natural products and phar-
maceuticals. 2H-1-Benzopyrans (chromenes) and 3,4-dihydro-2H-
1-benzopyrans (chromans) are important classes of oxygenated
heterocycles that have attracted much synthetic interest because of
the biological activity of naturally occurring representatives [9,10].
2. Results and discussion
2.1. Chemistry
The synthetic procedures adopted to obtain the target
compounds are depicted in Schemes 1–4. The starting compound,
2-cyano-N-(9,10-dioxo-9,10-dihydro-anthracen-2-yl)-acetamide (1)
[17] was prepared with high yield and purity via fusion of 2-ami-
noanthraquinone with ethylcyanoacetate at 120–130 ꢀC. The
structure of compound 1 was established by the spectral data. The IR
spectrum showed a characteristicabsorption band at 2265 cmꢁ1 due
to CN group. Its 1H NMR spectrum exhibited presence of two singlet
* Corresponding author. Tel.: þ20 50 6432235; fax: þ20 50 2246781.
E-mail address: dr_mostafa_chem@yahoo.com (M.A. Gouda).
0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.01.021

1844
M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1843–1848
OEt
O
NC
O
AQ
O
CN
NH
Fusion, 120-130oC
1
NH2
O
4 hrs
O
NH2
N
KOH/ DMF
PhNCS
AQ
AQ
NH2NH2
NH
N
PhHN
H
O
3
O
AQ
AQ
CN
SMe
Me2SO4
CN
NH
PhHN
NH
O
PhHN
S-K+
CN
NH
2
Fusion
Sand bath
2'
PhHN
NH
O
O
O
O
CH3
CH3
H2N
H3C
N Ph
N
N
AQ =
N
Ph
CH3
4
Scheme 1.
signals at
d
4.00 and 10.91 ppm characteristic to CH2 and NH protons,
the NH2, NHPh and NH–C]O groups, respectively. The 1H NMR
spectrum of 4 displayed two singlet signals at 2.53 and 3.32 ppm
corresponding to the C]C–CH3 and (N–CH3) protons, respectively
(Scheme 1).
Pyrazolo[3,4-a]pyrimidine are of considerable chemical and
pharmacological importance as purine analogues [18,19]. Various
related compounds of these also have antitumor, anti-leukemic
activities. Several biological activities have been established for
some pyrazolo derivatives [20,21]. Also, the insecticidal activities
have been investigated for some pyrazolo derivatives [22,23]. We
reported herein the synthesis of some pyrazolo[1,5-a]pyrimidine
respectively. Thus, treatment of compound 1 with phenyl iso-
thiocyanate in DMF, and in the presence of potassium hydroxide, at
room temperature, followed by treatment with dimethyl sulphate
afforded the novel ketene N,S-acetal 2. The structure of 2 was
established on the basis of its elemental analysis and spectral data.
d
The 1H NMR spectrum displayed singlet signal at
responding tothe CH3 protons. Also, its 13C NMR spectrum displayed
signals at 162.0, 115.2, 79.6 and 18.1 corresponding to acrylonitrile
moiety and methyl group, respectively. The Reaction of 2 with
hydrazine or 4-aminoantipyrine in refluxing ethanol gave the cor-
responding pyrazole derivatives 3 and 4, respectively (Scheme 1).
The chemical structure of 3 and 4 were established on the basis
of analytical and spectral data. The 1H NMR spectrum of 3 displayed
d 2.34 ppm cor-
d
from
3-amino-5-phenylamino-1H-pyrazole-4-carboxylic
acid
(9,10-dioxo-9,10-dihydro-anthracen-2-yl)-amide (3).
Thus, compound 3 was reacted with DMF–DMA in dry DMF
afforded the corresponding pyrazolo[3,4-d]pyrimidine derivative 5.
three broad signal at
d
6.17, 9.40 and 11.21 ppm corresponding to
AQ
CHO
Cl
O
N
AQ
N
N
NH
DMF-DMA
DMF
N
O
N
N
PhHN
DMF
NH
PhHN
7
5
3
OHC
Cl
CH3
O
O
HN
NH
AQ
N
O
N
CH3
N
Ph
AQ
NH
PhHN
DMF
N
NH
PhHN
N
N
N
O
N
Ph
N
DMF
OCH3
8'
6
MeO
O
O
O
N
AQ
NH
N
AQ =
N
PhHN
OCH3
8
Scheme 2.

M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1843–1848
1845
intermediacy of 3-oxo-propylamino]-3-phenylamino-1H-pyrazole
(80) followed by cyclization and aromatization via loss of both water
and hydrogen molecules. Although the endocyclic imino group in
compound 3 is the most nucleophilic center [27–29], nevertheless, it is
the most sterically hindered site [30] (Scheme 2).
Moreover, we also investigated the reactivity of aminopyrazole
derivative 3 towards diketo compound with the aim of formation of
pyrazolo[1,5-a]pyrimidine Thus, reaction of 3 with acetylacetone or
2,5 hexadione in acetic acid afforded the corresponding pyr-
azolo[1,5-a]pyrimidine 9 and pyrrolo-1H-pyrazole 10 derivatives,
respectively (Scheme 3). The structure of compounds 9 and 10 were
confirmed on the basis of the analytical and spectral data. The mass
spectrum of 9 showed the base peak at m/z 265 due to 5,7-
dimethyl-2-phenylamino-pyrazolo[1,5-a]pyrimidine-3-carbonyl
moiety. Also, the mass spectrum of 10 showed the base peak at m/z
278 due (2,5-dimethyl-pyrrol-1-yl)-5-phenylamino-1H-pyrazole-
4-carbonyl moiety (Scheme 3).
CH3
O
N
O
O
AQ
NH
N
CH3
N
PhHN
acetic acid
O
9
3
H3C
O
N
N
AQ
CH3
O
NH
acetic acid
N
H
O
O
PhHN
10
AQ =
On the other hand, the reaction of 1 with DMF-DMA in dry
dioxane afforded 2-cyano-3-dimethylamino-N-(9,10-dioxo-9,10-
dihydro-anthracen-2-yl)-acrylamide (11), which could be trans-
formed to pyrazole derivative 12 upon heating with hydrazine
hydrate. The structure of compound 11 and 12 were elucidated on
the basis of spectral data. The 1H NMR spectrum of compound 11
Scheme 3.
The IR and mass spectra were consistent with the proposed
structure. Cyclocondensation of 3 with 5-chloro-3-methyl-phe-
nylpyrazolo-4-carboxaldehyde [24], and 2-chloro-3,4-dihydro-
naphthalene-1-carbaldehyde [25], in DMF gave the corresponding
pentaaza-as-indacene 6 and triaza-cyclopenta[c]phenanthrene 7
derivatives, respectively.
displayed two singlet signals at
methyl groups of dimethylamine group, also, the 13C NMR spec-
trum showed two signals at 43.6 and 43.3 due to dimethylamine
d 3.24 and 3.31 ppm due to two
d
moiety. The mass spectrum of compound 11 showed the base peak
at m/z 123 due to 2-cyano-3-dimethylamino-propenone moiety. In
addition, the mass spectrum of compound 12 displayed the base
peak at m/z 110 due to 3-amino-1H-pyrazole-4-carbonyl moiety.
In continuation of our interest in the synthesis of bridged head
nitrogen heterocyclic systems [31], we have found that diazotized
heterocyclic amine is an excellent building block for the synthesis of
the target compound. Thus, coupling of compound 1 with 4,6-
dimethyl-1H-pyrazolo[3,4-b]pyridin-3-diazonium chloride [32], in
pyridine at 0–5 ꢀC afforded the corresponding hydrazono compound
13. When compound 13 is refluxed in acetic acid, it can be cyclized to
pyrazolo[5,1-c][1,2,4]triazine-derivative 14 (Scheme 4).
The spectral data were in agreement with the proposed struc-
tures. The 1H NMR spectrum of compound 6 revealed singlet signal
at
d
3.28 ppm due to methyl protons. The 1H NMR spectrum of 7
displayed multiplite signals at
protons of napthalene moiety.
d 2.73 and 2.89 ppm due to ethene
Furthermore, wealso investigated the reactivityofaminopyrazole 3
towards Mannich base with the aim of preparing pyrazolo[1,5-
a]pyrimidine. Thus, reaction of 3 with 1-(4-methoxyphenyl)-3-piper-
idin-1-yl-propan-1-one [26], in glacial acetic acid afforded pyr-
azolo[1,5-a]pyrimidine derivative 8 (Scheme 2). Structure of the latter
product was confirmed on the basis of its correct elemental analysis
and spectral data. It’s 1H NMR spectrum showed singlet signal at
d 3.78
assigned to methoxy protons. This reaction may be explained by the
The formation of 14 may be interpreted through the nucleo-
philic attack of ring nitrogen on cyano group. It’s 1H NMR spectrum
O
N2+Cl-
N
AQ
CH3
N
CN
NH
O
AQ
N
CN
N
H3C
CH3
DMF-DMA
dioxane
NH
HN
H
1
Pyridine
N
CH3
N
H3C
N
H
H3C
N
11
13
NH2NH2
AcOH
N
O
NH2
NH2
N
AQ
O
NH
AQ
N
NH
O
O
N
N
N
H
N
CH3
12
AQ =
H3C
14
Scheme 4.

1846
M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1843–1848
revealed two singlet signals at
d
2.68, and 2.89 ppm assignable for
4.1.1. Synthesis of 2-cyano-N-(9,10-dioxo-9,10-dihydro-anthracen-
two methyl groups of the pyridine ring.
2-yl)-acetamide (1)
A mixture of 2-aminoanthraquinone (0.89 g; 4 mmol) and
ethylcyanoacetate (0.566 g; 5 mmol) was refluxed at 120–130 ꢀC for
5 h in air condenser, then dioxane (15 mL) was added. The reaction
mixture was refluxed for additional 1 h, then cool; the separated
product was filtered, washed with ethanol, dried and crystallized
from benzene to give compound (1) [17].
3. Pharmacology
The new synthesized compounds were screened in vitro for their
antimicrobial activity. The diameter of inhibition zone was
measured as an indicator for the activity of the compounds.
The results for antibacterial activities depicted in Table 1
revealed that compounds 4, 7, 8 and 13 exhibited good activities
against the reference chemotherapeutics, where 9 and 12 exhibited
good activities against Staphylococcus epidermidis and moderate
against Pseudomonas aeruginosa, also compound 5 and 14 exhibited
good activities against P. aeruginosa and moderate against S. epi-
dermidis. On the other hand, most of the prepared compounds
exhibited moderate antifungal activities against the reference
drugs, whereas, 4, 7, 13 and 14 exhibited good antifungal activities
against Alternaria solani. It is worth mentioning that the incorpo-
ration of anthraquinone nucleus to pyrazole moiety caused signif-
icant activity against S. epidermidis, P. aeruginosa, A. solani and
Fusarium solani.
Reddish brown powder; Yield 80%; 0.929 g; mp 295 ꢀC [Lit,
290 ꢀC]; IR (KBr):
n
/cmꢁ1 ¼ 3298 (NH); 2265 (CN), 1695, 1670 (br,
3C]O); 1H NMR (DMSO): dppm ¼ 4.00(s, 2H, CH2), 7.35–8.36 (m, 7H,
Ar–H), 10.91 (s, H, NH). Anal. for C17H10N2O3 (290.27): calcd.: C
70.34, H 3.47, N 9.65%; found: C 70.42, H 3.53, N 9.76%.
4.1.2. Synthesis of 2-cyano-N-(9,10-dioxo-9,10-dihydro-anthracen-
2-yl)-3-methylsulfanyl-3-phenylamino-acrylamide (2)
To a cold suspension of finally divided KOH (0.22 g; 4 mmol) in
dry DMF (10 mL) were added the cyanoacetamide derivative 1 (1.16
g; 4 mmol) followed by phenyl isothiocyanate (0.54 g; 4 mmol). The
mixture was stirred at room temperature over night, then (0.505 g;
4 mmol) dimethyl sulfate was added and stirring over night during
which a brown crystalline product separated out. The separated
product was filtered, washed with ethanol, dried and crystallized
from EtOH–DMF (2:1) to give compound 2.
In conclusion, we reported herein a simple and convenient route
for the synthesis of some new heterocyclic based on anthraquinone
for antimicrobial evaluation.
Brown crystals; Yield 65%; 1.14 g; mp 232 ꢀC; IR (KBr):
n
/cmꢁ1
¼
3411 (NH), 2195 (CN), 1668, 1639 (3C]O); 1H NMR (DMSO): dppm
¼
4. Experimental
2.34 (s, 3H, S–CH3), 7.15–8.37 (m, 7H, Ar–H), 10.24 (br, 1H, NH–Ph),
11.40 (br, 1H, NH–C]O); 13C NMR (CF3COOD, 500 MHz)
d: 182.8,
4.1. General
179.6, 165.3 (3CO), 162.0, 145.7, 134.5, 133.8, 133.6, 130.8, 128.5,
127.1, 124.6, 116.9, 115.2, 108.0, 79.6, 18.1; EIMS (m/z) (%) ¼ 441 (Mþ
þ 2, 0.5), 440 (Mþ þ 1, 2.2), 439 (Mþ, 7), 393 (9.1), 392 (30.8), 391
(7.9), 390 (11), 250 (6.3), 249 (26), 248 (2.5), 217 (45.8), 169 (40.2),
77 (100). Anal. for C25H17N3O3S (439.49): calcd.: C 68.32, H 3.90, N
9.56%; found: C 68.38, H 3.96, N 9.63%.
All melting points are recorded on Gallenkamp electric melting
point apparatus. The IR spectra
y
(cmꢁ1) (KBr) were recorded on
a Perkin Elmer Infrared Spectrophotometer Model 157. The 1H NMR
spectra were obtained on a Varian Spectrophotometer at 200 MHz,
using TMS as an internal reference and DMSO-d6 as solvent. The 13
C
NMR spectra were recorded on JEOL-ECA500 (National Research
Center, Egypt). The mass spectra (EI) were recorded on 70 eV with
Kratos MS equipment and/or a Varian MAT 311 A Spectrometer.
Elemental analyses (C, H and N) were carried out at the Microan-
alytical Center of Cairo Univ., Giza, Egypt.
4.1.3. Synthesis of 3-amino-5-phenylamino-1H-pyrazole-4-
carboxylic acid (9,10-dioxo-9,10-dihydro-anthracen-2-yl)-amide (3)
A suspension of product 2 (1.758 g; 4 mmol) in hydrazine
hydrate (0.2 g; 4 mmol) was refluxed in water bath for 2 h. Then,
(20 mL) ethanol was added, the reaction mixture was refluxed for
further 2 h during which a reddish brown crystalline product
separated out. The separated product was filtered, washed with
ethanol, dried and crystallized from EtOH–DMF (3:1) to give
compound 3.
Table 1
Inhibition zone (mean diameter of inhibition in mm) as a criterion of antibacterial
activities of the newly synthesized compounds.
Reddish brown crystals; Yield 75%; 1.27 g; mp 255 ꢀC; IR (KBr):
Compound
Inhibition zone in mm
Bacteria
n
/cmꢁ1 ¼ 3425 (NH2), 3425, 3332, 3175 (3NH), 1663, 1621 (3C]O);
1H NMR (DMSO): dppm ¼ 6.17 (br, 2H, NH2), 6.77 (br, 1H, pyrazole
NH), 7.23–8.51 (m, 12H, Ar–H), 9.40 (br, 1H, NH–Ph), 11.21 (br, 1H,
NH–C]O); EIMS (m/z) (%) ¼ 331 (Mþ ꢁ NHPh, 27.8), 223 (61.1), 221
(33.3), 164 (88.9), 99 (100). Anal. for C24H17N5O3 (423.42): calcd.: C
68.08, H 4.05, N 16.54%; found: C 68.14, H 16.60, N 16.62%.
Fungi
Gram Positive
Bacteria;
Gram negative
Bacteria;
A.
F.
Solani Solani
S. Epidermidis
P. Auregenosa
2
3
4
5
6
7
8
9
10
11
12
13
14
12
11
24
15
17
25
21
20
19
–
13
14
22
20
19
20
20
17
16
14
16
27
21
12
14
21
11
–
22
17
14
–
–
16
16
–
14
14
15
13
–
12
16
13
17
4.1.4. Synthesis of 2-cyano-3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-ylamino)-N-(9,10-dioxo-9,10-dihydro-
anthracen-2-yl)-3-phenylamino-acrylamide (4)
A mixture of compound 2 (1.758 g; 4 mmol) and 4-amino-1,2-
dihydro-2,3-dimethyl-1-phenylpyrazol-5-one (0.813 g; 4 mmol)
was fused at 170–180 ꢀC in sand bath for 2 h. Then, (20 mL) ethanol
was added, the reaction mixture was refluxed for further 2 h during
which a brown crystalline product separated out. The separated
product was filtered, washed with ethanol, dried and crystallized
from EtOH–DMF (4:1) to give compound 4.
–
22
19
14
17
18
19
Reference drugs
Ampicillin
Chloramphenicol 27
Cloxacillin 22
Brown crystals; Yield 75%; 1.78 g; mp >310 ꢀC; IR (KBr): /cmꢁ1
n
19
21
24
30
19
18
20
17
17
22
¼ 3244 (br, 3NH),1700,1650 (3C]O); 1H NMR (DMSO): dppm ¼ 2.53
(s, 3H, C]C–CH3), 3.32 (s, 3H, N–CH3), 7.50–8.20 (m,19H,17 Ar–H, 2

M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1843–1848
1847
NH), 11.61 (br, 1H, NH–CO); EIMS (m/z) (%) ¼ 596 (Mþ þ 2, 20), 595
Brown crystals; Yield 90%; 2.036 g; mp 280 ꢀC; IR (KBr):
n
/cmꢁ1
(Mþ þ 1, 16), 411 (24), 410 (20), 266 (44), 265 (76), 264 (64). Anal.
for C35H26N6O4 (594.62): calcd.: C 70.70, H 4.41, N 14.13%; found: C
70.63, H 4.37, N 14.07%.
¼ 3412, 3318 (3NH), 1700, 1670 (3C]O); 1H NMR (DMSO): dppm
¼
3.78 (s, 3H, CH3), 6.95–8.90 (m, 18H, Ar–H), 8.91 (br, 1H, NH–Ph),
10.20 (br, 1H, NH–C]O); EIMS (m/z) (%) ¼ 566 (Mþ þ 2, 3.7), 567
(Mþ þ 1, 3.7), 565 (Mþ, 9.3), 442 (9.3), 441 (11.8), 440 (49.1), 344
(17.4), 343 (30.4), 342 (26.1), 300 (16.8), 258 (22.4), 223 (28), 135
(36), 78 (100). Anal. for C34H23N5O4 (565.58): calcd.: C 72.20, H 4.10,
N 12.38%; found: C 72.26, H 4.19, N 12.45%.
4.1.5. Synthesis of 2-(4-oxo-3-phenylamino-2,4-dihydro-
pyrazolo[3,4-d]pyrimidin-5-yl)-anthraquinone (5)
To a solution of 3 (1.694 g; 4 mmol) in DMF (20 mL), dimethoxy-
N,N-dimethylmethanamine (0.477 g; 4 mmol) was added. The
reaction mixture was refluxed for 5 h; the reaction mixture was
poured into ice. The resulting precipitate was filtered off, dried and
crystallized from EtOH–DMF to give compound 5.
4.1.9. Synthesis of 5,7-dimethyl-2-phenylamino-pyrazolo[1,5-
a]pyrimidine-3-carboxylic acid (9,10-dioxo-9,10-dihydro-
anthracen-2-yl)-amide (9)
/cmꢁ1
¼
A mixture of 3 (1.694 g; 4 mmol) and pentane-2,4-dione (0.4 g; 4
mmol) in DMF (15 mL) with drops of glacial acetic acid was refluxed
for 4 h, then the reaction mixture was poured into crushed ice, and
the separated solid was filtered off, dried well and recrystallized
from DMF-benzene mixture (4:1) afforded compound 9.
Gray crystals; Yield 70%; 1.21 g; mp 305 ꢀC; IR (KBr):
n
3310–3250 (3NH),1700,1671 (3C]O); 1H NMR (DMSO): dppm ¼ 7.22–
8.34 (m, 15H, 12Ar–H, 2NH, N]CH); EIMS (m/z) (%) ¼ 435 (Mþ þ 2,
22.70), 434 (Mþ þ 1, 21.10); 433 (Mþ, 61.40), 272 (8.80), 269 (10.50),
224 (10.50), 223 (8.80), 217 (12.30). Anal. for C25H15N5O3 (433.42):
calcd.: C 69.28, H 3.49, N 16.16%; found: C 69.35, H 3.58, N 16.27%.
Brown crystals; Yield 82%; 1.599 g; mp 305 ꢀC; IR (KBr): /cmꢁ1
n
¼ 3310, 3226 (3NH), 1700, 1667 (3C]O); 1H NMR (DMSO): dppm
¼
1.87 (br, 6H, 2CH3), 6.93–8.63 (m, 13H, Ar–H), 9.18 (br, 1H, NH–Ph),
10.45 (br, 1H, NH–C]O); EIMS (m/z) (%) ¼ 488 (Mþ þ 1, 8.0), 487
(Mþ, 22.8), 426 (2.5), 395 (3.7), 394 (3.1), 266 (19.1), 265 (100), 264
(92.6). Anal. for C29H21N5O3 (487.51): calcd.: C 71.45, H 4.34, N
14.37%; found: C 71.37, H 4.32, N 14.35%.
4.1.6. Synthesis of 3-methyl-1-phenyl-7-phenylamino-1H-
1,2,5,8,8a-pentaaza-as-indacene-6-carboxylic acid (9,10-dioxo-
9,10-dihydro-anthracen-2-yl)-amide (6)
To a suspension of product 3 (1.694 g; 4 mmol) in DMF (20 mL),
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (0.883
g; 4 mmol) were added. The reaction mixture was heated under
reflux for 20 h; the mixture was poured into ice. The resulting
precipitate was filtered off, dried and crystallized from EtOH–DMF
afforded compound 6.
4.1.10. Synthesis of 3-(2,5-dimethyl-pyrrol-1-yl)-5-phenylamino-
1H-pyrazole-4-carboxylic acid (9,10-dioxo-9,10-dihydro-anthracen-
2-yl)-amide (10)
A mixture of compound 3 (1.694 g; 4 mmol) and 2,5-hex-
anedione (0.457 g; 4 mmol) in DMF (15 mL) with drops of glacial
acetic acid was refluxed for 4 h, then the reaction mixture was
poured into crushed ice, and the separated solid was filtered off,
dried well and recrystallized from DMF–benzene mixture (4:1) to
give compound 10.
Brown crystals; Yield 60%; 1.415 g; mp >310 ꢀC; IR (KBr): /cmꢁ1
n
¼ 3358, 3264 (3NH), 1699, 1669 (3C]O); 1H NMR (DMSO): dppm
¼
3.28 (s, 3H, CH3), 6.88–8.42 (m, 18H, Ar–H), 8.71 (br, 1H, NH–Ph)
and 13.14 (s, 1H, NH–C]O); EIMS (m/z) (%) ¼ 589 (Mþ, 7.2), 369
(5.8), 368 (40.6), 367 (42), 366 (33.33), 340 (20.3), 312 (7.2), 253
(7.2), 223 (21.7), 221 (20.3), 139 (27.5), 77 (100). Anal. for
C35H23N7O3 (589.60): calcd.: C 71.30, H 3.93, N 16.63%; found: C
71.38, H 4.02, N 16.69%.
Brown crystals; Yield 76%; 1.525 g; mp 295 ꢀC; IR (KBr): /cmꢁ1
n
¼ 3362, 3257 (3NH), 1700, 1664 (3C]O); 1H NMR (DMSO): dppm
¼
2.04 (br, 6H, 2CH3), 6.11 (m, 2H, pyrole), 7.21–8.12 (m, 13H, 12Ar–H,
NHpyrazole), 8.9 (br, 1H, NH–Ph), 13.14 (br, 1H, NH–C]O); EIMS (m/z)
(%) ¼ 503 (Mþ þ 2, 5.9), 502 (Mþ þ 1, 29.8), 501 (Mþ, 86.7), 500
(3.7), 499 (0.6), 280 (10.6), 279 (66), 278 (100), 77 (50.4). Anal. for
C30H23N5O3 (501.54): calcd.: C 71.84, H 4.62, N 13.96%; found: C
71.92, H 4.69, N 14.04%.
4.1.7. Synthesis of 2-phenylamino-6,7-dihydro-1,4,11c-triaza-
cyclopenta[c]phenanthrene-3-carboxylic acid (9,10-dioxo-9,10-
dihydro-anthracen-2-yl)-amide (7)
To a suspension of product 3 (1.694 g; 4 mmol) in DMF (20 mL),
2-chloro-3,4-dihydro-naphthalene-1-carbaldehyde (0.771 g;
4
mmol) was added. The reaction mixture was heated under reflux
for 20 h; the mixture was poured into ice cold-water. The resulting
precipitate was filtered off, dried and crystallized from EtOH–DMF
afforded compound 7.
4.1.11. Synthesis of 2-cyano-3-dimethylamino-N-(9,10-dioxo-9,10-
dihydro-anthracen-2-yl)-acrylamide (11)
To a solution of 2-cyano-N-(9,10-dioxo-9,10-dihydro-anthracen-
2-yl)-acetamide (1) (1.161 g; 4 mmol) in DMF (20 mL) and dime-
thoxy-N,N-dimethylmethanamine (0.477 g; 4 mmol) was added.
The reaction mixture was refluxed for 3 h; the mixture was poured
into ice. The resulting precipitate was filtered off, dried and crys-
tallized from EtOH-DMF afforded compound 11.
Brown crystals; Yield 63%; 1.415 g; mp 295 ꢀC; IR (KBr): /cmꢁ1
n
¼ 3358, 3226 (3NH), 1700, 1671 (3C]O); 1H NMR (DMSO): dppm
¼
2.73 (m, 2H, C–H7, triaza-cyclopenta[c]phenanthrene), 2.89 (m, 2H,
C–H6, triaza-cyclopenta[c]phenanthrene), 6.82–8.40 (m, 17 H, Ar–
H), 8.70 (br, 1H, NH–Ph), 9.70 (br, 1H, NH–CO); EIMS (m/z) (%) ¼ 561
(Mþ, 35.30), 339 (100), 338 (35.3), 223 (23.50), 221 (35.3), 140 (2.9),
139(26.5), 123 (76.5), 55 (94.1). Anal. for C35H23N5O3 (561.59):
calcd.: C 74.85, H 4.13, N 12.47%; found: C 74.88, H 4.21, N 12.52%.
Gray crystals; Yield 86%; 1.188 g; mp 280 ꢀC; IR (KBr):
n
/cmꢁ1
¼
3431, 3305 (NH), 2188 (CN), 1667 (br C]O); 1H NMR (DMSO): dppm
¼ 3.24, 3.31 (2s, 6H, N(CH3)2), 7.90–8.13 (m, 7H, Ar–H), 8.51 (s,
1H,]CH–N), 9.83 (br, 1H, NH–C]O); 13C NMR (CF3COOD, 500
MHz) d: 183.3, 180.1, 164.1 (3CO), 158.2, 138.9, 134.7, 134.4, 133.7,
4.1.8. Synthesis of 7-(4-methoxyphenyl)-2-phenylamino-
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (9,10-dioxo-9,10-
dihydro-anthracen-2-yl)-amide (8)
A solution of product 3 (1.694 g; 4 mmol) in dioxane (15 mL)
with drops of glacial acetic acid which was treated with 1-(4-
methoxyphenyl)-3-piperidin-1-yl-propan-1-one (0.989 g; 4 mmol)
was heated under reflux for 2 h. The solvent was then evaporated
under vacuo and triturated with ethanol. The solid deposited was
collected by filtration and recrystallized from EtOH–DMF (4:1)
afforded compound 8.
133.4, 133.0, 129.4, 129.1, 121.3, 116.8, 114.3, 108.7, 43.6, 43.3; EIMS
(m/z) (%) ¼ 347 (Mþ þ 2, 0.4), 346 (Mþ þ 1, 2.5), 345 (Mþ, 12.6), 344
(0.4), 343 (0.2), 124 (7.7), 123 (100), 122 (3.3), 80 (11.6), 77 (1.4).
Anal. for C20H15N3O3 (345.35): calcd.: C 69.56, H 4.38, N 12.17%;
found: C 69.50, H 4.33, N 12.14%.
4.1.12. Synthesis of 3-amino-1H-pyrazole-4-carboxylic acid (9,10-
dioxo-9,10-dihydro-anthracen-2-yl)-amide (12)
A mixture of 11 (1.381 g; 4 mmol) and hydrazine hydrate (0.2 g;
4 mmol) was fused on water bath for 1 h. Then ethanol (10 mL) was

1848
M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1843–1848
added. The reaction mixture was heated under reflux for further 1
h; the separated product was filtered and crystallized from DMF–
EtOH gave compound 12.
Ampicillin, Chloramphenicol and Cloxacillin were purchased form
The Egyptian market and used in a concentration 2 mg/mL as
reference drugs. The bacteria and fungi were tested on nutrient
agar and potato dextrose agar media, respectively. Three plates
were used for each compound as replicates. The plates were incu-
bated for 24 h and seven days for bacteria and fungi, respectively.
After the incubation period, the diameter of inhibition zone was
measured as an indicator for the activity of the compounds.
Gray crystals; Yield 78%; 1.037 g; mp >300 ꢀC; IR (KBr): /cmꢁ1
n
¼ 3416 (2NH), 1700, 1610 (3C]O); 1H NMR (DMSO): dppm ¼ 7.91–
8.47 (m, 8H, Ar–H and ]CH–N), 9.83 (br, 1H, NH–C]O); 13C NMR
(CF3COOD, 500 MHz) d: 183.2,180.2, 165.3 (3CO),153.4, 145.3, 140.2,
134.7, 134.1, 133.7, 133.0, 126.5, 126.4, 120.1, 116.8, 115.2, 108.1; EIMS
(m/z) (%) ¼ 334 (Mþ þ 2, 0.3), 333 (Mþ þ 1, 2.5), 332 (Mþ, 11.8), 331
(0.4), 290 (1.3), 224 (3.9), 223 (14.4), 222 (2.2),110 (100), 77 (3.2), 54
(20.3). Anal. for C18H12N4O3 (332.31): calcd.: C 65.06, H 3.64, N
16.86%; found: C 65.13, H 3.68, N 16.97%.
References
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4.1.13. Synthesis of 2-cyano-2-[(4,6-dimethyl-1H-pyrazolo[3,4-
b]pyridin-3-yl)-hydrazono]-N-(9,10-dioxo-9,10-dihydro-anthracen-
2-yl)-acetamide (13)
To a solution compound 1 (1.161 g; 4 mmol) in pyridine (10 mL),
an ice-cooled solution of the appropriate diazonium solution
[prepared by the addition of a solution of sodium nitrite (0.276 g; 4
mmol) in water (5 mL) to the required arylamine (0.839 g; 4 mmol)
in hydrochloric acid (12 mL)] was added drop wise with stirring.
Stirring was maintained for 30 min. The precipitated product was
filtered, washed with water, dried and crystallized from EtOH-DMF
afforded compound 13.
Brown crystals; Yield 71.5%; 1.325 g; mp >300 ꢀC; IR (KBr):
n/
cmꢁ1 ¼ 3307 3274, 3259 (NH), 2199 (CN), 1669, 1640 (3C]O), 1527
(N]N); 1H NMR (DMSO): dppm ¼ 2.83 (br, 6H, 2CH3), 6.87 (br, 1H,
NHpyrazole) 7.91–8.22 (m, 9H, Ar–H), 8.71 (br, 1H, NH]N), 11.20 (br,
1H, NH–CO); 13C NMR (CF3COOD, 500 MHz)
d: 183.1, 180.3, 166.1
(3CO), 158.8, 154.2, 146.3, 144, 140.1, 134.4, 133.6, 129.3, 123.9, 121.1,
114.3, 112.5, 108.3, 20.9, 20.1; EIMS (m/z) (%) ¼ 463 (Mþ, 40), 163
(66.7), 162 (100), 139 (93.3), 132 (53.3), 131 (86.7), 122 (20), 121
(40). Anal. for C25H17N7O3 (463.45): calcd.: C 64.79, H 3.70, N
21.16%; found: C 64.83, H 3.76, N 21.28%.
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4.1.14. Synthesis of 8-amino-2,4-dimethyl-1,5,6,8a,9-pentaaza-
fluorene-7-carboxylic acid (9,10-dioxo-9,10-dihydro-anthracen-2-
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Compound 13 (0.927 g; 2 mmol) was heated under reflux for 6 h
in glacial acetic acid (10 mL). The solvent was then evaporated
under vacuo and triturated with ethanol. The solid deposited was
collected by filtration and recrystallized from DMF–EtOH (4:1)
afforded compound 14.
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Brown crystals; Yield 84.3%; 0.781 g; mp >300 ꢀC; IR (KBr):
n/
cmꢁ1 ¼ 3406, 3327, 3291 (NH), 1673, 1633 (3C]O); 1H NMR
(DMSO): dppm ¼ 2.68 (s, 3H, C4–CH3), 2.71 (s, 3H, C2–CH3), 6.92 (br,
2H, NH2), 7.91–8.40 (m, 8H, Ar–H), 10.94 (br, 1H, NH–C]O); EIMS
(m/z) (%) ¼ 463 (Mþ, 22.7), 229 (22.7), 164 (72.7), 139 (27.3), 133
(31.8), 132 (100), 105 (4.5), 104 (59.1). Anal. for C25H17N7O3
(463.45): calcd.: C 64.79, H 3.70, N 21.16%; found: C 64.86, H 3.73, N
21.24%.
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4.2. In vitro antimicrobial activity
The tested compounds were evaluated by the agar diffusion
technique [33] using a 2 mg mLꢁ1 solution in DMSO. The test
organisms were two bacterial strains: S. epidermidis and P. aerugi-
nosa and two fungi: A. solani and F. solani. A control using DMSO
without the test compound was included for each organism.
Chem. Abstr. 116 (1992) 106161g.
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