Design, synthesis, and antitubercular evaluation of novel series of 3-benzofuran-5-aryl-1-pyrazolyl-pyridylmethanone and 3-benzofuran-5-aryl-1- pyrazolylcarbonyl-4-oxo-naphthyridin analogs

Article abstract of DOI:10.1016/j.ejmech.2010.05.035

Twenty-eight newer 3-benzofuran-5-aryl-1-pyrazolyl-pyridylmethanone and 3-benzofuran-5-aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridin analogs were synthesized by microwave irradiation method and evaluated for in-vitro and in-vivo antitubercular activity agai

Full text of DOI:10.1016/j.ejmech.2010.05.035

European Journal of Medicinal Chemistry 45 (2010) 3831e3839
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis, and antitubercular evaluation of novel series of
3-benzofuran-5-aryl-1-pyrazolyl-pyridylmethanone and
3-benzofuran-5-aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridin analogs
,
b
Kuntal Manna a , Yadvendra K. Agrawal
*
a Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad 382 481, Gujarat, India
b Institute of Research and Development, Gujarat Forensic Sciences University, Sector 18-A, Near Police Bhavan, Gandhinagar 382007, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Twenty-eight newer 3-benzofuran-5-aryl-1-pyrazolyl-pyridylmethanone and 3-benzofuran-5-aryl-1-
pyrazolylcarbonyl-4-oxo-naphthyridin analogs were synthesized by microwave irradiation method and
evaluated for in-vitro and in-vivo antitubercular activity against multidrug-resistant M. tuberculosis
stains. Structureeactivity relationship study was carried out and found NO2 (o) substituted 3-benzo-
furan-5-aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridin was most potent antitubercular agent against M.
tuberculosis, even better than standard drug isoniazid and comparable with rifampin. Other synthesized
compounds 7j, 7f, 7a, 7e and 5d, 5f were found moderate to good activity in in-vitro model at lower IC50
Received 11 January 2010
Received in revised form
4 May 2010
Accepted 17 May 2010
Available online 24 May 2010
Keywords:
values 85
mM, 154 mM, 157 mM, 164 mM, 170 mM and 190mML respectively. In in-vivo animal model
Nalidixic acid hydrazide
Isonicotinic acid hydrazide
Pyrazoline
compound 7j was drastically reduced the bacterial load in lung and spleen tissues at the dose of 25 mg/
kg body weight.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Benzofuran
Antitubercular activity
Structureeactivity relationship
Microwave synthesis
1. Introduction
infections [5] as a result gatifloxacin and moxifloxacin are in last
stage of antitubercular drug discovery pipeline, shortly FDA will
Mycobacterium tuberculosis, the causative agent of tuberculosis
(TB), is the greatest single infection cause of higher mortality
worldwide; roughly two million peoples were killed by tubercu-
losis every year [1]. In addition; HIV-1 and 2 infections has been
a major factor in the actual resurgence of tuberculosis [2]. Multi-
drug-resistant (MDR) strains of M. tuberculosis are another problem
of antitubercular chemotherapy, two most effective chemothera-
peutic agents, rifampin and isonicotinic acid hydrazide (INH) are to
be resistant against M. tuberculosis [3]. Moreover, strains that are
even more resistant than MDR, so-called extensively drug resistant
(XDR) [4]. So there is a pressing need for new chemotherapeutic
agents to combat the emergence of drugs resistance and shorten
duration of treatment to improve the patient compliances. Nali-
dixic acid is the first lead quinolone antibiotic use in UTIs. Recently,
quinolone analogs have been examined for different mycobacterial
approve gatifloxacin and moxifloxacin as antitubercular agents [6].
Pyridine ring is another heterocyclic interest has been present in
isoniazid (INH), which was first reported as a potent antitubercular
agent in 1952. Recent chemotherapy of tuberculosis, isoniazid and
rifampin are the key components of first-line treatment of tuber-
culosis. The modification of pyridine and quinolone rings contrib-
uting broad-spectrum antimicrobial and potent antitubercular
activity [7]. In recent years, 1,3,5 trisubstituted pyrazole bearing
benzofuran derivatives were exhibited broad-spectrum antimi-
crobial activities [8,9,10,11]. Pyrazoline containing substituted
benzofuran exhibited remarkable antitubercular activity [6,12,14].
All those finds, we inspired to design and synthesize different
benzofuran pyrazoline containing pyridine and quinolone rings and
examined for their in-vitro and in-vivo antitubercular activities. 3-
benzofuran-5-aryl-1-pyrazolyl-pyridylmethanones (5ae5n) and 3-
benzofuran-5-aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridins
(7ae7n) are the great combination of pyrazoline, benzofuran with
pyridine and quinolone rings. These types of novel ring systems
have not been studied yet as antitubercular agents against multi-
drug-resistant M. tuberculosis.
* Corresponding author. Tel.: þ91 2717 241911/12/13/14/15x724; fax: þ91 2717
241917.
E-mail address: k_manna2002@yahoo.com (K. Manna).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.05.035

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K. Manna, Y.K. Agrawal / European Journal of Medicinal Chemistry 45 (2010) 3831e3839
2. Chemistry
pyridylmethanones
5ae5n
and
3-benzofuran-5-aryl-1-pyr-
azolylcarbonyl-4-oxo-naphthyridins 7ae7n (Scheme 1). Microwave
irradiation method was adapted for the synthesis of all compounds to
reduce the reaction time and better yield. Nalidixic acid hydrazide 6
was prepared from ester derivative of nalidixic acid as described [7].
The moisture-sensitive reactions were carried out under nitrogen
atmosphere. Mostof the solventsand all reagents wereobtained from
commercial sources and used without further purification. All dry
solvents were prepared according to standard procedures and stored
over molecular sieves. First crucial intermediates 1-benzo[b]furan-2-
yl-3-phenyl-2-propen-1-ones (chalcone) 3ae3n were synthesized
from 2-acetyl benzofuran 1 with various aromatic aldehydes 2ae2n.
The chalcones were further treated with two different hydrazides
(isonicotinic acid hydrazide 4 and nalidixic acid hydrazide 6) to give
corresponding final compounds 3-benzofuran-5-aryl-1-pyrazolyl-
3. Pharmacology
3.1. In-vitro antitubercular activity
The in-vitro antitubercular activity was performed by measuring
the growth of M. tuberculosis (H37RV) using Lowensteine Jensen
Scheme 1. Synthetic pathway of compounds 5ae5n and 7ae7n. Reagents and conditions: (i) EtOH, 10% KOH/20% NaOH sol., M.W.10e25 min. (ii) CH3COOH. 6e10 h. (iii)CH3COOH,
M.W., 12e22 min.

K. Manna, Y.K. Agrawal / European Journal of Medicinal Chemistry 45 (2010) 3831e3839
3833
Table 1
medium (L. J. medium) [15,16]. Briefly, eggs were broken aseptically
to obtain 200 mL of egg solution. The solution was filtered through
a sterile muslin cloth into a sterile conical flask containing glass
beads. Sterilized mineral salt solution (120 mL) (consisting of 4.0 g
potassium phosphate, 0.4 g of magnesium sulfate, 1.6 g magnesium
citrate, 6.0 g of asparagine, 20 mL of glycerol, distilled water
makeup upto 1000 mL) and 4 mL of sterilized malachite green
solution (2.0%) were added to the 200 mL of egg solution. The
contents were mixed well to form a uniform medium. Compounds
(10 mg) were dissolved in 10.0 mL of dimethyl sulfoxide (DMSO)
In-vitro antitubercular activity and cytotoxic results of all the compounds against
MTB and MDR-TB.
c
Name of
comp.
eR
Results against
MTBa
Results against
MDR-TBb
IC50
(
m
M)
MIC (
mg/mL)
MIC (mg/mL)
5a
5b
5c
5d
5e
5f
eOH (o)
3.7
6.5
9.2
2.2
7.5
3.3
6.2
5.7
11.5
3.2
6.9
4.5
>195.2
>202.4
>210.7
>170.9
>240.5
>190.7
eOCH3 (o)
eN (CH3)2 (p)
eCOOH (o)
eNO2 (m)
eOH (o), OCH3
(p)
eOH (p)
eCl (p)
eCl (o)
eNO2 (o)
eOCH3 (p)
eH
Furan Ring
eCH]CHeAr
eOH (o)
eOCH3 (o)
eN (CH3)2 (p)
eCOOH (o)
eNO2 (m)
eOH (o), OCH3
(p)
and were diluted with DMSO to make 250 mg/mL and 10 mg/mL
stock solutions. A 0.8 mL aliquot of each concentration was trans-
ferred into different McCartney bottles. To this, 7.2 mL of L. J.
medium was added and mixed well. Isoniazid and rifampin (10 mg)
were chosen as the standard drugs for the comparison of antitu-
bercular activity. The drug was dissolved in DMSO and diluted as
described above. The bottles were incubated at 75e80 ꢀC for 3 days
for solidification and sterilization.
5g
5h
5i
5j
5k
5l
5m
5n
7a
7b
7c
7d
7e
7f
4.5
11.5
10.6
8.2
6.8
8.5
9.6
8.6
1.2
5.5
9.2
4.5
2.3
4.2
6.2
10.6
9.5
7.5
5.5
9.5
10.4
7.5
6.4
8.5
>200.3
>220.7
>210.6
>245.4
>200.3
>209.6
>208.4
>212.2
>157.6
>187.5
>206.8
>196.4
>164.5
>154.4
Procedure for inoculation: A sweep from multidrug-resistant
H37Rv strain of M. tuberculosis culture was transferred with the help
of 22 S.W. nichrome wire loop of 3 mm external diameter into
a sterile bijou bottle containing six 3 mm glass beads and 4 mL of
sterile distilled water. Each loop of culture delivered approximately
4 mg of bacilli cells. The bottle was shaken with the help of vertex
mixture for 2 min. The suspension was inoculated on the surface of
each L. J. medium containing test compounds using 27 S.W.G
nichrome wire loop of 3 mm external diameter and L. J. medium
containing isoniazide and rifampin. The medium containing DMSO
(control) was inoculated with the test organism for positive and
negative controls. Medium without any test compound/DMSO was
also inoculated with the test organism to check whether the media
supports the growth of the tubercle bacilli or not. The inoculated
bottles were incubated at 37 ꢀC for 6 weeks, at the end of which
readings were taken. Bacterial counts were measured and
compared with the standard drugs and controls (vehicle-treated).
In-vitro antitubercular activity was examined for all the synthesized
compounds (5ae5n and 7ae7n) and found satisfactory activity by
measuring the growth of multidrug-resistant M. tuberculosis
(H37RV). The MICs of the compounds were obtained a satisfactory
10.6
7.8
3.7
5.4
7g
7h
7i
7j
7k
7l
7m
7n
eOH (p)
eCl (p)
eCl (o)
eNO2 (o)
eOCH3 (p)
eH
Furan Ring
eCH]CHeAr
3.2
8.3
7.8
1.9
6.3
9.8
7.5
5.5
0.60
0.32
3.8
6.3
8.4
3.6
8.5
10.8
8.5
7.4
4.2
8.5
>148.5
>160.5
>178.4
>85.4
>156.5
>210.4
>185.5
>168.6
>74.5
Rifampin
Isoniazid
>130.5
a
M. tuberculosis stain H37RV.
Multidrug-resistant M. tuberculosis.
Cytotoxicity in VERO cell line.
b
c
lung and spleen tissues, which comparable with standard drug and
control.
range at 85.45 mg/mL to 240.5 mg/mL. Compounds 5d, 5f, 5a, 5g, 7a,
3.3. MICs determination
7e, 7j and 7g were found moderate to good in-vitro antitubercular
activity in Table 1. Among all the synthesized compounds, 7j and 5d
exhibited maximum in-vitro antitubercular activity against both
MTB and MDR-TB which could be compared with standard drugs.
Rests of compounds were found moderate to low antitubercular
activity.
The minimum inhibitory concentrations (MICs) were deter-
mined for all the test drugs using fresh colonies of M. tuberculosis
H37RV. Fresh colonies were collected and suspended in distilled
water; the turbidity of the suspension was adjusted with distilled
water to match with standard 1 mg/mL suspension of M. bovis BCG
(containing approximately 108 cfu per mL) [18]. The suspension was
further diluted to 10ꢁ1 and 10ꢁ2 mg/mL. The MICs were measured
using 10% oleic acidealbuminedextroseecatalase-enriched 7H11
agar medium. All the test compounds, rifampin, and gatifloxacin
(standard drugs) were dissolved and diluted with dimethyl form-
amide (DMF). One volume of drug solution was added to 99
volumes of culture medium, and made two fold dilutions, final
concentration of test drugs and standards were in the range
3.2. In-vivo antitubercular activity
In-vivo antitubercular activity was examined in selective 6-
week-old female CD-1 mice models against MTB at a dose of 25 mg/
kg body weight, six animals per group. The stain was administered
intravenously through the caudal vein with 106 to 107 viable M.
tuberculosis ATCC 35801 [17]. Test drugs were administered by
intra-peritoneal route initiated after 10 days of inoculation. After
thirty-five days, the spleen and right lung were aseptically removed
and grounded in a tissue homogenizer. The numbers of viable
organisms were determined by serial 10-fold dilution and subse-
quent inoculation onto 7H10 agar plates. Cultures were incubated
at 37 ꢀC in ambient air for upto 6 weeks prior to the counts.
Bacterial counts were measured and compared with the standard
drugs and negative control (vehicle-treated). The bacterial load in
lung and spleen tissues was reduced, when animals were treated
with test drugs mention in Table 2. Compounds 7e, 7a, 7n and 5d
were found to be most promising in reducing of bacterial count in
between 14 mg/mL to 0.12 mg/mL. The bacterial suspensions were
plated in duplicate on both drug-free and drug-containing media.
The result of MICs of all the test drugs and standard drugs were
reported in Table 1.
3.4. Cytotoxicity study
Cytotoxic study was carried out for finding drug toxicity (IC50) in
a mammalian Vero cell line [19] at the concentration of 50 mg/mL.
After 72 h of exposure, the viability was assessed on the basis of

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K. Manna, Y.K. Agrawal / European Journal of Medicinal Chemistry 45 (2010) 3831e3839
Table 2
of pyrazoline (m, 1H) and 3.6e4.00 ppm for CH2 of pyrazoline (m,
2H) for the evidence of pyrazoline ring. The structure of compound
5a was confirmed by 13C NMR peaks at 34.7 (CH2 in pyrazole ring),
167.4 (isonicotinic ring), 158.8, 152.6, 125.5 (C in benzofuran ring),
124.8, 122.6, 110.7, 15.5 (CH in benzofuran ring) and molecular ion
peak of 5a in mass spectra (FAB) was found identical with actual
molecular weight of the compound at 383.98 (m þ 1) and base peak
was recorded at 145.20 (100%). Another thirteen derivatives of 3-
benzofuran-5-aryl-1-pyrazolyl-pyridylmethanone 5be5n were
established similar way. Second series of 3-benzofuran-5-aryl-1-
pyrazolylcarbonyl-4-oxo-naphthyridins were characterized by
satisfactory spectral data. In second series compound 7a was
characterized by IR peak at 3368 cmꢁ1 for OH(o) group in phenyl
ring, other peaks like 3118e2952 cmꢁ1 for aromatic CH, 1680 cmꢁ1
for C]O, 1626 cmꢁ1 for C]N, Pyrazoline, 1483e1448 cmꢁ1 for
aromatic C]C, 1352e1171 cmꢁ1 for CeO, str. In 1H NMR peaks were
reconfirmed the structure at 10.12 ppm (s, OH) for hydroxyl one
proton, 8.86 ppm peak was found for H-6 in naphthyridin ring (d,
1H, J6-5 ¼ 7.3), 7.43 ppm for furan one proton (s,1H), 6.32e5.84 ppm
for CH of pyrazoline (m, 1H,) and 3.6e4.20 ppm for CH2 of pyr-
azoline (m, 2H) established the structure of pyrazoline, 4.36 ppm (s,
2H), 2.32 ppm (s, 2H), 1.3 ppm (s, 3H) were also found for C2H5
group at C-1 position in naphthyridin ring. In 13C NMR peaks were
found like 180.27, 171.21, 164.63 (isonicotinic ring), 152.34, 143.77,
137.22, 133.81, 128.82, 123.26, 110.2, 106.8, 98.73, 45.7, 34.77 (CH2 in
pyrazole ring), 24.23, 14.27 (CH in benzofuran ring) were help to
reconfirm the structure. In MS (FAB) m/z was found at 492.53 (mþ),
which was same with actual molecular weight of the compound 5a
and 100% base peak of important fragment was recorded at 145.22
(100%). Another thirteen derivatives of 3-benzofuran-5-aryl-1-
pyrazolylcarbonyl-4-oxo-naphthyridin 7be7n were interpreted
and characterized similar way like 7a. The elementals analysis
confirmed the purity of the compounds, theoretical percentages
were found similar ꢂ0.4% with experimental elementals data.
In-vivo antitubercular activities of all the synthesized compounds against M.
tuberculosis ATCC 35801 in mice.
Name of
comp.
eR
Lungs
(log cfu ꢂ SEM)
Spleen
(log cfu ꢂ SEM)
5a
5b
5c
5d
5e
5f
5g
5h
5i
eOH (o)
7.2 ꢂ 0.12
9.65 ꢂ 0.24
14.4 ꢂ 0.56
6.24 ꢂ 0.16
10.8 ꢂ 0.42
6.98 ꢂ 0.19
7.46 ꢂ 0.18
13.8 ꢂ 0.21
12.5 ꢂ 0.26
9.5 ꢂ 0.18
9.45 ꢂ 0.22
10.6 ꢂ 0.24
15.8 ꢂ 0.38
5.42 ꢂ 0.22
11.6 ꢂ 0.36
6.52 ꢂ 0.15
8.20 ꢂ 0.20
12.4 ꢂ 0.24
12.2 ꢂ 0.22
10.5 ꢂ 0.26
9.24 ꢂ 0.22
10.6 ꢂ 0.24
12.6 ꢂ 0.26
11.6 ꢂ 0.22
5.36 ꢂ 0.31
6.13 ꢂ 0.52
6.53 ꢂ 0.33
6.16 ꢂ 0.36
3.25 ꢂ 0.28
9.28 ꢂ 0.24
7.21 ꢂ 0.22
12.12 ꢂ 0.43
10.96 ꢂ 0.21
6.12 ꢂ 0.33
10.77 ꢂ 0.29
12.98 ꢂ 0.27
10.52 ꢂ 0.37
6.32 ꢂ 0.19
9.42 ꢂ 0.19
3.98 ꢂ 0.09
5.45 ꢂ 0.12
eOCH3 (o)
eN (CH3)2 (p)
eCOOH (o)
eNO2 (m)
eOH (o), OCH3 (p)
eOH (p)
eCl (p)
eCl (o)
eNO2 (o)
eOCH3 (p)
eH
Furan Ring
eCH]CHeAr
eOH (o)
eOCH3 (o)
eN (CH3)2 (p)
eCOOH (o)
eNO2 (m)
eOH (o), OCH3 (p)
eOH (p)
eCl (p)
eCl (o)
eNO2 (o)
eOCH3 (p)
eH
5j
5k
5l
8.6 ꢂ 0.16
9.4 ꢂ 0.21
5m
5n
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
11.4 ꢂ 0.22
10.8 ꢂ 0.21
4.11 ꢂ 0.62
6.87 ꢂ 0.27
4.82 ꢂ 0.42
5.12 ꢂ 0.28
2.65 ꢂ 0.43
8.42 ꢂ 0.38
5.49 ꢂ 0.31
11.52 ꢂ 0.23
10.85 ꢂ 0.46
5.67 ꢂ 0.22
9.32 ꢂ 0.42
12.23 ꢂ 0.37
9.66 ꢂ 0.38
4.61 ꢂ 0.12
8.24 ꢂ 0.21
3.21 ꢂ 0.11
4.62 ꢂ 0.10
7m
7n
Control
Rifampin (25 mg/Kg)
Isoniazid (25 mg/Kg)
Furan Ring
eCH]CHeAr
cellular conversion of [3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-
nyltetrazolium bromide] (MTT) into a formazan product using
Promega Cell Titer 96 non-radioactive cell proliferation assay [20].
Cytotoxicity was reported in Table 1. Most of the tested compounds
were found to be non-toxic in Vero cell line assay; compounds with
nitrogen containing (5e, 5j and 7e, 7j) showed 72e75% toxicity in
Vero cell line.
5. Structureeactivity relationships
The structure-activity relationship (structure-MTB/MDR
activity) study demonstrated that, 2-[3-benzo[b]furan-2-yl-1-(2,3-
dihydro-4-pyridinylcarbonyl)-4,5-dihydro-1H-5-pyrazolyl] phenyl
derivatives (5a-5n) and 3-(3-benzo[b]furan-2-yl-5-phenyl-4,5-
dihydro-1H-1-pyrazolylcarbonyl)-1-ethyl-7-methyl-1,4-dihydro
[1,8]naphthyridin-4-one derivatives (7a-7n) exhibiting good to
moderate antitubercular activity. The naphthyridin ring is more
favorable group then pyridinylcarbonyl ring for the potent activity.
The antitubercular activity was found by synthesized compounds,
may be due to formation of free isonicotinoyl-NAD complex, which
may be responsible for the inhibition of mycobacterium cell wall
biosynthesis [13]. Carboxylic group containing compound 5d was
found more active against multidrug-resistant M. Tuberculosis.
Hence, the acidic medium is favorable for the formation of
isonicotinoyl-NAD complex, which produced by carboxylic group.
The electron-withdrawing group (-NO2 groups) containing naph-
thyridine ring (compound 7j) produced better activity than pres-
ence of halogen, furan and other groups in same ring system. Nitro
derivatives of pyrazoline containing benzofuran with naphthyr-
idine or pyridines are highly favorable moieties for antitubercular
activity.
3.5. Statistical analysis
The viable counts were converted to logarithms, which were
then evaluated by a one-way ANOVA followed by a multiple
comparison analysis of variance by a one-way Tukey test (Sigma-
Stat software program). Differences were considered significant at
the 95% level of confidence.
4. Results and discussion
The structures of the synthesize compounds were established
on the basis of spectroscopic analysis. In 1H NMR spectra, the
signals of the individual protons of the drugs were verified by their
chemical shifts, multiplicities and coupling constants. The structure
of isonicotinic acid hydrazide 4 was established by IR peaks at
3366 cmꢁ1 for NH, 1679 cmꢁ1 for C]O, 1492 cmꢁ1 for C]N. In 1H
NMR a sharp peak at 8.12 ppm was recorded for NHNH2 (s, 1H) and
5.73 ppm (s, 2H) for NHNH2 were found and confirmed the
hydrazide ring. The NHNH2 characterized peaks were absent in
final structure, in IR peaks at 3121e2963 cmꢁ1 were recorded for
aromatic CH starching, 1686 cmꢁ1 for C]O and 1622, 1517 cmꢁ1 for
C]N and C]C in pyrazoline ring following peaks confirmed the
structure of pyrazoline ring. In 1H NMR, a sharp peaks at 7.23 ppm
was recorded for one proton of furan (s, 1H), 6.30e5.8 ppm for CH
6. Conclusion
In conclusion, the in-vitro and in-vivo antimycobacterial activity
of the novel series of 3-benzofuran-5-aryl-1-pyrazolyl-pyr-
idylmethanones and 3-benzofuran-5-aryl-1-pyrazolylcarbonyl-4-
oxo-naphthyridin analogs were a new chemical classes endowed

K. Manna, Y.K. Agrawal / European Journal of Medicinal Chemistry 45 (2010) 3831e3839
3835
with high antitubercular activity towards MDR-TB, exhibiting MICs
values between 85 g/mL to 240 g/mL. The potency, selectivity
and low cytotoxic compounds were valid leads for better antitu-
bercular activity.
in microwave irradiation using 78 ꢀC with 10 bar pressure for 4 min.
at microwave synthesizer. After completing the reaction, the reac-
tion mixture was poured into ice cold water. A yellowish-orange
solid was separated immediately. Yield: 92%, m.p.: 217e219 ꢀC.
Spectroscopic analysis: IR (KBr) ymax (cmꢁ1): I.R. (KBr): 3309
(Amide NH), 3205(NH2), 1936, 1697, 1616 (C]O), 1496 (Ar. C]C),
1352 (CeN), 1255, 1220, 744; 1H NMR (300 MHz, CDCl3): 8.86 (d,
1H, J6e5 ¼ 7.30, H-6), 8.65 (m, 1H, H-19), 7.73 (s, 1H, H-10), 6.80 (d,
1H, J5e6 ¼ 7.30, H-5), 4.52 (q, 2H, J11e12 ¼ 6.80, H-11), 2.70 (s, 3H, H-
13), 1.40 (t, 3H, J12e11 ¼ 6.80, H-12).
m
m
7. Experimental protocols
Microwave assisted synthetic routes were adopted for synthe-
sizing all the compounds using microwave synthesizer, Synthon-
3000, Anton Paar. Melting points were determined in one end open
capillary tubes on a Buchi-530 melting point apparatus and were
uncorrected. An infrared spectrum (FTIR) was recorded in Shi-
madzu-FTIR 8300 using KBr. Mass spectra, 1H NMR and elemental
analysis data were recorded using Joel-GSX 400 m, Advance Bruker
(300 MHz) in DMSO-d6 using TMS as an internal standard, Per-
kineElmer 2400 Series II analyzer respectively. 13C NMR spectra
were recorded in Bruker Aspect 300. The purity of compounds was
confirmed by thin layer chromatography (TLC) using silica gel G
glass plates and various solvent systems. The spots were visualized
in iodine vapor. Elemental analysis results were reordered for C, H
and N in the range of ꢂ0.4% of the theoretical value. Chemicals and
solvents were procured from E. Merck, SD-Fine, India, Sigma-
eAldrich, USA, and Ranbaxy, India.
7.4. Synthesis of 2-[3-benzo[b]furan-2-yl-1-(2,3-dihydro-4-
pyridinylcarbonyl)-4,5-dihydro-1H-5-pyrazolyl] phenyl derivatives
(5ae5n) [23]
General procedure for the synthesis of 2-[3-benzo[b]furan-2-yl-
1-(2,3-dihydro-4-pyridinylcarbonyl)-4,5-dihydro-1H-5-pyrazolyl]
phenyl derivatives from different benzofuran chalcones (0.01 mol)
and isoniazide (0.02 mol) were dissolved in 2 mL of glacial acetic acid
into 5 mL polystyrene containers and then kept into the microwave
synthesizer at 110 ꢀC with 10 bar pressure for 12 min. Reactions were
monitored by TLC using benzene and ethyl acetate (3:2 ratio) mobile
phase system. The excess of solvent was evaporated under reduced
pressure using rotary evaporator and resulting solution was poured
in ice cold water with constant stirring. Solid was separated by
vacuum filtration and recrystallized from suitable solvent.
7.1. Synthesis of benzofuran chalcones 3ae3n
Benzofuran chalcones were synthesized according to reported
methods from 2-acetyl benzofuran and various aromatic aldehydes
[21,22,23].
7.5. Synthesis of 3-(3-benzo[b]furan-2-yl-5-phenyl-4,5-dihydro-
1H-1-pyrazolylcarbonyl)-1-ethyl-7-methyl-1,4-dihydro[1,8]
naphthyridin-4-one derivatives (7ae7n) [23]
7.1.1. Microwave assisted synthesis of benzofuran chalcones 3ae3n
2-acetyl benzofuran (0.05 mol) 1 and different aromatic alde-
hydes (0.05 mol) 2ae2n were dissolved in 98% ethanol (2 mL) and
added 10% KOH solution (1 mL) into the 5 mL polystyrene
containers and then close the containers tightly with lids and live to
exposed in microwave irradiation using 130 ꢀC with 10 bar pressure
for 10 min. at microwave synthesizer. Excess of solvent was
removed under reduced pressure. The reaction solution was poured
into 10 mL ice cold water and acidified with conc. HCl. and solid was
separated by filtration.
General procedure for the synthesis 3-(3-benzo[b]furan-2-yl-5-
phenyl-4,5-dihydro-1H-1-pyrazolylcarbonyl)-1-ethyl-7-methyl-
1,4-dihydro[1,8]naphthyridin-4-one derivatives from benzofuran
chalcones (0.01 mol) and nalidixic acid hydrazide (0.02 mol) were
dissolved in 2 mL of glacial acetic acid into 5 mL polystyrene
containers and then kept into the microwave synthesizer at 120 ꢀC
with 10 bar pressure for 14 min. Reactions were monitored by TLC
using benzene and ethyl acetate (3:2 ratio) mobile phase system.
The excess of solvent was evaporated under reduced pressure using
rotary evaporator and resulting solution was poured in ice cold
water with constant stirring. Solid was separated by vacuum
filtration and recrystallized from suitable solvent.
7.2. Synthesis of 3-[(chlorooxy) carbonyl]-1-ethyl-7-methyl-1,8-
naphthyridin-4(1H)-one [7,24]
Nalidixic acid (1 g) was taken into a dry 100 mL iodine flask, and
then added 2 mL of thionyl chloride through dropping funnel. The
thionyl chloride was added drop by drop inside the fuming hood
with suitable air circulation. The reaction mixture was then kept in
room temperature for 30 min for completing the reaction. Without
separated and purified the acid chloride derivative of nalidixic acid
was immediately used for the preparation of ester derivative using
2 mL of methanol. Methanol was added drop by drop with constant
stirring in fuming hood with great care. Reaction mixture was then
transferred into the 5 mL polystyrene containers and then exposed
in microwave irradiation using 80 ꢀC with 10 bar pressure for 6 min
at microwave synthesizer. Ester derivatives was then poured into
10 mL ice cold water and extracted with diethyl ether.
Synthesized compounds and their spectral data are summarized
below. FTIR, 1H NMR, 13C NMR, MS, and other data for character-
ization the structures.
7.6. 3-Benzo[b]furan-2-yl-5-(2-hydroxyphenyl)-4,5-dihydro-1H-1-
pyrazolyl-4-pyridylmethanone (5a)
Yield: 88%, m.p.: 145e146 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3373 (OeH str.), 3121e2963 (Ar-CH), 1686 (C]O),
1622 (C]N, Pyrazoline), 1517 (C]C), 1454 (Ar), 1345, 1169 (CeO
str.); 1H NMR (CDCl3, 300 MHz,
d, ppm): 9.92 (s, OH), 8.2 (m, 6H,
7.3. Synthesis of 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-
naphthyridine-3-carbohydrazide [7,24]
J ¼ 3.43, 6.3 Hz, Ar-H), 7.79 (dd, 2H, J ¼ 3.41, 6.2 Hz), 7.75e7.39 (m,
12H, Ar-H), 7.23 (s, 1H, Furan-H), 6.30e5.8 (m, 1H, CH of pyrazo-
line), 3.6e4.00 (m, 2H, CH2 of pyrazoline), 2.3 (s, 2H); 13C NMR
0.005 mol amount of ester derivatives of nalidixic acid was
equally distributed into the 5 mL polystyrene containers then
added 0.02 mol of hydrazine hydrate through micropipette drop by
drop, then close the container tightly with lids and live to exposed
(DMSO-d6) d ppm: 167.25, 158.21, 152.27, 150.56, 144.98, 131.45,
128.65, 122.5, 106.92, 45.52, 34.74; MS (FAB) m/z: 383.98 (m þ 1),
145.20 (100%). Anal. calcd. for C23H17N3O3, C: 72.05, H: 4.47, N:
10.96%; found: C: 72.35, H: 4.42, N: 10.16%.

3836
K. Manna, Y.K. Agrawal / European Journal of Medicinal Chemistry 45 (2010) 3831e3839
7.7. 3-Benzo[b]furan-2-yl-5-(2-methoxyphenyl)-4,5-dihydro-1H-
7.11. 3-Benzo[b]furan-2-yl-5-(2-hydroxy-4-methoxyphenyl)-4,5-
1-pyrazolyl-4-pyridylmethanone (5b)
dihydro-1H-1-pyrazolyl-4-pyridylmethanone (5f)
Yield: 82%, m.p.: 120e121 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 1169e1026 (CeOeC str.), 2839 (CH3 str.), 1456 (CH3
def.); 3115e2981 (Ar-CH), 1682 (C]O), 1621 (C]N, Pyrazoline),
1516 (C]C), 1450 (Ar), 1341, 1167 (CeO str.); 1H NMR (CDCl3,
Yield: 90%; m.p.: 123e124 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3372 (OeH str.), 3117e2955 (Ar-CH), 1676 (C]O), 1616
(C]N, Pyrazoline), 1521 (C]C), 1450 (Ar), 1383 (OeH ben.), 1346,
1170 (CeO str.), 1020 (CeOeC str.), 2927 (CH3 str.), 1450 (CH3 def.);
300 MHz,
d
, ppm): 8.33 (m, 6H, J ¼ 4.43, 6.5 Hz, Ar-H), 7.87 (dd, 2H,
1H NMR (CDCl3, 300 MHz,
d, ppm): 9.98 (s, OH), 8.30 (m, 6H,
J ¼ 3.66, 6.42 Hz), 7.71e7.32 (m, 12H, Ar-H), 7.25 (s, 1H, Furan-H),
6.30e5.8 (m, 1H, CH of pyrazoline), 3.55e4.10 (m, 2H, CH2 of pyr-
J ¼ 3.66, 6.34 Hz, Ar-H), 7.68 (dd, 2H, J ¼ 4.41, 6.28 Hz), 7.68e7.32
(m, 12H, Ar-H), 7.27 (s, 1H, Furan-H), 6.32e5.86 (m, 1H, CH of pyr-
azoline), 3.65e4.80 (m, 2H, CH2 of pyrazoline), 2.34 (s, 2H); 13C
azoline), 2.32 (s, 2H); 13C NMR (DMSO-d6)
d ppm: 167.46, 158.36,
152.26, 144.55, 132.32, 122.73, 56.53, 46.22, 34.62; MS (FAB) m/z:
397.12 (mþ), 145.20 (100%). Anal. calcd. for C24H19N3O3, C: 72.53, H:
4.82, N: 10.57%; found: C: 72.12, H: 4.63, N: 10.22%.
NMR (DMSO-d6) d ppm: 167.34, 158.22, 152.25, 150.22, 148.55,
145.46, 125.53, 123.52, 122.74, 56.13, 46.67, 34.67; MS (FAB) m/z:
412.97 (mþ), 145.22 (100%). Anal. calcd. for C24H19N3O4, C: 69.72, H:
4.63, N: 10.16%; found: C: 69.26, H: 4.93, N: 10.22%.
7.8. 3-Benzo[b]furan-2-yl-5-(4-dimethylaminophenyl)-4,5-
dihydro-1H-1-pyrazolyl-4-pyridyl methanone (5c)
7.12. 3-Benzo[b]furan-2-yl-5-(4-hydroxyphenyl)-4,5-dihydro-1H-
1-pyrazolyl-4-pyridylmethanone (5g)
Yield: 72%; m.p.: 113e114 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 2925, 2804 (AreNeCH3 str.), 1446 (CH3 ban.), 1365,
1317 (CeN str.), 3131e2973 (Ar-CH), 1680 (C]O), 1624 (C]N,
Pyrazoline), 1521 (C]C), 1451 (Ar), 1350, 1164 (CeO str.); 1H NMR
Yield: 86%, m.p.: 154e156 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3367 (OeH str.), 3120e2960 (Ar-CH), 1680 (C]O),
1620 (C]N, Pyrazoline), 1516,1450 (Ar, C]C), 1342, 1170 (CeO str.);
1H NMR (CDCl3, 300 MHz,
d, ppm): 9.95 (s, OH), 8.28 (m, 6H,
(CDCl3, 300 MHz,
d
, ppm): 8.26 (m, 6H, J ¼ 3.32, 6.42 Hz, Ar-H), 7.81
(dd, 2H, J ¼ 3.53, 6.41 Hz), 7.72e7.42 (m, 12H, Ar-H), 7.28 (s, 1H,
Furan-H), 6.28e5.86 (m, 1H, CH of pyrazoline), 3.42e4.11 (m, 2H,
J ¼ 3.66, 6.63 Hz, Ar-H), 7.86 (dd, 2H, J ¼ 3.46, 6.28 Hz), 7.78e7.33
(m, 12H, Ar-H), 7.28 (s, 1H, Furan-H), 6.35e5.85 (m, 1H, CH of pyr-
azoline), 3.66e4.06 (m, 2H, CH2 of pyrazoline), 2.35 (s, 2H); 13C
CH2 of pyrazoline), 2.34 (s, 2H); 13C NMR (DMSO-d6)
d ppm: 166.89,
157.93, 152.34, 150.55, 144.25, 137.21, 129.77, 122.16, 110.32, 53.52,
40.68, 34.45; MS (FAB) m/z: 410.88 (m þ 1), 145.20 (100%). Anal.
calcd. for C25H22N4O2, C: 73.15, H: 5.40, N: 13.65%; found: C: 73.42,
H: 5.73, N: 13.22%.
NMR (DMSO-d6)
d ppm: 166.85, 158.71, 151.27, 150.26, 145.18,
132.15, 126.85, 122.21, 107.12, 47.02, 35.24; MS (FAB) m/z: 383.88
(m þ 1),145.30 (100%). Anal. calcd. for C23H17N3O3, C: 72.05, H: 4.47,
N: 10.96%; found: C: 72.26, H: 4.63, N: 11.02%.
7.9. 2-[3-Benzo[b]furan-2-yl-1-(4-pyridylcarbonyl)-4,5-dihydro-
1H-5-pyrazolyl]benzoic acid (5d)
7.13. 3-Benzo[b]furan-2-yl-5-(4-chlorophenyl)-4,5-dihydro-1H-1-
pyrazolyl-4-pyridylmethanone (5h)
Yield: 86%; m.p.: 178e179 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3402 (carbonyl OeH str.), 3124e2961 (Ar-CH), 1715
(C]O str.), 1682 (C]O), 1171e1074 (CeO str.), 1624 (C]N, Pyr-
azoline), 1521 (C]C), 1455 (Ar), 1347, 1161 (CeO str.); 1H NMR
Yield: 91%; m.p.: 113e114 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3128e2958 (Ar-CH), 1678 (C]O), 1622 (C]N, Pyr-
azoline), 1515, 1452 (Ar, C]C), 1350, 1168 (CeO str.), 786, 746 (CeCl
str.); 1H NMR (CDCl3, 300 MHz,
d
, ppm): 8.27 (m, 6H, J ¼ 3.49,
(CDCl3, 300 MHz,
d
, ppm): 9.82 (s, OH), 8.24 (m, 6H, J ¼ 3.45, 6.2 Hz,
6.37 Hz, Ar-H), 7.82 (dd, 2H, J ¼ 3.48, 6.23 Hz), 7.82e7.43 (m, 12H,
Ar-H), 7.28 (s, 1H, Furan-H), 6.33e5.86 (m, 1H, CH of pyrazoline),
3.67e4.08 (m, 2H, CH2 of pyrazoline), 2.35 (s, 2H); 13C NMR (DMSO-
Ar-H), 7.82 (dd, 2H, J ¼ 5.41, 6.44 Hz), 7.71e7.42 (m, 12H, Ar-H), 7.32
(s, 1H, Furan-H), 6.26e5.78 (m, 1H, CH of pyrazoline), 3.65e4.60 (m,
2H, CH2 of pyrazoline), 2.33 (s, 2H); 13C NMR (DMSO-d6)
d ppm:
d6)
d ppm: 167.55, 158.71, 152.47, 150.56, 144.22, 131.23, 128.45,
167.55, 160.92, 157.57, 150.43, 141.34, 133.90, 124.82, 122.43, 110.23,
48.83, 35.15; MS (FAB) m/z: 411.89 (m þ 1), 145.20 (100%). Anal.
calcd. for C24H17N3O4, C: 70.07, H: 4.16, N: 10.21%; found: C: 70.26,
H: 4.93, N: 10.22%.
122.62, 107.12, 46.12, 34.34; MS (FAB) m/z: 401.55 (mþ), 144.95
(100%). Anal. calcd. for C23H16N3O2Cl, C: 68.74, H: 4.01, N: 10.46%;
found: C: 68.26, H: 4.63, N: 10.02%.
7.10. 3-Benzo[b]furan-2-yl-5-(2-nitrophenyl)-4,5-dihydro-1H-1-
7.14. 3-Benzo[b]furan-2-yl-5-(2-chlorophenyl)-4,5-dihydro-1H-1-
pyrazolyl-4-pyridylmethanone (5e)
pyrazolyl-4-pyridylmethanone (5i)
Yield: 78%; m.p.: 110e111 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3118e2978 (Ar-CH), 1682 (C]O), 1620 (C]N, Pyr-
azoline), 1516 (C]C), 1527 (NO2 str.), 1450 (Ar), 1346 (NO2 str.), 1172
Yield: 92%; m.p.: 135e136 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3118e2963 (Ar-CH), 1682 (C]O), 1622 (C]N, Pyr-
azoline), 1520, 1450 (Ar, C]C), 1344, 1174 (CeO str.); 1H NMR
(CeO str.), 883 (CeN str.); 1H NMR (CDCl3, 300 MHz,
d
, ppm): 8.26
(CDCl3, 300 MHz,
d
, ppm): 8.28 (m, 6H, J ¼ 4.43, 6.38 Hz, Ar-H), 7.82
(m, 6H, J ¼ 3.46, 6.45 Hz, Ar-H), 7.77 (dd, 2H, J ¼ 3.46, 6.24 Hz),
7.78e7.31 (m, 12H, Ar-H), 7.33 (s, 1H, Furan-H), 6.32e5.86 (m, 1H,
CH of pyrazoline), 3.66e4.12 (m, 2H, CH2 of pyrazoline), 2.35 (s,
(dd, 2H, J ¼ 3.41, 6.2 Hz), 7.68e7.32 (m, 12H, Ar-H), 7.26 (s, 1H,
Furan-H), 6.36e5.77 (m, 1H, CH of pyrazoline), 3.68e4.65 (m, 2H,
CH2 of pyrazoline), 2.38 (s, 2H); 13C NMR (DMSO-d6)
d ppm: 166.95,
2H); 13C NMR (DMSO-d6)
d
ppm: 166.77, 153.54, 150.32, 133.65,
157.91, 152.57, 150.66, 144.12, 132.05, 125.85, 122.22, 107.12, 45.92,
35.74; MS (FAB) m/z: 402.12 (m þ 1), 145.40 (100%). Anal. calcd. for
C23H16N3O2Cl, C: 68.74, H: 4.01, N: 10.46%; found: C: 68.86, H: 4.23,
N: 10.82%.
123.54, 122.65, 106.82, 53.67, 34.42; MS (FAB) m/z: 416.11(m þ 1),
145.84 (100%). Anal. calcd. for C23H16N4O4, C: 66.99, H: 3.91, N:
13.59%; found: C: 67.06, H: 3.93, N: 13.22%.

K. Manna, Y.K. Agrawal / European Journal of Medicinal Chemistry 45 (2010) 3831e3839
3837
7.15. 3-Benzo[b]furan-2-yl-5-(2-nitrophenyl)-4,5-dihydro-1H-1-
7.19. 3-Benzo[b]furan-2-yl-5-[(E)-2-phenyl-1-ethenyl]-4,5-
pyrazolyl-4-pyridylmethanone (5j)
dihydro-1H-1-pyrazolyl-4-pyridylmethanone (5n)
Yield: 94%; m.p.: 105e107 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3126e2963 (Ar-CH), 1683 (C]O), 1626 (C]N, Pyr-
azoline), 1552 (asy., NO2 str.), 1516, 1450 (Ar, C]C), 1344 (sym., NO2
Yield: 72%; m.p.: 143e144 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3122e2942 (Ar-CH), 1680 (C]O), 1630 (C]N, Pyr-
azoline), 1520, 1450 (Ar, C]C), 1346, 1172 (CeO str.), 978 (eCH]
str.), 1170 (CeO str.), 815 (CeN str.); 1H NMR (CDCl3, 300 MHz,
d
,
CHe); 1H NMR (CDCl3, 300 MHz,
d
, ppm): 8.86 (m, 6H, J ¼ 6.42,
ppm): 8.2 (m, 6H, J ¼ 3.43, 6.32 Hz, Ar-H), 7.79 (dd, 2H, J ¼ 3.41,
6.2 Hz), 7.75e7.39 (m, 12H, Ar-H), 7.23 (s, 1H, Furan-H), 6.30e5.8
(m, 1H, CH of pyrazoline), 3.63e4.20 (m, 2H, CH2 of pyrazoline),
6.24 Hz, Ar-H), 7.77 (dd, 2H, J ¼ 6.61, 6.82 Hz), 7.75e7.38 (m, 12H,
Ar-H), 7.53 (s, 1H, Furan-H), 6.82e5.74 (m, 1H, CH of pyrazoline),
3.67e4.28 (m, 2H, CH2 of pyrazoline), 2.35 (s, 2H); 13C NMR (DMSO-
2.33 (s, 2H); 13C NMR (DMSO-d6)
d
ppm: 167.75, 158.91, 152.17,
d6) d ppm: 166.46, 157.19, 153.62, 151.06, 144.75, 138.12, 132.06,
150.48, 144.17, 131.69, 128.55, 122.15, 106.22, 45.82, 34.94; MS (FAB)
m/z: 411.88 (mþ), 145.14 (100%). Anal. calcd. for C23H16N4O4, C:
66.99, H: 3.91, N: 13.59%; found: C: 67.06, H: 3.63, N: 13.22%.
128.09, 122.77, 106.43, 56.75, 37.32; MS (FAB) m/z: 394.13 (m þ 1),
145.30 (100%). Anal. calcd. for C25H19N3O2, C: 76.32, H: 4.87, N:
10.68%; found: C: 76.46, H: 4.23, N: 10.22%.
7.20. 3-[3-Benzo[b]furan-2-yl-5-(2-hydroxyphenyl)-4,5-dihydro-
1H-1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]
naphthyridin-4-one (7a)
7.16. 3-Benzo[b]furan-2-yl-5-(4-methoxyphenyl)-4,5-dihydro-1H-
1-pyrazolyl-4-pyridylmethanone (5k)
Yield: 78%, m.p.: 172e173 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3368 (OeH str.), 3118e2952 (Ar-CH), 1680 (C]O),
1626 (C]N, Pyrazoline), 1483e1448 (Ar, C]C), 1352e1171 (CeO
Yield: 95%; m.p.: 164e165 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3126e2968 (Ar-CH), 2837 (CH3 str.), 1678 (C]O), 1623
(C]N, Pyrazoline), 1520, 1454 (Ar, C]C), 1446 (CH3 def.),
str.); 1H NMR (CDCl3, 300 MHz,
d, ppm): 10.12 (s, OH), 8.86 (d,1H, J6-
1170e1026 (CeOeC str.); 1H NMR (CDCl3, 300 MHz,
d, ppm): 8.42
¼ 7.3, H-6, naphthyridin), 8.62 (m, 6H, J ¼ 4.43, 6.34 Hz, Ar-H), 7.82
5
(m, 6H, J ¼ 3.63, 6.34 Hz, Ar-H), 7.82 (dd, 2H, J ¼ 3.42, 6.24 Hz),
7.80e7.42 (m, 12H, Ar-H), 7.28 (s, 1H, Furan-H), 6.34e5.82 (m, 1H,
CH of pyrazoline), 3.62e4.20 (m, 2H, CH2 of pyrazoline), 2.36 (s,
(dd, 2H, J ¼ 3.61, 6.22 Hz), 7.65e7.32 (m, 12H, Ar-H), 7.43 (s, 1H,
Furan-H), 6.32e5.84 (m, 1H, CH of pyrazoline), 3.6e4.20 (m, 2H,
CH2 of pyrazoline), 4.36 (s, 2H, C2H5), 2.32 (s, 2H), 1.3 (s, 3H, C2H5);
2H); 13C NMR (DMSO-d6)
d ppm: 166.96, 157.92, 152.27, 150.42,
13C NMR (DMSO-d6)
d ppm: 180.27, 171.21, 164.63, 152.34, 143.77,
144.75, 140.97, 130.68, 128.23, 127.85, 122.46, 110.22, 106.72, 53.22,
34.92; MS (FAB) m/z: 398.22 (m þ 1), 145.20 (100%). Anal. calcd. for
C24H19N3O3, C: 72.53, H: 4.82, N: 10.57%; found: C: 72.46, H: 4.93,
N: 10.22%.
137.22, 133.81, 128.82, 123.26, 110.2, 106.8, 98.73, 45.7, 34.77, 24.23,
14.27; MS (FAB) m/z: 492.53 (mþ), 145.22 (100%). Anal. calcd. for
C29H24N4O4, C: 70.72, H: 4.91, N: 11.38%; found: C: 70.65, H: 4.92, N:
11.16%.
7.21. 3-[3-Benzo[b]furan-2-yl-5-(2-methoxyphenyl)-4,5-dihydro-
1H-1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]
naphthyridin-4-one(7b)
7.17. 3-Benzo[b]furan-2-yl-5-phenyl-4,5-dihydro-1H-1-pyrazolyl-
4-pyridylmethanone (5l)
Yield: 84%; m.p.: 218e219 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3123e2955 (Ar-CH), 1678 (C]O), 1620 (C]N, Pyr-
azoline), 1480e1452 (Ar, C]C), 1360 (CeN), 1350e1170 (CeO str.),
Yield: 88%; m.p.: 115e116 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3118e2958 (Ar-CH), 1686 (C]O), 1626 (C]N, Pyr-
azoline), 1518, 1452 (Ar, C]C), 1348, 1170 (CeO str.); 1H NMR
1169e1026 (CeOeC str.), 992 (Ar, CH); 1H NMR (CDCl3, 300 MHz,
d,
(CDCl3, 300 MHz,
d
, ppm): 8.62 (m, 6H, J ¼ 4.43, 6.34 Hz, Ar-H), 7.82
ppm): 8.78 (d, 1H, J6-5 ¼ 7.42, H-6, naphthyridin), 8.82 (m, 6H,
J ¼ 6.42, 3.44 Hz, Ar-H), 7.62 (dd, 2H, J ¼ 3.62, 6.24 Hz), 7.61e7.33
(m, 12H, Ar-H), 7.42 (s, 1H, Furan-H), 6.22e5.82 (m, 1H, CH of pyr-
azoline), 3.64e4.33 (m, 2H, CH2 of pyrazoline), 4.34 (s, 2H, C2H5),
4.14 (s, 3H, OCH3), 2.33 (s, 2H), 1.62 (s, 3H, C2H5); 13C NMR (DMSO-
(dd, 2H, J ¼ 3.61, 6.22 Hz), 7.65e7.32 (m, 12H, Ar-H), 7.43 (s, 1H,
Furan-H), 6.32e5.84 (m, 1H, CH of pyrazoline), 3.6e4.20 (m, 2H,
CH2 of pyrazoline), 2.32 (s, 2H); 13C NMR (DMSO-d6)
d ppm: 166.45,
158.29, 152.77, 151.32, 143.81, 140.88, 125.66, 123.54, 122.18, 109.21,
103.83, 50.82, 34.76; MS (FAB) m/z: 368.12 (m þ 1), 145.00 (100%).
Anal. calcd. for C23H17N3O2, C: 75.19, H: 4.66, N: 11.44%; found: C:
75.46, H: 4.13, N: 11.22%.
d6)
d ppm: 181.11, 171.73, 165.03, 152.34, 143.77, 138.22, 132.81,
126.82, 122.26, 107.2, 106.8, 98.53, 56.77, 45.27, 34.51, 24.77, 14.03;
MS (FAB) m/z: 506.56 (mþ), 145.12 (100%). Anal. calcd. for
C30H26N4O4, C: 71.13, H: 5.17, N: 11.06%; found: C: 71.53, H: 5.22, N:
11.57%
7.18. 3-Benzo[b]furan-2-yl-5-(2-furyl)-4,5-dihydro-1H-1-
pyrazolyl-4-pyridylmethanone (5m)
7.22. 3-[3-Benzo[b]furan-2-yl-5-(4-dimethylaminophenyl)-4,5-
dihydro-1H-1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro
[1,8]naphthyridin-4-one (7c)
Yield: 84%; m.p.: 185e187 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3122e2950 (Ar-CH), 1686 (C]O), 1622 (C]N, Pyr-
azoline), 1518 (furan), 1452 (Ar, C]C), 1346, 1170 (CeO str.); 1H
Yield: 82%; m.p.: 205e205 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3128e2942 (Ar-CH), 3005, 2820 (AreNeCH3 str.),1678
(C]O), 1631 (C]N, Pyrazoline), 1480e1450 (Ar, C]C), 1352 (C]N),
NMR (CDCl3, 300 MHz,
d
, ppm): 8.66 (m, 6H, J ¼ 4.33, 6.36 Hz, Ar-H),
7.86 (dd, 2H, J ¼ 5.61, 6.82 Hz), 7.45e7.22 (m, 12H, Ar-H), 7.47 (s, 1H,
Furan-H), 6.36e5.88 (m, 1H, CH of pyrazoline), 3.68e4.20 (m, 2H,
1347e1170 (CeO str.); 1H NMR (CDCl3, 300 MHz,
d, ppm): 8.72 (d,
CH2 of pyrazoline), 2.37 (s, 2H); 13C NMR (DMSO-d6)
d
ppm: 166.62,
1H, J6-5 ¼ 6.56, H-6, naphthyridin), 8.77 (m, 6H, J ¼ 4.54, 6.84 Hz, Ar-
H), 7.42 (dd, 2H, J ¼ 3.68, 6.82 Hz), 7.68e7.37 (m, 12H, Ar-H), 7.52 (s,
1H, Furan-H), 6.32e5.84 (m,1H, CH of pyrazoline), 3.6e4.22 (m, 2H,
CH2 of pyrazoline), 4.36 (s, 2H, C2H5), 2.32 (s, 2H), 2.24 (s, 6H, N
158.39, 152.82, 150.66, 144.15, 138.92, 132.03, 128.06,122.27, 106.43,
56.45, 37.92; MS (FAB) m/z: 357.30 (m þ 1), 145.10 (100%). Anal.
calcd. for C21H15N3O3, C: 70.58, H: 4.23, N: 11.76%; found: C: 70.46,
H: 4.13, N: 11.22%.
(CH3)2), 1.43 (s, 3H, C2H5); 13C NMR (DMSO-d6)
d ppm: 180.81,

3838
K. Manna, Y.K. Agrawal / European Journal of Medicinal Chemistry 45 (2010) 3831e3839
170.53, 164.43, 156.14, 143.17, 136.02, 131.21, 124.82, 112.26, 106.28,
98.73, 49.77, 45.33, 40.21, 34.77, 15.13; MS (FAB) m/z: 520.60
(m þ 1), 145.38 (100%). Anal. calcd. for C31H29N5O3, C: 71.66, H:
5.63, N: 13.48%; found: C: 71.42, H: 5.73, N: 13.22%.
7.26. 3-[3-Benzo[b]furan-2-yl-5-(4-hydroxyphenyl)-4,5-dihydro-
1H-1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]
naphthyridin-4-one (7g)
Yield: 89%, m.p.: 186e187 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3343 (OeH str.), 3121e2952 (Ar-CH),1672 (C]O),1618
(C]N, Pyrazoline), 1358 (CeN), 1170 (CeO str.), 1624 (C]N),
1482e1454 (Ar, C]C), 1352e1172 (CeO str.), 1170e1024 (CeOeC
7.23. 3-[3-Benzo[b]furan-2-yl-5-(2-carboxyphenyl)-4,5-dihydro-
1H-1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]
naphthyridin-4-one (7d)
str.), 992 (Ar, CH); 1H NMR (CDCl3, 300 MHz,
d, ppm): 10.88 (s, OH),
8.72 (d, 1H, J6-5 ¼ 6.62, H-6, naphthyridin), 8.86 (m, 6H, J ¼ 6.46,
3.55 Hz, Ar-H), 7.32 (dd, 2H, J ¼ 4.12, 6.33 Hz), 7.64e7.23 (m, 12H,
Ar-H), 7.46 (s, 1H, Furan-H), 6.32e5.62 (m, 1H, CH of pyrazoline),
3.34e4.63 (m, 2H, CH2 of pyrazoline), 4.24 (s, 2H, C2H5), 4.12 (s, 3H,
Yield: 87%; m.p.: 188e189 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3412 (OeH str.), 3116e2942 (Ar-CH), 1674 (C]O), 1616
(C]N, Pyrazoline), 1488e1452 (Ar, C]C), 1350e1174 (CeO str.); 1H
OCH3), 2.11 (s, 2H), 1.60 (s, 3H, C2H5); 13C NMR (DMSO-d6)
d ppm:
NMR (CDCl3, 300 MHz,
d
, ppm): 9.97 (s, OH), 8.82 (d, 1H, J6-5 ¼ 7.66,
181.44, 170.21, 163.63, 150.34, 142.77, 135.22, 132.81, 128.82, 122.26,
110.2, 106.8, 98.73, 45.7, 34.77, 24.23, 14.27; MS (FAB) m/z: 493.74
(m þ 1),145.63 (100%). Anal. calcd. for C29H24N4O4, C: 70.72, H: 4.91,
N: 11.38%; found: C: 70.66, H: 4.73, N: 11.22%.
H-6, naphthyridin), 8.64 (m, 6H, J ¼ 5.43, 6.74 Hz, Ar-H), 7.68 (dd,
2H, J ¼ 4.61, 6.42 Hz), 7.45e7.30 (m, 12H, Ar-H), 7.40 (s, 1H, Furan-
H), 6.30e5.82 (m, 1H, CH of pyrazoline), 3.64e4.21 (m, 2H, CH2 of
pyrazoline), 4.42 (s, 2H, C2H5), 2.36 (s, 2H), 1.38 (s, 3H, C2H5); 13C
NMR (DMSO-d6)
d
ppm: 180.65, 171.21, 164.62, 157.34, 143.78,
7.27. 3-[3-Benzo[b]furan-2-yl-5-(4-chlorophenyl)-4,5-dihydro-1H-
1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]
naphthyridin-4-one (7h)
137.32, 133.65, 124.66, 122.26, 106.98, 98.09, 45.67, 44.23, 35.67,
15.10; MS (FAB) m/z: 520.69 (mþ), 145.20 (100%). Anal. calcd. for
C30H24N4O5, C: 69.22, H: 4.65, N: 10.76%; found: C: 69.26, H: 4.73,
N: 10.52%.
Yield: 78%; m.p.: 203e205 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3122e2950 (Ar-CH), 1682 (C]O), 1622 (C]N, Pyr-
azoline), 1480e1450 (Ar, C]C), 1350e1176 (CeO str.), 778, 753
(CeCl str.); 1H NMR (CDCl3, 300 MHz,
d
, ppm): 8.86 (d, 1H, J6-5 ¼ 7.3,
7.24. 3-[3-Benzo[b]furan-2-yl-5-(3-nirtophenyl)-4,5-dihydro-1H-
1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]
naphthyridin-4-one (7e)
H-6, naphthyridin), 8.62 (m, 6H, J ¼ 4.43, 6.34 Hz, Ar-H), 7.82 (dd,
2H, J ¼ 3.61, 6.22 Hz), 7.25e7.33 (m, 12H, Ar-H), 7.23 (s, 1H, Furan-
H), 6.32e5.84 (m, 1H, CH of pyrazoline), 3.62e4.23 (m, 2H, CH2 of
pyrazoline), 4.36 (s, 2H, C2H5), 2.33 (s, 2H), 1.34 (s, 3H, C2H5); 13C
Yield: 78%; m.p.: 168e169 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3116e2950 (Ar-CH), 1682 (C]O), 1624 (C]N, Pyr-
azoline), 1532 (asy., NO2 str.), 1350 (sym., NO2 str.), 1483e1448 (Ar,
NMR (DMSO-d6) d ppm: 181.11, 170.32, 163.22, 152.62, 143.63,
136.28, 132.81, 126.82, 122.26, 110.2, 109.8, 97.63, 45.64, 34.37,
23.23, 15.27; MS (FAB) m/z: 510.66 (mþ), 144.95 (100%). Anal. calcd.
for C29H23ClN4O3, C: 68.17, H: 4.54, N: 10.96%; found: C: 68.28, H:
4.53, N: 10.82%.
C]C), 1352e1171 (CeO str.); 1H NMR (CDCl3, 300 MHz,
d, ppm):
10.12 (s, OH), 8.86 (d, 1H, J6-5 ¼ 7.3, H-6, naphthyridin), 8.62 (m, 6H,
J ¼ 4.43, 6.34 Hz, Ar-H), 7.82 (dd, 2H, J ¼ 3.61, 6.22 Hz), 7.65e7.32
(m, 12H, Ar-H), 7.43 (s, 1H, Furan-H), 6.32e5.84 (m, 1H, CH of pyr-
azoline), 3.6e4.20 (m, 2H, CH2 of pyrazoline), 4.36 (s, 2H, C2H5),
7.28. 3-[3-Benzo[b]furan-2-yl-5-(2-chlorophenyl)-4,5-dihydro-1H-
1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]
naphthyridin-4-one (7i)
2.32 (s, 2H), 1.3 (s, 3H, C2H5); 13C NMR (DMSO-d6)
d ppm: 181.22,
170.21, 164.23, 152.24, 144.13, 137.1, 132.81, 127.82, 122.26, 109.21,
105.8, 98.73, 46.7, 36.77, 25.23,15.27; MS (FAB) m/z: 522.62 (m þ 1),
145.19 (100%). Anal. calcd. for C29H23N5O5, C: 66.79, H: 4.44, N:
13.43%; found: C: 66.26, H: 4.53, N: 13.28%.
Yield: 82%; m.p.: 175e176 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3116e3002 (Ar-CH), 1680 (C]O), 1622 (C]N, Pyr-
azoline), 1481e1448 (Ar, C]C), 1352e1172 (CeO str.), 840, 748
(CeCl str.); 1H NMR (CDCl3, 300 MHz,
d, ppm): 10.12 (s, OH), 8.86 (d,
1H, J6-5 ¼ 7.3, H-6, naphthyridin), 8.64 (m, 6H, J ¼ 5.43, 6.54 Hz, Ar-
H), 7.62 (dd, 2H, J ¼ 3.41, 7.22 Hz), 7.75e7.22 (m, 12H, Ar-H), 7.43 (s,
1H, Furan-H), 6.32e5.84 (m, 1H, CH of pyrazoline), 3.63e4.25 (m,
2H, CH2 of pyrazoline), 4.36 (s, 2H, C2H5), 2.32 (s, 2H), 1.3 (s, 3H,
7.25. 3-[3-Benzo[b]furan-2-yl-5-(2-hydroxy, 3-methoxyphenyl)-
4,5-dihydro-1H-1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro
[1,8] naphthyridin-4-one (7f)
C2H5); 13C NMR (DMSO-d6)
d ppm: 180.31, 170.82, 162.52, 153.33,
142.83, 135.12, 132.81, 124.82, 122.35, 110.27, 109.82, 96.63, 46.64,
34.37, 28.23, 14.27; MS (FAB) m/z: 510.26 (mþ), 144.75 (100%). Anal.
calcd. for C29H23ClN4O3, C: 68.17, H: 4.54, N: 10.96%; found: C:
68.58, H: 4.21, N: 10.76%.
Yield: 85%; m.p.: 142e143 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3216 (OeH str.), 3123e2952 (Ar-CH), 1676 (C]O),
1621 (C]N, Pyrazoline), 1360 (CeN), 1174 (CeO str.), 1622 (C]N),
1482e1452 (Ar, C]C), 1350e1176 (CeO str.), 1169e1026 (CeOeC
str.), 992 (eCH); 1H NMR (CDCl3, 300 MHz,
d, ppm): 10.33 (s, OH),
7.29. 3-[3-Benzo[b]furan-2-yl-5-(2-nitrophenyl)-4,5-dihydro-1H-
1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]
naphthyridin-4-one (7j)
8.76 (d, 1H, J6-5 ¼ 7.52, H-6, naphthyridin), 8.84 (m, 6H, J ¼ 6.62,
3.47 Hz, Ar-H), 7.60 (dd, 2H, J ¼ 4.62, 6.44 Hz), 7.60e7.34 (m, 12H,
Ar-H), 7.42 (s, 1H, Furan-H), 6.22e5.82 (m, 1H, CH of pyrazoline),
3.64e4.33 (m, 2H, CH2 of pyrazoline), 4.34 (s, 2H, C2H5), 4.14 (s, 3H,
Yield: 84%; m.p.: 165e167 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3119e2942 (Ar-CH), 1674 (C]O), 1616 (C]N, Pyr-
azoline), 1565 (asy., NO2 str.), 1488e1452 (Ar, C]C), 1350e1174
(CeO str.), 1338 (sym., NO2 str.), 822 (CeN str.); 1H NMR (CDCl3,
OCH3), 2.33 (s, 2H), 1.62 (s, 3H, C2H5); 13C NMR (DMSO-d6)
d ppm:
181.27, 170.21, 165.63, 152.34, 143.75, 136.22, 134.81, 126.82, 122.26,
108.2, 103.8, 98.33, 45.7, 35.77, 24.23, 14.27; MS (FAB) m/z: 522.77
(mþ), 145.88 (100%). Anal. calcd. for C30H26N4O5, C: 68.96, H: 5.01,
N: 10.72%; found: C: 68.76, H: 5.13, N: 10.52%.
300 MHz,
d
, ppm): 8.82 (d, 1H, J6-5 ¼ 7.66, H-6, naphthyridin), 8.64
(m, 6H, J ¼ 5.43, 6.74 Hz, Ar-H), 7.68 (dd, 2H, J ¼ 4.61, 6.42 Hz),

K. Manna, Y.K. Agrawal / European Journal of Medicinal Chemistry 45 (2010) 3831e3839
3839
7.46e7.30 (m, 12H, Ar-H), 7.64 (s, 1H, Furan-H), 6.40e5.62 (m, 1H,
CH of pyrazoline), 3.64e4.31 (m, 2H, CH2 of pyrazoline), 4.32 (s, 2H,
C2H5), 2.16 (s, 2H), 1.38 (s, 3H, C2H5); 13C NMR (DMSO-d6)
ppm:
7.33. 3-[3-Benzo[b]furan-2-yl-5-[(E)-2-phenyl-1-ethenyl]-4,5-
dihydro-1H-1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro
[1,8]naphthyridin-4-one (7n)
d
180.42, 170.81, 163.26, 153.28, 143.13, 136.1, 130.81, 126.82, 122.24,
108.21, 104.8, 97.73, 45.7, 36.12, 25.03, 14.87; MS (FAB) m/z: 521.58
(mþ), 145.34 (100%). Anal. calcd. for C29H23N5O5, C: 66.79, H: 4.44,
N: 13.43%; found: C: 66.06, H: 4.23, N: 13.29%.
Yield: 88%; m.p.: 212e213 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3118e2946 (Ar-CH), 1678 (C]O), 1620 (C]N, Pyr-
azoline), 1483e1454 (Ar, C]C), 1354e1173 (CeO str.), 972 (eCH]
CHe); 1H NMR (CDCl3, 300 MHz,
d, ppm): 8.82 (d, 1H, J6-5 ¼ 7.32, H-
6, naphthyridin), 8.63 (m, 6H, J ¼ 5.43, 6.54 Hz, Ar-H), 7.85 (dd, 2H,
J ¼ 3.71, 6.27 Hz), 7.95e7.73 (m, 12H, Ar-H), 7.23 (s, 1H, Furan-H),
6.32e5.84 (m, 1H, CH of pyrazoline), 3.62e4.23 (m, 2H, CH2 of
pyrazoline), 4.34 (s, 2H, C2H5), 2.37 (s, 2H), 1.37 (s, 3H, C2H5); 13C
7.30. 3-[3-Benzo[b]furan-2-yl-5-(4-methoxyphenyl)-4,5-dihydro-
1H-1-pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]
naphthyridin-4-one (7k)
NMR (DMSO-d6)
d ppm: 180.11, 170.73, 164.03, 152.34, 143.67,
Yield: 78%; m.p.: 264e265 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3124e2955 (Ar-CH), 1668 (C]O), 1622 (C]N, Pyr-
azoline), 1478e1456 (Ar, C]C), 1354e1172 (CeO str.), 1162e1033
137.22, 132.21, 128.82, 125.26, 122.2, 106.8, 99.53, 51.77, 45.27, 36.51,
23.77, 14.93; MS (FAB) m/z: 502.77 (mþ), 145.30 (100%). Anal. calcd.
for C31H26N4O3, C: 74.09, H: 5.21, N: 11.15%; found: C: 74.26, H: 5.23,
N: 11.22%.
(CeOeC str.); 1H NMR (CDCl3, 300 MHz,
d, ppm): 8.86 (d, 1H, J6-
¼ 7.36, H-6, naphthyridin), 8.62 (m, 6H, J ¼ 5.23, 6.72 Hz, Ar-H),
5
7.82 (dd, 2H, J ¼ 5.31, 6.45 Hz), 7.55e7.20 (m, 12H, Ar-H), 7.46 (s, 1H,
Furan-H), 6.32e5.83 (m, 1H, CH of pyrazoline), 3.65e4.25 (m, 2H,
CH2 of pyrazoline), 4.46 (s, 2H, C2H5), 2.30 (s, 2H), 1.44 (s, 3H, C2H5);
Acknowledgement
The authors would like to thank to Institute of Pharmacy, Nirma
University of Science and Technology, Ahmadabad, India and
Department of Microbiology and Pharmacology, Kasturba Medical
College, Manipal, India for providing laboratory facilities to carry
over the necessary laboratory works and in-vivo and in-vitro anti-
tubercular activities. We also gratefully acknowledge to IISc. Ban-
galore and SPIC Foundation, Chennai and Tuberculosis Research
Center (Chennai, India) for providing 1H NMR and 13C NMR spectra,
elemental analysis and Mass spectra and MDR-TB stain,
respectively.
13C NMR (DMSO-d6)
d ppm: 180.11, 172.73, 165.63, 153.34, 142.77,
137.22, 133.81, 124.82, 122.11, 107.28, 106.82, 97.54, 55.57, 45.22,
34.32, 23.77, 15.03; MS (FAB) m/z: 507.15 (m þ 1), 145.55 (100%).
Anal. calcd. for C30H26N4O4, C: 71.13, H: 5.17, N: 11.06%; found: C:
71.26, H: 5.13, N: 11.22%.
7.31. 3-[3-Benzo[b]furan-2-yl-5-phenyl-4,5-dihydro-1H-1-
pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]naphthyridin-
4-one (7l)
Yield: 76%; m.p.: 195e196 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3120e2946 (Ar-CH), 1674 (C]O), 1616 (C]N, Pyr-
azoline), 1482e1452 (Ar, C]C), 1350e1172 (CeO str.); 1H NMR
References
[1] B.G. Williams, C. Dye, Science 301 (2003) 1535e1537.
[2] E.L. Corbett, C.J. Watt, J. Catherine, N. Walker, D. Maher, B.G. Williams, Arch.
Med. 163 (2003) 1009e1021.
[3] M. Zignol, M.S. Hosseini, A. Wright, W.C. Lambregts, P. Nunn, C.J. Watt, J.
Infect. Dis. 194 (2006) 479e487.
[4] A. Jain, R. Mondal, FEMS Immunol. Medi. Microbiol. 53 (2008) 145e150.
[5] K. Sato, H. Tomioka, C. Sano, T. Shimizu, K. Sano, K. Ogasawara, J. Antimicrob.
Chemother. 52 (2003) 199e203.
[6] P. Senthilkumar, M. Dinakaran, D. Banerjee, R.V. Devakaram, P. Yogeeswari,
A. China, V. Nagarajab, D. Sriram, Bioorg. Med. Chem. 16 (2008) 2558e2569.
[7] G. Grover, S.G. Kini, Eur. J. Med. Chem. 41 (2006) 256e262.
[8] B.F. Abdel-Wahab, A.H. Abdel-Aziz, E.M. Ahmed, Eur. J. Med. Chem. 44 (2009)
2632e2635.
[9] M.A. Ali, M. Shaharyar, A.A. Siddiqui, Eur. J. Med. Chem. 42 (2007) 268e275.
[10] A.O. zdemir, G.T. Zitouni, Z.A. Kaplancikli, G. Revial, K. Guven, Eur. J. Med.
Chem. 42 (2007) 403e409.
(CDCl3, 300 MHz,
d
, ppm): 9.97 (s, OH), 8.82 (d, 1H, J6-5 ¼ 7.66, H-6,
naphthyridin), 8.64 (m, 6H, J ¼ 5.43, 6.74 Hz, Ar-H), 7.68 (dd, 2H,
J ¼ 4.61, 6.42 Hz), 7.45e7.30 (m, 12H, Ar-H), 7.40 (s, 1H, Furan-H),
6.30e5.82 (m, 1H, CH of pyrazoline), 3.64e4.21 (m, 2H, CH2 of
pyrazoline), 4.42 (s, 2H, C2H5), 2.36 (s, 2H), 1.38 (s, 3H, C2H5); 13C
NMR (DMSO-d6)
d ppm: 180.51, 170.23, 165.63, 152.34, 144.17,
129.82, 124.26, 106.2, 98.73, 45.25, 33.51, 24.77, 14.93; MS (FAB) m/
z: 477.68 (m þ 1), 145.71 (100%). Anal. calcd. for C29H24N4O3, C:
73.09, H: 5.08, N: 11.76%; found: C: 73.26, H: 5.13, N: 11.62%.
7.32. 3-[3-Benzo[b]furan-2-yl-5-(2-furyl)-4,5-dihydro-1H-1-
pyrazolylcarbonyl]-1-ethyl-7-methyl-1,4-dihydro[1,8]naphthyridin-
4-one (7m)
[11] M. Abid, A. Azam, Bioorg. Med. Chem. 13 (2005) 2213e2220.
[12] V.H. Babu, K. Manna, J. Sneha, K.K. Srinivasan, V.G. Bhat, Indian J. Heterocycl.
Chem. 13 (2004) 253e256.
[13] L.W. Nancy, M.H. Heidi, R. Frank, J. Am. Chem. Soc. 41 (1999) 9748e9749.
[14] D. Zampieri, M.G. Mamolo, E. Laurini, G. Scialino, E. Banfib, L. Vioa, Bioorg.
Med. Chem. 16 (2008) 4516e4522.
[15] M. Rescifina, A. Chiacchio, A. Corsaro, De. Clercq, D. Iannazzo, A. Mastino,
A. Piperno, G. Romeo, R. Romeo, V. Valveri, J. Med. Chem. 16 (2006) 709e715.
[16] C.K. Stover, P. Warrener, D.R. Van Devanter, D.R. Sherman, T.M. Arain,
M.H. Langhorne, S.W. Anderson, J.A. Towell, Y. Yuan, D.N. McMurray,
B.N. Kreiswirth, C.E. Barry, W.R. Baker, Nature 405 (2000) 962e966.
[17] D. Sriram, P. Yogeeswari, S.J. Basha, Bioorg. Med. Chem. 13 (2005) 5774e5778.
[18] S. Tyagi, E. Nuermberger, T. Yoshimatsu, K. Williams, I. Rosenthal, N. Lounis,
W. Bishai, J. Grosset, Antimicrobial Agents Chemother. 49 (2005) 2289e2293.
[19] L.L. Gundersen, M.J. Nissen, B. Spilsberg, J. Med. Chem. 45 (2002) 1383e1386.
[20] J. Mustafa, S.I. Khan, G. Ma, L.A. Walker, I.A. Khan, Lipids 40 (2005) 375e382.
[21] K. Manna, Y.K. Agrawal, Indian J. Heterocycl. Chem. 17 (2008) 250e252.
[22] Y.K. Agrawal, K. Manna, V.K. Babu, K.K. Srinivasan, H. Bhatt, P.J. Gogoi, Indian J.
Heterocycl. Chem. 16 (2007) 263e266.
Yield: 87%; m.p.: 287e288 ꢀC. Spectroscopic analysis: IR (KBr)
ymax (cmꢁ1): 3121e2952 (Ar-CH), 1684 (C]O), 1624 (C]N, Pyr-
azoline), 1548 (furan), 1483e1452 (Ar, C]C), 1355e1174 (CeO str.);
1H NMR (CDCl3, 300 MHz,
d
, ppm): 8.86 (d, 1H, J6-5 ¼ 7.3, H-6,
naphthyridin), 8.64 (m, 6H, J ¼ 4.43, 6.34 Hz, Ar-H), 7.82 (dd, 2H,
J ¼ 3.61, 6.22 Hz), 7.25e7.33 (m, 12H, Ar-H), 7.23 (s, 1H, Furan-H),
6.32e5.84 (m, 1H, CH of pyrazoline), 3.62e4.24 (m, 2H, CH2 of
pyrazoline), 4.34 (s, 2H, C2H5), 2.33 (s, 2H), 1.35 (s, 3H, C2H5); 13C
NMR (DMSO-d6)
d ppm: 180.11, 170.23, 164.03, 150.34, 142.27,
136.22, 132.41, 126.12, 122.26, 106.42, 97.25, 53.72, 45.17, 34.71,
24.27, 14.13; MS (FAB) m/z: 467.52 (m þ 1), 145.72 (100%). Anal.
calcd. for C27H22N4O4, C: 69.52, H: 4.75, N: 12.01%; found: C: 70.46,
H: 4.13, N: 11.22%.
[23] K. Manna, Y.K. Agrawal, Bioorg. Med. Chem. Lett. 19 (2009) 2688e2692.
[24] Z.A. Kaplancikli, G.T. Zitouni, A. Ozdemira, O.D. Can, P. Chevallet, Eur. J. Med.
Chem. 44 (2009) 2606e2610.