Further derivatives of 4-benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid and their antibacterial activities

Article abstract of DOI:10.1007/s00044-007-9082-z

Compound 4, 5, 6, 7, and 8 were synthesized from 4-benzoyl-1,5-diphenyl-1H- pyrazole-3-carboxylic acid 1 as a starting material. The pyrazolo[4,3-d] oxazinone 4 was obtained from direct reaction of the acid 1 with hydroxylamine hydrochloride. Acid chloride 2 was converted easily into the new derivatives consisting of 1-(4-benzoyl-1,5-diphenyl-1H-pyrazol-3-oyl)-sulfamide 5 and 3,4-dibenzoyl-1,5-diphenyl-1H-pyrazole 6. The nitrile derivative 7 was obtained by dehydration of the amide 3 in a mixture of SOCl₂ and Dimethylformamide (DMF). Cyclocondensation reaction of 7 with anhydrous hydrazine led to the formation of 7-aminopyrazolo[3,4-d]pyridazine 8 derivative. These new synthesized compounds evaluated for their antibacterial activities against Gram-positive and Gram-negative bacteria using the tube dilution method. The finding of antibacterial activity study showed that the sulfamide derivative 5 was the best compound of the series, exhibiting antibacterial activity against both Gram-positive and Gram-negative bacteria.

Full text of DOI:10.1007/s00044-007-9082-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2007) 16:418–426
DOI 10.1007/s00044-007-9082-z
ORIGINAL RESEARCH
Further derivatives of 4-benzoyl-1,5-diphenyl-1H-
pyrazole-3-carboxylic acid and their antibacterial
activities
_
_
Ishak Bildirici Æ Ahmet S¸ener Æ Israfil Tozlu
Received: 30 April 2007 / Accepted: 12 December 2007 / Published online: 12 January 2008
¨
Ó Birkhauser Boston 2008
Abstract Compound 4, 5, 6, 7, and 8 were synthesized from 4-benzoyl-1,5-diphe-
nyl-1H-pyrazole-3-carboxylic acid 1 as a starting material. The pyrazolo[4,3-
d]oxazinone 4 was obtained from direct reaction of the acid 1 with hydroxylamine
hydrochloride. Acid chloride 2 was converted easily into the new derivatives con-
sisting of 1-(4-benzoyl-1,5-diphenyl-1H-pyrazol-3-oyl)-sulfamide 5 and 3,4-
dibenzoyl-1,5-diphenyl-1H-pyrazole 6. The nitrile derivative 7 was obtained by
dehydration of the amide 3 in a mixture of SOCl2 and Dimethylformamide (DMF).
Cyclocondensation reaction of 7 with anhydrous hydrazine led to the formation of 7-
aminopyrazolo[3,4-d]pyridazine 8 derivative. These new synthesized compounds
evaluated for their antibacterial activities against Gram-positive and Gram-negative
bacteria using the tube dilution method. The finding of antibacterial activity study
showed that the sulfamide derivative 5 was the best compound of the series, exhibiting
antibacterial activity against both Gram-positive and Gram-negative bacteria.
Introduction
Natural antibiotic compounds have become indispensable to the current health care
system, assisting and complementing the natural immune system against microbial
pathogens. However, because conventional antibiotics are often abused to treat
microbial infections, some microorganisms have developed tolerance to these
antibiotics. Because of the appearance of antibiotics-resistant strains, the continuous
development of novel efficient antibiotic agents is more crucial than ever (Berber
et al., 2003; Mitscher et al., 1999; Sung et al., 2007). So the medical community
faces a serious problem against infections caused by pathogen bacteria and needs an
_
_
I. Bildirici (&) Á A. S¸ener Á I. Tozlu
Organic Chemistry Division, Chemistry Department, Faculty of Arts and Sciences, Yu¨zu¨ncu¨ Yıl
University, Van 65080, Turkey
e-mail: ishak@yyu.edu.tr

Med Chem Res (2007) 16:418–426
419
effective therapy and search for novel antibacterial agents (Lee and Hecker, 1999).
It has been reported that some pathogen bacteria are susceptible to sulfamide or
sulfonamide derivatives (Pellerin et al., 1998; Peraira et al., 2003).
\On the other hand, pyrazole and fused pyrazole compounds possess numerous
chemical, biological, medicinal, and agricultural applications because of their
versatile biological activities appearing as antimicrobial (Akbas and Berber, 2005;
Mahajan et al., 1991; Sridhar et al., 2004; Sivaprasad et al., 2006), antiviral
(Baraldi et al., 1998; Janus et al., 1999), antitumor (Suzuki and Inoue, 1990;
Hatheway et al., 1978; Katayama and Oshiyama, 1997; Manfredini et al., 1992),
anti-inflammatory (Badawey and El-Ashmawey, 1998; Bruno et al., 1992;
Manfredini et al., 1996; Tewari and Mishra, 2001), antihistaminic (Mishra et al.,
1998), pesticidal (Londershausen, 1996), antifungal (Badiger and Bennur, 1996;
Graneto and Phillips, 1992), and antipyretic (Wiley and Wiley, 1964) agents.
Concerning the attempt to synthesize novel pyrazole and fused pyrazole
derivatives from 4-benzoyl-5-phenyl-2,3-furandione 1 and various hydrazines or
hydrazones, the synthesis of 4-benzoyl-1,5-substituted-1H-pyrazole-3-carboxylic
acids and some of their derivatives have recently been reported (S¸ener et al.,
2002; S¸ener and Bildirici, 2004; S¸ener et al., 2004a-c; S¸ener et al., 2007). A
literature survey revealed that, so far, the following reactions of some of these
1,4,5-trisubstitute-pyrazol-3-carboxylic acids, particularly 4-benzoyl-1,5-diphenyl-
1H-pyrazole-3-carboxylic acid 1, obtained 4-benzoyl-5-phenyl-2,3-furandione
have been partly investigated. In an attempt to help remedy this situation we
decided both to extend our previous studies (Akc¸amur et al., 1986; Akc¸amur
et al., 1997) on the further reactions of 4-benzoyl-1,5-diphenyl-1H-pyrazole-3-
carboxylic acid 1 and to evaluate the antibacterial activities of the resulting
compounds.
Results and discussion
Chemistry
Compounds 4, 5, 6, 7, and 8, which been studied for their antibacterial activities,
were mainly synthesized from pyrazole-3-carboxylic acid 1 together with acid
chloride 2 and its amide 3 derivatives. Both pyrazole-3-carboxylic acid 1 and its
derivatives 2 and 3 were synthesized via published procedures (Akc¸amur et al.,
1986; Akc¸amur et al., 1997) (Scheme 1).
O
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
OH
Cl
NH2
Ph NHNH2
Ref. [34]
SOCl2
NH3
Ref. [35]
N
N
N
Ph
Ph
Ph
O
N
N
N
O
Ref. [35]
Ph
Ph
Ph
3
2
1
Scheme 1

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Med Chem Res (2007) 16:418–426
Direct reaction of the acid 1 with hydroxylamine hydrochloride, on an oil bath at
approximately 150–155°C led to the formation of the pyrazolo[4,3-d]oxazinone 4 in
about 55% yield (Scheme 2). The structure of 4 was proven based on elemental
analysis and spectral data (see the Experimental section).
Acid chloride 2 was converted into new derivatives consisting of 1-(4-benzoyl-
1,5-diphenyl-1H-pyrazol-3-oyl)-sulfamide 5 and 3,4-dibenzoyl-1,5-diphenyl-1H-
pyrazole 6 via its reactions with sulfamide and benzene, containing a catalytic
amount of AlCl3, respectively. Furthermore, a cold solution of the acid amide 3 in a
mixture of DMF and Thionylchloride (SOCl2) was stirred at 0–5°C for 2 hours to
give a nitrile 7 derivative (Scheme 3). The structures of the title compounds 5, 6,
1
and 7 were confirmed by analytical, infrared (IR), H nuclear magnetic resonance
(NMR) and 13C-NMR spectroscopic data. 13C-NMR and IR absorptions of the
nitrile group in 7 were found at 114.51 ppm and 2239 cm-1, respectively (see the
Experimental section).
Pyrazole-3-carbonitrile 7 with anhydrous hydrazine in boiling n-butanol
containing a catalytic amount metallic sodium was also cyclized to the 7-
aminopyrazolo[3,4-d]pyridazine
8
derivative in approximately 40% yield
N O
Ph
Ph
O
NH2OH; HCl
1
N
N
Ph
4
Scheme 2
O
O
O
O
S
NH2
Ph
N
Sulfamide
- HCl
H
N
O
O
Ph
N
Ph
Ph
Cl
Ph
5
N
N
O
O
Ph
2
Ph
Ph
Ph
AlCl3
Benzene
N
N
Ref. [35]
O
Ph
6
O
O
CN
Ph
Ph
NH2
Ph
SOCl2 + DMF
0-5 oC
N
N
Ph
N
N
Ph
3
Ph
7
Scheme 3

Med Chem Res (2007) 16:418–426
421
H
N N
N N
Ph
Ph
NH2
Ph
Ph
NH
NH2NH2
7
N
N
N
N
Ph
Ph
8
Scheme 4
(Scheme 4). Structure elucidation of 8 was mainly based on 13C-NMR spectroscopy
(see the Experimental section for details).
In vitro antibacterial activity
In the present study, the antibacterial activities of five different newly synthesized
derivatives of 4-benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid were evalu-
ated against ten test microorganisms: the Gram-positive and Gram-negative bacteria
shown in Table 1. The antimicrobial effects of new synthesized agents 4, 5, 6, 7,
and 8 (some part omitted) were investigated by the microdilution method (Clause,
1989; Lee et al., 1999; Lee et al., 2003) and the minimum inhibitory concentration
(MIC) was determined. In the current study, a bioassay with the commercial
antibiotic chloroamphenicol as a standard was carried out for comparison. It is well
known that chloroamphenicol is active against a wide range of Gram-positive and
Gram-negative bacteria. Since chloroamphenicol is poorly soluble in water,
esterifications of the primary alcohol at C-3 with palmitoyl chloride were carried
out to produce the water-insoluble palmitate of chloroamphenicol (Mascaretti,
2003). The comparative activities of the new synthesized agents 4, 5, 6, 7, and 8 and
the control antibiotic chloroamphenicol on the bacterial test strains are summarized
in Table 1.
Compound 5 exhibited a strong inhibition effect against most of test bacteria
except Enterococcus facealis and Bacillus subtilus, whereas compound 6 exhibited
the weakest effect, showing an inhibition effect only against one of the test strains,
namely, Proteus vulgaris. An important point is that most of compounds exerted
inhibition effects at the 512 lg/mL concentration while the minimal inhibition
concentration (MIC) of compound 5 was 32 lg/mL. Chloroamphenicol showed
significant antibacterial activity against all the investigated bacteria strains with
MIC values of 32–512 lg/mL. It may be suggested that compound 5 has a better
inhibition effect than the other compounds. Interestingly, none of compounds
showed inhibition effects against Enterococcus facealis. However, four out of the
five compounds were active against Escherichia coli, while the growth of Proteus
vulgaris was inhibited by all of compounds. Also, Salmonella enteridis was
inhibited only by one compound, 5. It may be concluded that compound 5 showed
reasonably good inhibitory activity against the investigated bacterial strains. In

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Med Chem Res (2007) 16:418–426
Table 1 The MICs of antibacterial activity of the newly synthesized pyrazole derivatives compounds
Bacterial strains
Newly synthesized compounds (lg/mL)*
4
5
6
7
8
Control**
Escherichia coli B3704
512
–
32
32
32
32
32
32
–
–
–
–
512
–
512
32
–
6
24
12
24
6
Pseudomonas aeruginosa ATCC 9027
Klebsiella pneumonia A137
–
–
Proteus vulgaris Kuk. 1329
512
–
512
–
512
–
512
–
Staphylococcus aureus ATCC 29213
Streptococcus pyogenes ATCC 176
Enterococcus facealis ATCC 29122
Bacillus subtilis ATCC 6633
Salmonella enteridis ATCC 1376
Xanthomonas compestris A235
512
–
–
–
–
12
12
24
24
12
–
–
–
–
–
–
–
–
–
32
32
–
–
–
256
512
512
512
–, No activity; *, minimal inhibitory concentrations (MICs) of compounds and antibiotics expressed as
(lg/mL); **, Chloramphenicol
general, only one of the compounds exhibited excellent antibacterial activity against
human pathogens. Therefore, it could be expected that compound 5 may have
potential as an anti-infective agent in human microbial infections. The results
obtained clearly indicate that some of the derivatives of 4-benzoyl-1,5-diphenyl-1H-
pyrazole-3-carboxylic acid discussed here are active in terms of growth inhibition of
selected human pathogens. However, further studies are required to determine their
potential against a wide range of human pathogens, their MIC mode of actions, and
to assess the usefulness of the synthesized compounds.
Experimental
All melting points were determined on an Electrothermal Gallenkamp apparatus and
are uncorrected. The compounds were routinely checked for their homogeneity by
thin-layer chromatography (TLC) using a DC Alufolien Kieselgel 60 F 254 Merck
and Camag TLC lamp (254/366 nm). Microanalyses were performed on a Carlo
Erba elemental analyzer model 1108. The IR spectra were obtained as potassium
bromide pellets using a Mattson 1000 Fourier-transform infrared (FTIR) spectrom-
1
eter. The H- and 13C-NMR spectra were recorded on Varian XL-200 (200 MHz)
and (50 MHz) spectrometers, respectively, using Tetramethylsilane (TMS) as an
internal standard. The title compounds 1, 2, and 3 were prepared according to the
literature procedure (Akc¸amur et al., 1986; Akc¸amur et al., 1997).
2,3,4-Triphenyl-pyrazolo[4,3-d][1,2]oxazin-7(2H)-one (4)
Pyrazole acid 1 (0.37 g, 1 mmole) and a large excess of hydroxylamine
hydrochloride were heated to about 150–155°C on an oil bath for approximately

Med Chem Res (2007) 16:418–426
423
30 min, until sublimation of excess hydroxylamine hydrochloride ceased, with
stirring. After cooling to room temperature, the resulting mixture was first washed
with water then treated with ether; the crude product formed in this way was
recrystallized from isobutanol to give 0.20 g (55%) of pure 4, m.p. 240°C. IR:
1
1685 cm-1 (C=O); H-NMR (CDCl3-d6): d = 7.37–6.77 ppm (Ar-H); 13C-NMR
(CDCl3-d6): d = 156.36 (C=O), 143.54 (C-7a), 140.57 (C-3), 139.65 (C-4), 132.24,
132.13, 131.71, 131.53, 131.46, 130.54, 130.31, 130.20, 130.12, 129.99, 129.89,
128.71, 127.76 ppm.
Anal. calcd. for C23H15N3O2: C, 75.60; H, 4.14; N, 11.50. Found: C, 75.70; H,
4.13; N, 11.49.
1-(4-benzoyl-1,5-diphenyl-1H-pyrazol-3-oyl)-sulfamide (5)
An equimolar mixture of acid chloride 2 (0.39 g, 1 mmole) and sulfamide (0.096 g,
1 mmole) was heated to 165–170°C for approximately 120 min without any
solvent. After cooling to room temperature, the residue was treated with ether and
the formed crude product was recrystallized from butyl alcohol to give 0.20 g (45%)
of 5, m.p. 259°C. IR: 3444, 3367 cm-1 (NH), 3062 cm-1 (Ar-H), 1749 cm-1 (C=O,
CONH-), 1670 cm-1 (C=O, Benzoyl); 13C-NMR (CDCl3-d6): d = 192.94 (C=O,
benzoyl), 159.62 (C=O, CONH-), 146.28 (C-3), 146.37 (C-5), 140.83, 139.91,
135.17, 131.76, 131.40, 131.04, 130.60, 130.33, 129.75, 127.24, 125.20 ppm.
Anal. calcd. for C23H18N4O4S: C, 61.87; H, 4.06; N, 12.55; S, 7.18. Found: C,
62.00; H, 4.06; N, 12.53; S, 7.17.
3,4-Dibenzoyl-1,5-diphenyl-1H-pyrazole (6)
Compound 2 (0.412 g, 1 mmole) and anhydrous AlCl3 (0.133 g, 1 mmole) were
refluxed for 2 h in benzene (20 mL). Then, reaction mixture was made alkaline by
adding solution of NaOH within ethyl alcohol (96%). Later, the formed precipitate
was removed by filtration and the filtrate was evaporated under vacuum. Resulting
crude product was crystallized from ethanol, to give yield 0.180 g (42%), m.p.
175°C. IR: 3080 cm-1 (Ar-H), 1676 and 1651 cm-1 (C=O, benzoyl); 13C-NMR
(CDCl3-d6): d = 193.41 and 188.78 (C=O, benzoyl), 152.02 (C–3), 145.44 (C–5),
141.08, 140.10, 138.61, 135.03, 134.93, 132.60, 131.94, 131.27, 131.21, 131.05,
130.52, 130.44, 130.33, 130.21, 130.00, 127.44, 126.29 ppm.
Anal. calcd. for C29H20N2O2: C, 81.29; H, 4.70; N, 6.54. Found: C, 82.03; H,
4.69; N, 6.53.
4-Benzoyl-1,5-diphenyl-1H-pyrazole-3-carbonitrile (7)
A cold solution of the acid amide 6a (0.37 g, 1 mmol) in a mixture of DMF
(0.7 mL) and SOCl2 (0.15 mL) was stirred at 0–5°C for 2 h and the solution was
left stirring overnight. Then the reaction mixture was poured over crushed ice and

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Med Chem Res (2007) 16:418–426
the solid formed was isolated by filtration, washed with water and recrystallized
from methyl alcohol to give 0.245 g (70%) of 7, m.p. 167°C. IR: 3081 cm-1 (Ar-
H), 2239 cm-1 (-C:N), 1649 cm-1 (C=O, benzoyl); 13C-NMR (CDCl3-d6):
d = 190.32 (C=O, benzoyl), 147.26 (C-3), 140.21 (C-5), 138.68, 135.39, 132.21,
131.82, 131.62, 131.24, 130.57, 130.29, 128.96, 128.79, 127.47, 126.77, 114.51
ppm (-C:N).
Anal. calcd. for C23H15N3O: C, 79.07; H, 4.33; N, 12.03. Found: C, 78.98; H,
4.34; N, 12.05.
2,3,4-Triphenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl-amine (8)
Compound 6 (0.35 g, 1 mmole) and anhydrous hydrazine (0.032 g, 1 mmole) were
refluxed in 1-butanol containing a catalytic amount of metallic sodium on an oil
bath for 7 h. The precipitate formed in boiling 1-butanol was isolated by filtration
and recrystallized from methyl alcohol to give 0.145 g (40%) of 8, m.p. 307°C. IR:
3490–3180 cm-1 (NH), 3055 cm-1 (Ar-H), 1680 cm-1 (C=NH); 13C-NMR
(CDCl3-d6): d = 158.83 (C=NH), 147.09 (C-3), 144.59 (C-4), 142.22 (C-7a),
140.92, 136.06, 132.47, 131.08, 130.89, 130.75, 130.56, 130.45, 129.93, 129.67,
127.98, 119.07 ppm (C-3a).
Anal. calcd. for C23H17N5: C, 76.01; H, 4.71; N, 19.27. Found: C, 75.93; H, 4.72;
N, 19.30.
Antimicrobial assay
Bacterial strains used in the present study were taken from Biology Department of
Science and Art Faculty of Yu¨zu¨ncu¨ Yil University, Van, Turkey. The bacterial
strains were Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 29213,
Pseudomonas aeruginosa ATCC 27853, Enterobacter facealis ATCC 29212,
Klebsiella pneumonia A137, Proteus vulgaris Kukem 1329, Streptococcus pyog-
enes ATCC 176, Bacillus subtilis ATCC 6633, Salmonella enteridis ATCC 1376,
and Xanthomonas compestris A235 (Table 1). Bacterial test organisms were
maintained a nutrient agar (Merck) slants at 4°C and subcultured in Petri plates prior
to use. Each combination of test microorganism and newly synthesized compounds
were repeated three times. The microdilution broth susceptibility assay (Clause,
1989; Lee et al., 1999; Lee et al., 2003) was used for the antimicrobial evaluation
of compounds. Stock solutions of the samples were prepared in distilled water and
serial dilutions were ranged from 2 to 512 lg/mL in micro test tubes and than
transferred into 10 mL test tubes containing 5 mL nutrient broth. Test microor-
ganisms were inoculated and incubated overnight. Also, one tube without
inoculation was used as a negative control while one that contained chloramphen-
icol antibiotic was used as a positive control. After incubation overnight, the first
tube with clear appearance determined the minimal inhibitory concentration (MIC).
The biological screening results of the five newly synthesized compounds and the
control antibiotic chloroamphenicol are detailed in Table 1.

Med Chem Res (2007) 16:418–426
425
Acknowledgments The authors would like to thank Prof. Dr. Ekrem Atalan and his M. Sc. student A.
Hamit Battal at the Biology Department of Yu¨zu¨ncu¨ Yıl University for providing the test bacteria and
helping with the microbiological study.
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