Synthesis, characterization of (E)-N'-(substituted-benzylidene) isonicotinohydrazide derivatives as potent antitubercular agents

Article abstract of DOI:10.2174/157018011795906866

A series of 19 isonicotinic acid hydrazide derivatives has been synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H₃₇R_v using alamar blue susceptibility test. The synthesized comp

Full text of DOI:10.2174/157018011795906866

Letters in Drug Design & Discovery, 2011, 8, 575-579
575
Synthesis, Characterization of (E)-N’-(substituted-benzylidene)isonicotino-
hydrazide Derivatives as Potent Antitubercular Agents
Manav Malhotra*,a, Rajiv Sharmaa, Vikramdeep Mongaa, Aakash Deep*,b, Kapendra Sahuc and
Abdul Samadd
aDepartment of Pharmaceutical Chemistry, ISF College of Pharmacy, Ferozepur Road, Moga, 142 001, India
bDepartment of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124001, India
cDepartment of Pharmaceutical Sciences, Rajiv Gandhi Technical University, Bhopal-462033, India
dDepartment of Pharmaceutical Chemistry, College of Pharmacy in Al-Kharj, King Saud, University, Riyadh, Saudi
Arabia
Received November 10, 2010: Revised March 16, 2011: Accepted March 28, 2011
Abstract: A series of 19 isonicotinic acid hydrazide derivatives has been synthesized and evaluated for their in vitro
antitubercular activity against Mycobacterium tuberculosis H37Rv using alamar blue susceptibility test. The synthesized
compounds inhibit Mycobacterium tuberculosis H37Rv strain with minimum inhibitory concentration ranging from
(0.00014-0.01174 mM). Among all synthesized compounds seven derivatives 2a, 2b, 2e, 2h, 2l, 2m and 2q were more
potent than isoniazid and the compound 2q emerged as the most potent derivative, being more effective than isoniazid
with an (MIC 0.00023 mM) in vitro. The results demonstrated the potential and importance of developing new isoniazid
derivatives against Mycobacterium infections.
Keywords: Isonicotinoyl hydrazones, Mycobacterium tuberculosis H37Rv, Antitubercular activity, IR, 1H NMR, 13C-NMR.
INTRODUCTION
chemotherapy made in 20th century, TB has emerged as the
most significant threat to global public health thus there is a
great demand for new TB drug that should shorten the
duration of effective treatment, improve the treatment of
MDR-TB, and provide more effective treatment of latent TB
infection [11]. But till now no novel antitubercular drug has
been introduced into clinical practice from past four decades
[12]. So, there is a search for chemical prototype capable of
rapid mycobactericidal action with shortened duration of
therapy reduced toxicity effective against resistance strain
and also against the latent bacteria for its growth [13-19].
The anti TB drugs were used in combination with other
drugs to prevent the emergence of drug resistance [20]. On
the other hand, in spite of toxicity on repeated dosing,
Isoniazid (INH) is still considered to be the first line drug for
chemotherapy of tuberculosis [21]. Recently it was
suggested that mechanism of resistance to INH is related to
KatG mutation and deletion, and secondly to chromosomal
mutation in inhA and KasA [22]. Antibacterial resistance to a
drug can be counteracted by designed new derivatives [23].
Tuberculosis is regarded as the most significant chronic
communicable disease in the world [1]. It is one of the
foremost reasons of mortality because of bacterial pathogens,
Mycobacterium tuberculi a slim, aerobic, acid resistant
microorganism [2]. About 32% of the world’s population is
infected with tuberculosis (TB). Every year, approximately 8
million of these infected people develop active TB, and
almost 2 million of them die from the disease [3]. Improved
sanitation and living circumstance appreciably reduced the
incident of disease even before the advent of chemotherapy.
However despite the wide spread use of drugs like amikacin,
kanamycin, or capreomycin which leads to the extensive
drug-resistant tuberculosis, is causing serious concern in
some countries, because patients could become virtually
untreatable using currently available anti-TB drugs. [4-6].
The incidence of TB infection has gradually risen in past
decades and this raise can attribute to a similar increase in
human immune deficiency virus (HIV) infection [7]. The
association of TB and HIV infection is so dramatic that
nearly two third of patients diagnosed with TB are also HIV-
1 seropositive [8]. Further numerous studies have shown that
TB is cofactor in progression of HIV infection [9]. The
recurrence of TB infection is further complexed by increase
in cases that are resistant to conventional antitubercular drug
therapy [10]. Despite the incredible advances in TB
Further,
pharmacokinetic
properties
and
cellular
permeability of a drug can be modulated by derivatization to
bioreversible form of this drug, namely hydrazones [24].
Here, we report the synthesis and preliminary
antimycobacterial data of new isonicotinoyl hydrazone.
RESULTS AND DISCUSSION
*Address correspondence to this author at the Department of
Pharmaceutical Chemistry, ISF College of Pharmacy, Ferozpur Road, Moga
142001, Punjab, India; Tel: +91 9915172881;
The synthetic strategies adopted to obtain the target
compounds 2a-2s are depicted in Scheme 1. Equimolar
quantity of substituted benzaldehydes, acetophenones or
benzophenones that reacts with the equimolar quantity of
isoniazid in ethanolic medium is refluxed for 7 h to form
E-mail: manavmalhotra99@yahoo.in
Department of Pharmaceutical Sciences, Maharshi Dayanand University,
Rohtak-124001, India, Mobile: +919896096727;
E-mail: aakashdeep82@gmail.com
1570-1808/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

576 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 6
Malhotra et al.
R1
R1
O
C
O
C
O
C
R
C
C2H5OH
N
NH
N
N
NH
NH2
R
CH3COOH
Substituted benzaldehydes,
acetophenones, benzophenones
Substituted hydrazones
Isoniazid
(I) 2a-2n: Benzaldehydes R= H
(II) 2o-2q: Acetophenone R= CH3
(III) 2r-2s: Benzophenone R= C6H5
Scheme 1. Synthetic protocol of compounds.
acid hydrazones. The completion of reaction was confirmed
by thin layer chromatography (TLC). The types of
substituted aldehydes, acetophenones and benzophenones are
given in Table 1. The purity of the compounds was checked
by TLC, elemental analyses and characterized by spectral
data. In general, IR spectra of all compounds showed
absorption band at around 3290-3186, 3176-3026, 1691-
1659, 1662-1625, 1583-1548 cm-1 regions, conforming the
Synthesis of Substituted Aryl Acid Hydrazones
Derivatives (2a-2s) (Scheme 1)
The synthesis of the 19 isonicotinohydrazide derivatives,
(2a-2s), among them 2j, 2n, 2r and 2s being unpublished,
was performed with good yields from commercially
available materials. Equimolar quantities of substituted
benzaldehydes, acetophenones or benzophenones (50 mmol)
were treated with isonicotinic acid hydrazide (50 mmol) in
absolute ethanol (50 ml) in a 100 ml round bottom flask
equipped with reflux condenser. The reaction mixture was
refluxed for 7 h, and the completion of reaction was
1
presence of NH, CH, C=N, C=O, C=C respectively. The H
NMR spectra, the signals of the respective prepared
derivatives were verified on the basis of their chemical
shifts, multiplicities, and coupling constants. The spectra of
most compounds showed the characteristic NH proton at (ꢀ
12.63-11.52 ppm), 4H proton of pyridine was at around (ꢀ
9.05-7.25 ppm), 1H proton of -N=C-H (ꢀ 8.92-8.30 ppm)
and characteristic protons of benzylidene at (ꢀ 8.79-6.75
ppm). 13C-NMR spectra of compounds 2a-2s characteristic
C=O signals appeared at around (ꢀ 163.59-162.92 ppm),
benzylidene (ꢀ 168.89-113.36 ppm), -N=C-H (ꢀ 143.72-
142.19 ppm), pyridine ꢀ (149.89-121.17 ppm). Data obtained
were found to be in good agreement with the calculated
values of proposed structure. All the synthesized acid
hydrazones were screened for in vitro activity against
Mycobacterium tuberculosis H37Rv using the microplate
alamar blue assay method in duplicate [25]. The MIC, IC50,
IC90 and % growth inhibition are specified in the Table 2.
Table 1. Detail of Different Substituted Aldehydes,
Acetophenones and Benzophenones
R1
O
C
R
C
N
NH
N
Sr. No.
R
R1
2a.
2b.
2c.
2d.
2e.
2f.
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3-F
4-F
2-I
2,4-NO2
2-OCH3
3-OCH3
4- OCH3
2-OC2H5
3-OC2H5
4- OC3H7
3,4-OCH3
3-OCH3, 4-OH
4-OH
EXPERIMENTAL
Melting points of the synthesized compounds were
determined in open-glass capillaries on Stuart SMP10
melting point apparatus and were uncorrected. The purity of
the compounds was checked by thin layer chromatography
(TLC). Silica gel plates kiesel gel 0.25 mm, 60G F254,
precoated sheets obtained from Merck, Darmstadt
(Germany) were used for TLC and the spots were visualized
by iodine vapors/ultraviolet light as visualizing agent. The
IR spectra (ꢁ, cm-1) were obtained with a Perkin-Elmer 1600
FTIR spectrometer in KBr pellets. 1H-NMR spectra (ꢀ, ppm)
were recorded in DMSO-d6 solutions on a Varian-Mercury
300 MHz spectrometer using tetramethylsilane as the
internal reference. 13C NMR spectra were recorded on in
DMSO-d6 solutions on a Bruker Avance II 400 spectrometer
at 400 MHz using tetramethylsilane as the internal reference.
Elemental analyses were performed on an ECS 4010
Elemental Combustion System. The necessary chemicals
were purchased from Sigma Aldrich companies.
2g.
2h.
2i.
2j.
2k.
2l.
2m.
2n.
2o.
2p.
2q.
2r.
2r.
4-N(CH3)2
4-OH
CH3
CH3
CH3
C6H5
C6H5
3-NH2
4-NH2
-
4-Br

Antitubercular Activity of Some Novel Derivatives of Isoniazid
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 6 577
confirmed by thin layer chromatography. After being cooled
and concentrated, the product was placed in ice cold water.
The precipitate was collected through filtration and dried in
oven at low temperature. The crude products were
recrystallized from 95 % v/v ethanol to give desired
products.
2.98 (s, 6H, CH3); 13C-NMR (400 MHz, DMSO-d6, ꢀ ppm):
163.18, 152.16, 149.77, 143.27, 139.86, 130.55, 121.79,
114.88, 41.56. Calculated (%) for C15H16N4O (268.31); C:
67.15, H: 6.01, N: 20.28, found (%); C: 67.18, H: 5.95, N:
20.31.
(E)-N’-(Diphenylmethylene)isonicotinohydrazide (2r)
(E)-N’-(4-Propoxybenzylidene)isonicotinohydrazide (2j)
Yield 68%, m.p. 112-115 °C; IR (ꢁ, cm-1): 3244, 3062,
Yield 58%, m.p. 157-160 °C; IR (ꢁ, cm-1): 3259, 3029,
1691, 1662, 1569. H NMR (300 MHz, DMSO-d6, ꢀ ppm):
1
1
1665, 1642, 1546, 1464, 1371, 1251, 1023. H NMR (300
11.52 (s, 1H, -NH-N=), 8.67 (d, 2H, pyridine, J= 4.6), 7.84
(d, 2H, pyridine, J= 4.1) 7.58 (m, 10 ArH, benzylidene); 13C-
NMR (400 MHz, DMSO-d6) ꢀ= 163.37, 156.18, 149.64,
139.79, 133.12, 131.28, 127.15, 122.84. Calculated (%) for
C19H15N3O (301.34); C: 75.73, H: 5.02, N: 13.94, found (%);
C: 75.82, H: 5.05, N: 13.82.
MHz, DMSO-d6, ꢀ ppm): 11.92 (s, 1H, -NH-N=), 8.77 (d,
2H, pyridine, J= 4.5 Hz), 8.39 (s, 1H, -N=C-H), 7.81 (d, 2H,
pyridine, J= 4.1 Hz), 7.68 (d, 2H, benzylidene, J= 8.2 Hz),
7.01 (d, 2H, benzylidene, J= 7.5 Hz), 3.97 (t, 2H,CH2), 1.75
(m, 2H, CH2) 0.98 (t, 3H, CH3); 13C-NMR (400 MHz,
DMSO-d6, ꢀ ppm): 163.49, 159.79, 149.82, 143.23, 139.79,
129.57, 125.55, 121.87, 114.18, 72.29, 22.36, 11.88.
Calculated (%) for C16H17N3O2 (283.33); C: 67.83, H: 6.05,
N: 14.83, found (%); C: 67.85, H: 6.07, N: 14.79.
(E)-N’-(4-Bromophenylphenylmethylene)isonicotinohydra-
zide (2s)
Yield 71%, m.p. 158-161 °C; IR (ꢁ, cm-1): 3256, 3054,
1
1689, 1662, 1557, 649. H NMR (400 MHz, DMSO-d6, ꢀ
(E)-N’-(4-Dimethylaminobenzylidene)isonicotinohydrazide
(2n)
ppm): 11.65 (s, 1H, -NH-N=), 8.68 (d, 2H, pyridine, J= 4.8),
7.72 (d, 2H, pyridine, J= 4.2), 7.50 (m, 4H, benzylidene),
Yield 69%, m.p. 207-210 °C; IR (ꢁ, cm-1): 3245, 3064,
7.37 (m, 5H, phenyl); 13C-NMR (400 MHz, DMSO-d6,
ꢀ
1
1675, 1637, 1555, 1168. H NMR (300 MHz, DMSO-d6, ꢀ
ppm): 163.33, 154.46, 149.77, 138.74, 131.81, 131.45,
131.15, 127.91, 125.43, 121.68. Calculated (%) for
C19H14BrN3O (380.24); C: 60.02, H: 3.71, N: 11.05, found
(%); C: 60.05, H: 3.69, N: 11.07.
ppm): 11.76 (s, 1H, -NH-N=), 8.75 (d, 2H, pyridine, J= 4.7),
8.30 (s, 1H, -N=C-H), 7.79 (d, 2H, pyridine, J= 4.2), 7.55 (d,
2H, benzylidene, J=8.7), 6.75 (d, 2H, benzylidene, J= 8.2),
Table 2. Antimycobacterial Data of Synthesized Compounds
Sr. No.
C log Pa
MICb (mM)
IC50c (mM)
% Growth Inhibition
2a.
2b.
1.40
1.76
2.03
0.73
1.26
1.69
1.69
1.78
2.21
2.74
1.36
1.21
1.44
2.00
2.09
1.53
1.53
4.19
5.05
-0.65
0.00032
0.00041
0.00213
0.00440
0.00026
0.00359
0.00084
0.00029
0.00137
0.00158
0.00143
0.00014
0.00037
0.00260
0.00156
0.00173
0.00023
0.01174
0.00344
0.00145
0.00032
0.00024
0.00011
0.00256
0.00017
0.00097
0.00057
0.00025
0.00025
0.00052
0.00038
0.00014
0.00037
0.00286
0.00043
0.00031
0.00027
0.00806
0.00312
0.00080
40.98
50.09
47.38
64.43
67.60
41.93
48.33
65.42
62.62
58.75
57.77
48.95
74.28
43.41
61.74
57.41
78.37
75.69
58.31
96.67
2c.
2d.
2e.
2f.
2g.
2h.
2i.
2j.
2k.
2l.
2m.
2n.
2o.
2p.
2q.
2r.
2s.
Isoniazid
aC log P was calculated using online www. LogP.com.site.
bMIC = minimum inhibitory concentration.
cMIC = Cytotoxicity represented as inhibitory concentration in 50% of cell lines.

578 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 6
Malhotra et al.
Antitubercular Activity
read at 540 nm in a plate reader (Biorad-450). The results are
represented as percentage cell viability in Table 3. This table
shows that the compounds were not toxic to host cells at the
same concentration.
The entire compounds were tested at the TAACF
screening (Tuberculosis Antimicrobial Acquisition and
Coordinating facility by the National Institute of Health of
US Government). All synthesized compounds 2a-2s were
screened for their antimycobacterial activity in in vitro
against Mycobacterium tuberculosis H37Rv using the
microplate alamar blue assay method in duplicate [25-26].
Minimum inhibitory concentrations (MIC) of the synthesized
compounds are reported in Table 2. MIC is defined as the
minimum inhibitory concentration of compound required to
produce 90% inhibition of bacterial growth. Lipophilicity of
the synthesized derivatives and the parent compound, INH,
is expressed in terms of their logP values. These values were
computed with a routine method called calculated logP
(ClogP) using Alchemy software. Result shows that
compounds 2a-2s show significant antimycobacterial
activity. The lipophilicity of the synthesized compounds
increased remarkably compared with the parent drug,
isoniazid. This may render them as being more capable of
penetrating various biomembranes [26-27], consequently
improving their permeation properties through mycobacterial
cell membranes. The entire synthesized compound inhibits
M. tuberculosis with MIC ranging from (0.00014-0.01174
mM). Seven compounds 2a, 2b, 2e, 2h, 2L, 2m and 2q were
more potent than isoniazid and the compound 2q emerged as
the most potent derivative, being more effective than
isoniazid (MIC 0.00023 mM) in vitro.
CONCLUSIONS
Development of novel class of compounds capable of
shortening the duration of effective treatment of tuberculosis,
considered promising in treating isoniazid resistant
tuberculosis is in demand now a days. In general, the new
compounds showed significant antimycobacterial activity,
the best results were found for compounds with higher
lipophilicity with respect to parent compound. In each of the
biological assays, it was assumed that high potency was
absorbed for compounds with value of C log P considerably
greater than that for isoniazid itself, and this appears to be
the most significant structure-activity relationship. In case of
all the evaluated compounds, the best result was shown by
compounds 2a (m-fluorophenyl), 2b (p-fluorophenyl), 2e (o-
methoxyphenyl), 2h (o-ethoxyphenyl), 2l (p-hydroxy m-
methoxyphenyl), 2m (p-hydroxyphenyl) and 2q (p-
aminophenyl) when compared with the first line drug
isoniazid. The results of antimycobacterial activity data
revealed that substitution at o, m and p position of phenyl
ring was more particular with electron releasing group
imparting good activity to the compounds (2e, 2h, 2l, 2m
and 2q). Further placement of fluoro group at m and p (2a,
2b) also shows good activity probably due to
electronegativity and bioisosteric resemblance of flourine
with hydrogen. As a consequence, the correlation between
higher lipophilicity and antimycobacterial activity may
depend on structural modifications mainly involving 2, 3 and
4 positions of phenyl ring [5-6]. Further it was well reported
that hydrazone, hydrazide get partially hydrolyzed in in-vitro
into active drug isoniazid at specific pH [29]. So, the
probable antimycobacterial activities of the synthesized
hydrazones were due to the release of active drug isoniazid
in mycobacterium tuberculi as the partial hydrolysis of
hydrazones into isoniazid took place at specific pH and these
compounds would act as a prodrug of isoniazid. So, it was
suggested that this class of compounds selectively targeted
M. tuberculosis growth, also considering that they were not
cytotoxic to host cells at the same concentration and thus
could be a good starting point to find new lead compounds.
Finally the hydrazones may serve as discovery tools in
Cell Viability Assay
Cellular viability in the presence and absence of test
compounds was determined by Mosman’s MTT(3-(4,5-
dimethylthylthiazol-2yl)-2,5-dimethyl tetrazolium bromide;
Merck) microcultured tetrazolium assay [28]. The cells were
plated in flat bottom 96 well plates (2.5 x 106 cells/mL)
cultured for 1 h in a controlled atmosphere (CO2 5% AT 37
°C), and nonadherent cells were washed by gentle flushing
with RPMI 1640. Adherent cells were cultured in the
presence of medium alone, between 20 (3%) (live and dead
controls, respectively) or different concentrations of
compounds (0.1, 1.0, 10.0, and 100 ꢀg/Ml) in a triplicate
assay. After 18 h, stock MTT solution (5mg/ml of saline; 20
ꢀL/well) was added to the culture and 4 h later supernatant
was discharged +and DMSO (100 ꢀL/well) was added for
formazan crystals, solubilization and the absorbance were
Table 3. Data of Cytotoxic Effects of the Test Compounds on Murine Macrophages Cells 18 h after the Treatment
Compound
% Cell viability/dose (ꢀg/ml)
1.0
0.1
10
100
2a
2b
2e
100
100
100
100
100
100
100
100
100
100
100
100
96
100
98
98
97
100
100
100
96
98
2h
2l
98
100
96
2m
2q
100
100
100

Antitubercular Activity of Some Novel Derivatives of Isoniazid
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 6 579
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ACKNOWLEDGEMENT
We wish to express our gratitude to Shri. Parveen Garg,
Honorable Chairman, ISF College of Pharmacy, Moga,
Punjab, India for his inspiration and constant support. One of
the authors Tina Parker deeply acknowledges NINDS,
NIH, Bethesda, MD, USA for undertaking the
pharmacological screening of synthesized compounds.
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