Med Chem Res (2012) 21:3940–3957
DOI 10.1007/s00044-011-9948-y
REVIEW ARTICLE
Isoniazid: the magic molecule
Vikramjeet Judge • Balasubramanian Narasimhan •
Munish Ahuja
Received: 16 October 2011 / Accepted: 10 December 2011 / Published online: 24 January 2012
Ó Springer Science+Business Media, LLC 2012
Abstract The resurgence of tuberculosis and emergence
of multidrug resistant isolates has focused attention on the
need for an improved understanding of molecular aspects
of the disease, and for elucidation of the factors responsible
for drug action and resistance. Isoniazid is the frontline
drug employed in the treatment of tuberculosis. Recent
research has probed the mechanism of action of isoniazid
(INH), a key drug in the chemotherapy of tuberculosis and
also the anti-mycobacterial potential of derivatives of iso-
niazid has been evaluated. We have made an attempt to
compile an account of various derivatives of isoniazid
reported for their diverse biological activities like anti-
mycobacterial, -bacterial, -fungal and -viral activities.
Keywords Isoniazid  Anti-mycobacterial 
Anti-microbial  Anti-bacterial  Anti-fungal
Introduction
Tuberculosis (TB) caused by the infectious agent Myco-
bacterium tuberculosis, is one of the most important killing
infectious diseases. According to alarming data from the
world health organization (WHO), TB has spread to every
corner of the globe. As much as one-third of the world’s
population is currently infected, and more than 5,000 people
die from TB everyday (Sriram et al., 2009). The factors
V. Judge  M. Ahuja
Department of Pharmaceutical Sciences, Guru Jambheshwar
University of Science and Technology, Hisar 125001, India
B. Narasimhan (&)
Faculty of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak 124001, India
e-mail: naru2000us@yahoo.com
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MEDICINAL
CHEMISTRY
RESEARCH
responsible for this are: (i) patient non-compliance to exist-
ing drug regimens which has resulted in the emergence of
single-drug-resistant strains to all major anti-TB drugs; (ii)
emergence of multidrug resistant TB (MDR-TB), which is
defined as the disease caused by the strains of M. tuberculosis
resistant to two mainstay first-line anti-TB drugs, isoniazid
and rifampicin; and (iii) association of human immunodefi-
ciency virus (HIV) with TB, in which TB is the leading cause
of death among patients who are HIV-positive. Conse-
quently, new drugs with divergent and unique structure and
with a mechanism of action possibly different from that of
existing drugs are urgently required (Nayyar et al., 2007). It
is estimated that nearly 2 billion people have been exposed to
M. tuberculosis and thus are at a risk of developing the active
disease (Nunn et al., 2002). In the developing countries, the
annual infection rate is 20–50 times greater than the devel-
oped countries and its high level shows little or no downward
trend (Shaharyar et al., 2007).
The world health organization (WHO) has reported that
about 33% of the world’s population is infected with TB,
and has predicted that by the year 2020 there will be one
billion new active cases if new anti-TB drugs or treatments
are not developed (Sinha et al., 2005). A peculiar aspect of
its pathogenicity comes from the fact that it remains qui-
escent and becomes active decades later. One of the most
significant risk factor for developing tuberculosis is human
immunodeficiency virus (HIV) infection. Streptomycin and
para-aminosalicylic acid (PAS) provided the first anti-
microbial treatment for tuberculosis in the mid-1940s, but it
was the introduction of the highly effective drug isoniazid
(isonicotinicacid hydrazide, INH) in 1952 that transformed
tuberculosis control. INH was first synthesized in 1912 and
its activity against M. tuberculosis was discovered inde-
pendently by three pharmaceutical companies following
leads based on preliminary results with nicotinamide and
Med Chem Res (2012) 21:3940–3957
with a series of thiosemicarbazone derivatives. In combi-
nation with rifampicin—introduced in 1963—INH has
formed the core of tuberculosis treatment regimens that,
until recently, seemed close to achieving complete elimi-
nation of the disease in many developed countries (Zhang
and Young, 1993).
The current treatment of active TB includes a dosage
regimen of four drugs (isoniazid, rifampicin, pyrazinamide,
and ethambutol) for at least 6 months. As a consequence of
the prolonged duration, irregular treatment, and highly
adaptive nature of the organisms to the surroundings,
multidrug resistant (MDR) strains of M. tuberculosis have
developed (Aparna et al., 2006). The emergence of AIDS,
decline in socioeconomic standards and a reduced
emphasis on TB control programs contribute to disease’s
resurgence in industrialized countries (Ali et al., 2007).
In this study, we have made an attempt to collect and
compile various strategies for the synthesis of isoniazid
derivatives along with their reported biological activities.
Reported isoniazid derivatives
Isoniazid derivatives as anti-tubercular agents
The novel Schiff bases of isoniazid were synthesized by
Hearn et al. and tested for their in vitro and in vivo anti-
tubercular activity. This structural modification of the INH
framework provided a lipophilic adaptation of isoniazid in
which the hydrazine unit has been chemically blocked from
the deactivating process of N2-acetylation by N-arylami-
noacetyl transferases (NATs). Across the class, these
compounds showed strong levels of activity both in vitro
and in vivo. In each of the biological assays, high potency
was observed for compounds with values of clog P con-
siderably greater than INH. The compounds 1 and 2 were
found to be highly active anti-mycobacterial agents and the
selectivity index for compound 2 was [40,000 (Hearn
et al., 2009).
NH N C NH N
O H O F
O
N N
2 (ISNEs), 20 -monosubstituted isonicotinohydrazides and
1 cyanoboranes was evaluated for its in vitro anti-mycobac-
Isonicotinoylhydrazones (INHs) and thiosemicarba-
zones (TSCs) of some 5a-ketosteroids were synthesized
from tigogenin by Merlani et al. They described synthesis
3941
and anti-mycobacterial activity of INHs and TSCs of
D16-pregnenolone, pregnenolone, epiandrosterone, andros-
terone, and 5a-androst-2-en-17-one. From the outcome of
study, it was established that a number of INHs exhibited
high activity towards M. tuberculosis, in vitro, with some
of them being equipotent to INH (Merlani et al., 2004). Out
of the synthesized derivatives, compound 3 was found to be
the highly effective anti-mycobacterial agent.
CH3 N NH
H3C O
N
HO
3
Various isonicotinoyl hydrazinocarbothioamides were
prepared by reacting isonicotinoyl hydrazide (INH) with
appropriate potassium salt of substituted phenyl thiocar-
bamate and were tested for their anti-mycobacterial activity
in vitro against M. tuberculosis H37Rv and INH resistant
M. tuberculosis using the agar dilution method. Among the
synthesized compounds, 2-isonicotinoyl-N-[2-(trifluoro-
methyl) phenyl] hydrazinecarbothioamide (4) was found to
be the most potent compound with a minimum inhibitory
concentration of 0.58 lM against M. tuberculosis H37Rv
and INH resistant M. tuberculosis. When compared to INH,
compound 4 was found to be 1.24 and 157 times more
active against M. tuberculosis H37Rv and INH resistant
M. tuberculosis, respectively, with a selectivity index of
[218. In this study, it was concluded that the lipophilicity
of synthesized compounds increased remarkably in com-
parison to the parent-drug, INH. This may render them
more capable of penetrating various biomembranes, con-
sequently improving their permeation properties through
mycobacterial cell membranes (Sriram et al., 2009).
S O
NH NH NH N
C F
F
4
A series of isoniazid-related isonicotinoyl hydrazones
terial activity. A general correlation emerged between
their lipophilicity and effectiveness against intracellular
M. tuberculosis. On the whole, the most interesting
result of this research was that some hydrazides and
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3942
isoniazid-related isonicotinoyl hydrazones (ISNEs) were
proved to be more effective anti-mycobacterial agents than
isoniazid in a TB-infected macrophage model. In the mac-
rophage assay, most of the tested compounds displayed
excellent activity against M. tuberculosis growing within
macrophages which represent the relevant physiological
environment for this pathogen. The increase in effectiveness
within the infected cells generally appeared to be correlated
to higher lipophilicity levels, observed in the fluorophenyl-
and trifluoromethylphenyl substituted derivatives as well as
in cyanoboranes. In this context, the most interesting goal
achieved in this research was that some compounds
belonging to the hydrazides and ISNEs series were shown to
be more effective than INH against intracellular M. tuber-
culosis. In this study compounds 5, 6 and 7 were found to be
highly active anti-mycobacterial agents with compound
being most active has got the MIC = 0.025 lg/ml against
M. tuberculosis H37Rv (Maccari et al., 2005).
R
NH N C
O R'
N 7; R = H, R’ = 4-CF3-Ph
Almeida da Silva et al. synthesized a series of 3-substi-
tuted 5-hydroxy-5-trifluoro[chloro]methyl-1H-1-isonicoti-
noyl-4,5-dihydropyrazoles by the cyclo-condensation
between 4-methoxy-1,1,1-trifluoro[chloro]-4-(substituted)-
alk-3-en-2-ones and isoniazid. The in vitro anti-microbial
activity of synthesized compounds was tested against INH-
susceptible M. tuberculosis H37Rv, INH-resistant clinical
M. tuberculosis isolates and non-tuberculous mycobacteria.
The compound, 3-(2-furyl)-5-hydroxy-5-trifluoromethyl-4,5-
dihydro-1H-1-(isonicotinoyl)pyrazole was active against all
the INH-resistant strains regardless of the genetic background
at concentrations two- to four-fold of its minimum inhibitory
concentration against M. tuberculosis H37Rv. Interestingly,
the most active compound against M. tuberculosis,
9; R = m-Cl
NH N CH
O R 11; R = p-F
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Med Chem Res (2012) 21:3940–3957
5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicoti-
noyl)-pyrazole (8) was more potent than INH against the
non-tuberculous mycobacteria (Almeida da Silva et al., 2008).
F3C
N
HO N
O
N
8
A series of (E)-N0 -(monosubstituted-benzylidene) ison-
icotinohydrazide derivatives was synthesized and evaluated
for its in vitro anti-mycobacterial activity against
M. tuberculosis H37Rv using Alamar Blue susceptibility
test. The synthesized compounds exhibited a significant
5; R = H, R’ = CH3
6; R = H, R’ = CF3
activity (0.31–0.62 lg/ml) when compared to first-line
drugs such as isoniazid (INH) and rifampicin (RIP) and
could be a good starting point to develop new lead com-
pounds in the fight against multidrug resistant tuberculosis.
The compounds 9, 10, 11 and 12 were the most potent ones
with MIC value of 0.31 lg/ml. These results suggested that
they may be selectively targeted to M. tuberculosis growth,
also considering that they were not cytotoxic to host cells at
the same concentration. Alluding to studies involving
structure, metabolism and anti-tuberculosis in vitro activity
of isoniazid derivatives, these compounds can be consid-
ered original isoniazid derivatives prodrugs since hydra-
zides are cleaved into isonicotinicacid that is the bioactive
form of isoniazid (Lourenco et al., 2008).
10; R = p-Cl
12; R = o-OCH3
Med Chem Res (2012) 21:3940–3957
The in vitro anti-mycobacterial activity of cobalt (II)
and copper (II) complexes of some fluorinated isonicoti-
noyl hydrazones was evaluated in a TB-infected macro-
phage model and all metal complexes exhibited excellent
activity against M. tuberculosis Erdman growing within
macrophages, at concentrations much lower than in culture
media. Moreover complexes 13 and 14 displayed EC99
values lower than that of the parent-drug, isoniazid. In
addition, all tested metal chelates significantly inhibited the
growth of single-drug-resistant M. tuberculosis strains;
complex 14 also possessed moderate activity against
M. avium complex. This study corroborated the hypothesis
that the coordination of active ISNEs to a metal ion could
ameliorate their anti-mycobacterial profile, particularly
favoring the uptake within cells and enhancing ability to
kill intracellular mycobacteria, which live and multiply
inside macrophages (Maccari et al., 2004).
H2O
N
N N
O N
H H
Co
N O
N N
N N
CF3
H2O
13
A series of N1-nicotinoyl-3-(40 -hydroxy-30 -methyl-
phenyl)-5-(substituted phenyl)-2-pyrazolines was synthe-
sized by the reaction between isoniazid (INH) and
chalcones and tested for its in vitro anti-mycobacterial
activity against M. tuberculosis H37Rv (MTB) and INH-
resistant M. tuberculosis (INHR-MTB) using the agar
dilution method. Among the 11 compounds synthesized,
four compounds were found to be most active with mini-
mum inhibitory concentration of less than 1 lM and were
found to be more active than INH against MTB. Com-
pounds with halogen substituted phenyl group showed
higher activity. Out of the synthesized compounds, com-
pound 15, N1-nicotinoyl-3-(40 -hydroxy-30 -methyl phenyl)-
5-(200 -chlorophenyl)-2-pyrazoline was found to be the most
active agent against MTB and INHR-MTB, with a mini-
mum inhibitory concentration of 0.26 lM. When compared
to INH, compound 15 was found to be 2.8- and 43.7-fold
3943
more active against MTB and INHR-MTB, respectively
(Shaharyar et al., 2006).
N
CH3
N N
O OH
Cl
15
Sriram et al. synthesized various isonicotinyl hydra-
zones by reacting isonicotinyl hydrazide with 1-(4-acetyl-
phenyl)-3-[(4-sub)phenyl]thiourea and tested their anti-
N H2O
CF3 O N F
H Cu H
N O
F
H2O
14
mycobacterial activity in vitro against M. tuberculosis
H37Rv and INH-resistant M. tuberculosis using the
BACTEC 460 radiometric system. Among the synthesized
compounds, 1-(4-fluorophenyl)-3-(4-{1-[(pyridine-4-car-
bonyl)-hydrazono]ethyl}phenyl) thiourea (16) was found to
be the most potent compound with a minimum inhibitory
concentration of 0.49 lM against M. tuberculosis H37Rv
and INH-resistant M. tuberculosis. When compared to
INH, 16 was found to be 3 and 185 times more active
against M. tuberculosis H37Rv and INH-resistant M.
tuberculosis, respectively, with a selectivity index of[300.
The lipophilicity of the synthesized compounds increased
remarkably compared with that of the parent-drug, INH.
This may render them more capable of penetrating various
biomembranes, consequently improving their permeation
properties through mycobacterial cell membranes (Sriram
et al., 2006).
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3944 Med Chem Res (2012) 21:3940–3957

O N H2O
S N NH N F
F NH NH CH3 N
F H O N
Co H
16 N O
N
Anti-mycobacterial activity of 5-aryl-1-isonicotinoyl-3- N
(pyridin-2-yl)-4,5-dihydro-1H-pyrazole derivatives syn- H2O
thesized by Mamolo et al. showed that compounds 17, 18,
19, 20 and 21 were active anti-mycobacterial agents with 22
MIC of 8 lg/ml against a strain of M. tuberculosis and a
human-pathogenic strain of M. tuberculosis H4. It was seen
Cocco et al. synthesized a series of hydrazones of iso-
in this study that the synthesized derivatives were less
niazid and their pyridyl methyleneamino derivatives and
active than isoniazid. The lack of anti-mycobacterial
tested its activity against mycobacteria, Gram-positive and
activity of the above 3,5-diaryl-1-isonicotinoyl-4,5-dihy-
-negative bacteria along with evaluation of their cytotox-
dro-1H-pyrazole derivatives was attributed to the inhibition
icity. Several compounds showed a good activity against
of isoniazid release through a possible stabilizing effect of
M. tuberculosis H37Rv and compounds 23 and 24 were
a hydrogen bond between the hydroxyl group in the ortho
found to be most effective against clinically isolated INH
position on the 3-aryl residue and the nitrogen atom at the
resistant M. tuberculosis strain. These derivatives were
2-position of the pyrazoline nucleus (Mamolo et al., 2001).

N 17; R = H 18; R = 2-Cl

N N N 19; R = 3-Cl 20; R = 4-Cl

O

21; R = 2-CH3
R

Octahedral cobalt (II) complexes of isonicotinoyl hydra- inactive against Gram-negative bacteria and moderately
zones, which were obtained from the primary anti-tuberculous active against Gram-positive Staphylococcus aureus
agent isoniazid, have been synthesized by Bottari et al. Their in (Cocco et al., 1999).

NH2 NH2
O O
N N
Cl HN N O2 N HN N
O O

23 24

vitro anti-mycobacterial activity has been evaluated against M.
tuberculosis H37Rv. The complexes exhibited MIC values
ranging from\0.1 to 0.39 lg/ml, showing them to be generally
more active than previously reported analogous Cu(II) and
Ni(II) complexes (Bottari et al., 2001).
Sriram et al. reacted ortho-hydroxy acetophenone with
isoniazid to form acid hydrazones. The C-Mannich bases of
these acid hydrazones were prepared by their reaction with
formaldehyde and various secondary amines. The synthe-
sized compounds were screened for anti-mycobacterial

123
Med Chem Res (2012) 21:3940–3957
activity against M. tuberculosis H37Rv using the Alamar
blue susceptibility test. The synthesized compounds
inhibit M. tuberculosis strain H37Rv with minimum
inhibitory concentrations ranging from 0.56 to 4.61 lM.
Compound N0 -{1-[2-hydroxy-3-(piperazin-1-ylmethyl)-
phenyl] ethylidene} isonicotinohydrazide, 25, was found
to be the most active compound with a MIC of 0.56 lM,
and was more potent than isoniazid (MIC of 2.04 lM).
After 10 days of treatment, compound 25 decreased the
bacterial load in murine lung tissue by 3.7-log10 as
compared to controls, which was equipotent to isoniazid
(Sriram et al., 2005).
CH3 O available programs. The higher lipophilicity of the new
N NH N compounds with respect to INH, PZA, p-aminosalicylic acid,
OH
CH2 N NH
25
Navarrete-Vazquez et al. synthesized a set of 4-(5-
substituted-1,3,4-oxadiazol-2-yl)pyridine derivatives and
evaluated its in vitro anti-mycobacterial activity. Some
compounds showed an interesting activity against M.
tuberculosis H37Rv and five clinical isolates (drug-sensi-
tive and -resistant strains). 4-(5-pentadecyl-1,3,4-oxa-
diazol-2-yl)pyridine (26) was ten times more active than
isoniazid, 20 times more active than streptomycin, and 28
times more potent than ethambutol against drug-resistant
strain CIBIN 112. 4-(5-heptadecyl-1,3,4-oxadiazol-2-
yl)pyridine (27) also showed the same behaviour as
compound 26. They concluded that both of these com-
pounds bear a high-lipophilic chain bonded to the
5-position of the oxadiazole moiety. This fact implies that
there exists a contribution of lipophilicity, which could
facilitate the entrance of these molecules through lipid-
enriched bacterial cell membrane (Navarrete-Vazquez
et al., 2007).
O N
N N N NH
H
O
N N
28
3945
N N NN
O O
N N
26 27
Imramovsky et al. have designed and prepared several
derivatives where either INH or PZA was linked with another
conventional drugs ciprofloxacin (CPF) and p-aminosali-
cylic acid (PAS) using the CH fragment. The lipophilicity, as
the capacity factor logK, was determined by RP-HPLC and
the results were compared by employing two commercially
and ciprofloxacin signifies a more effective transport of these
molecules through cellular membranes. The hydrolysis in a
water–acetonitrile solution of the most active compounds
was investigated. The half-time of the degradation was
determined from the hydrolysis curve. The rate of hydrolysis
of the new products was found to depend on the fragments
involved in the molecule. The anti-tuberculosis activity was
evaluated against M. tuberculosis H37Rv and three non-
tuberculous strains. The compound 28 was the most active
anti-mycobacterial agent against M. tuberculosis H37Rv
with MIC of 0.1 lg/ml. The higher activity seems to be
connected with an increase in the lipophilicity factor. In
addition, the hydrolysis of new compounds ensures a pro-
longed liberation of the active components (INH, CPF, PZA
or PAS) (Imramovsky et al., 2007).
A new series of isonicotinicacid N0 -arylidene-N-[2-oxo-
2-(4-aryl-piperazin-1-yl)-ethyl]-hydrazides as anti-tuber-
culosis agents was designed, synthesized, and evaluated for
anti-tuberculosis activity against M. tuberculosis H37Rv
and clinical isolates by Sinha et al. Some of these com-
pounds showed good potency and their in vitro activity
against sensitive and resistant strains of M. tuberculosis
were found to be equivalent or better than isoniazid.
Compound 29 was one of the most active derivatives
synthesized in this series (Sinha et al., 2005).
Cl
O Cl
N N
O
N
N
Cl
29
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Ali et al. synthesized a series of 2-methoxy-4-[5-
(substituted phenyl)1-(4-pyridylcarbonyl)-4,5-dihydro-1H-
3-pyrazolyl] phenoxy acetic acid by the reaction between
isoniazid and chalcones and tested its anti-mycobacterial
activity, in vitro, against M. tuberculosis H37Rv and INH
resistant M. tuberculosis using BACTEC-460 radiometric
system and agar dilution method. 2-4-[5-(4-hydroxy-
phenyl)-1-(4-pyridylcarbonyl)-4,5-ihydro-1H-3-pyrazolyl]-
2-methoxy- phenoxy acetic acid (30) was found to be most
active agent against M. tuberculosis H37Rv (MTB) and
INH resistant M. tuberculosis (INHR-MTB), with a mini-
mum inhibitory concentration of 0.12 lM, when compared
to INH 5.6-fold more active against MTB and 78-fold more
active against INHR-MTB, respectively (Ali et al., 2007).
OH
O (33). These isonicotinoyl hydrazones of anacardic alde-
N
N
HOOC O M. smegmatis mc2155. The synergistic studies of 32 and
N
OCH3
30
Hearn and Cynamon synthesized acylated derivatives of
isoniazid and tested their anti-mycobacterial activity
OH
COOH
O O
N NH
N
32
against M. tuberculosis. The results of anti-mycobacterial
activity suggested that the minimum inhibitory concentra-
tion (MIC) values were several fold greater than that of
INH. They found that among these derivatives isonicotin-
icacid-N0 -propionyl-hydrazide, 31, closely homologous to
the INH metabolite, N2-acetylisoniazid, provided unex-
pected protection in tuberculosis-infected mice. Further,
they concluded that such close structural congeners of
metabolites of INH may serve as significant leads in anti-
tubercular drug discovery and in the exploration of the
mode of action of INH (Hearn and Cynamon, 2003).
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Med Chem Res (2012) 21:3940–3957
O
O NH NH CH 3
N
31
Isonicotinoyl hydrazones were synthesized from a nat-
ural product, anacardic acid, a major constituent of cashew
nut shell liquid, by Swamy et al. The unsaturated side
chain in anacardic acid and its 5-nitro derivative were
converted into C80 -aldehydes by oxidative cleavage.
C80 -aldehydes were then coupled with isoniazid to obtain
N-isonicotinoyl-N0 -8-[(20 -carbohydroxy-30 -hydroxy)phenyl]
octanal hydrazone (32) and N-isonicotinoyl-N0 -8-[(20 -car-
bohydroxy-30 -hydroxy-6-nitro)phenyl]octanal hydrazone
hydes showed potent anti-mycobacterial activity against
33 with isoniazid showed more inhibitory activities than
isoniazid alone. Compounds 32 and 33 also showed
activity against M. tuberculosis H37Rv. Both the com-
pounds showed complete inhibition at 10 lg/ml concen-
tration and no inhibition at 0.5 lg/ml, there by indicating
that MIC values should fall between these two values
(Swamy et al., 2007).
OH
COOH
N NH
NO2
N
33
Jaju et al. synthesized a novel series of 14 new isoni-
cotinyl hydrazide derivatives containing a 4-thiazolidi-
none/2-azetidinone nucleus by reacting N0 -substituted
arylidene/heteroarylidene isonicotinyl hydrazide with
thioglycollic acid in the presence of dry benzene and with
chloroacetyl chloride in the presence of triethylamine,
respectively. All the compounds were tested for their in
vitro anti-mycobacterial activity against M. tuberculosis
H37Rv using Alamar blue susceptibility test and com-
pounds 34 and 35 were found to be highly effective with
MIC value of 0.31 lg/ml (Jaju et al., 2009).
Med Chem Res (2012) 21:3940–3957 3947

OCH 3 OCH3

OH OH
H O
O S NH N
N N
Cl
N
N O
O

34 35

A fullerene–isoniazid conjugate (36) was synthesized by
1,3-dipolar cycloaddition reaction of fullerene (C60) with
isonicotinicacid (4-formyl-benzylidene) hydrazide and
N-methylglycine. Stable water suspension, in which the
particles of the synthesized conjugate were made to
aggregate in nanosize, was successfully tested for anti-
mycobacterial activity against M. avium and strains of
M. tuberculosis—H37Rv and H6/99 at concentration as low
as 0.50 lg/ml. The fullerene–INH conjugate was designed
and tested to probe the influence of lipophilicity on anti-
mycobacterial activity, based on the hypothesis that an
increase of lipophilicity could improve inhibitory activity
towards mycobacteria. The conjugate thus synthesized had
a high log P value or lipophilicity as compared with INH
and previously reported ionic fullerene derivatives. The
results of anti-mycobacterial screening indicated that a
linear relationship exists between the log P value and MIC
value of synthesized conjugates (Kumar et al., 2009).
O with an expected dual anti-mycobacterial mechanism. The
CH3
N N N
H tallography. The minimal inhibitory concentration (MIC)
N determination of this compound proved to be promising
TB-infected macrophage model. The most promising com-
pound, 5-(3-chlorobenzylidene)-2-(isonicotinoylhydrazino)-
imidazoline-4-one (37), with activity in vitro comparable
with rifampin (MIC = 0.8 lg/ml, SI [ 78) was tested in
vivo in the animal tuberculosis model but exhibited insig-
nificant activity (Szymanska and Kiec-Kononowicz, 2002).
O
HC
NH
N O
Cl
HN N N
H
37
Rando et al. obtained a duplicated nitrothienyl deriva-
tive as a by-product from the synthesis of a proposed
molecular hybrid of a nitrothienyl derivative and isoniazid
structure was shown to be the 5,50 -dinitro-2-(2,3-diaza-4-
(20 -thienyl)buta-1,3-dienyl)thiophene (38) by X-ray crys-
against M. pathogenic strains such as M. avium and M.
kansasei, although it had a high level of mutagenicity, as
observed in mutagenic activity tests. The higher activity of
compound 38 against M. avium and M. maomoense in
comparison to isoniazid is very promising, considering the
high pathogenicity of these strains (Rando et al., 2006).

36
Szymanska and Kiec-Kononowicz synthesized 5-(chlo-
robenzylidene)-2-isoniazido and 5-(chlorobenzylidene)-2-
amino substituted derivatives of imidazoline-4-one and
evaluated their anti-mycobacterial activity against M.
tuberculosis H37Rv. Eight of them exhibited [90% inhi-
bition in the primary screening at 12.5 lg/ml. For these
primarily selected compounds the actual MIC and IC50
values were determined. Two of the isoniazid derivatives,
for which MIC B3.13 lg/ml and SI [ 10, were selected for
further screening and investigated for efficacy in vitro in a
S N NO2
O 2N N S
38
Mohamad et al. measured the susceptibility of M.
tuberculosis to isoniazid compared with its derivative,
1-isonicotinyl-2-nonanoyl hydrazine (INH-C9, 39), pre-
pared synthetically. Compound 39 was found to lower the
MIC of INH from 0.05 to 0.025 lg/ml. Further studies on
the effects of INH and INH-C9 (39) on M. tuberculosis

123
3948
were assessed by exposing the cells to the above at the MIC
level. M. tuberculosis cells grown on Middlebrook 7H10
agar were harvested at different stages of their growth
cycle, exposed to the MICs of INH and INHC9, and stained
with acid-fast staining. The observations were made for a
week. The cellular morphologies and staining characteris-
tics were examined using a bright field microscope. The
results indicated that the cells only at the initial stage of
growth were most susceptible to the drugs resulting in the
loss of acid-fastness and intact cellular morphology in the
majority of cells (Mohamad et al., 2004).
O
HN N CH3
O H
N Maccari et al. evaluated the in vitro anti-mycobacterial
39
Carvalho et al. reported the synthesis and anti-myco-
bacterial evaluation of new trans-cinnamic acid derivatives
of isonicotinicacid and benzoic acid series, designed by
exploring the molecular hybridization approach between
isoniazid and trans-cinnamic acid derivative. The mini-
mum inhibitory concentration (MIC) of the compounds
exhibited activity between 3.12 and 12.5 lg/ml and could
be a good starting point to find new lead compounds
against multidrug resistant tuberculosis. Compound 40 was
the most active one among the synthesized series (Carvalho
et al., 2008).
O among the synthesized compounds with MIC value
H N
N \0.05 lg/ml (Maccari et al., 2002).
N
O 2N H CH3
O
40
Rastogi and Goh investigated the resistance of organ-
isms belonging to the M. avium complex to isoniazid
caused by the bacterial cell envelope, with the cell wall and
the outer layer acting as an exclusion barrier. They
observed that this exclusion barrier was most efficient in
excluding the hydrophilic drug INH, as this drug could not
penetrate a wall matrix formed of various polymethylated
lipidic or amphipathic substances. Two main strategies
were proposed for circumventing this drug resistance:
(i) synthesis of amphipathic derivatives of otherwise highly
hydrophilic drugs and (ii) inhibition of synthesis of the
123
Med Chem Res (2012) 21:3940–3957
bacterial outer layer. They concluded that attaching a pal-
mitic acid side chain to INH, 41, rendered it growth
inhibitory against M. avium complex bacteria and that the
concomitant use of this amphipathic INH derivative with
m-fluorophenylalanine, 42, (an inhibitor of mycoside C
biosynthesis which causes the disruption of the bacterial
outer layer) resulted in further enhancement of its activity,
leading to a bactericidal effect (Rastogi and Goh, 1990).
H HO
N N O O
O
H
F NH2
N CH3 42
41
activities of isonicotinohydrazides and their cyanoborane
adducts. Most of the tested compounds displayed moderate
to high activity against M. tuberculosis H37Rv, with MICs
ranging from 0.2 to 12.5 lg/ml. In particular, some
hydrazides showed activity similar to that of rifampin
(MIC = 0.2 lg/ml) and rather low cytotoxicity. The
coordination to a cyanoborane (BH2CN) group brought
about a decrease in anti-mycobacterial activity, while
cytotoxicity increased. The synthesized compounds were
effective in killing M. tuberculosis growing within mac-
rophages at concentrations in culture medium which were
much lower than the corresponding MICs. These com-
pounds also displayed good activity against drug-resistant
M. tuberculosis strains. Isonicotinicacid-[1-(3-fluoro-phe-
nyl)-ethylidene]-hydrazide (43) was the most effective one
O HN N C
F
N
43
A new series of quinoxaline-1,4-di-N-oxide derivatives
containing isoniazid was synthesized and evaluated for in
vitro anti-tuberculosis activity against M. tuberculosis
H37Rv by Torres et al. Compound 44 was found to be
the most promising one with SI [ 93.02 (Torres et al.,
2011).
Med Chem Res (2012) 21:3940–3957 3949

Isoniazid derivatives as anti-microbial agents

O- H N
+
N N Biologically active Mannich bases with heteroaromatic
N ring system were synthesized employing Mannich reaction
O of isonicotinyl hydrazide with various sulphonamides/sec-
N+
- ondary amines by Joshi et al. The Mannich bases were
O screened for their anti-bacterial activity against various
44 Gram-positive and -negative bacteria. The results have
shown that the compounds were quiet active against
Sankar and Pandiarajan (2010) synthesized a series of 2r, pathogens under study and were nontoxic. The newly
4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one N-isonicotinoylhy- synthesized Mannich bases were better and more potent
drazone derivatives and evaluated their anti-tuberculosis, anti-bacterial agents than sulphonamides themselves.
-bacterial and -fungal activities. The anti-tubercular activity Amongst the synthesized derivatives, compound 47 was
was performed by luciferase reporter phage assay method the most active one (Joshi et al., 2004).
against M. tuberculosis H37Rv and INH-resistant M. tuber-
culosis (INHTB) at two different concentrations level of 1.00
and 2.00 lg/ml. All the compounds showed good anti-tuber-
cular activity against M. tuberculosis H37Rv and INHTB. The
anti-microbial activity was tested against Gram-positive NH NH O O
Staphylococcus aureus, Bacillus subtilis and Gram-negative O NH S NH
Escherichia coli, Klebsiella pneumonia, Pseudomonas aeru- CH3
ginosa, and fungal strains viz., C. albicans, Aspergillus niger O
and Aspergillus flavus. The substituents in the aromatic ring do
not have significant effect on the anti-tubercular activity. N
Compound 45 was found to be the most active one. 47

O
HN N Cobalt(II), nickel(II), copper(II) and zinc(II) complexes
N
of 2-thiophenecarbonyl and isonicotinoyl hydrazones of
3-(N-methyl)isatin (HL1 and HL2, respectively) were
synthesized and their in vitro anti-microbial activity was
Cl Cl tested against several bacteria and fungi. HL1 and its
N
H complexes exhibited a strong growth inhibition of
45 Haemophilus influenzae (MIC = 0.15–1.50 lg/ml) and
good anti-bacterial properties towards Bacillus subtilis
(MIC = 3–25 lg/ml). The anti-bacterial effectiveness was
Vavrikova et al. synthesized a series of isoniazid hydra-
confirmed against a number of Gram-positive bacteria,
zones linked with electron-withdrawing substituents and
including methicillin-resistant Staphylococcus aureus.
evaluated their anti-mycobacterial potential against M.
Yeasts and moulds showed a low susceptibility, except
tuberculosis by using two different methods. In the first iso-
the dermatophyte mould, Epidermophyton floccosum
niazid was activated with diethoxymethyl acetate and con-
which was inhibited at concentrations ranging from 6 to
densed with the appropriate anilines. In the second method,
50 lg/ml. In general, the anti-microbial activity of the
substituted anilines were activated by diethoxymethyl acetate
thiophene derivatives was greater than that of the isoni-
and subsequently condensed with isoniazid. Compound 46
cotinic analogues. Amongst the synthesized complexes,
was the most potent one (Vavrikova et al., 2011).
complex 48 and 49 were found to be the most effective
Br ones. The different lipophilic behaviour of the two hetero-
N
aromatic rings, thiophene and pyridine, is involved in the
F
biological activity mechanisms. In fact, log P values of
thiophene (1.82) and pyridine (0.62) gave a clear indi-
O cation that the thiophene residue is endowed with an
N N NH
increased lipophilicity and, so, with a higher capability to
H penetrate the microorganisms (Rodriguez-Arguelles et al.,
46 2007).

123
3950 Med Chem Res (2012) 21:3940–3957

CH3 H
Bayrak et al. synthesized a series of 1,2,4-triazoles
N N derived from isonicotinicacid hydrazide and evaluated
O
O its anti-microbial potential against various bacteria
O S
NH
N NH N and fungi. The results of anti-microbial activity sug-
N O
Cl Zn Cl Cl Co Cl gested that compound 50 was the most active one
O
NH
N NH N amongst the synthesized compounds (Bayrak et al.,
N
S 2009b).
O O
O
N N
CH H
3

48 49

Bayrak et al. synthesized some newer 1,2,4-triazoles,

their Mannich and Schiff bases and evaluated their
anti-microbial activities against various Gram-positive,
-negative bacteria and fungal species. The results of anti- N N
microbial activity studies demonstrated that all the com- SH
N
pounds screened showed good and moderate anti-microbial N
activities and the compound which contains a pyridyl ring NH2
in their structures displayed diverse anti-microbial activi- 53
ties due to the position of nitrogen atom in the heterocyclic
ring. Compound 50 was the most active anti-microbial
agent in this study (Bayrak et al., 2009a).

N N
O N
N N S NH N CH
Isoniazid derivatives as anti-mycobacterial, -microbial
and -viral agents

Judge et al. synthesized a series of isoniazid derivatives

50
Kini and Gandhi synthesized 1,3,5-trisubstituted pyraz-
olines starting from isoniazid and tested their anti-micro-
bial potential against Staphylococcus aureus, Bacillus
subtilis, Escherichia coli, Pseudomonas aeruginosa and
Aspergillus niger and found out that compounds 51 and 52
were the most effective anti-bacterial and -fungal agents,
respectively (Kini and Gandhi, 2008).
and tested its in vitro anti-mycobacterial activity against
M. tuberculosis, anti-viral activity against a broad variety
of RNA and DNA viruses and anti-microbial potential
against Staphylococcus aureus, Bacillus subtilis, Esche-
richia coli, Candida albicans and Aspergillus niger.
Compounds 54, 55 and 56 were the most active anti-
mycobacterial, -microbial and -viral agents, respectively
(Judge et al., 2011a).

Cl Cl

O O
N N
N N
N N
F H3CO

51 52

123
Med Chem Res (2012) 21:3940–3957 3951

O
O OCH3
NH N CH OH
N N C
OC2H5 O H
H3CO
N
54
N
55

HN N C
O H
N
H
N
56

Judge et al. evaluated a series of isonicotinicacid-1-
(substituted phenyl)-ethylidene/cycloheptylidene hydrazide
derivatives for its in vitro anti-mycobacterial activity
against M. tuberculosis, anti-viral activity and -microbial
activity and reported that compounds 57, 58 and 59 were
the most potent anti-mycobacterial, -microbial and -viral
agents, respectively (Judge et al., 2011b).
hydrazide (60) and 2,3,5-triiodo-benzoic acid-N0 -(pyri-
dine-4-carbonyl)-hydrazide (61) were the most active
anti-mycobacterial and -microbial agents. None of the
synthesized compounds was found to be active anti-viral
agent (Judge et al., 2011c).

Br HO
HN N C Br
O CH3 HN N C HN N C
O CH3 O CH3

N
57 N N
58 59

O O O
CH3
NH NH HN N I
O H
I
I
N
60 N
61

A series of isonicotinicacid hydrazide derivatives was Isoniazid derivatives in Alzheimer’s disease

synthesized and tested for in vitro anti-mycobacterial,
-viral and -microbial activity by Judge et al. and the
compounds with bromo, N2-2,4-hexadienoyl, N2-lauryl
and N2-octadecanoyl groups were found to be the most
effective ones. The isonicotinicacid-N0 -octadecanoyl
Alzheimer’s disease (AD) represents a major unmet med-
ical need. Despite substantial effort, there exists no disease
modifying treatment for AD. It has been proposed that the
biological pathway leading to the observed disease

123
3952
pathology is reliant on the processing of amyloid precursor
protein (APP). Proteolysis of APP by the secretase enzymes
(a, b and c) generates peptide fragments, with the most rel-
evant to AD being Ab40 and Ab42. These fragments are
derived from the action of both c- and b-secretase and are the
primary components of the insoluble amyloid plaques in AD
patients. Disruption of this cascade via c- and more recently
b-secretase inhibition has and continues to be a central focus
of drug discovery efforts. b-Secretase inhibition offers
an exciting opportunity for therapeutic intervention in the
N N
Cl
O S
N N
Cl
63
progression of Alzheimer’s disease. A series of isonicoti-
namides derived from traditional aspartyl protease transition
state isostere inhibitors were optimized to yield low-nano-
molar inhibitors with sufficient penetration across the blood–
brain barrier to demonstrate b-amyloid lowering in a murine
model. The challenges surrounding b-secretase inhibitor
design are substantial and are highlighted by the difficulty in
uncovering small molecules that maintain potency while
demonstrating desirable penetration across the blood–brain
barrier. Starting from compounds containing a known
aspartyl protease transition state isostere, isonicotinamide-
based inhibitors were discovered that allowed for truncation
of the HEA isostere to a simple amine. Optimization for
potency and brain penetration led to 62, a low-nanomolar
BACE-1 inhibitor that was effective in reducing Ab levels in
a murine model in a dose-dependent manner (Stanton et al.,
2007).
O S O
H3C
N CH3
H3C
N NH2
NH
N F
H O
62
Isoniazid derivatives as anti-inflammatory
and analgesic agents
A series of triazolo-thiadiazole and 1,3,4-oxadiazole
derivatives of isoniazid was synthesized by Gilani et al.
123
Med Chem Res (2012) 21:3940–3957
6-(4-nitrophenyl)-3-(pyridin-4-yl)-[1,2,4]triazolo[3,4-b]
[1,3,4] thiadiazole (63) and 2-(2,4-dichlorophenyl-5-(pyri-
din-4-yl)-1,3,4-oxadiazole (64) had shown maximum anti-
inflammatory and analgesic activity. They concluded that
triazolo-thiadiazole and 1,3,4-oxadiazole derivatives of
isoniazid may afford a safer alternative to isoniazid for the
treatment of inflammatory disease, pain and hepatotoxicity
caused by acetyl hydrazine, a metabolite of isoniazid
(Gilani et al., 2010).
N N
N
N NO2
64
In silico studies of isonicotinicacid hydrazides
Andrade et al. performed classical 2D quantitative structure–
activity relationships (QSAR) and hologram QSAR
(HQSAR) studies on a training set of 91 isoniazid deriva-
tives. Significant statistical models (classical QSAR,
q2 = 0.68 and r2 = 0.72; HQSAR, q2 = 0.63 and
r2 = 0.86) were obtained, indicating their consistency for
untested compounds. The models were then used to evaluate
an external test set containing 24 compounds which were not
included in the training set, and the predicted values were in
good agreement with the experimental results (HQSAR,
2 2
rpred = 0.87; classical QSAR, rpred = 0.75). The classical
and hologram QSAR models described by them exhibited
both good internal and external consistency, with substantial
predictive power (Andrade et al., 2008).
Wahab et al. performed molecular docking and molec-
ular dynamics simulation (MD) to study the binding of
isoniazid onto the active site of M. tuberculosis enoyl-acyl
carrier protein reductase (InhA) in an attempt to address the
mycobacterial resistance against isoniazid. They found that
isonicotinic acyl-NADH (INADH) has an extremely high-
binding affinity towards the wild-type InhA by forming
stronger interactions compared to the parent-drug (isonia-
zid) (INH). Owing to the increase of hydrophobicity and
reduction in the side chain’s volume of A94 of mutant type
InhA, both INADH and the mutated protein become more
mobile. Owing to this reason, the molecular interactions of
INADH with mutant type are weaker than that observed
with the wild type. However, the reduced interaction
caused by the fluctuation of INADH and the mutant protein
only inflected minor resistance in the mutant strain as
inferred from free energy calculation. MD results also
showed there exists a water-mediated hydrogen bond
Med Chem Res (2012) 21:3940–3957
between INADH and InhA. As the bridged water molecule
is only present in the INADH-wild-type complex, reflect-
ing the putative role of the water molecule in the binding of
INADH to the wild-type protein. The results support the
assumption that the conversion of prodrug isoniazid into its
active form INADH is mediated by KatG as a necessary
step prior to target binding on InhA (Wahab et al., 2009).
H NADH
O N NH2 H2N
O
KatG
+ N+
N
INH
H2N
O O
Inhibit InhA
N N
N
Ventura and Martins used a QSAR/QSPR methodology
to analyze a set of 173 hydrazides, a great part of which
were isoniazid (INH) derivatives. Nineteen molecular
descriptors of various types (physicochemical, steric, geo-
metrical and electronic) were systematically tested through
a careful application of MLR. Their analysis revealed that
the biological activity of these compounds against M.
tuberculosis does not depend on lipophilicity, as measured
by log P. They also identified the properties that account
for the biological response of isoniazid and related com-
pounds, consistent with a mechanism involving the for-
mation of radical species and also studied the role of
substituents in the stabilization of the intermediate species
that gives rise to the active agent, the acyl radical. They
postulated that the activation of INH derivatives’ prodrugs
(hydrazines and hydrazones) occurs near the surface of
M. tuberculosis (Ventura and Martins, 2008).
The Multiple Computer Automated Structure Evaluation
(MultiCASE) program was used to study the relationship
between the structure and the anti-tuberculosis activity of
some derivatives of INH by Klopman et al. The Multi-
CASE output confirmed that the whole molecule of INH is
3953
important, not only the hydrazide moiety. However, the
hydrazide group is seen to play the primary role in the
INH-receptor interaction. The formation of INH as a
metabolite from several hydrazones by rapid hydrolysis is
suggested by the MultiCASE analysis, which generated the
–CO–NH–N= fragment as the main pharmacophore. This
group is modulated by a distance descriptor between the
O O
O P O P O
CH2 O O CH2
O O
N N
OH OH OHHO
N NH2
O O
O P O P O
CH2 O O CH2
O O
N
OH OH OHHO
N NH2
INADH N
pyridinic and the hydrazidic nitrogens suggesting that
Schiff base chemistry similar to that encountered for
Vitamin B6, may take place. Alkyl and acyl substitution
on the hydrazide function also bring about increased
anti-tuberculous activity and the program identified the
pharmacophore CO–NH–NH–CH– as responsible for that
effect. Reactivity is more important than binding and
MultiCASE found the elements characteristics of INH
reactivity, i.e. the hydrazide group with its nucleophilic
nitrogen and the distance between the pyridinic and the
hydrazidic nitrogens that is associated with the Schiff
base chemistry of the Vitamin B6 (Klopman et al.,
1996).
The QSAR studies, for the prediction of anti-mycobac-
terial activity of 4-(5-substituted-1,3,4-oxadiazol-2-yl)pyr-
idines, carried out by Judge et al. revealed that topological
molecular descriptors best described the anti-mycobacterial
of 4-(5-substituted-1,3,4-oxadiazol-2-yl)pyridines. The mt-
QSAR models depicted that valence first order molecular
connectivity index (1vv) governed the overall anti-myco-
bacterial activity of 4-(5-substituted-1,3,4-oxadiazol-2-
yl)pyridines (Judge et al., 2011d).
123
3954 Med Chem Res (2012) 21:3940–3957

Mechanism of action of isoniazid and its deactivation
Isoniazid is a prodrug that targets mycolic acid biosyn-
thesis and is activated inside the mycobacterial cell. Iso-
niazid is activated either to the isonicotinic acyl anion
(Shoeb et al., 1985) or radical (Johnson and Schultz, 1994)
by KatG, a catalase-peroxidase enzyme (Zhang et al.,
1992). When activated by the catalase-peroxidase katG,
INH attaches itself to NADH to form a covalent adduct
INH-NAD. This is the actual drug that binds the inhA
enzyme and inhibits its function (Khasnobis et al., 2002).
Isoniazid (INH) is the most frequently prescribed primary
prophylactic and chemotherapeutic drug against M. tuber-
culosis. Enzymatic acylation of the isoniazid (INH) by
N-arylaminoacetyl transferases (NATs) reduces the thera-
peutic effectiveness of the drug. Because it represents a
major metabolic pathway for INH in human beings, such
suitable INH-susceptible host, M. smegmatis, the resultant
organism becomes more resistant to INH. Resistance to
INH in mycobacteria can thus be related to increased
expression of NAT (Hearn and Cynamon, 2003).
The correlations found for isoniazid derivatives and
related compounds are consistent with a mechanism of
action involving an electrophilic intermediate species
(hydrazil radical or ion). The ability of the substituents to
stabilize this intermediate should influence the rate of
formation of the subsequent species, the acyl radical, which
coupled to NADH or NAD? originates an adduct respon-
sible for the inhibition of InhA, thus restraining myco-
bacterial cell wall synthesis (Ventura and Martins, 2008).
These findings can be represented as:
(a) Activation of isoniazid-related hydrazines.

KatG

H
H
O N R
O N R O
N
N .
H
.
N
+ HN
R
N
N N
Hydrazil radical isonicotinic acyl radical

acetylation has serious consequences for tuberculosis (b) Activation of isoniazid-related hydrazones
treatment regimens. Among patients in whom this process
is efficient, the ‘‘rapid acetylators,’’ the resultant chronic

H H H
C C C
N R' HN R' HN R' NH2 H
N
NH NH NH NH NH2 O
O O O O O

O
H + H2N NH2
+ HC
R' KatG N N
N N N N

underdosing of INH may give rise to the development of
resistance, as well as inadequate therapy. NATs occur in
mycobacteria and in their mammalian hosts. It is thought
that the resultant chemical change prevents the activation
of INH that is required for proper drug action. A recom-
binant NAT from M. tuberculosis acetylates INH in vitro.
When the corresponding nat gene is over expressed in a
Strategies for the synthesis of isoniazid derivatives
The aforementioned literature revealed a variety of syn-
thetic procedures that can be employed for the synthesis of
isoniazid derivatives. As isoniazid molecule is highly
versatile molecule that can be easily incorporated into
various synthetic strategies to obtain an enormous number

123
Med Chem Res (2012) 21:3940–3957 3955

Fig. 1 Strategies employed for R"

the synthesis of isoniazid O N N C R
derivatives O N N CH3 H
H R1
N C
R2
N
Sinha et al., 2005
N N N R5
O R3
H3C R4
R' O Maccari et al., 2002
R5 R"X
R1
R"
Shaharyar et al., 2006 R4
R2 O N N C R

Ch
R3 H H

a lc
N N

on
R'

es
O
N H O
N
R'C RC Maccari et al., 2005
Navarrete-Vazquez et al., 2007 OC O N NH2
PO l H
Cl O N N
R1
3 H HC
H O R2
H O
N NH H CH R5 R1
O R' H R" N N R5
H2C R'N R4 R2
R3
N R3 R4
"R O C Cl Lourenco et al., 2008
RCOCl R5
N

Chlo
R1

cid
R4

ic a

roac
Joshi et al., 2004 R2

co ll

etyl
R3

ogly

chlo
rid
Thi

e
O N N R Ar'
O N NH O Ar'
H H R1 H
O H S
O N N O NHN Cl
R2
O O
N N R5
R3 N N
R4
Jaju et al., 2009.
Hearn and Cynamon, 2003 Carvalho et al., 2008

of derivatives that are active anti-mycobacterial agents References

themselves, so it can be truly stated that isoniazid is a
magic molecule. The large number of synthetic procedures
that can be employed for the synthesis of isoniazid deriv-
atives is in Fig. 1.
Conclusion
The magic molecule isoniazid and its derivatives were
reported to have various biological potentials such anti-
microbial, -viral and -alzheimer apart from their well
known anti-mycobacterial potential. Further, it has been
found that isoniazid derivatives can be synthesized in a
number of ways. Summarizingly, the isoniazid is really a
magic molecule which has the potential to be explored
further for the development of new chemical entities
(NCEs) to treat the mycobacterial infections.
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