Synthesis and antitubercular activities of substituted benzoic acid N′-(substituted benzylidene/furan-2-ylmethylene)-N-(pyridine-3-carbonyl)- hydrazides

Article abstract of DOI:10.1016/j.ejmech.2010.08.030

A series of benzoic acid hydrazones and its nicotinyl derivatives (1-10) were prepared and evaluated for their antitubercular activity towards a strain of Mycobacterium tuberculosis (MTB). The structures of newly synthesized compounds were confirmed by infrared (IR) and ¹H-nuclear magnetic resonance (NMR) spectral data and elemental analysis. The in vitro antitubercular activity of synthesized compounds against MTB was carried out in Middlebrook 7H11agar medium supplemented with OADC by agar dilution method. The antitubercular activity results indicated that nicotinic acid N-(3,5-dinitro-benzoyl)-N′-(4-methoxy-benzylidene)-hydrazide (1) is the most potent among the synthesized compounds with MIC of 3.5 × 10 ^-3 μM.

Full text of DOI:10.1016/j.ejmech.2010.08.030

European Journal of Medicinal Chemistry 45 (2010) 6085e6089
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and antitubercular activities of substituted benzoic acid
N0-(substituted benzylidene/furan-2-ylmethylene)-N-(pyridine-3-carbonyl)-
hydrazides
,
b
b
Pradeep Kumar a, Balasubramanian Narasimhan a , Perumal Yogeeswari , Dharmarajan Sriram
*
a Faculty of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, India
b Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Hyderabad 500078, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of benzoic acid hydrazones and its nicotinyl derivatives (1e10) were prepared and evaluated for
their antitubercular activity towards a strain of Mycobacterium tuberculosis (MTB). The structures of
newly synthesized compounds were confirmed by infrared (IR) and 1H-nuclear magnetic resonance
(NMR) spectral data and elemental analysis. The in vitro antitubercular activity of synthesized
compounds against MTB was carried out in Middlebrook 7H11agar medium supplemented with OADC by
agar dilution method. The antitubercular activity results indicated that nicotinic acid N-(3,5-dinitro-
benzoyl)-N0-(4-methoxy-benzylidene)-hydrazide (1) is the most potent among the synthesized
compounds with MIC of 3.5 ꢀ 10ꢁ3 mM.
Received 18 March 2010
Received in revised form
2 August 2010
Accepted 12 August 2010
Available online 18 August 2010
Keywords:
Benzoic acid hydrazones
Synthesis
Ó 2010 Elsevier Masson SAS. All rights reserved.
Antitubercular
MIC
1. Introduction
registered to treat TB in the past four decades. This reflects the
inherent difficulties in discovery and clinical testing of new
Tuberculosis (TB) is most serious infectious lung disease in the
world, claims over two million lives worldwide each year and
dwells hidden in as many as two billion people [1]. It is estimated
that between 2005 and 2020, one billion people will be new
infected, over 125 million people will get sick and 30 million will
die of tuberculosis if control is not further strengthened. The
worsening situation has prompted the world health organization
(WHO) to declare tuberculosis a global public health crisis [2]. The
first line drugs currently used for treatment of tuberculosis are
streptomycin, isoniazid, ethambutol, pyrazinamide and rifampicin.
Moreover the emergence of multi drug resistant (MDR) strains of
mycobacterium tuberculosis, which are insensitive to one or more of
the first line drugs, isoniazid and rifampicin, has further worsened
the situation. Furthermore, the association of TB and HIV infections
has caused an urgent need in search of alternative chemothera-
peutics for Mycobacterium tuberculosis infections [3].
agents and the lack of pharmaceutical industry research in this
area [4].
There are two basic approaches to develop a new drug for
tuberculosis: (a) synthesis of analogue, modifications or deriva-
tives of existing compounds for shortening and improving TB
treatment and (b) searching for novel structures that TB organism
has never been presented with before, for the treatment of MDR-
TB [5].
Hydrazide derivatives represent an overwhelming and rapid
developing field in modern medicinal chemistry. A degree of
respectability has been bestowed for hydrazide derivatives due to
their antimicrobial, antitubercular, antitumour, analgesic and anti-
inflammatory, trypanocidal, leishmanicidal, anti-HIV, anthrax
lethal factor inhibitory, antidiabetic and antimalarial properties
[6e15].
Prompted by these observations and in continuation of
our research into bioactive molecules [16e21], we designed
the synthesis with a series of substituted benzoic acid N0-
(substituted benzylidene/furan-2-ylmethylene)-N-(pyridine-3-
carbonyl)-hydrazides (1e10) with the aim of obtaining more
potent antitubercular compounds to improve current chemo-
therapeutic antitubercular treatments.
Although many compounds are in clinical trials, it is aston-
ishing that with this background, there have been no new drugs
* Corresponding author. Tel.: þ91 1262 272535; fax: þ91 1262 274133.
E-mail address: naru2000us@yahoo.com (B. Narasimhan).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.030

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P. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 6085e6089
2. Results and discussion
presence of aromatic primary amino group is indicated by the
existence of NH stretch in compound 6 [3396.4 cmꢁ1 (symm.);
3550.0 cmꢁ1 (asymm)] and 10 [3404.1 cmꢁ1 (symm.); 3535.2 cmꢁ1
(asymm)]. Moreover presence of NO2 group in compounds 1, 4 and
7 were indicated by appearance of asymmetric and symmetric NO2
stretching bands at 1560e1510 cmꢁ1 and 1365e1335 cmꢁ1
respectively. The presence of furan-2-ylmethylene group in
compound 10 was confirmed by the appearance of IR bands at
920.9 cmꢁ1 and 1020.2 cmꢁ1 corresponds to CH-out of plane
bending and ring breathing respectively. The C]O stretch of
tertiary amide of nicotinic acid moiety in synthesized compounds
(1e10) is demonstrated by the appearance of IR absorption band at
1670e1630 cmꢁ1. Further the presence of pyridine ring in the
synthesized compounds were confirmed by the presence of IR
bands at 1615e1565 cmꢁ1 corresponds to C]C and C]N stretching
of pyridine ring.
2.1. Chemistry
The different carboxylic acids were refluxed with ethanol in the
presence of sulphuric acid to yield their ethyl esters. The ethyl ester
was refluxed with hydrazine-hydrate in ethanol to yield the cor-
responding hydrazides. The substituted hydrazides were then
condensed with substituted aromatic aldehydes to yield the
substituted benzoic acid benzylidene/furan-2-yl-methylene
hydrazides. Further the reaction of substituted benzoic acid ben-
zylidene/furan-2-yl-methylene hydrazides with nicotinyl chloride
resulted in the formation of title compounds (1e10) (Scheme 1). It
is important to note here that the yield of the synthesized
compounds were very poor. The low yield of synthetic compounds
may be attributed to any one or more of the following reasons [22]:
(a) the reaction may be reversible and position of equilibrium is
unfavorable to the product; (b) the incursion of side reactions
leading to the formation of by-products; (c) the premature work-up
of the reaction before its completion; (d) the volatilization of
products during reaction or work-up; (e) the loss of product due to
incomplete extraction, inefficient crystallization or other work-up
procedures; (f) the presence of contaminants in the reactants or
reagents leading to a less efficient reaction. The physicochemical
data of synthesized compounds are presented in Table 1. The
synthesized compounds were characterized by their IR and 1H-
NMR as well by elemental analysis studies. The elemental analysis
results were within ꢂ0.4% of the theoretical values.
1H-NMR spectra study gave the multiplet signal between 6.50
and 7.70
compound 1, 4 and 6 showed singlet at
ence of OCH3 of ArOCH3. Similarly the presence of NH2 group in
compounds 6 and 10 were confirmed by the presence of 3.92. The
presence of multiplets at 7.10e7.40 and 7.83e8.02 indicated the
d
ppm which is indicative of aromatic proton. The
d
3-85e3-95 due to pres-
d
d
presence of aromatic protons of furan (3H) and benzene (4H) ring of
compound 10. Further the presence of pyridine ring in synthesized
compounds (1e10) was indicated by the appearance of
7.70e9.90.
d at
2.2. Antitubercular activity
The appearance of medium out of plane deformation bands
(CeC bending) at 738.7 cmꢁ1 and 810.9 cmꢁ1 indicated the pres-
ence of 1,3-disubstituted benzene ring (ArNO2) and 1,4-disubsti-
tuted benzene ring (ArOCH3) in compound 4. In contrast, the
1,3,5-trisubstituted benzene ring (compound 1) showed CeC out of
The in vitro antitubercular activity of synthesized compounds
against MTB, was carried out in Middlebrook 7H11agar medium
supplementedwithOADCbyagardilutionmethodandtheresultsare
presented in Table 1. In general the antitubercular activity of
synthesized hydrazides (Table 1) were not appreciable except
nicotinic acid N-(3,5-dinitro-benzoyl)-N0-(4-methoxy-benzylidene)-
hydrazide (1) and nicotinic acid N-(2-chloro-5-nitro-benzoyl)-
plane band deformation at 725.2 cmꢁ1
. The presence of 3-
substituted pyridine in structures of compounds (1e10) was
confirmed by strong out of plane deformation bands (CeH bending)
at 820e770 cmꢁ1 which were visible from their IR spectra. The
N0-(3,4-dimethoxy-benzylidene)-hydrazide (5). Compound
1
R2
R4
R1
R5
R2
R4
R1
R5
R2
R4
R1
NH2NH2
EtOH
R3
COOH
R3
COOEt
R3
CONHNH2
R5
X-CHO
R2
R1
O
X
N
H
R3
N
R4
R5
Cl
O
HO
O
SOCl2
N
N
R2
R4
R1
O
X
N
R3
N
R5
1-10
O
N
Scheme 1. Scheme for the synthesis of substituted benzoic acid N0-(substituted benzylidene/furan-2-ylmethylene)-N-(pyridine-3-carbonyl)-hydrazides.

P. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 6085e6089
6087
Table 1
Physicochemical characteristics and antitubercular activity of synthesized Substituted benzoic acid hydrazones.
R2
R1
X
O
N
R3
N
O
R4
N
R5
1-10
Comp.
R1
H
R2
R3
H
R4
R5
H
X
Mol. formula
C21H15O7N5
M. wt.
449
m.p. (ꢃC)
Rf valuea
0.65
% yield
20.6
MIC (
m
M ꢀ 10ꢁ3
)
OMe
1
NO2
NO2
94e97
3.5
OMe
OMe
2
Br
H
H
H
H
C22H18O4N3Br
468
149e152
0.76
15.8
13.4
OMe
OMe
3
4
H
H
H
CH3
H
H
H
H
H
C22H19O3N3
373
404
168e171
158e161
0.44
0.63
27.0
14.5
67.0
30.9
NO2
C21H16O5N4
OMe
OMe
5
Cl
H
H
NO2
H
C22H17O6N4Cl
468
69e72
0.31
22.4
6.7
OMe
6
7
H
H
H
H
NH2
NH2
H
H
H
H
C21H18O3N4
374
389
189e192
79e82
0.85
0.80
28.9
38.0
>66.8
NO2
C20H15O4N5
64.3
OMe
OMe
8
H
H
NH2
H
H
C22H20O4N4
404
44e47
0.58
35.2
>61.9
OMe
9
H
H
H
H
Cl
H
H
H
H
C21H16O3N3Cl
394
335
88e91
0.80
0.56
18.8
58.7
63.5
10
NH2
C18H14O3N4
219e222
>74.6
O
Isoniazid
Ethambutol
Ciprofloxacin
0.8
7.6
9.4
a
TLC mobile phase e chloroform:acetone (9:1).
(MIC ¼ 3.5 ꢀ10ꢁ3 mM) has shown antitubercular activity equivalent
withdrawing group in improving antimicrobial activities is
supported by the studies of Sharma et al. [23].
2. The low antitubercular activity of compound 5 in comparison
to compound 1 may be attributed to the presence of an addi-
tional electron donating methoxy group in it.
to the standard drug ethambutol whereas compound
5
(MIC ¼ 6.7 ꢀ 10ꢁ3 mM) has shown activity equivalent to the standard
drug ciprofloxacin.
3. Compound 2 (Br) and compound 4 (NO2) have the electron
withdrawing groups but compound 2 is more active than the
compound 4 which indicates the fact that the electron
1. The presence of electron withdrawing groups on the aromatic
ring increases the antitubercular activity as evidenced by
compound
1 and compound 5. The role of electron

6088
P. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 6085e6089
3.1. Synthesis of nicotinic acid N-(3,5-dinitro-benzoyl)-N0-(4-
withdrawing halo group is more effective in improving the
antitubercular activity than electron withdrawing nitro
group.
methoxy-benzylidene)-hydrazide (1)
4. The presence of halo group in para postion is not suitable for
antitubercular activity of synthesized compounds. Cf. high
antitubercular activity of compound 2 and 5 than compound 9
which has the electron withdrawing chloro group at para
position.
5. Introduction of electron withdrawing group on the aldehyde
portion i.e. on benzylidene moiety (NO2 in compound 7) has
not shown any improvement in antitubercular activity.
6. The low antitubercular activity of compounds 3, 6, 7, 8 and 10
may be due to the presence of electron donating groups (NH2
or CH3) in their structure.
The mixture of 3,5-dinitrobenzoic acid (0.08 mol) and ethanol
(0.74 mol) was heated under reflux in presence of mineral acid till
the completion of reaction. Once the reaction has been completed,
the reaction mixture was added to 200 mL ice cold water and the
ester formed was extracted with ether (50 mL). The ether layer was
separated and on evaporation yielded the crude ester which was
then recrystallized from alcohol. Hydrazine-hydrate (99%)
(0.015 mol) was added in ethanolic solution of ester (0.01 mol) and
refluxed for 5 h. The reaction mixture was then cooled and the
precipitates were filtered off, washed with water, dried and
recrystallized from ethanol.
7. In order to improve the antitubercular activity we have
attempted to replace the benzylidene moiety with the
heterocyclic nucleus furan (10). The aforesaid modification
didn’t improve the antitubercular activity of the synthesized
hydrazides. This is similar to the results obtained by us in one
of our previous study [17]. These results are summarized in
Fig. 1.
A solution of 0.05 mol of p-methoxy benzaldehyde in ethanol
was added to a solution of 0.05 mol of above prepared 3,5-dini-
trobenzoic acid hydrazide in 50 mL ethanol. The mixture was
refluxed on a water bath for 3 h. Then the reaction mixture was
allowed to cool at room temperature and the precipitate
(3,5-dinitrobenzoic acid p-methoxybenzyilidene hydrazide)
obtained was filtered, dried and recrystallized from ethanol. A
solution of 3,5-dinitrobenzoic acid p-methoxybenzyilidene hydra-
zide (0.002 mol) in diethyl ether (50 mL) was added with a solution
of nicotinyl chloride (0.002 mol) in diethyl ether (50 mL). The above
mixture was stirred for 24 h at room temperature. The resultant
product is isolated by evaporation of ether and purified by recrys-
tallization with methanol.
In conclusion, the appreciable antitubercular activity shown by
the nicotinic acid N-(3,5-dinitro-benzoyl)-N0-(4-methoxy-benzyli-
dene)-hydrazide (1) and nicotinic acid N-(2-chloro-5-nitro-
benzoyl)-N0-(3,4-dimethoxy-benzylidene)-hydrazide (5) make them
to be selected as valid leads for synthesizing new compounds that
possess better antitubercular activity.
The compounds 2e10 were prepared by following the above
procedure using different substituted benzoic acid and corre-
sponding aromatic aldehydes.
3.1.1. Nicotinic acid N-(3,5-dinitro-benzoyl)-N0-(4-methoxy-
benzylidene)-hydrazide (1).
3. Experimental
Mp (ꢃC) 94e97; Yield e 20.6%; 1H-NMR (CDCl3)
d: 3.86 (s, 3H, CH
of OCH3), 7.80e7.84 (s, 1H, CH of C2 and C6 of dinitro benzene),
6.88e6.93 (d, 2H, CH of C3 and C5 of ArOCH3; J-15 Hz), 7.70e7.73 (d,
2H, CH of C2 and C6 of ArOCH3; J-9 Hz), 7.75e7.77 (t, 1H, CH of C5 of
pyridine), 8.32e8.35 (d, 1H, CH of C4 of pyridine; J-9 Hz), 8.84e8.88
(d, 1H, CH of C6 of pyridine; J-12 Hz), 9.18 (s, 1H, CH of C2 of pyri-
Starting materials were obtained from commercial sources and
were used without further purification. Solvents were dried by
standard procedures. Reaction progress was observed by thin layer
chromatography making use of commercial silica gel plates
(Merck), Silica gel F254 on aluminum sheets. Melting points were
determined in open capillary tubes on a Sonar melting point
apparatus and are uncorrected. 1H-nuclear magnetic resonance
(1H-NMR) spectra were determined by Bruker Avance II 400 NMR
spectrometer in appropriate deuterated solvents and are expressed
dine), 8.25 (s, 1H, CH of N ¼ CH); 13C NMR (CDCl3)
d: 56.1, 114.2,
122.3, 123.4, 124.8, 128.6, 129.8, 130.1, 135.1, 137.1, 148.3, 149.2,
152.6, 154.6, 164.4, 168.1, 169.5; IR (KBr pellets): cmꢁ1 1726.4 (C]O,
COeArNH2), 3099.0 (CH, aromatic), 1609 (C]O, tertiary amide),
2927.3 (CH, aliphatic OCH3), 1345.7 (NO2 asymmetric stretching,
aromatic NO2 group), 1544.5 (NO2 symmetric stretching, aromatic
NO2 group). Anal. Calculated for C21H15O7N5: C, 56.13; H, 3.36; N,
15.58; O, 24.92. Found: C, 56.18; H, 3.34; N, 15.61; O, 24.89.
in parts per million (d, ppm) downfield from tetramethylsilane
(internal standard) NMR data are given as multiplicity (s, singlet; d,
doublet; t, triplet; m, multiplet) and number of protons. Infrared
(IR) spectra were recorded on a Shimadzu FTIR spectrometer.
Carbocyclic ring - Improves
antitubercular activity
Electron donating groups - Decreases
antitubercular activity
Heterocyclic ring - No role on
antitubercular activity
O
R
N N
Electron donating groups - Decreases
antitubercular activity
O
X
N
Electron withdrawing groups - No significant
role on antitubercular activity
Electron withdrawing groups - Improves
antitubercular activity
Fig. 1. Structural requirements for the antitubercular activity of substituted benzoic acid N0-(substituted benzylidene/furan-2-ylmethylene)-N-(pyridine-3-carbonyl)-hydrazides.

P. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 6085e6089
6089
3.1.2. Nicotinic acid N0-(4-methoxy-benzylidene)-N-(3-nitro-
1634.56 (C]O, tertiary amide). Anal. Calculated for C18H14O3N4: C,
64.66; H, 4.22; N, 16.76; O, 14.36. Found: C, 64.62; H, 4.18; N, 16.72;
O, 14.35.
benzoyl)-hydrazide (4).
Mp (ꢃC) 158e161; Yield e 14.5%; 1H-NMR (CDCl3)
d: 6.64e7.08
(m, 4H, CH of ArOCH3), 3.93 (s, 3H, CH of OCH3), 7.64e8.0 (m, 4H,
CH of ArNO2), 8.79e8.82 (d, 1H, CH of C4 of pyridine; J-9 Hz),
8.92e8.95 (d, 1H, CH of C6 of pyridine; J-9 Hz), 9.87 (s, 1H, CH of C2
3.2. Evaluation of antitubercular activity
of pyridine), 8.25 (s, 1H, CH of N ¼ CH); 13C NMR (CDCl3)
d: 56.2,
All compounds were screened for their in vitro antitubercular
activity against MTB, in Middlebrook 7H11agar medium supple-
mented with OADC by agar dilution method similar to that rec-
ommended by the National Committee for Clinical Laboratory
Standards for the determination of MIC in triplicate. The minimum
inhibitory concentration (MIC) is defined as the minimum
concentration of compound required to give complete inhibition of
bacterial growth.
114.1, 122.4, 123.6, 124.8, 127.1, 129.6, 129.8, 130.1, 133.5, 134.3, 137.1,
148.4, 148.6, 152.3, 154.6, 164.2, 168.1, 169.5; IR (KBr pellets): cmꢁ1
1718.1 (C]O, COeArNH2), 3050.0 (CH, aromatic), 1667.8 (C]O,
tertiary amide), 2934.3 (CH, aliphatic OCH3), 1383.6 (NO2 asym-
metric stretch, aromatic NO2 group), 1560.6 (NO2 symmetric
stretching, aromatic NO2 group), 1600.1 (two bands, C]C and C]N
stretching of pyridine ring). Anal. Calculated for C21H16O5N4: C,
62.37; H, 3.99; N, 13.86; O, 19.78. Found: C, 62.31; H, 3.95; N, 13.88;
O, 19.74.
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benzylidene)-hydrazide (6).
Mp (ꢃC) 189e192; Yield e 28.9%; 1H-NMR (CDCl3)
d: 3.85 (s, 3H,
CH of OCH3), 3.92 (s, 2H, NH2 of ArNH2), 6.68e6.70 (d, 2H, CH of C3
and C5 of ArNH2; J-6 Hz), 7.75e7.79 (d, 2H, CH of C2 and C6 of
ArNH2; J-12 Hz), 6.85e6.91 (d, 2H, CH of C3 and C5 of ArOCH3; J-
18 Hz), 7.65e7.66 (d, 2H, CH of C2 and C6 of ArOCH3; J-3 Hz),
7.70e7.72 (t, 1H, CH of C5 of pyridine), 8.34e8.38 (d, 1H, CH of C4 of
pyridine; J-12 Hz), 8.87e8.88 (d, 1H, CH of C6 of pyridine; J-3 Hz),
9.22 (s,1H, CH of C2 of pyridine), 8.21 (s,1H, CH of N ¼ CH); 13C NMR
(CDCl3) d: 56.1, 114.1, 115.3, 123.4, 124.7, 128.0, 129.6, 130.1, 137.2,
148.5, 150.2, 152.3, 154.6, 164.2, 168.1, 169.1; IR (KBr pellets): cmꢁ1
1716.9 (C]O, COeArNH2), 3396.4 (NH symmetric stretching,
primary amine NH2), 3550.0 (NH asymmetric stretching, primary
amine NH2), 3080.0 (CH, aromatic), 1653.7 (C]O, tertiary amide),
2917.5 (CH, aliphatic OCH3). Anal. Calculated for C21H18O3N4: C,
67.37; H, 4.85; N, 14.96; O, 12.82. Found: C, 67.40; H, 4.88; N, 14.92;
O, 12.85.
3.1.4. Nicotinic acid N-(4-amino-benzoyl)-N0-furan-2-ylmethylene-
hydrazide (10).
Mp (ꢃC) 219e222; Yield e 58.7%; 1H-NMR (CDCl3)
d: 7.1e7.4 (m,
3H, furan), 7.83e8.02 (m, 4H, ArNH2), 3.92 (s, 2H, NH2 of ArNH2),
8.63e8.66 (d, 1H, CH of C5 of pyridine; J-9 Hz), 8.80e8.81 (d, 1H, CH
of C4 of pyridine; J-3 Hz), 8.95e8.96 (d, 1H, CH of C6 of pyridine; J-
3 Hz), 9.20e9.22 (s, 1H, CH of C2 of pyridine); 13C NMR (CDCl3)
d:
110.1, 115.3,123.6, 124.7,128.0, 128.6, 129.4, 137.1,143.2, 148.2,150.0,
152.4,154.8, 168.1, 169.6; IR (KBr pellets): cmꢁ1 1732.92 (C]O,
COeArNH2), 3404.13 (NH symmetric stretching, primary amine
NH2), 3535.28 (NH asymmetric stretching, primary amine NH2),
3084.97 (CH, aromatic), 1020.27 (ring breathing, 2-substituted
furan), 1920.25 (CH-out of plane bending, 2-substituted furan),
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