Synthesis of some pyrazolylaldehyde N-isonicotinoyl hydrazones and 2,5-disubstituted 1,3,4-oxadiazoles as DNA photocleaving agents

Article abstract of DOI:10.1007/s00044-015-1340-x

In search of potential biologically active compounds, some novel 2,5-disubstituted 1,3,4-oxadiazole derivatives have been prepared conveniently via oxidation of newly synthesized pyrazolylaldehyde N-isonicotinoyl hydrazones by (diacetoxyiodo)benzene in di

Full text of DOI:10.1007/s00044-015-1340-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1340-x
ORIGINAL RESEARCH
Synthesis of some pyrazolylaldehyde N-isonicotinoyl hydrazones
and 2,5-disubstituted 1,3,4-oxadiazoles as DNA photocleaving
agents
•
M. Kumar V. Kumar V. Beniwal
•
Received: 12 August 2014 / Accepted: 9 February 2015
ꢀ Springer Science+Business Media New York 2015
Abstract In search of potential biologically active com-
pounds, some novel 2,5-disubstituted 1,3,4-oxadiazole
derivatives have been prepared conveniently via oxidation of
newly synthesized pyrazolylaldehyde N-isonicotinoyl hy-
drazones by (diacetoxyiodo)benzene in dichloromethane
under mild reaction conditions. Compounds were obtained
in excellent yields, and their structures have been established
on the basis of their FT-IR, 1H, 13C NMR, and mass spectral
data. The DNA photocleavage potential for all the synthe-
sized compounds was evaluated using agarose gel elec-
trophoresis. It has been observed that oxadiazole derivatives
showed a significant level of DNA photocleavage activity
when compared with their corresponding hydrazones, and
some modifications in the basic structure may lead to con-
struct some potential chemotherapeutic agents in future.
compounds (Judge et al., 2012a). Compounds containing
isoniazid moiety possess a wide range of biological sig-
nificance as anti-mycobacterial (Nikaljea et al., 2012), an-
timicrobial (Deep et al., 2012), anticancer (Kumar et al.,
2011), anti-tubercular (Sriram et al., 2011, 2012), analgesic
(Deodhar et al., 2012), and anti-viral and antifungal agents
(Judge et al., 2012b). Pyridine nucleus is a basic unit of
many drugs, vitamins, dyes, insecticides, and herbicides
(Elguero et al., 1996). Some isonicotinoyl hydrazones are
´
known to exhibit anti-tubercular (Sousa et al., 2014; Rıkova
et al., 2011), antitumor (Martins et al., 1999), DNA-binding,
and photocleavage activity (Gowda et al., 2013).
On the other hand, azoles derivatives are well known for
their great biological (Kaur et al., 2014; Lu et al., 2012;
Bondock et al., 2013) and medicinal significance (Kumar
et al., 2013a; Hassan et al., 2012). Among azoles, substituted
pyrazoles have possessed a broad spectrum of biological
properties such as anti-tumor (Mohareb et al., 2012), anti-
tubercular (Ravala et al., 2011), antioxidant (Al-Ayed, 2011),
anti-inflammatory (Kumar et al., 2013b; Bekhit et al., 2009),
anti-bacterial (Kumar et al., 2005), anti-obesity (Gupta et al.,
2011), and antidepressant (Aziz et al., 2009) activities.
Similarly, 2,5-disubstituted 1,3,4-oxadiazoles and their
derivatives have proven their role as bioactive agents and thus
play an important role in the field of medicinal chemistry.
These compounds in particular are well known for their great
biological potential specifically in the presence of some other
potent heterocycles. Several, 1,3,4-oxadiazoles derivatives
have shown biological and pharmacological activities like
antifungal (Merugu et al., 2011; Chandrakantha et al., 2010),
anticancer (Dash et al., 2011), immunosuppressive (Zhang
et al., 2012; Tang et al., 2012), and antimicrobial (Bakht et al.,
2010; Joshi and Parikh, 2014).
Keywords Pyrazole ꢀ Oxadiazole ꢀ Hydrazone ꢀ
Isonicotine ꢀ DNA photocleavage ꢀ
(Diacetoxyiodo)benzene
Introduction
Isoniazid, a heterocyclic compound containing pyridine
moiety, is still being considered as one of the leading
pharmacophore in the development of potential bioactive
M. Kumar ꢀ V. Kumar (&)
Department of Chemistry, Maharishi Markandeshwar
University, Mullana, Ambala 133207, India
e-mail: vinodbatan@gmail.com
V. Beniwal
Department of Biotechnology, Maharishi Markandeshwar
University, Mullana, Ambala 133207, India
e-mail: beniwalvikash@gmail.com
Inrecentyears, attentionhasbeenpaidtoevaluatetheDNA
photocleavage potential of some azoles such as oxadiazoles
123

Med Chem Res
(Kulkarni et al., 2011; Hanumanagoud and Basavaraja, 2012;
Taj et al., 2012) or heteroaryl-linked hydrazones (Gowda
et al., 2013) may be because of their binding or interacting
ability with the DNA structure. Therefore, such nitrogen-
containing heterocyclic compounds could be used as probes
for DNA structure, potential chemotherapeutic and diagnostic
agents(Kurdekar etal., 2011). DNA is a site wheremostofthe
chemotherapeutic drugs act and interact, which may result in
DNA photocleavage leading to inhibition or death of cancer-
ous cells (Raman and Raja, 2007). In light of the above facts, it
was decided to synthesize some novel pyrazole-linked
isonicotinoyl hydrazones which were further converted into
2,5-disubstituted 1,3,4-oxadiazoles under mild conditions and
evaluate their DNA photocleavage activity. In past years, or-
ganic synthesis has acquired various advantages such as
shorter reaction time and higher regio-selectivity (Aggarwal
et al., 2007, Gupta et al., 2014; Pal et al., 2014), use of greener
solvents or reagents with low toxicity profile. In this concern,
organoiodine (III) reagents like (Diacetoxyiodo)benzene
(DIB), hydroxy tosyloxy iodobenzene (HTIB). etc. are well
knownfortheirnon-toxicandeco-friendlybehaviorinorganic
synthesis (Vorvoglis, 1997; Zhdankin, 2009). Due to low
toxicity and selective nature (Kumar, 2012; Yang and Dai,
1993), these reagents have been extensively used for the
synthesis of various heterocycles such as triazoles, oxa-
diazoles, etc. Herein also, some disubstituted 1,3,4-oxa-
diazoles were prepared using DIB.
reagents like phosphorus oxychloride (Jha et al., 2010),
phosphorus pentaoxide (Rostamizadeh and Ghamkhar,
2008), and acetic anhydride (Oliveira et al., 2012), etc.
which are toxic in nature. In continuation of our interest to
synthesize biologically active compounds, herein, we re-
port the synthesis of some novel pyrazole-linked
isonicotinoyl hydrazones which on oxidative transforma-
tion by iodobenzene diacetate (IBD) in dichloromethane
under mild conditions gave 2,5-disubstituted 1,3,4-oxa-
diazoles (Scheme 1).
The pyrazolylaldehyde isonicotinoyl hydrazones 3 were
obtained by the condensation of 1 with substituted 3-aryl-
1-phenyl-1H-pyrazole-4-carbaldehydes 2 in ethanol and
dichloromethane (DCM) in the presence of a catalytic
amount of concentrated sulfuric acid under reflux condi-
tions as adopted by Prakash et al. (2010, 2011) for different
derivatives. The final products (4) were obtained in
88–92 % yields with high purity by oxidative cyclization
of 3 in the presence of 1.1 equivalent of IBD under mild
conditions (Scheme 1). Various 1,3,4-oxadiazole deriva-
tives were also prepared via oxidation of substituted hy-
drazones such as N-acylhydrazones (Yang and Dai, 1993)
with 1.1 equivalent of (diacetoxyiodo)benzene in dichlor-
omethane at room temperature. In the present investigation,
total fourteen novel compounds were prepared and char-
1
acterized on the basis of FT-IR, H, 13C NMR, and mass
spectral data. The absorption bands for –NH and –C=O
stretching vibration appeared in the IR spectra of the
compounds 3a–g at 3421 and 1665 cm-1, respectively.
The compounds 3a–g displayed two singlets due to 5-H of
pyrazole ring and N=CH around at d 9.05 and 8.59, re-
Result and discussion
1
Chemistry
spectively. In H NMR spectra of 3a–g, the characteristic
downfield signal at d 11.97 is attributed to the NH proton,
and rest of the protons exhibit multiplet in the aromatic
region. The chemical shifts in 13C NMR spectra at around d
It has already been reported in the literature that disubsti-
tuted 1,3,4-oxadiazoles were synthesized using different
Ph
Ar
NH
N
N
NHNH2
O
N
N
Conc. H2SO4
EtOH
N
+
N
Ph
N
O
H
OHC
Ar
3a-g
2
1
DCM
IBD
4
N
3
3'''
N
2'''
1'''
6'''
4'''
5'''
5'
2'
2
5''
4''
6'
5
O
4'
3'
1
N
1''
N
1'
6''''
N
3''
1''''
2''
5''''
R
2''''
4''''
3''''
4a-g
Scheme 1 Synthesis of isonicotinoyl hydrazones (3a–g) and oxadiazoles (4a–g)
123

Med Chem Res
142.0–142.4, 127.2, and 161.1 correspond to N=CH,
pyrazole-5, and carbonyl carbons, respectively.
cross-signals by the carbons, C-500 and C-2¢¢¢, 6¢¢¢ at d 131.6
and 118.9, respectively. Moreover, 20, 60 and 30, 50-H
protons shared signals at d 8.84 and 7.90, respectively,
which gave correlation with carbons, C-20, 60 and C-30, 50 at
d 150.9 and 119.98. The disappearance of NMR signal at d
142.2 also indicated the formation of oxadiazole.
The COSY spectra have shown well correlation between
protons with adjacent protons. It has been observed from
1H NMR and COSY spectra that signals at d 7.83 and 8.78
correspond to pyridine ring, while 60-H and –NH signals at
d 8.59 and 11.97 did not show coupling with any other
proton.
The structures of the final products (4) were established
1
by comparing FT-IR, H, and 13C NMR spectral data with
those of the compounds 3a–g. The FT-IR spectrum of 4
was transparent in the region of –NH and –C=O stretching
and thus confirmed the successful oxidation of 3 into 4.
Disappearance of chemical shifts at d 8.59–8.66 (N=CH)
1
and 11.91–11.99 (NH) in H NMR spectrum of each pro-
duct (4a–g) confirmed the oxidative transformation of
isonicotinoyl hydrazones into 2,5-disubstituted 1,3,4-oxa-
diazoles. The 13C NMR spectra displayed signals at around
d 160.2, 161.5 for oxadiazole carbons and other signals at d
150.8, 105.5 and 131.6 correspond to pyrazole ring carbon-
300, 400, 500, respectively. In 13C NMR spectrum, disap-
pearance of a signal in range of d 142.0–142.4 due to
N=CH functionality further confirmed the formation of ti-
tled compounds.
The formation of compound 4 was also confirmed on the
basis of disappearance of signals at d 8.59 and 11.97. The
COSY spectra indicated that the signals at d 7.90 and 8.84
correspond to pyridine ring. However, the pyrazole proton,
500-H is resonated at d 9.48.
1
The H and 13C correlation of compound 3 or 4 was
ROESY experiment
assigned on the basis of DEPT-135, COSY, HSQC, and
ROESY experiments. In the 13C NMR spectrum, 16 carbon
signals were appeared. Further, the DEPT-135 spectra
showed only 10 signals corresponding to methine carbons
and other six quaternary carbons. The HSQC spectrum of
compound 3 indicated that 50 and 60-H resonated at d 9.05
and 8.59, respectively, with the corresponding carbon sig-
nals of C-50 and C-60 at d 127.2 and 142.2, respectively. In
the same spectrum, two set of protons 2, 6-H and 3, 5-H
appeared at d 8.78 and 7.83, respectively, which gave
correlation by carbon signals of carbons 2, 6 and 3, 5 at d
150.3 and, 121.5, respectively.
The stereochemistry of the compound 3 or 4 was estab-
lished by analyzing the ROESY spectra. The ROESY
spectra of isonicotinoyl hydrazones 3 have shown a clear
space interaction between the –NH proton with 60 and 3,
5-H protons. The protons 50-H and 60-H showed a close
relationship in space with 200, 600 and 2¢¢¢, 6¢¢¢-H, respec-
tively. The four possible configurations for 3a are given in
Fig. 1.
The configuration I was in full agreement with the ob-
servation drawn from the ROESY spectra. Therefore, the
confirmed structure of compound 3 should be of type-
I. The ROESY experiment also provided a great help for
assigning the structure of compound 4 in which the spectra
were clearly showing the ROEs between 500-H with 2¢¢¢, 6¢¢¢-
H. Further, the proton signals due to 20000 and 60000-H are
Furthermore, the correlation between carbons and pro-
tons in spectrum of the compound 4 was also estimated by
HSQC spectrum. In this case, protons 500 and 2¢¢¢, 6¢¢¢-H
gave signals at d 9.48 and 8.02, respectively, along with
3''
2''
1''
4''
5''
2'
1'
N
N
3'
N
N
N
N
6''
2'''
1'''
6'''
3'''
4'''
H
5'
H
N
N
H
H
4'
N
N
H
N
N
H
H
N
N
H
6'
5'''
O
O
O
O
7
4
H
H
N N
H
N
3
5
H
3
6
2
N
N
N
1
I
IV
II
III
Fig. 1 Possible configurations of isonicotinoyl hydrazone 3a
123

Med Chem Res
Fig. 2 Plasmid DNA photocleavage picture
shifted to higher value because of the anisotropic effect of
oxygen atom of the oxadiazole formed after cyclization of
the corresponding hydrazone compound.
decreased or diminished to a great extent in comparison
with hydrazones.
In case of hydrazone 3b in which nitro group is present
at para-position of phenyl ring attached to pyrazole moiety,
both the forms of DNA appeared with low intensity in
comparison with control. On the other hand, its corre-
sponding oxadiazole (4b) was found to be the most ef-
fective agent due to its selective nature to convert the Form
I into Form II to a large extent. The most effective nature of
oxadiazole nucleus was further indicated by the results of
other oxadiazoles in comparison with hydrazones (Fig. 2).
The hydrazones (3f–g) as well as their corresponding
oxadiazoles (4f–g) bearing bromo or methyl substitution at
para-position of phenyl ring attached to pyrazole ring
completely degraded the Form I and reduced intensity of
Form II to a large extent in comparison with control. The
hydrazone bearing fluoro substitution is responsible for
converting the Form II to Form I; however, its corre-
sponding oxadiazole was found to be responsible for di-
minishing the Form I and reducing the intensity of Form II.
The overall results observed from the present study have
indicated that oxadiazole derivatives possessed more po-
tential for DNA photocleavage as compared to isonicoti-
noyl hydrazones.
Biological evaluation
Plasmid DNA photocleavage study
Figure 2: Lane C: Control plasmid DNA ? UV ? DMSO,
Lane 1 DNA ? 40 lg 3a, Lane 2 DNA ? 40 lg 3b, Lane
3 DNA ? 40 lg 3c, Lane 4 DNA ? 40 lg 3d, Lane 5
DNA ? 40 lg 3e, Lane 6 DNA ? 40 lg 3f, Lane 7
DNA ? 40 lg 3g, Lane 8 DNA ? 40 lg 4a, Lane 9
DNA ? 40 lg 4b, Lane 10 DNA ? 40 lg 4c, Lane 11
DNA ? 40 lg 4d, Lane 12 DNA ? 40 lg 4e, Lane 13
DNA ? 40 lg 4f, Lane 14 DNA ? 40 lg 4g, respectively.
The DNA photocleavage study was performed using
agarose gel electrophoresis, and the overall pattern is
shown in Fig. 2. No DNA cleavage was observed for
negative control (lane C). A significant change in intensity
of DNA Forms (I, II) in case of isonicotinoyl hydrazones as
well as oxadiazoles in comparison with untreated DNA
indicated some kinds of fragmentations or interactions
caused by the compounds. In case of isonicotinoyl hydra-
zones, compounds 3a, 3b, 3d, and 3e (Lane 1, 2, 4, and 5,
respectively), the intensity of Form I of pBR322 DNA was
found to be increased, while Form II was either decreased
or completely diminished as compared to the control (Lane
C). However, compound 3c (Lane 3) decreased the inten-
sity of both the forms in comparison with control. The
compounds 3f and 3g (Lane 6 and 7) were found respon-
sible to a significant decrease in intensity of Form II and
complete disappearance of Form I, whereas for oxadiazoles
(4), the intensity of open circular DNA (Form II) was found
to be increased to a large extent in comparison with control
in cases of compounds 4b and 4c (Lane 9 and 10, re-
spectively). However, rest of the oxadiazoles (4a, 4d–
g) was responsible for either complete disappearance of
Form I or highly reduced value of its intensity. It has been
observed in case of oxadiazoles intensity of Form I is either
Conclusion
In present investigation, we have reported the synthesis of
some novel unsymmetrical 1,3,4-oxadiazole derivatives via
oxidative cyclization of some newly synthesized
isonicotinoyl hydrazones using IBD as a mild oxidizing
agent and thus extended potential of organoiodine (III)
reagents in heterocycles synthesis. Structures of the syn-
thesized compounds have been established by rigorous
analysis of their NMR spectral data. The DNA photo-
cleavage potential was evaluated for all the synthesized
compounds using agarose gel electrophoresis. A significant
change in intensity of both the Forms (I and II) of pBR322
DNA was observed in case of isonicotinoyl hydrazones as
123

Med Chem Res
H-2¢¢¢, H-6¢¢¢), 7.39–7.55 (6H, m, H-300, H-400, H-500 & H-3¢¢¢,
H-4¢¢¢, H-5¢¢¢); 13C NMR (DMSO-d6, 100 MHz,):
d = 161.1 (C, C-7), 152.1 (C, C-30), 150.3 (CH, C-2, C-6),
142.2 (CH, C-60), 140.5 (C, C-100), 139.0 (C, C-4), 131.9
(C, C-1¢¢¢), 129.6 (CH, C-3¢¢¢, C-5¢¢¢), 128.8 (CH, C-300,
C-500), 128.7 (C, C-4¢¢¢), 128.4 (CH, C-2¢¢¢, C-6¢¢¢), 127.2
(CH, C-50), 127.0 (CH, C-400), 121.5 (CH, C-3, C-5), 118.8
(CH, C-200, C-600), 116.6 (C, C-40); MS (ESI) m/z: 368.14
(M ? 1)?; Anal. Calcd. for C22H17N5O: C, 71.91; H, 4.63;
N, 19.07. Found: C, 71.89; H, 4.62; N, 19.05.
well as oxadiazoles. Compounds 3c, 3f, 3g, 4b, and 4d–g
have emerged as the most active DNA photocleaving
agents among all the synthesized compounds. Furthermore,
the present study have indicated that oxadiazole derivatives
possessed more potential for DNA photocleavage as
compared to isonicotinoyl hydrazones and some modifi-
cations in the basic structure may lead to construct some
potential chemotherapeutic agents in future.
N-Isonicotinoyl-N0-[30-(4¢¢¢-nitrophenyl)-10-phenyl-40-pyra-
zolylmethylidene]hydrazine (3b) Yield 87.5 %; mp
256–257 ꢁC; Rf = 0.05 [ethylacetate: hexane (1:1)]; IR
(KBr) tmax: 3430 (N–H str.), 1667 (C=O str.), 1540
Experimental
Chemistry-materials and methods
(NO2 asymmetric str.), 1351 (NO2 symmetric str.) cm-1
;
Melting points of all compounds were determined in open
capillary using digital melting point apparatus and are
uncorrected. IR spectra were recorded as KBr disks on a
PerkinElmer Spectrophotometer in the 4000–450 cm-1
1H NMR (DMSO-d6, 400 MHz,): d = 11.99 (1H, s, H–
N, D2O exchangeable), 9.01 (1H, s, H-50), 8.77 (2H, d,
J = 5.9 Hz, H-2, H-6), 8.66 (1H, s, H-60), 8.36 (2H, d,
J = 8.4 Hz, H-3¢¢¢, H-5¢¢¢), 8.14 (2H, d, J = 8.0 Hz,
H-2¢¢¢, H-6¢¢¢), 8.00 (2H, d, J = 8.4 Hz, H-200, H-600), 7.85
(2H, d, J = 5.9 Hz, H-3, H-5), 7.37–7.57 (3H, m, H-300,
H-400, H-500); 13C NMR (DMSO-d6, 100 MHz,):
d = 161.1 (C, C-7), 150.6 (C, C-30), 150.1 (CH, C-2,
C-6), 146.3 (C, C-4¢¢¢), 142.1 (CH, C-60), 140.4 (C,
C-100), 138.8 (C, C-4), 137.1 (C, C-1¢¢¢), 128.6 (CH, C-300,
C-500), 127.5 (CH, C-50), 127.0 (CH, C-400), 126.4 (CH,
C-2¢¢¢, C-6¢¢¢), 124.5 (CH, C-3¢¢¢, C-5¢¢¢), 121.4 (CH, C-3,
C-5), 118.7 (CH, C-200, C-600), 116.6 (C, C-40); MS (ESI)
m/z: 413.13 (M ? 1)?; Anal. Calcd. for C22H16N6O3: C,
64.06; H, 3.88; N, 20.38. Found: C, 64.05; H, 3.86; N,
20.35.
1
range. Both H and 13C NMR (CDCl3/DMSO-d6) spectra
of the synthesized compounds were recorded on a Bruker
Advance at 400 and 100 MHz, respectively. Chemical
shifts were measured relative to internal standard TMS
(d = 0) on d scale (ppm). Mass spectra were recorded on
Agilent Mass Spectrometer, and carbon, nitrogen, hydro-
gen contents were analyzed using LECO 9320 analyzer.
Isoniazid 1 (Manjunatha et al., 2010), 4-formylpyrazoles
(2) (Rajput and Rajput, 2011) utilized in present investi-
gation were synthesized according to the literature
methods.
Synthesis of Isonicotinoyl hydrazones (3a–g)
N-Isonicotinoyl-N0-[30-(4¢¢¢-methoxyphenyl)-10-phenyl-40-pyra-
zolylmethylidene]hydrazine (3c) Yield 88.4 %; mp
209–210 ꢁC; Rf = 0.04 [ethylacetate: hexane (1:1)]; IR
General procedure
A
solution of an appropriate
4-formylpyrazole derivative (2, 0.01 mol) in dichlor-
omethane was added to an ethanolic solution of isoniazid
(1, 0.01 mol). One drop of concentrated sulfuric acid was
added to the reaction mass and refluxed it for 40–45 min
till completion of reaction. The reaction was monitored by
thin-layer chromatography. The excess of solvent was
evaporated and then cooled to room temperature. The ob-
tained product was filtered, washed with alcohol, and re-
crystallized from ethanol. Noted m.p. and submitted to
analysis.
1
(KBr) tmax: 3421 (N–H str.), 1665 (C=O str.) cm-1; H
NMR (DMSO-d6, 400 MHz,): d = 11.91 (1H, s, H–N,
D2O exchangeable), 8.92 (1H, s, H-50), 8.77 (2H, d,
J = 5.2 Hz, H-2, H-6), 8.59 (1H, s, H-60), 7.98 (2H, d,
J = 8.0 Hz, H-200, H-600), 7.85 (2H, d, J = 5.6 Hz, H-3,
H-5), 7.68 (2H, d, J = 8.0 Hz, H-2¢¢¢, H-6¢¢¢), 7.35–7.54
(3H, m, H-300, H-400, H-500), 7.07 (2H, d, J = 8.0 Hz, H-3¢¢¢,
H-5¢¢¢), 3.86 (3H, s, 4¢¢¢-OCH3); 13C NMR (DMSO-d6,
1000 MHz,): d = 161.2 (C, C-7), 159.2 (C, C-4¢¢¢), 150.6 (C,
C-3 ), 150.1 (CH, C-2, C-6), 142.0 (CH, C-60), 140.4 (C,
C-100), 138.9 (C, C-4), 128.4 (CH, C-300, C-500), 127.8 (CH,
C-50), 127.4 (CH, C-2¢¢¢, C-6¢¢¢), 126.9 (CH, C-400), 121.3
(CH, C-3, C-5), 120.3 (C, C-1¢¢¢), 118.8 (CH, C-200, C-600),
116.6 (C, C-40), 114.3 (CH, C-3¢¢¢, C-5¢¢¢), 55.3 (CH3,
OCH3); MS (ESI) m/z: 398.15 (M ? 1)?; Anal. Calcd. for
C23H19N5O2: C, 69.49; H, 4.78; N, 17.62. Found: C, 69.48;
H, 4.77; N, 17.59.
N-Isonicotinoyl-N0-(10,30-diphenyl-40-pyrazolylmethylidene)hy-
drazine (3a) Yield 92 %; mp 195–197 ꢁC; Rf = 0.09
[ethylacetate: hexane (1:1)]; IR (KBr) tmax: 3427 (N–H
str.), 1668 (C=O str.) cm-1
;
1H NMR (DMSO-d6,
400 MHz,): d = 11.97 (1H, s, H–N, D2O exchangeable),
9.05 (1H, s, H-50), 8.79 (2H, d, J = 3.6 Hz, H-2, H-6), 8.59
(1H, s, H-60), 8.04 (2H, d, J = 7.6 Hz, H-200, H-600), 7.83
(2H, d, J = 3.2 Hz, H-3, H-5), 7.75 (2H, d, J = 6.8 Hz,
123

Med Chem Res
N0-[30-(4¢¢¢-Fluorophenyl)-10-phenyl-40-pyrazolylmethylidene]-
N-isonicotinoylhydrazine (3d) Yield 84 %; mp
(CH, C-2¢¢¢, C-6¢¢¢), 127.0 (CH, C-400), 123.9 (C, C-4¢¢¢),
121.3 (CH, C-3, C-5), 118.7 (CH, C-200, C-600), 116.5 (C,
C-40); MS (ESI) m/z: 446.05 (M ? 1)?, 448.05 (M ? 2)?
in the ratio showing typical bromine isotope profile (1:1);
Anal. Calcd. for C22H16BrN5O: C, 59.32; H, 3.59; N,
15.73. Found: C, 59.30; H, 3.58; N, 15.69.
258–259 ꢁC; Rf = 0.14 [ethylacetate: hexane (1:1)]; IR
1
(KBr) tmax: 3422 (N–H str.), 1663 (C=O str.) cm-1; H
NMR (DMSO-d6, 400 MHz,): d = 11.92 (1H, s, H–N,
D2O exchangeable), 8.95 (1H, s, H-50), 8.77 (2H, d,
J = 5.0 Hz, H-2, H-6), 8.59 (1H, s, H-60), 7.98 (2H, d,
J = 8.0 Hz, H-200, H-600), 7.50–7.85 (6H, m, H-300, H-500,
H-2¢¢¢, H-6¢¢¢ & H-3, H-5), 7.28–7.38 (3H, m, H-3¢¢¢, H-5¢¢¢
& H-400); 13C NMR (DMSO-d6, 100 MHz,): d = 161.4 (C,
N-Isonicotinoyl-N0-[30-(4¢¢¢-methylphenyl)-10-phenyl-40-pyra-
zolylmethylidene]hydrazine (3g) Yield 90 %; mp
199–200 ꢁC; Rf = 0.07 [ethylacetate: hexane (1:1)]; IR
1
(KBr) tmax: 3426 (N–H str.), 1666 (C=O str.) cm-1; H
1
d, JC-F = 245.3 Hz, C-4¢¢¢), 161.2 (C, C-7), 150.7 (C,
NMR (CDCl3, 400 MHz,): d = 9.93 (1H, s, H–N, D2O
exchangeable), 8.74 (2H, d, J = 5.2 Hz, H-2, H-6), 8.61
(1H, s, H-50), 8.42 (1H, s, H-60), 7.45–7.80 (9H, m, H-Ph00,
H-2¢¢¢, H-6¢¢¢ & H-3, H-5), 7.25 (2H, d, J = 8.0 Hz, H-3¢¢¢,
H-5¢¢¢), 2.17 (3H, s, 4¢¢¢-CH3); 13C NMR (DMSO-d6,
100 MHz,): d = 161.1 (C, C-7), 152.1 (C, C-30), 150.2
(CH, C-2, C-6), 142.4 (CH, C-60), 140.5 (C, C-100), 139.0
(C, C-4), 138.0 (C, C-4¢¢¢), 129.4 (CH, C-2¢¢¢, C-6¢¢¢), 129.2
(CH, C-3¢¢¢, C-5¢¢¢), 129.1 (C, C-1¢¢¢), 128.5 (CH, C-300,
C-500), 126.9 (CH, C-50), 126.8 (CH, C-400), 121.4 (CH, C-3,
C-5), 118.7 (CH, C-200, C-600), 116.5 (C, C-40), 20.8 (C,
CH3); MS (ESI) m/z: 382.16 (M ? 1)?; Anal. Calcd. for
C23H19N5O: C, 72.41; H, 4.98; N, 18.36. Found: C, 72.40;
H, 4.96; N, 18.32.
C-30), 150.1 (CH, C-2, C-6), 141.9 (CH, C-60), 140.5 (C,
3
C-100), 138.9 (C, C-4), 129.6 (C, d, JC-F = 8.3 Hz, C-2¢¢¢,
C-6¢¢¢), 128.8 (C, C-1¢¢¢), 128.5 (CH, C-300, C-500), 127.7
(CH, C-50), 127.0 (CH, C-400), 121.5 (CH, C-3, C-5), 118.7
2
(CH, C-200, C-600), 116.6 (C, C-40), 116.0 (C, d, JC-
= 21.6 Hz, C-3¢¢¢, C-5¢¢¢); MS (ESI) m/z: 386.13
F
(M ? 1)?; Anal. Calcd. for C22H16FN5O: C, 68.55; H,
4.15; N, 18.17. Found: C, 68.54; H, 4.14; N, 18.15.
N0-[30-(4¢¢¢-Chlorophenyl)-10-phenyl-40-pyrazolylmethylidene]-
N-isonicotinoylhydrazine
(3e) Yield
247–248 ꢁC; Rf = 0.11 [ethylacetate: hexane (1:1)]; IR
89.3 %;
mp
(KBr) tmax: 3430 (N–H str.), 1668 (C=O str.) cm-1; H
1
NMR (DMSO-d6, 400 MHz,): d = 11.93 (1H, s, H–N,
D2O exchangeable), 8.96 (1H, s, H-50), 8.77 (2H, d,
J = 5.8 Hz, H-2, H-6), 8.59 (1H, s, H-60), 7.98 (2H, d,
J = 8.0 Hz, H-200, H-600), 7.79–7.85 (4H, m, H-2¢¢¢, H-6¢¢¢ &
H-3, H-5), 7.35–7.56 (5H, m, H-3¢¢¢, H-5¢¢¢ & H-300, H-400,
H-500); 13C NMR (DMSO-d6, 100 MHz,): d = 161.0 (C,
C-7), 150.6 (C, C-30), 150.0 (CH, C-2, C-6), 141.9 (CH,
C-60), 140.4 (C, C-100), 138.9 (C, C-4), 133.5 (C, C-4¢¢¢),
130.8 (CH, C-2¢¢¢, C-6¢¢¢), 130.0 (C, C-1¢¢¢), 129.5 (CH,
C-3¢¢¢, C-5¢¢¢), 128.5 (CH, C-300, C-500), 127.6 (CH, C-50),
126.9 (CH, C-400), 121.4 (CH, C-3, C-5), 118.8 (CH, C-200,
C-600), 116.7 (C, C-40); MS (ESI) m/z: 402.10 (M ? 1)?,
404.10 (M ? 2)? in the ratio showing typical chlorine
isotope profile (3:1); Anal. Calcd. for C22H16ClN5O: C,
65.82; H, 3.99; N, 17.45. Found: C, 65.78; H, 3.97; N,
17.41.
Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles
General procedure IBD (0.011 mol) was added in a lot-
wise manner to the suspension or solution of an appropriate
isonicotinoyl hydrazone (3, 0.01 mol) in dichloromethane
under stirring. The reaction mass was further stirred for 1.
0 h, and the reaction was monitored by TLC. After com-
pletion of the reaction, the solvent was evaporated and
residues were triturated with petroleum ether twice to ob-
tain crude product (4) which was recrystallised from
ethanol.
2-(100,300-Diphenyl-pyrazol-400-yl)-5-(pyridin-40-yl)-1,3,4-oxa-
diazole (4a) Yield 91 %; mp 177–178 ꢁC; Rf = 0.22
[ethylacetate: hexane (1:1)]; IR (KBr) tmax: transparent in
the region of (N–H str.) and (C=O str.), 1251 (C–O str.)
N0-[30-(4¢¢¢-Bromophenyl)-10-phenyl-40-pyrazolylmethylidene]-
1
N-isonicotinoylhydrazine
(3f) Yield
239–240 ꢁC; Rf = 0.16 [ethylacetate: hexane (1:1)]; IR
89.4 %;
mp
cm-1; H NMR (DMSO-d6, 400 MHz,): d = 9.48 (1H, s,
H-500), 8.85 (2H, d, J = 5.4 Hz, H-20, H-60), 8.03 (2H, d,
J = 8.0 Hz, H-2¢¢¢, H-6¢¢¢), 7.99 (2H, d, J = 7.6 Hz, H-20000,
H-60000), 7.91 (2H, d, J = 5.6 Hz, H-30, H-50), 7.43–7.59
(6H, m, H-3¢¢¢, H-4¢¢¢, H-5¢¢¢ & H-30000, H-40000, H-50000); 13C
NMR (DMSO-d6, 100 MHz,): d = 161.6 (C, C-5), 160.2
(C, C-2), 150.9 (CH, C-20, C-60), 150.8 (C, C-300), 138.6 (C,
C-40), 131.6 (CH, C-500), 131.3 (C, C-1¢¢¢), 130.3 (C, C-10000),
129.7 (CH, C-30000, C-50000), 129.1 (C, C-40000), 128.8 (CH,
C-20000, C-60000), 128.2 (CH, C-3¢¢¢, C-5¢¢¢), 127.5 (CH, C-4¢¢¢),
120.0 (CH, C-30, C-50), 118.9 (CH, C-2¢¢¢, C-6¢¢¢), 105.5 (C,
C-400); MS (ESI) m/z: 366.13 (M ? 1)?; Anal. Calcd. for
(KBr) tmax: 3433 (N–H str.), 1665 (C=O str.) cm-1; H
1
NMR (CDCl3, 400 MHz,): d = 11.93 (1H, s, H–N, D2O
exchangeable), 8.99 (1H, s, H-50), 8.77 (2H, d, J = 5.9 Hz,
H-2, H-6), 8.58 (1H, s, H-60), 7.99 (2H, d, J = 8.0 Hz,
H-200, H-600), 7.83 (2H, d, J = 5.8 Hz, H-3, H-5), 7.37–7.76
(7H, m, H-3¢¢¢, H-5¢¢¢, H-Ph00 & H-2¢¢¢, H-6¢¢¢); 13C NMR
(DMSO-d6, 100 MHz,): d = 160.0 (C, C-7), 150.6 (C,
C-30), 150.0 (CH, C-2, C-6), 142.0 (CH, C-60), 140.5 (C,
C-100), 138.9 (C, C-4), 132.7 (CH, C-3¢¢¢, C-5¢¢¢), 129.9 (C,
C-1¢¢¢), 128.5 (CH, C-300, C-500), 127.9 (CH, C-50), 127.5
123

Med Chem Res
C22H15N5O: C, 72.30; H, 4.11; N, 19.17. Found: C, 72.28;
H, 4.10; N, 19.15.
160.2 (C, C-2), 150.9 (CH, C-20, C-60), 150.8 (C, C-300),
138.6 (C, C-40), 131.9 (CH, C-500), 130.6 (C, C-1¢¢¢), 130.4
3
(C, d, JC-F = 8.4 Hz, C-20000, C-60000), 129.8 (C, C-10000),
2-[300-(40000-Nitrophenyl)-100-phenyl-pyrazol-400-yl]-5-(pyridin-
128.4 (CH, C-3¢¢¢, C-5¢¢¢), 127.6 (CH, C-4¢¢¢), 120.1 (CH,
40-yl)-1,3,4-oxadiazole
(4b) Yield
88.5 %;
mp
2
C-30, C-50), 118.9 (CH, C-2¢¢¢, C-6¢¢¢), 115.8 (C, d, JC-
241–242 ꢁC; Rf = 0.18 [ethylacetate: hexane (1:1)]; IR
(KBr) tmax: transparent in the region of (N–H str.) and
(C=O str.), 1543 (NO2 symmetric str.), 1349 (NO2 asym-
;
metric str.), 1247 (C–O str.) cm-1 1H NMR (CDCl3,
= 21.5 Hz, C-30000, C-50000), 105.3 (C, C-400); MS (ESI)
F
m/z: 384.1 (M ? 1)?; Anal. Calcd. for C22H14FN5O: C,
68.91; H, 3.65; N, 18.27. Found: C, 68.90; H, 3.64; N,
18.25.
400 MHz,): d = 9.52 (1H, s, H-500), 8.87 (2H, d,
J = 5.2 Hz, H-20, H-60), 8.39 (2H, d, J = 7.8 Hz, H-30000,
H-50000), 8.18 (2H, d, J = 8.0 Hz, H-20000, H-60000), 8.06 (2H,
d, J = 8.0 Hz, H-2¢¢¢, H-6¢¢¢), 7.99 (2H, d, J = 5.4 Hz,
H-30, H-50), 7.46–7.62 (3H, m, H-3¢¢¢, H-4¢¢¢, H-5¢¢¢); 13C
NMR (DMSO-d6, 100 MHz,): d = 161.5 (C, C-5), 160.1
(C, C-2), 150.8 (CH, C-20, C-60), 150.7 (C, C-300), 145.7 (C,
C-40000), 138.7 (C, C-40), 137.2 (C, C-10000), 131.4 (CH,
C-500), 130.5 (C, C-1¢¢¢), 129.6 (CH, C-20000, C-60000), 127.5
(CH, C-3¢¢¢, C-5¢¢¢), 126.7 (CH, C-30000, C-50000), 126.3 (CH,
C-4¢¢¢), 119.8 (CH, C-30, C-50), 118.7 (CH, C-2¢¢¢, C-6¢¢¢),
105.3 (C, C-400); MS (ESI) m/z: 411.1 (M ? 1)?; Anal.
Calcd. for C22H14N6O3: C, 64.37; H, 3.41; N, 20.48.
Found: C, 64.36; H, 3.39; N, 20.45.
2-[300-(40000-Chlorophenyl)-100-phenyl-pyrazol-400-yl]-5-(pyrid-
in-40-yl)-1,3,4-oxadiazole
(4e) Yield
214–215 ꢁC; Rf = 0.35 [ethylacetate: hexane (1:1)]; IR
(KBr) tmax: transparent in the region of (N–H str.) and
91.2 %;
mp
(C=O str.), 1246 (C–O str.) cm-1; H NMR (DMSO-d6,
1
400 MHz,): d = 9.51 (1H, s, H-500), 8.86 (2H, d,
J = 5.2 Hz, H-20, H-60), 8.02–8.07 (4H, m, H-20000, H-60000-
H & H-2¢¢¢, H-6¢¢¢), 7.94 (2H, d, J = 5.6 Hz, H-30, H-50),
7.58–7.60 (4H, m, H-30000, H-50000 & H-3¢¢¢, H-5¢¢¢), 7.43–7.46
(1H, t, H-4¢¢¢); 13C NMR (DMSO-d6, 100 MHz,):
d = 162.2 (C, C-5), 160.6 (C, C-2), 151.5 (CH, C-20, C-60),
150.0 (C, C-300), 139.0 (C, C-40), 134.4 (C, C-40000), 132.4
(CH, C-500), 131.0 (CH, C-20000, C-60000), 130.8 (C, C-1¢¢¢),
130.7 (C, C-10000), 130.2 (CH, C-30000, C-50000), 128.8 (CH,
C-3¢¢¢, C-5¢¢¢), 128.2 (CH, C-4¢¢¢), 120.6 (CH, C-30, C-50),
119.5 (CH, C-2¢¢¢, C-6¢¢¢), 106.1 (C, C-400); MS (ESI) m/z:
400.08 (M ? 1)?, 402.08 (M ? 2)? in the ratio showing
typical chlorine isotope profile (3:1); Anal. Calcd. for
C22H14ClN5O: C, 66.15; H, 3.51; N, 17.54. Found: C,
66.10; H, 3.50; N, 17.50.
2-[300-(40000-Methoxyphenyl)-100-phenyl-pyrazol-400-yl]-5-(pyrid-
in-40-yl)-1,3,4-oxadiazole
(4c) Yield
195–196 ꢁC; Rf = 0.15 [ethylacetate: hexane (1:1)]; IR
(KBr) tmax: transparent in the region of (N–H str.) and
90 %;
mp
(C=O str.), 1249 (C–O str.) cm-1; H NMR (DMSO-d6,
1
400 MHz,): d = 8.83 (2H, d, J = 5.6 Hz, H-20, H-60), 8.71
(1H, s, H-500), 7.83–7.94 (6H, m, H-30, H-50, H-20000, H-60000-
H & H-2¢¢¢, H-6¢¢¢), 7.39–7.56 (3H, m, H-3¢¢¢, H-4¢¢¢, H-5¢¢¢),
7.05 (2H, d, J = 7.2 Hz, H-30000, H-50000), 3.91 (3H, s, 40000-
OCH3); 13C NMR (DMSO-d6, 100 MHz,): d = 161.5 (C,
C-5), 160.5 (C, C-2), 159.7 (C, C-40000), 151.0 (CH, C-20,
C-60), 150.9 (C, C-300), 138.7 (C, C-40), 131.8 (CH, C-500),
130.5 (C, C-1¢¢¢), 128.6 (CH, C-20000, C-60000), 128.5 (CH,
C-3¢¢¢, C-5¢¢¢), 126.9 (CH, C-4¢¢¢), 120.1 (CH, C-30, C-50),
119.1 (C, C-10000), 118.9 (CH, C-2¢¢¢, C-6¢¢¢), 114.2 (CH,
C-30000, C-50000), 105.4 (C, C-400), 55.3 (CH3, OCH3); MS
(ESI) m/z: 396.2 (M ? 1)?; Anal. Calcd. for C23H17N5O2:
C, 69.84; H, 4.30; N, 17.71. Found: C, 69.82; H, 4.30; N,
17.69.
2-[300-(40000-Bromophenyl)-100-phenyl-pyrazol-400-yl]-5-(pyrid-
in-40-yl)-1,3,4-oxadiazole
(4f) Yield
90.2 %;
mp
203–204 cm-1; Rf = 0.37 [ethylacetate: hexane (1:1)]; IR
(KBr) tmax: transparent in the region of (N–H str.) and (C=O
str.), 1246 (C–O str.) cm-1; 1H NMR (DMSO-d6, 400 MHz,):
d = 8.86 (2H, d, J = 5.4 Hz, H-20, H-60), 8.70 (1H, s, H-500),
7.82–7.89 (6H, m, H-20000, H-60000 & H-Ph¢¢¢), 7.65 (2H, d,
J = 5.2 Hz, H-30, H-50), 7.41–7.57 (3H, m, H-30000, 50000
&
H-4¢¢¢); 13C NMR (DMSO-d6, 100 MHz,): d = 161.6 (C,
C-5), 160.0 (C, C-2), 151.0 (CH, C-20, C-60), 150.7 (C, C-300),
138.2 (C, C-40), 133.7 (CH, C-30000, C-50000), 132.0 (CH, C-500),
131.6 (C, C-10000), 130.8 (C, C-1¢¢¢), 130.6 (CH, C-20000, C-60000),
128.5 (CH, C-3¢¢¢, C-5¢¢¢), 127.6 (CH, C-4¢¢¢), 124.6 (C, C-40000),
120.2 (CH, C-30, C-50), 119.3 (CH, C-2¢¢¢, C-6¢¢¢), 105.8 (C,
C-400); MS (ESI) m/z: 444.03 (M ? 1)?, 446.03 (M ? 2)? in
the ratio showing typical bromine isotope profile (1:1); Anal.
Calcd. for C22H14BrN5O: C, 59.59; H, 3.16; N, 15.80. Found:
C, 59.57; H, 3.14; N, 15.78.
2-[300-(40000-Fluorophenyl)-100-phenyl-pyrazol-400-yl]-5-(pyridin-
40-yl)-1,3,4-oxadiazole
(4d) Yield
237–238 ꢁC; Rf = 0.38 [ethylacetate: hexane (1:1)]; IR
(KBr) tmax: transparent in the region of (N–H str.) and
89.3 %;
mp
(C=O str.), 1253 (C–O str.) cm-1; H NMR (DMSO-d6,
1
400 MHz,): d = 8.85 (2H, d, J = 5.4 Hz, H-20, H-60), 8.72
(1H, s, H-500), 7.83–7.97 (6H, m, H-30, H-50, H-20000, H-60000
& H-2¢¢¢, H-6¢¢¢), 7.20–7.57 (5H, m, H-30000, H-50000 & H-3¢¢¢,
H-4¢¢¢, H-5¢¢¢); 13C NMR (DMSO-d6, 100 MHz,):
d = 162.3 (C, d, 1JC-F = 246.1 Hz, C-40000), 161.5 (C, C-5),
2-[300-(40000-Methylphenyl)-100-phenyl-pyrazol-400-yl]-5-(pyrid-
in-40-yl)-1,3,4-oxadiazole
(4g) Yield
185–186 ꢁC; Rf = 0.25 [ethylacetate: hexane (1:1)]; IR
(KBr) tmax: transparent in the region of (N–H str.) and
92 %;
mp
123

Med Chem Res
(C=O str.), 1253 (C–O str.) cm-1 1H NMR (CDCl3,
;
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400 MHz,): d = 8.81 (2H, d, J = 5.6 Hz, H-20, H-60), 8.72
(1H, s, H-500), 7.79–7.88 (6H, m, H-30, H-50, H-20000, H-60000
& H-2¢¢¢, H-6¢¢¢), 7.39–7.56 (3H, m, H-3¢¢¢, H-4¢¢¢, H-5¢¢¢),
7.33 (2H, d, J = 7.6 Hz, H-30000, H-50000), 2.47 (3H, s, 40000-
CH3); 13C NMR (DMSO-d6, 100 MHz,): d = 161.6 (C,
C-5), 160.3 (C, C-2), 150.9 (CH, C-20, C-60), 150.8 (C,
C-300), 138.6 (C, C-40), 138.5 (C, C-40000), 131.6 (CH, C-500),
130.5 (CH, C-20000, C-60000), 129.6 (C, C-1¢¢¢), 128.8 (C,
C-10000), 128.6 (CH, C-30000, C-50000), 128.5 (CH, C-3¢¢¢,
C-5¢¢¢), 127.5 (CH, C-4¢¢¢), 120.0 (CH, C-30, C-50), 118.9
(CH, C-2¢¢¢, C-6¢¢¢), 105.4 (C, C-400), 20.9 (C, CH3); MS
(ESI) m/z: 380.14 (M ? 1)?; Anal. Calcd. for C23H17N5O:
C, 72.80; H, 4.48; N, 18.46. Found: C, 72.78; H, 4.46; N,
18.45.
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DNA photocleavage experiment was performed by taking
10 ll solution containing pBR322 DNA in TE (Tris
10 mM, EDTA 0.01 mM, pH 8.0) buffer in the presence of
40 lg of synthesized compounds (Sharma et al., 2014).
The sample solution held in caps of polyethylene micro-
centrifuge tubes were placed directly on the surface of a
transilluminator (8000 mW/cm) at 360 nm and were irra-
diated for 30 min at room temperature. After irradiation,
samples were further incubated at 37 ꢁC for 1 h. Irradiated
samples were mixed with 6X loading dye containing
0.25 % bromophenol blue and 30 % glycerol. The samples
were then analyzed by electrophoresis on a 0.8 % agarose
horizontal slab gel in Tris–acetate EDTA buffer (40 mM
Tris, 20 mM acetic acid, 1 mM EDTA, pH: 8.0). Untreated
plasmid DNA was maintained as a control in each run of
gel electrophoresis which was carried out at 5 V/cm for
2.0 h. Gel was stained with ethidium bromide (1 lg/mL)
and photographed under UV light. To account the effect of
synthesized compounds on DNA, the band intensities were
analyzed using the GelQuant.NET software provided by
biochemlabsolutions.com.
Acknowledgments The authors are grateful to the Chairman, Ma-
harishi Markandeshwar University, Mullana (Ambala), for providing
the necessary research facilities. We are also grateful to Manish
Kumar and Avtar Singh of the SAIF, Panjab University, Chandigarh,
for providing IR, 1H, 13C NMR, mass spectra, and elemental analysis.
Judge V, Narasimhan B, Ahuja M (2012a) Isoniazid: the magic
molecule. Med Chem Res 21:3940–3957
Judge V, Narasimhan B, Ahuja M, Sriram D, Yogeeswari P (2012b)
Synthesis, antimycobacterial, antiviral, antimicrobial activities,
and QSAR studies of isonicotinic acid-1-(substituted phenyl)-
ethylidene/cyclohep-tylidene hydrazides. Med Chem Res
21:1935–1952
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