Synthesis and antimicrobial activity of some (3-phenyl-5-(1-phenyl-3-aryl- 1H-pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanones: New derivatives of 1,3,5-trisubstituted pyrazolines

Article abstract of DOI:10.1007/s00044-012-0045-7

A series of (3-phenyl-5-(1-phenyl-3-aryl-1H-pyrazol-4-yl)-4,5-dihydro-1H- pyrazol-1-yl)(pyridin-4-yl)methanones was synthesized by condensing suitably substituted chalcones, i.e., 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2- en-1-ones, and isoniazi

Full text of DOI:10.1007/s00044-012-0045-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:433–439
DOI 10.1007/s00044-012-0045-7
ORIGINAL RESEARCH
Synthesis and antimicrobial activity of some (3-phenyl-5-
(1-phenyl-3-aryl-1H-pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-
1-yl)(pyridin-4-yl)methanones: new derivatives of 1,3,5-
trisubstituted pyrazolines
•
•
•
Satyender Kumar Meenakshi Sunil Kumar
Parvin Kumar
Received: 20 December 2011 / Accepted: 27 March 2012 / Published online: 11 April 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A series of (3-phenyl-5-(1-phenyl-3-aryl-1H-
pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)
methanones was synthesized by condensing suitably substi-
tuted chalcones, i.e., 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1-
phenylprop-2-en-1-ones, and isoniazid in acetic acid. The
structure of newly synthesized compounds has been estab-
lished on the basis of analytical and spectral data. The new
compounds were screened for antimicrobial activity and most
of them showed good activity comparable with that of standard
drugs ciprofloxacin and fluconazole. Compounds containing
methoxy group showed high antimicrobial activity.
Introduction
Nitrogen containing heterocyclic compounds are core
structure of numerous biological active compounds and
exhibit wide varieties of application in pharmacological
and agrochemical industries. Pyrazole motif and its deriv-
atives are well established in literature as important bio-
logically active heterocyclic compounds due to their
widespread potential pharmacological activities such as
anti-inflammatory (Tewari and Mishra, 2001), antipyretic
(Wiley and Wiley, 1964), antimicrobial (Sridhar et al.,
2004), antiviral (Janus et al., 1999), antitumour (Xia et al.,
2007), anticonvulsant (Michon et al., 1995), and antide-
pressant (Bailey et al., 1985) activities. The widely pre-
scribed anti-inflammatory pyrazole derivatives, celecoxib
(Cheng et al., 2006) and deracoxib (Chowdhury et al.,
2008; Abdel-Hafez et al., 2009) are selective COX-2
inhibitors with reduced ulcerogenic side effects.
Keywords Pyrazole ꢀ Isoniazid ꢀ Chalcones ꢀ Pyrazoline ꢀ
Antimicrobial activity
Isoniazid, a first line drug used in the treatment of
tuberculosis, is a prodrug, which is transformed to isoni-
cotinic acid (Marrakchi et al., 2000), isonicotinamide, and
isonicotinaldehyde on the surface of M. tuberculosis by
KatG enzyme (Nguyen et al., 2002; Argyrou et al., 2006).
Literature survey shows that none of the stable derivatives
of isonicotinic acid, isonicotinamide, and isonicotinalde-
hyde has demonstrated bactericidal effect (Johnsson et al.,
1995). Thus, it is presumed that the activity of isoniazid is
due to the reaction of a reactive intermediate species with
the b-nicotinamide adenine dinucleotide (NAD?/NADH),
which is a cofactor of the long-chain 2-trans-enoyl-acyl
carrier protein reductase InhA (Delaine et al., 2007;
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-012-0045-7) contains supplementary
material, which is available to authorized users.
S. Kumar ꢀ S. Kumar
Department of Chemistry, Govt P G College,
Hisar 125001, India
Meenakshi
Department of Chemistry, Guru Jambheshwar University
of Science & Technology, Hisar, Haryana 125001, India
P. Kumar (&)
Department of Chemistry, Kurukshetra University,
Kurukshetra 136119, India
e-mail: drpkawasthignkc@rediffmail.com;
parvinjangra@gmail.com
´
Quemard et al., 1996), a key enzyme involved in the bio-
synthesis of mycolic acids, specific components of the
´
mycobacterial cell wall (Daffe and Draper, 1998). Isoniazid
may be bacteriostatic or bactericidal in action, depending on
123

434
Med Chem Res (2013) 22:433–439
the concentration of the drug attained at the site of infection
and the susceptibility of the infecting organism. The drug is
active against susceptible bacteria only during bacterial cell
division (Sriram and Yogeeshwari, 2008).
Kumar, 2010; Kumar et al. 2011a, b), we planned to syn-
thesize (3-phenyl-5-(1-phenyl-3-aryl-1H-pyrazol-4-yl)-4,5-
dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanones: new
derivatives of 1,3,5-trisubstituted pyrazoline.
Diverse pharmacological activities such as anti-inflam-
matory (Sharma et al. 2010), anti-hypertensive (Turan-
Zitouni et al. 2000), antimicrobial (Manna and Agrawal,
2009), anticancer (Shaharyar et al., 2010), antimalarial
(Acharya et al., 2010), antidepressant (Prasad et al., 2005),
anticonvulsant (Ozdemir et al., 2007), antioxidant (Jeong
et al., 2004) and MAO inhibitors (Jagrat et al., 2011) have
been reported for pyrazoline derivatives. Recently Ali et al.
(2007) and Acharya et al., (2010) have reported that 1,3,5-
trisubstituted pyrazolines having isonicotinyl or nicotinyl
group at 1-position exhibit anti-HIV and antimalarial
activity, respectively.
Result and discussion
Chemistry
The synthetic scheme used for the synthesis of (3-phenyl-5-
(1-phenyl-3-aryl-1H-pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-
yl)(pyridin-4-yl)methanones (3a–g) is outlined in Scheme 1.
First, 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2-en-
1-ones (2a–g) were synthesized by grinding the pyrazole
aldehydes and acetophenone with activated barium hydroxide
in a mortar and pestle without solvent (Kumar et al., 2011a,
b). Then these propenone derivatives were condensed with
isoniazid by refluxing in glacial acetic acid for 12–14 h. After
Keeping the above observation in our mind and in
continuation of our program on the synthesis of biological
active heterocyclic compounds (Kumar, 2009; Kumar and
O
H
O
Activated Ba(OH)2
N
O
N
CH3
N
Grinding
N
R
R
acetophenone
2a-g
1a-g
O
NHNH2
Acetic acid,
Reflux for 12-14 hr
N
isoniazid
N
N
N
O
2
N
2
1
N
1
N
N
3
3
NH
O
N
O
Hc
Hc
5
5
4
Ha
4
OR
Ha
Hb
Hb
N
N
N
N
N
N
R
R
R
4a-g
3a-g
Recemic Mixture
Not formed
R= (a) 4-OCH3; (b) 2-OCH3;(c) 4-CH3; (d) 4-F; (e) 4-Cl; (f) 4-Br; (g) H
Scheme 1 Synthesis of 1,3,5-trisubstituted pyrazolines
123

Med Chem Res (2013) 22:433–439
435
completion of reaction (TLC), the reaction mixture was
poured on to crushed ice and recrystallized the filtered product
with ethanol, afforded the final products 3a–g in 70–80 %
yields. Noelectronic effects of substituent were observed. The
purity of compounds was checked by TLC. Spectral data (IR,
1H-NMR, 13C-NMR, and mass) of newly synthesized com-
pounds 3a–g were in full agreement with their proposed
structure. The IR spectra of compounds 3a–g exhibited
characteristic peak at 1628–1643 cm-1 due to the presence of
isonicotinyl group. In 1H-NMR, the signals of the respective
protons of the prepared titled compounds 3a–g were verified
on the basis of their chemical shifts, multiplicities and cou-
pling constants. The spectra of 3a showed three doublet of
doublets (dd) at d for C5-Hc = 5.925, Hb = 3.361, C4-
Ha = 3.608 ppm with coupling constants Ja,b = 17.7 Hz
(geminal), Ja,c = 11.7 Hz (cis), Jb,c = 4.5 Hz (trans) corre-
sponding to methyne proton and methylene protons. In case of
chalcones of formyl pyrazole 2a–g, the pyrazolyl proton
which resonated as a singlet at 8.3–8.5 ppm, showed a sig-
nificant downfield shift in 3a–g and it appeared as a singlet at
7.9–8.0 ppm. Hence, three dd with different J values indicate
theformationofonlypyrazoline3a–g andnottheotherisomer
4 (Scheme 1). 1H-NMR spectra also clearly indicates that Ha
and Hb are diastereotropic hydrogens.
All the newly synthesized compounds (3a–g) showed
the promising antimicrobial activity against different
strains of bacterium and fungus. Compounds bearing
methoxy group (3a, 3b) showed highest activity against
different strains of bacterium and fungus. Only compound
3b displayed broad spectrum antimicrobial activity. The
higher antifungal activity of ortho-methoxy substituent
may be due to position of oxygen of methoxy group in
relation to the heterocyclic ring. As can be seen in Fig. 1,
the heterocyclic ring and methoxy group in the synthe-
sized compound are almost overlapping triazole and
hydroxyl group in fluconazole. In many antifungal agents
like Econazole, Miconazole, Ticonazole, and Fentico-
nazole, oxygen atom is placed at ortho like position to
heterocyclic ring. The better activity of fluoro and chloro
derivatives than bromo is a general trend in antimicro-
bials, e.g., fluoroquinolones and griseofulvin (Foye et al.,
1995).
Conclusion
Outcome of the condensation reactions of isoniazid with
pyrazole chalcones may result the formation of recemic
mixture (3a–g), where C4-atom indicates the chiral center
and protons on adjacent carbon atom C5 are diastereotropic
in nature. It is shown by coupling constant of Ha and Hb
with Hc [Ja,c = 11.7 Hz (cis), Jb,c = 4.5 Hz (trans)].
By comparing the antibacterial and antifungal potential
of compounds with different substituent, the following
conclusions were drawn: (a) the presence of methoxy group
increases the antimicrobial activity of compounds, (b) at
ortho position methoxy group increases antifungal activity
also, (c) out of halogen substituted pyrazolines, fluorine
substituted pyrazoline have maximum antimicrobial
activity, (d) all compounds are more active against bacte-
rium in comparison to fungus strain.
Biological result and discussion
All the newly synthesized compounds 3a–g have been eval-
uated for their antibacterial and antifungal activity against five
standard bacterial species including gram-positive (Staphy-
lococcus aureus, Bacillus pumilis, and Bacillus subtilis) and
gram-negative (Escherichia coli and Pseudomonas aerugin-
osa) bacteria and four standard fungi (Candida albicans,
Candida tropicalis, Aspergillusniger, and Aspergillus flavus).
Antimicrobial activity tests were performed by using a broth
micro dilution method (NCCLS, 2000; Lorian, 1986) and
results are summarized in Table 1.
Table 1 MIC of synthesized compounds
S. no. Compounds
Microorganisms and MIC (mg/L)
S. aureus B. pumilis B. subtillus E. coli P. aeruginosa C. albicans C. tropicalis A. niger A. flavus
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
6.25
6.25
6.25
6.25
12.5
12.5
25
6.25
6.25
12.5
25
6.25
6.25
12.5
12.5
25
6.25
6.25
12.5
12.5
25
12.5
6.25
25
12.5
6.25
25
12.5
6.25
50
50
50
50
50
100
200
[200
[200
100
100
200
200
200
[200
12.5
25
50
50
25
100
50
100
100
200
25
25
50
50
3g
50
50
50
50
200
Ciprofloxacin 3.125
Fluconazole
3.125
3.125
3.125
3.125
3.125
6.25
12.5
12.5
123

436
Med Chem Res (2013) 22:433–439
Perkin Elmer 1600, FTIR spectrophotometer using KBr
pellets. The elemental analyses were performed on a Carlo
Erba 1106 elemental analysis. TLC was run on silica gel G
plates using acetone–benzene (1:3) as irrigant.
All the starting pyrazole aldehydes and their chalcones
with acetophenone were prepared according to literature
procedures (Kumar et al., 2011a, b).
General procedure for the synthesis of pyrazole
substituted chalcones (2a–g) with activated barium
hydroxide
A mixture of acetophenone (4 mmol), pyrazole aldehyde
(4 mmol) and activated barium hydroxide (C-200)
(1.515 g, 8 mmol) was blended thoroughly in mortar and
pestle and resulting homogeneous mixture was ground at
room temperature for 5–10 min. The completion of reac-
tion was indicated by wetting with formation of yellow
colored reaction mixture. The progress of reaction was
monitored by TLC. 30 g crushed ice was added to the
reaction mixture and acidified with conc HCl. Filtered the
yellow colored product on suction pump and recrystallized
the product from isopropyl alcohol. Spectra of some rep-
resentative chalcones:
Fig. 1 Overlapping of compound 3b with fluconazole
Antimicrobial activity
Microdilution assays
The minimal inhibitory concentration (MIC) values for all the
newly synthesized compounds, 3a–g, defined as the lowest
concentration of the compound preventing the visible growth,
were determined by using microdilution broth method
according to NCCLS standards. The inocula of microorgan-
isms(106 cfu/mL)werepreparedfrom24 hbrothculturesand
suspensions were adjusted to 0.5 McFarland standard turbid-
ity (McFarland, 1907). The test compound dissolved in
dimethyl sulfoxide (DMSO) was first diluted to the highest
concentration (800 lg/mL) to be tested. Then serial twofold
dilutions were made in concentration ranges from 1.562 to
800 lg/mL in 10 mL sterile tubes. A prepared suspension of
the standard microorganisms was added to each dilution in a
1:1 ratio. Growth (or its lack) of microorganisms was deter-
mined visually after incubation for 24 h at 37 °C. The lowest
concentration at which there was no visible growth (turbidity)
was taken as the MIC. The MIC values were studied for five
reference bacterial (Staphylococcus aureus, Bacillus pumilis,
Bacillus subtillus, Escherichia coli, and Pseudomonas aeru-
ginosa) and three fungal (Candida albicans, Aspergillus
niger, and Aspergillus flavus) strains. In this case, ciproflox-
acin and fluconazole were used as standard drugs for com-
parison in the antimicrobial study. Control experiments using
DMSO were done for antimicrobial activity studies.
1-Phenyl-3-[3-(4-methoxyphenyl)-1-phenyl-4-
pyrazolyl]prop-2-en-1-one (2a)
M.p.: 164–166 °C. IR (mmax, in KBr): 3033, 3011, 1653,
1601, 1427, 1322, 1300, 1242, 966, 847, 754. H NMR
1
(CDCl3, 300 MHz, d): 3.74 (s, 3H, OCH3); 7.31–8.00 (m,
16H, ArH, C2-H, C3-H); 8.35 (s, 1H, pyrazolyl-H). Anal.
Calcd. for C25H20N2O2; C, 78.93; H, 5.30; N, 7.36. Found
C 79.08, H 5.42, N 7.45.
1-Phenyl-3-[3-(2-methoxyphenyl)-1-phenyl-4-
pyrazolyl]prop-2-en-1-one (2b)
M.p.: 156–158 °C. IR (mmax, in KBr): 1654 cm-1 (CO
stretch) 3062, 3019, 1654, 1589, 1511, 1422, 1237, 1101,
1057, 966, 832, 787. 1H NMR (CDCl3, 400 MHz, d): 3.786
(s, 3H, OCH3); 7.017(d, 1H, J = 8.04 Hz); 7.073 (t, 1H,
J = 7.36 Hz); 7.126 (1H, d, J = 16.12 Hz); 7.304 (t, 1H,
J = 7.29 Hz); 7.409–7.518 (m, 7H); 7.675 (1H, d,
J = 16.12 Hz); 7.759 (2H, d, J = 8.08); 7.853 (2H, m);
8.318 (s, 1H, pyrazolyl-H). Anal. Calcd. for C25H20N2O2;
C, 78.93; H, 5.30; N, 7.36. Found C 78.98, H 5.18, N 7.41.
Experimental
All chemicals (Qualigens) used in this study were of the
highest purity available and purchased from local vendors.
Melting points were determined on a buchi oil heated
1-Phenyl-3-[3-(4-bromophenyl)-1-phenyl-4-
pyrazolyl]prop-2-en-1-one (2f)
1
melting apparatus and are uncorrected. H-NMR spectra
were recorded in CDCl3 on Bruker (400, 300, and
200 MHz) spectrometer using TMS as internal standard
(chemical shift in d, ppm). IR spectra were taken on a
M.p.: 162–164 °C. IR (mmax, in KBr): 3077, 3012, 1653,
1588, 1522, 1431, 1220, 1166, 827, 765, 689, 638. 1H
123

Med Chem Res (2013) 22:433–439
437
NMR (CDCl3, 400 MHz, d): 7.344 (d, 1H, J = 8.04 Hz);
7.359 (d, 1H, J = 14.40 Hz); 7.456–7.619 (m, 9H); 7.767
(d, 2H, J = 7.32 Hz); 7.823 (d, 1H, J = 14.40 Hz); 7.948
(d, 2H, J = 7.32 Hz) 8.336 (s, 1H, pyrazolyl-H). Anal.
Calcd. for C24H17BrN2O; C 67.14; H 3.99; N 6.53. Found
C 67.34, H 4.11, N 6.48.
Jc,a = 11.7 Hz and Jc,b = 4.5 Hz), 6.840 (1H, d,
J = 8.4 Hz), 6.994 (1H, t, J = 7.2 Hz), 7.328 (1H, d,
J = 7.5 Hz), 7.339–7.481 (6H, m, J = 8.4 Hz, J = 8.7 Hz
and J = 7.5 Hz), 7.617 (2H, d, J = 7.5 Hz), 7.703–7.745
(4H, m, J = 4.8 Hz and J = 7.8 Hz), 7.980 (1H, s, pyr-
azolyl-H), 8.736 (2H, d, J = 5.1 Hz). 13C-NMR (CDCl3,
100 MHz, d): 164.48, 157.99, 156.30, 150.41, 149.91,
141.62, 139.75, 133.23, 130.78, 130.33, 129.39, 129.33,
128.66, 128.41, 128.22, 126.58, 126.23, 125.78, 119.78,
118.98, 111.26, 56.10, 53.66, 41.42. Mass, m/z: 500.30
(M ? 1). Anal. Calcd. for C31H25N5O2: C, 74.53; H, 5.04;
N, 14.02. Found: C, 74.66; H, 5.15; N, 14.22.
General procedure for the synthesis of (3-phenyl-5-(1-
phenyl-3-aryl-1H-pyrazol-4-yl)-4,5-dihydro-1H-
pyrazol-1-yl)(pyridin-4-yl)methanones
To the solution of the appropriate pyrazole chalcone
(5 mol) (2a–g) in 20 mL of acetic acid, isoniazid (5 mol)
was added and the reaction mixture was refluxed for
8–10 h. Progress of reaction was monitored on TLC. After
completion of reaction, the reaction mass was poured on to
crushed ice. The products thus separated were filtered and
recrystallized from ethanol to give final products. Purity of
the products was checked by TLC.
(3-Phenyl-5-(1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)-4,5-
dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanone (3c)
Yield: 75 %, m.p.: 232–234 °C. IR (KBr, cm-1): 3051,
2987, 1643, 1597, 1551, 1504, 1435, 1335, 1234, 1065,
1
964, 825, 756, 687, 625. H-NMR (CDCl3, 200 MHz, d):
2.371 (3H, s, CH3), 3.204 (Hb, dd, Jb,c = 4.7 Hz, and
Jb,a = 17.6 Hz), 3.703 (Ha, dd, Ja,c = 11.6 Hz and
Ja,b = 17.6 Hz), 6.090 (Hc, dd, Jc,a = 11.6 Hz and
Jc,b = 4.7 Hz), 7.216–7.453 (8H, m), 7.609–7.765 (6H, m),
7.846 (2H, d, J = 5.9 Hz), 7.885 (1H, s, pyrazolyl-H),
8.736 (2H, d, J = 5.9 Hz). 13C-NMR (CDCl3, 100 MHz,
d): 164.42, 156.35, 150.48, 149.78, 141.71, 139.78, 133.11,
130.81, 130.33, 129.35, 129.33, 128.75, 128.65, 128.36,
128.24, 126.83, 126.53, 126.35, 125.76, 119.10, 53.66,
41.33, 21.28. Mass: m/z: 484.2093 (M ? 1). Anal. Calcd.
for C31H25N5O: C, 77.00; H, 5.21; N, 14.48. Found: C,
77.12; H, 5.32; N, 14.61.
[5-(3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-3-
phenyl-4,5-dihydro-1H-pyrazol-1-yl](pyridin-4-
yl)methanone (3a)
Yield: 76 %, m.p.: 270–272 °C. IR (KBr, cm-1): 3056,
3020, 2988, 1643, 1597, 1504, 1435, 1335, 1296, 1250,
1173, 1065, 1034, 964, 833, 756, 687, 609. 1H-NMR
(CDCl3, 200 MHz, d): 3.207 (Hb, dd, Jb,c = 4.7 Hz, and
Jb,a = 17.7 Hz), 3.699 (Ha, dd, Ja,c = 11.7 Hz and
Ja,b = 17.7 Hz), 3.810 (3H, s, CH3), 6.072 (Hc, dd,
Jc,a = 11.7 Hz and Jc,b = 4.7 Hz), 6.955 (2H, d,
J = 8.8 Hz), 7.267–7.453 (6H, m), 7.601–7.715 (6H, m),
7.845 (2H, d, J = 5.9 Hz), 7.887 (1H, s, pyrazolyl-H),
8.737 (2H, d, J = 5.9 Hz). 13C-NMR (CDCl3, 100 MHz,
d): 164.48, 158.20, 156.28, 150.45, 149.87, 141.66, 139.88,
133.19, 130.81, 130.37, 129.34, 129.31, 128.77, 128.66,
128.39, 128.25, 126.88, 126.57, 126.22, 125.85, 119.10,
114.79, 114.73, 55.65, 53.84, 41.35. Mass: m/z: 500.32
(M ? 1). Anal. Calcd. for C31H25N5O2: C, 74.53; H, 5.04;
N, 14.02. Found: C, 74.71; H, 5.09 N, 14.18.
(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-
phenyl-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-
yl)methanone (3d)
Yield: 70 %, m.p.: 242–244 °C. IR (KBr, cm-1): 3066,
2991, 1640, 1592, 1555, 1499, 1431, 1336, 1228, 1071,
1
959, 821, 759, 682. H-NMR (CDCl3, 200 MHz, d): 3.205
(Hb, dd, Jb,c = 4.7 Hz, and Jb,a = 17.6 Hz), 3.729 (Ha, dd,
Ja,c = 11.6 Hz and Ja,b = 17.6 Hz), 6.042 (Hc, dd,
Jc,a = 11.6 Hz and Jc,b = 4.7 Hz), 7.133–7.462 (8H, m),
7.462–7.786 (6H, m), 7.838 (2H, d, J = 5.7 Hz), 7.883
(1H, s, pyrazolyl-H), 8.738 (2H, d, J = 5.7 Hz). 13C-NMR
(CDCl3, 100 MHz, d): 164.49, 161.98, 156.32, 150.39,
149.91, 141.64, 139.79, 133.23, 130.79, 130.39, 129.36,
129.29, 128.76, 128.59, 128.40, 128.29, 126.86, 126.58,
126.25, 125.91, 119.15, 116.79, 116.70, 53.85, 41.39.
Mass: m/z: 488.1842 (M ? 1). Anal. Calcd. for
C30H22FN5O: C, 73.91; H, 4.55; N, 14.37. Found: C, 74.05;
H, 4.66; N, 14.48.
[5-(3-(2-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-3-
phenyl-4,5-dihydro-1H-pyrazol-1-yl](pyridin-4-
yl)methanone (3b)
Yield: 80 %, m.p.: 128–130 °C. IR (KBr, cm-1): 3055,
3022, 2987, 1636, 1597, 1551, 1504, 1435, 1335, 1242,
1119, 1057, 1026, 964, 833, 756, 687, 617. 1H-NMR
(CDCl3, 300 MHz, d): 3.361 (Hb, dd, Jb,c = 4.8 Hz, and
Jb,a = 17.7 Hz), 3.608 (Ha, dd, Ja,c = 11.7 Hz and
Ja,b = 17.7 Hz), 3.698 (3H, s, CH3), 5.925 (Hc, dd,
123

438
Med Chem Res (2013) 22:433–439
(5-(3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-
phenyl-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-
yl)methanone (3e)
156.39, 150.70, 149.86, 141.66, 139.81, 133.15, 130.93,
130.83, 129.42, 129.36, 128.86, 128.74, 128.57, 128.45,
128.34, 126.90, 126.69, 126.64, 125.87, 123.76, 121.88,
119.19, 53.69, 41.53. Mass: 469.1903 m/z: 470.25
(M ? 1). Anal. Calcd. for C30H23N5O: C, 76.74; H, 4.94;
N, 14.92. Found: C, 76.91; H, 5.07; N, 15.11.
Yield: 76 %, m.p.: 254–256 °C. IR (KBr, cm-1): 3077,
3042, 2966, 1645, 1596, 1545, 1500, 1423, 1340, 1219,
1157, 1066, 827, 764, 688, 638. 1H-NMR (CDCl3,
Acknowledgments Financial support by UGC, New Delhi, is
gratefully acknowledged. Thanks to Mr Ashwani Kumar, GJUST-
Hisar, for his valuable suggestions for carrying out antimicrobial activity.
200 MHz, d): 3.202 (Hb, dd, Jb,c = 4.7 Hz, and Jb,a
17.5 Hz), 3.734 (Ha, dd, Ja,c = 11.6 Hz and Ja,b
=
=
17.5 Hz), 6.052 (Hc, dd, Jc,a = 11.6 Hz and Jc,b = 4.7 Hz),
7.315–7.502 (8H, m), 7.621–7.786 (6H, m), 7.840 (2H, d,
J = 5.7 Hz), 7.887 (1H, s, pyrazolyl-H), 8.783 (2H, d,
J = 5.7 Hz). 13C-NMR (CDCl3, 100 MHz, d): 164.40,
156.32, 149.82, 139.68, 134.77, 132.81, 131.96, 131.82,
130.99, 130.51, 130.28, 130.06, 129.58, 129.45, 128.86,
128.62, 127.40, 126.80, 125.87, 121.95, 121.87, 119.41,
119.21, 53.47, 41.49. Mass: m/z: 504.1546, 506.1517
(M ? 1), Anal. Calcd. for C30H22ClN5O: C, 71.49; H,
4.40; N, 13.90. Found: C, 71.61; H, 4.46; N, 14.02.
References
Abdel-Hafez ESMN, Abuo-Rahma G, El-D AA, Abdel-Aziz M,
Radwan MF, Farag HH (2009) Design, synthesis and biological
investigation of certain pyrazole-3-carboxylic acid derivatives as
novel carriers for nitric oxide. Bioorg Med Chem 17:3829–3837
Acharya BN, Saraswat D, Tiwari M, Shrivastava AK, Ghorpade R,
Bapna S, Kaushik MP (2010) Synthesis and antimalarial
evaluation of 1,3,5-trisubstituted pyrazolines. Eur J Med Chem
45:430–438
Ali MA, Shaharyar M, Siddiqui AA, Sriram D, Yogeeswari P, Clercq
ED (2007) Synthesis and anti-HIV activity of N1-nicotinoyl-3-
(40-hydroxy-30-methylmrthylphenyl)-5-[substituted phenyl]-2-
pyrazolones. Acta Pol Pharma Drug Res 63:435–439
(5-(3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-
phenyl-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-
yl)methanone (3f)
Argyrou A, Jin L, Siconilfi-Baez L, Angeletti RH, Blanchard JS
(2006) Proteome-wide profiling of isoniazid targets in myco-
bacterium tuberculosis. Biochemistry 45:13947–13953
Bailey DM, Hansen PE, Hlavac AG, Baizman ER, Pearl J, Defelice
AF, Feigenson ME (1985) 3,4-Diphenyl-1H-pyrazole-1-propa-
namine antidepressants. J Med Chem 28:256–260
Yield: 73 %, m.p.: 236–238 °C. IR (KBr, cm-1): 3033,
2991, 1640, 1600, 1535, 1504, 1435, 1328, 1288, 1219,
1173, 1142, 1072, 1011, 963, 826, 760, 687, 625. 1H-NMR
(CDCl3, 200 MHz, d): 3.197 (Hb, dd, Jb,c = 4.7 Hz, and
Cheng H, Lundy DeMello KM, Li J, Sakya SM, Ando K, Kawamura
K, Kato T, Rafka RJ, Jaynes BH, Ziegler CB, Stevens R, Lund
LA, Mann DW, Kilroy C, Haven ML, Nimz EL, Dutra JK, Li C,
Minich ML, Kolosko NL, Petras C, Silivia AM, Seibel SB
(2006) Synthesis and SAR of heteroaryl-phenyl-substituted
pyrazole derivatives as highly selective and potent canine
COX-2 inhibitors. Bioorg Med Chem Lett 16:2076
Chowdhury MA, Abdellatif KRA, Dong Y, Das D, Suresh MR,
Knaus EE (2008) Synthesis of celecoxib analogs that possess a
N-hydroxypyrid-2(1H)one 5-lipoxygenase pharmacophore: Bio-
logical evaluation as dual inhibitors of cyclooxygenases and
5-lipoxygenase with anti-inflammatory activity. Bioorg Med
Chem Lett 18:6138–6141
Jb,a = 17.6 Hz), 3.736 (Ha, dd, Ja,c = 11.5 Hz and Ja,b
=
17.6 Hz), 6.049 (Hc, dd, Jc,a = 11.5 Hz and Jc,b = 4.7 Hz),
7.386–7.452 (7H, m), 7.549–7.705 (7H, m), 7.835 (2H, d,
J = 5.8 Hz), 7.886 (1H, s, pyrazolyl-H), 8.782 (2H, d,
J = 5.8 Hz). 13C-NMR (CDCl3, 100 MHz, d): 164.38,
156.30, 149.84, 139.63, 134.84, 132.79, 131.98, 131.86,
131.00, 130.65, 130.30, 130.12, 129.63, 129.42, 128.88,
128.64, 127.45, 126.83, 125.93, 123.67, 122.60, 121.97,
121.89, 119.42, 119.19, 53.49, 41.50. Mass: m/z:
548.15 (100.0 %), 550.22 (97.3 %). Anal. Calcd. for
C30H22BrN5O: C, 65.70; H, 4.04; N, 12.77. Found: C,
65.84; H, 4.11; N, 12.93.
´
Daffe M, Draper P (1998) The envelope layers of mycobacteria with
reference to their pathogenicity. Adv Microb Physiol 39:131–203
Delaine T, Genisson VB, Meunier B, Bernadou J (2007) Synthesis of
the isonicotinoylnicotinamide scaffolds of the naturally occur-
ring isoniazid-NAD(P) adducts. J Org Chem 72:675–678
Foye WO, Lemke TL, Williams DA (1995) Principles of medicinal
chemistry, 4th edn. B.I. Waverly Pvt Ltd, New Delhi,
pp 768–769, 806–811
Jagrat M, Behera J, Yabanoglu S, Ercan A, Ucar G, Sinha BN,
Sankaran V, Basu A, Jayaprakash V (2011) Pyrazoline based
MAO inhibitors: synthesis, biological evaluation and SAR studies.
Bioorg Med Chem Lett. doi:10.1016/j.bmcl.2011.05.057
Janus SL, Magdif AZ, Erik BP, Claus N (1999) Synthesis of
triazenopyrazole derivatives as potential inhibitors of HIV-1.
Monatsh Chem 130:1167–1173
(5-(1,3-Diphenyl-1H-pyrazol-4-yl)-3-phenyl-4,5-
dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanone (3g)
Yield: 75 %, m.p.: 246–248 °C. IR (KBr, cm-1): 3078,
3066, 1628, 1597, 1551, 1504, 1435, 1373, 1353, 1242,
1157, 1103, 1034, 918, 825, 756, 694, 617. 1H-NMR
(CDCl3, 200 MHz, d): 3.217 (Hb, dd, Jb,c = 4.8 Hz, and
Jb,a = 17.6 Hz), 3.718 (Ha, dd, Ja,c = 11.5 Hz and Ja,b
=
17.6 Hz), 6.093 (Hc, dd, Jc,a = 11.5 Hz and Jc,b = 4.8 Hz),
7.383–7.477 (8H, m), 7.676–7.807 (7H, m), 7.835 (2H, d,
J = 5.9 Hz), 7.897 (1H, s, pyrazolyl-H), 8.788 (2H, d,
J = 5.9 Hz). 13C-NMR (CDCl3, 100 MHz, d): 164.44,
Jeong TS, Kim KS, Kim JR, Cho KY, Lee S (2004) Novel 3,5-diaryl
pyrazolines and pyrazole as low-density lipoprotein (LDL)
oxidation inhibitor. Bioorg Med Chem Lett 14:2719–2723
123

Med Chem Res (2013) 22:433–439
439
Johnsson K, King DS, Schultz PG (1995) Studies on the mechanism
of action of isoniazid and ethionamide in the chemotherapy of
tuberculosis. J Am Chem Soc 117:5009–5010
Kumar P (2009) Solid state oxidative aromatization of Hantzsch 1,4-
dihydropyridines to pyridines using iodobenzene diacetate or
hydroxy(tosyloxy)iodobenzene. Chin J Chem 27:1487–1491
Kumar P, Kumar A (2010) An expeditious synthesis of isoxazoline
using cetyltrimethylammonium cerium nitrate: a phase transfer-
ring oxidative 1,3-dipolar cycloaddition. Chin Chem Lett
21:1287–1290
Kumar A, Chawla A, Jain S, Kumar P, Kumar S (2011a) 3-Aryl-2-{4-
[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxy]-phenyl}-acrylic
acid alkyl ester: synthesis and antihyperglycemic evaluation.
Med Chem Res 20:678–686
Kumar P, Kumar S, Husain K, Kumar A (2011b) An efficient
synthesis of pyrazole chalcones under solvent free conditions at
room temperature. Chin Chem Lett 22:37–40
Ozdemir Z, Kandilci HB, Gumusel B, Alıs UC, Bilgin AA (2007)
Synthesis and studies on antidepressant and anticonvulsant
activities of some 3-(2-furyl)-pyrazoline derivatives. Eur J Med
Chem 42:373–379
Prasad YR, Rao AL, Prasoona L, Murali K, Kumar PR (2005)
Synthesis and antidepressant activity of some 1,3,5-triphenyl-2-
pyrazolines and 3-(200-hydroxy naphthalen-100-yl)-1,5-diphenyl-
2-pyrazolines. Bioorg Med Chem Lett 15:5030–5034
´
Quemard A, Dessen A, Sugantino M, Jacobs WR Jr, Sacchetini JC,
Blanchard JS (1996) Binding of catalase-peroxidase-activated
isoniazid to wild-type and mutant mycobacterium tuberculosis
enoyl-ACP reductases. J Am Chem Soc 118:1561–1562
Shaharyar M, Abdullah MM, Bakht MA, Majeed J (2010) Pyrazoline
bearing benzimidazoles: search for anticancer agent. Eur J Med
Chem 45:114–119
Sharma PK, Kumar S, Kumar P, Kaushik P, Kaushik D, Dhingra Y,
Aneja KR (2010) Synthesis and biological evaluation of some
pyrazolylpyrazolines as anti-inflammatory-antimicrobial agents.
Eur J Med Chem 45:2650–2655
Lorian V (1986) Antibiotics in laboratory medicine, 2nd edn.
Williams & Wilkins, London, p 116
Manna K, Agrawal YK (2009) Microwave assisted synthesis of new
indophenazine 1,3,5-trisubstruted pyrazoline derivatives of ben-
zofuran and their antimicrobial activity. Bio Med Chem Lett
19:2688–2692
Sridhar R, Perumal PT, Etti S, Shanmugam G, Ponnuswamy MN,
Prabavathy VR, Mathivanan N (2004) Design, synthesis and
anti-microbial activity of 1H-pyrazole carboxylates. Bioorg Med
Chem Lett 14:6035–6040
´
Marrakchi H, Laneelle G, Quemard A (2000) InhA, a target of the
Sriram D, Yogeeshwari P (2008) Medicinal chemistry, 2nd edn.
Pearson Education, Dorling Kindersley, Noida, pp 329–333
Tewari AK, Mishra A (2001) Synthesis and anti-inflammatory
activities of N4,N5-disubstituted-3-methyl-1H-pyrazolo[3,4-
c]pyridazines. Bioorg Med Chem 9:715
Turan-Zitouni G, Chevallet P, Kilic FS, Erol K (2000) Synthesis of
some thiazolyl-pyrazoline derivatives and preliminary investiga-
tion of their hypotensive activity. Eur J Med Chem 35:635–641
Wiley RH, Wiley P (1964) Pyrazolones, pyrazolidones and deriva-
tives. Wiley, New York
antituberculous drug isoniazid, is involved in a mycobacterial
fatty acid elongation system, FAS-II. Microbiology 146:289–296
McFarland J (1907) Nephelometer: an instrument for estimating the
number of bacteria in suspension used for calculating the
opsonic index and for vaccines. J Am Med Assoc 49:1176–1178
Michon V, Du Penhoat CH, Tombret F, Gillardin JM, Lepagez F,
Berthon L (1995) Preparation, structural analysis and anticon-
vulsant activity of 3- and 5-aminopyrazole N-benzoyl deriva-
tives. Eur J Med Chem 30:147–155
NCCLS (2000) Method for dilution antimicrobial susceptibility test for
bacteria that grow aerobically approved standard, 5th edn. National
Committee for Clinical Laboratory Standards, Villanova, PA
Nguyen M, Claparols C, Bernadou J, Meunier B (2002) Is the
isonicotinoyl radical generated during activation of isoniazid by
MnIII-pyrophosphate? C. R. Chimie 5:325–330
Xia Y, Dong ZW, Zhao BX, Ge X, Meng N, Shin DS, Miao JY (2007)
Synthesis and structure–activity relationships of novel 1-aryl-
methyl-3-aryl-1H-pyrazole-5-carbohydrazide derivatives as
potential agents against A549 lung cancer cells. Bioorg Med
Chem 15:6893–6899
123