Synthesis and antimycobacterial activity of a novel series of isonicotinylhydrazide derivatives

Article abstract of DOI:10.1002/ardp.200900001

A novel series of 14 new isonicotinyl hydrazide derivatives 2a-g, 3a-g containing a 4-thiazolidinone / 2-azetidinone nucleus were synthesized by reacting N9-substituted arylidene / heteroarylidene isonicotinyl hydrazide 1a-g with thioglycollic acid in the presence of dry benzene and with chloroacetyl chloride in the presence of triethylamine, respectively. Structures of all newly synthesized compounds were characterized on the basis of elemental analyses and spectral data (IR and 1H-NMR). All the title compounds were tested for their in-vitro antimycobacterial activity against Mycobacterium tuberculosis H ₃₇Rv using Alamar-Blue susceptibility test, and the activity is expressed as the minimum inhibitory concentration (MIC) in μg/mL. Among the series, compounds 2b, 2g, 3b, and 3g displayed an encouraging antimycobacterial activity profile as compared to that of the reference drugs isoniazid / rifampicin.

Full text of DOI:10.1002/ardp.200900001

Arch. Pharm. Chem. Life Sci. 2009, 342, 723–731
S. Jaju et al.
723
Full Paper
Synthesis and Antimycobacterial Activity of a Novel Series of
Isonicotinylhydrazide Derivatives
Sandip Jaju1, Mahesh Palkar1, Veeresh Maddi1, Pradeepkumar Ronad1, Shivalingarao
Mamledesai1, Darbhamulla Satyanarayana2, and Mangala Ghatole3
1 Department of Pharmaceutical Chemistry, KLES' College of Pharmacy, Vidyanagar, Hubli, Karnataka, India
2 Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences, Paneer, Deralakatte,
Mangalore, Karnatka, India
3 Department of Microbiology, Dr. V. M. Medical College, Solhapur, Maharastra, India
A novel series of 14 new isonicotinyl hydrazide derivatives 2a–g, 3a–g containing a 4-thiazolid-
inone / 2-azetidinone nucleus were synthesized by reacting N9-substituted arylidene / heteroaryl-
idene isonicotinyl hydrazide 1a–g with thioglycollic acid in the presence of dry benzene and
with chloroacetyl chloride in the presence of triethylamine, respectively. Structures of all newly
synthesized compounds were characterized on the basis of elemental analyses and spectral data
(IR and 1H-NMR). All the title compounds were tested for their in-vitro antimycobacterial activity
against Mycobacterium tuberculosis H37Rv using Alamar-Blue susceptibility test, and the activity is
expressed as the minimum inhibitory concentration (MIC) in lg/mL. Among the series, com-
pounds 2b, 2g, 3b, and 3g displayed an encouraging antimycobacterial activity profile as com-
pared to that of the reference drugs isoniazid / rifampicin.
Keywords: Antimycobacterial activity / Azetidinones / Isonicotinyl hydrazide / Mycobacterium tuberculosis / Thiazolidin-
ones /
Received: January 1, 2009; accepted: April 3, 2009
DOI 10.1002/ardp.200900001
eted; the increase was so dramatic that the World Health
Organization (WHO) declared TB a global health emer-
gency in 1993, the first time, an infectious disease
achieved that dubious distinction [3–5] The risk becomes
even greater if the person is co-infected with the human
immunodeficiency virus (HIV). In addition, life threaten-
ing strains of Multidrug-resistant Tuberculosis (MDR-TB)
are appearing, some of which can lead to high mortality
rates with death occurring in a short period.
The introduction of the first-line drugs like streptomy-
cin, para-aminosalicylic acid, isoniazid, etc., for treat-
ment some 50 years ago led to optimism that the disease
could be controlled if not eradicated [6]. These drugs,
coupled with generally increasing standards of health
care, caused a rapid decrease of tuberculosis in many
industrialized countries, which produced a climate of
indifference to the need for fresh drugs. As a result of this
apathy and the perception by the pharmaceutical indus-
try that such agents would be unlikely to generate a suit-
able return on investment, few new drugs have been
Introduction
Tuberculosis (TB) is a chronic necrotizing bacterial infec-
tion with a wide variety of manifestations caused by
Mycobacterium tuberculosis, which has been a scourge of
humanity for thousands of years and remains to be one
of the prevalent health tribulations in the world [1]. TB is
an ancient enemy and present threat that ranks among
the foremost killers of the 21st century. About one third
of the world's population is infected with M. tuberculosis
resulting in eight million new cases of tuberculosis and
around 2.9 million deaths annually [2]. In developing
countries, where rates of both infection and active dis-
ease have always been high, the number of cases skyrock-
Correspondence: Dr. Veeresh S. Maddi, M. Pharm., Ph.D., Department
of Pharmaceutical Chemistry, KLE'S College of Pharmacy, Vidyanagar,
Hubli-580031, Karnataka, India.
E-mail: veeresh_m@rediffmail.com
Fax: + 91 836 237-1694
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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S. Jaju et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 723–731
introduced in the last 30 years [7]. However, since the activities such as antifungal, antitubercular, antitumor,
1980's, the disease has been undergoing a resurgence cholesterol absorption inhibition, etc. have been
driven by a variety of changes in social, medical, and eco- reported in compounds containing an 2-azetidinone ring
nomic factors. Thus, a dramatic increase in the immuno- [22]. The b-lactams also serve as synthons for many biolog-
suppressed individuals mainly due to AIDS, coupled ically important classes of organic compounds [23, 24]. In
increasing urbanization and poverty in developing coun- view of these observations and in continuation of our
tries, has compromised primary health care structures research program on the synthesis of heterocyclic com-
and led to large increases in TB incidence [8]. Concomi- pounds [25–28], we report herein the synthesis of some
tant with the resurgence of TB has been the occurrence of new INH derivatives possessing 4-thiazolidinone and 2-
the multidrug-resistant disease that has exposed the frail- azetidinone moieties, which have been synthesized, see
ties of the current drug armamentarium [9].
Scheme 1, and evaluated for their in-vitro antimycobacte-
There is now recognition that innovative drugs to com- rial activity against M. tuberculosis.
bat TB are urgently required. With the completion of the
genome of M. tuberculosis comes the promise of a new gen-
eration of potent drugs to combat the emerging epi-
demic of TB. The emphasis of mycobacterial research
Results and discussion
now has shifted from gene hunting to interpretation of Chemistry
the biology of the whole organism in an effort to better 4-Thiazolidinones are derivatives of thiazolidine with a
define which activities are likely to be critical for survival carbonyl group at the 4-position. Several protocols for
and, thus, amenable to the development of new drugs the synthesis of 4-thiazolidinones are available in the lit-
[10]. Therefore, there is an urgent need for anti-TB drugs erature [29–31]. Essentially they are three-component
with improved properties such as enhanced activity reactions involving an amine, a carbonyl compound,
against MDR strains, reduced toxicity, shortened dura- and a mercapto-acid. The process can be either a one-pot
tion of therapy, rapid mycobactericidal mechanism of three-component condensation or a two-step process
action, and the ability to penetrate host cells and exert [32, 33]. Likewise, the most common method for the syn-
antimycobacterial effects in the intracellular environ- thesis of 2-azetidinones is the Staudinger-keteneimine
ment.
cyclo-addition, which involves the reaction of imines
Isonicotinic acid hydrazide (INH) has very high in-vivo with acid chloride in the presence of a tertiary base [34].
inhibitory activity towards M. tuberculosis H37Rv. Ipronia- The synthesis of N-(4-oxo-2-(substituted)aryl/heteroaryl-
zide, like INH, is used in the treatment of tuberculosis. In thiazolidin-3-yl)isonicotinamide 2a–g and N-(3-chloro-2-
the search of new antimycobacterial agents, INH deriv- oxo-4-(substituted)aryl/heteroarylazetidin-1-yl)isonicotin-
atives have been found to possess potential tuberculo- amide 3a–g was achieved through the versatile and effi-
static activities [11–13]. Studies suggest that INH, a pro- cient synthetic route outlined in Scheme 1. It is appa-
drug which is converted into its active form by mycobac- rent from the scheme that the new heterocyclic com-
terial catalase-eperoxidase, acts on the mycobacterial cell pounds contain 2-azetidinone and 4-thiazolidinone moi-
wall by preventing the FAS-II (fatty acid synthetase II) sys- eties. Reaction of N9-substituted arylidene / heteroaryli-
tem from producing long-chain fatty-acid precursors for dene isonicotinyl hydrazide (Schiff base) with thioglycol-
mycolic acid synthesis [14, 15].
lic acid and chloroacetyl chloride seemed to be a con-
4-Thiazolidinone is an imperative scaffold that is not venient route to fulfill this aim. Starting materials N9-
only synthetically important but also possesses a wide substituted arylidene / heteroarylidene isonicotinyl
range of promising biological activities. 4-Thiazolidinone hydrazide 1a–g were synthesized by condensation of
derivatives are known to possess antibacterial [16], anti- INH with appropriately substituted aromatic / hetero-
fungal [17], antiviral [18], and antituberculosis [19] prop- aromatic aldehydes in the presence of ethanol and gla-
erties. 4-Thiazolidinones have been reported as novel cial acetic acid. The various N-(4-oxo-2-(substituted)aryl/
inhibitors of the bacterial enzyme Mur B which is a pre- heteroarylthiazolidin-3-yl)isonicotinamide
derivatives
cursor acting during the biosynthesis of peptidoglycan 2a–g were synthesized by cyclo-condensation of 1a–g
[20]. 2-Azetidinones, commonly known as b-lactams, are with thioglycollic acid in the presence of dry benzene
well-known heterocyclic compounds among the organic while the N-(3-chloro-2-oxo-4-(substituted)aryl/heteroaryl-
and medicinal chemists [21]. The activity of the famous azetidin-1-yl)isonicotinamides 3a–g were synthesized by
antibiotics such as penicillins, cephalosporins, and car- cyclo-addition of 1a–g with chloroacetyl chloride in the
bapenems are attributed to the presence of 2-azetidinone presence of triethylamine. The structure of all newly
ring in them. Recently, some other types of biological synthesized 4-thiazolidinone and 2-azetidinone deriv-
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Arch. Pharm. Chem. Life Sci. 2009, 342, 723–731
A Novel Series of Isonicotinylhydrazide Derivatives
725
Reagents and conditions: (a) H – C – Aryl / Het., ethanol, glacial acetic acid, reflux, 3 h; (b) thioglycollic acid, dry benzene, reflux, 15 h; (c) chlor-
oacetyl chloride, triethylamine, dry dioxan, stirring, 20 h.
Scheme 1. Synthesis of a novel series of isonicotinylhydrazide derivatives 2a–g and 3a–g.
atives of INH were confirmed on the basis of analytical thesized compounds were verified on the basis of their
and spectral data. chemical shifts, multiplicities, and coupling constants.
The synthesis of N9-(substituted)arylidene/heteroaryli- In particular, it must be pointed out that in compounds
dene isonicotinylhydrazide (Schiff base) derivatives 1a–g 1a–g the presence of a singlet between d = 8.85–
involved the reaction between appropriately substituted 8.37 ppm indicate the formation of imine / Schiff base
aromatic / heteroaromatic aldehydes and isoniazid, as (>CH=N-) by a simple condensation process; this singlet
described in the general procedure. Further, we have syn- was not observed in the title compounds. Further, the
thesized a novel series of N-(4-oxo-2-(substituted)aryl/het- appearance of two singlets at around d = 4.3 and 2.9 ppm
eroaryl thiazolidin-3-yl)isonicotinamide 2a–g and N-(3- in compounds 2a–g evidently confirms the formation of
chloro-2-oxo-4-phenylazetidin-1-yl)isonicotinamide 3a–g 4-thiazolidinone. Similarly, compounds 3a–g showed
by reacting the appropriately substituted Schiff bases two doublets around d = 4.9 and 4.6 ppm demonstrating
with thioglycollic acid and chloroacetyl chloride, respec- the formation of 2-azitidinone. The peaks appearing at d
tively, as illustrated in Scheme 1. Structures of the syn- = 2.73–2.82, 3.78–3.88, 5.25–5.42, and 6.83–7.92 ppm
thesized compounds were established on the basis of confirm the presence of -N(CH3)2, -OCH3, -OH, and aro-
physicochemical, elemental analysis, and spectral data matic protons, respectively.
(IR and1H-NMR), which are presented in Tables 1–4.
In general, IR spectra of compounds 2a–g and 3a–g Antimycobacterial activity
showed two absorption bands ranging around 1705–
The Minimum Inhibitory Concentration (MIC) was deter-
1728 and 1672–1698 cm– 1 indicating the presence of mined for compounds 2a–g and 3a–g against the M.
two C=O groups in their structure (one C=O group as tuberculosis strain H37Rv using the micro plate Alamar
-CONH- and the other is in the cyclic ring) and also the Blue assay (MABA) [35] (Table 5). This methodology is non-
NH stretching vibrations appeared between 3226–
toxic, uses a thermally stable reagent and shows good
3273 cm– 1. In the nuclear magnetic resonance spectra correlation with proportional and BACTEC radiometric
(1H-NMR), the signals of the respective protons of the syn- methods [36, 37]. The purpose of the screening program
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Arch. Pharm. Chem. Life Sci. 2009, 342, 723–731
Table 1. Physicochemical data of N-(4-oxo-2-(substituted)aryl/heteroarylthiazolidin-3-yl) isonicotinamide 2a–g.
Compound
Aryl / Het.
Yield (%)
45
Mp (8C)
Rf Valuea)
0.42
Mol. Formula
C15H13N3O2S
Mol. Wt.
299.32
2a
168–170
2b
59
208–210
0.54
C15H13N3O3S
315.36
2c
42
55
272–275
256–260
0.5
C13H11N3O3S
C15H12N4O4S
289.29
344.35
2d
0.62
2e
2f
39
52
120–122
130–133
0.52
0.49
C17H18N4O2S
C16H15N3O3S
342.44
329.37
2g
48
212–214
0.51
C16H15N3O4S
345.40
a)
All synthesized compounds were purified by column chromatography using chloroform / methanol (9.3 : 0.7) as mobile phase
and iodine vapor as visualizing agent.
is to provide a resource whereby new experimental com- matic ring (compounds 2b, 2f, 2g, 3b, 3f and 3g), resulted
pounds can be tested for their capacity to inhibit the in compounds with an enhanced antimycobacterial
growth of virulent M. tuberculosis.
activity (with MIC values ranging from 0.31–5.0 lg/mL).
The synthesized compounds 2a–g and 3a–g were eval- Amongst them, compounds 2g and 3g (MIC = 0.31 lg/mL)
uated for their in-vitro antimycobacterial activity against exhibited a significant activity and also compounds 2b
M. tuberculosis strain H37Rv by using MABA method. The and 3b (MIC = 0.62 lg/mL) showed a respectable activity
result of antimycobacterial activity is presented in when compared with first-line drugs such as INH (MIC =
Table 5. All the synthesized compounds exhibited an 0.2 lg/mL) and rifampicin (RIP, MIC = 1.0 lg/mL). How-
interesting activity profile against the tested mycobacte- ever, when a nitro group was introduced on the aromatic
rial strain. The results reveal that the activity is consider- ring (compounds 2d and 3d) and also when the substi-
ably affected by various substituents on the aromatic tuted aromatic ring was replaced by a heterocyclic group
ring of either 4-thiazolidinone or 2-azetidinone nucleus. (compounds 2c and 3c), a moderate antimycobacterial
It has been observed that compounds 2a and 3a having activity was observed. We have also studied the influence
no substitution on the aromatic ring did not show any of the 4-thiazolidinone nucleus in compounds 2a–g and
considerable activity. It is interesting to note that the the 2-azetidinone nucleus in compounds 3a–g on the
introduction of a hydroxyl or methoxyl group on aro- biological activity. We observed that the replacement in
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Arch. Pharm. Chem. Life Sci. 2009, 342, 723–731
A Novel Series of Isonicotinylhydrazide Derivatives
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Table 2. Analytical data of N-(4-oxo-2-(substituted)aryl/heteroaryl thiazolidin-3-yl)isonicotinamide 2a–g.
Compound Aryl / Het.
IR (KBr, cm– 1
)
1H-NMR (DMSO-d6, d, ppm)
Elemental
Analysisa)
2a
3268.34 (N–H), 1719.84 (C=O of
amide), 1685. 49 (C=O of thiazo-
lidinone), 1604.06 (C=N).
3462.33 (O–H), 3245.82 (N–H),
1728.01 (C=O of amide), 1696.75
(C=O of thiazolidinone), 1599.13
(C=N).
10.22 (s, 1H, NH), 7.25–7.92 (m, 9H,
Ar-H), 4.45 (s, 1H, CH-N), 2.83 (s, 2H,
CH2).
10.41 (s, 1H, NH), 7.18–7.79 (m, 8H,
Ar-H), 5.25 (s, 1H, Ar-OH), 4.39 (s, 1H,
CH-N), 2.92 (s, 2H, CH2).
C15H13N3O2S
C15H13N3O3S
2b
3252.88 (N–H), 1721.46 (C=O of
amide), 1690.18 (C=O of thiazo-
lidinone), 1602.89 (C=N).
3258.64 (N–H), 1717.90 (C=O of
amide), 1686.33 (C=O of thiazo-
lidinone), 1596.14 (C=N).
10.05 (s, 1H, NH), 6.91–7.67 (m, 7H,
Ar-H), 4.34 (s, 1H, CH-N), 2.87 (s, 2H,
CH2)
10.52 (s, 1H, NH), 7.15–7.84 (m, 8H,
Ar-H), 4.32 (s, 1H, CH-N), 2.89 (s, 2H,
CH2)
C13H11N3O3S
C15H12N4O4S
2c
2d
3261.25 (N–H), 1705.13 (C=O of
amide), 1679.21 (C=O of thiazo-
lidinone), 1595.47 (C=N).
10.37 (s, 1H, NH), 7.17–7.79 (m, 8H,
Ar-H), 4.35 (s, 1H, CH-N), 2.90 (s, 2H,
CH2), 2.73 (s, 6H, Ar-N(CH3)2).
C17H18N4O2S:
2e
2f
3273.27 (N–H), 1712.42 (C=O of
amide), 1679.21 (C=O of thiazo-
lidinone), 1601.51 (C=N).
3477.43 (O–H), 3265.41 (N–H),
1708.10 (C=O of amide), 1675.69
(C=O of thiazolidinone), 1600.04
(C=N).
10.25 (s, 1H, NH), 7.16–7.79 (m, 8H,
Ar-H), 4.36 (s, 1H, CH-N), 3.78 (s, 3H,
Ar-OCH3), 2.85 (s, 2H, CH2).
10.09 (s, 1H, NH), 6.85–7.68 (m, 7H,
Ar-H), 5.29 (s, 1H, Ar-OH), 4.27 (s, 1H,
CH-N), 3.85 (s, 3H, Ar-OCH3), 2.87 (s,
2H, CH2).
C16H15N3O3S
C16H15N3O4S
2g
a)
All compounds were within acceptable range in the elemental analyses (l 0.4%).
the core nucleus did not alter the antimycobacterial
activity to a greater extent.
The preliminary in-vitro antimycobacterial screening
results of the title compounds, reported here, evidenced
that some of the compounds from both new series have
emerged as potential antimycobacterial compounds
endowed with moderate to good activity. Further
improvements in the antitubercular activity can possibly
Conclusion
In the present paper, we report the synthesis, spectral be achieved by slight modifications in the ring substitu-
studies, and antimycobacterial activity of some new ser- ents. Yet, extensive additional functioning warrants fur-
ies of 4-thiazolidinone and 2-azitidinone derivatives of ther investigations. Our findings will have impact on
INH. The various 4-thiazolidinone derivatives of INH chemists and pharmacists for further investigations in
were synthesized by cyclo-condensation of N9-substituted this field in search of potent antimycobacterial agents.
arylidene / heteroarylidene isonicotinyl hydrazide with
thioglycollic acid in the presence of dry benzene while The authors express their heartfelt thanks to Dr. B. M. Patil,
the 2-azetidinone derivatives of INH were synthesized by Principal, KLES' College of Pharmacy, Hubli, for providing nec-
cyclo-addition of N9-substituted arylidene / heteroaryli- essary facilities to carry out this research work. We honestly
dene isonicotinyl hydrazide with chloroacetyl chloride express our gratitude to Dr. M. N. A. Rao, General Manager (R
in the presence of triethylamine.
& D), Divi's Laboratory, Hydrabad and Dr. Y. S. Agasimundin,
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Arch. Pharm. Chem. Life Sci. 2009, 342, 723–731
Table 3. Physicochemical data of N-(3-chloro-2-oxo-4-(substituted)aryl/heteroarylazetidin-1-yl) isonicotinamide 3a–g.
Compound
Aryl / Het.
Yield (%)
52
Mp (8C)
Rf Valuea)
0.51
Mol. Formula
C15H12ClN3O2
Mol. Wt.
301.69
3a
140–142
3b
3c
45
39
210–212
198–200
0.58
0.61
C15H12ClN3O3
C13H10ClN3O3
317.72
291.65
3d
3e
3f
48
37
57
312–316
180–182
152–154
0.52
0.47
0.63
C15H11ClN4O4
C17H17ClN4O2
C16H14ClN3O3
346.74
344.83
331.70
3g
44
246–248
0.43
C16H14ClN3O4
347.78
a)
All synthesized compounds were purified by column chromatography using chloroform / methanol (8.2 : 1.8) as mobile phase
and iodine vapor as visualizing agent.
used as such for the reactions. Solvents, except laboratory
reagent grade, were dried and purified according to the litera-
ture when necessary. Reactions were monitored by thin-layer
chromatography (TLC) on pre-coated silica gel plates from E.
Merck and Co. (Darmstadt, Germany). Melting points of the syn-
thesized compounds were determined in a Thermonik melting
point apparatus (Mumbai, India) and are uncorrected. IR spectra
were recorded on a Thermo Nicolet IR200 FT-IR Spectrometer
(Nicolet, Madison, WI, USA) by using KBr pellets. 1H-NMR spectra
were recorded on Bruker AVANCE 300 (Bruker, Rheinstetten/
Karlsruhe, Germany) using CDCl3 / DMSO-d6 as solvent. Chemical
shifts are reported in d ppm units with respect to TMS as internal
standard. The elemental analysis (C, H, N) of the compounds
were performed on Heraus CHN rapid analyzer. Results of ele-
mental analysis were within l 0.4% of the theoretical values.
Purity of the compounds was checked on TLC plates using silica
gel G as stationary phase and iodine vapors as visualizing agent.
Professor, K.L.E.S' College of Pharmacy Hubli, for his encourage-
ment. We are also thankful to Lupin Pharmaceutical Industry,
Aurangabad, for providing the gift sample of INH and Rifam-
picin. We are grateful to the Director, SAIF, Punjab University
and The Chairman, USIC, Karnataka University, for providing
elemental and spectral analysis.
The authors have declared no conflict of interest.
Experimental
Chemistry
All research chemicals were purchased from Sigma–Aldrich (St.
Louis, MO, USA) or Lancaster Co. (Ward Hill, MA, USA) and were
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Arch. Pharm. Chem. Life Sci. 2009, 342, 723–731
A Novel Series of Isonicotinylhydrazide Derivatives
729
Table 4. Analytical data of N-(3-chloro-2-oxo-4-(substituted)aryl/heteroarylazetidin-1-yl)isonicotinamide 3a–g.
Compound Aryl / Het.
IR (KBr, cm– 1
)
1H-NMR (DMSO-d6, d, ppm)
Elemental
Analysisa)
3a
3243.86 (N–H), 1714.89 (C=O of
amide), 1689.54 (C=O of azetidinone), Ar-H), 4.93 (d, 1H, CH-Cl), 4.53 (d, 1H,
1606.40 (C=N).
10.49 (s, 1H, NH), 7.18–7.86 (m, 9H,
C15H12ClN3O2
C15H12ClN3O3
C13H10ClN3O3
C15H11ClN4O4
C17H17ClN4O2
C16H14ClN3O3
C16H14ClN3O4
-N-CH).
3b
3c
3d
3e
3f
3433.26 (O–H), 3242.58 (N–H),
1720.18 (C=O of amide), 1687.56 (C=O Ar-H), 5.31 (s, 1H, Ar-OH), 4.89 (d, 1H,
of azetidinone), 1604.37 (C=N).
3232.23 (N–H), 1716.24 (C=O of
10.02 (s, 1H, NH), 7.13–7.77 (m, 8H,
CH-Cl), 4.58 (d, 1H, -N-CH).
10.30 (s, 1H, NH), 6.95–7.71 (m, 7H,
amide), 1698.10 (C=O of azetidinone), Ar-H), 4.95 (d, 1H, CH-Cl), 4.62 (d, 1H,
1598.02 (C=N).
-N-CH).
3245.86 (N–H), 1709.71 (C=O of
amide), 1681.97 (C=O of azetidinone), Ar-H), 4.88 (d, 1H, CH-Cl), 4.55 (d, 1H,
1597.68 (C=N).
10.22 (s, 1H, NH), 7.17–7.88 (m, 8H,
-N-CH).
3251.62 (N–H), 1713.50 (C=O of
amide), 1692.17 (C=O of azetidinone), Ar-H), 4.84 (d, 1H, CH-Cl), 4.39 (d, 1H,
1595.47 (C=N).
10.10 (s, 1H, NH), 6.83–7.62 (m, 8H,
-N-CH), 2.82 (s, 6H, Ar-N(CH3)2).
3226.34 (N–H), 1706.27 (C=O of
amide), 1672.19 (C=O of azetidinone), Ar-H), 4.89 (d, 1H, CH-Cl), 4.63 (d, 1H,
1599.93 (C=N).
10.36 (s, 1H, NH), 6.94–7.66 (m, 8H,
-N-CH), 3.88 (s, 3H, Ar-OCH3).
3g
3463.54 (O–H), 3274.71 (N–H),
10.20 (s, 1H, NH), 7.19–7.74 (m, 7H,
1710.38 (C=O of amide), 1685.26 (C=O Ar-H), 5.44 (s, 1H, Ar-OH), 4.91 (d, 1H,
of azetidinone), 1604.76 (C=N).
CH-Cl), 4.60 (d, 1H, -N-CH), 3.82 (s, 3H,
Ar-OCH3).
a)
All compounds were within acceptable range in the elemental analyses (l 0.4%).
obtained was recrystallized from appropriate solvent to yield
the title compounds.
General procedure for N9-(substituted)arylidene/
heteroarylidene isonicotinylhydrazide 1a–g
To a constantly stirred solution of INH (2.74 g, 0.02 mol) in
30 mL of ethanol containing few drops of glacial acetic acid
(2 mL) was added an appropriate aromatic / heteroaromatic alde-
hyde (0.02 mol). The reaction mixture was refluxed for 3 h,
cooled to room temperature, and poured into crushed ice. The
resulting mixture was filtered and the solid obtained was
washed with cold water and dried. By this procedure, com-
pounds 1a–g were obtained starting from benzaldehyde, 2-
hydroxybenzaldehyde, furan-2-carboxaldehyde, 4-nitrobenz-
aldehyde, 4-N,N9-dimethylbenzaldehyde, 4-methoxybenzalde-
hyde, 3-methoxy-4-hydroxybenzaldehyde, respectively. The solid
General procedure for N-(4-oxo-2-(substituted)aryl/
heteroarylthiazolidin-3-yl) isonicotinamide 2a–g
To a solution of compounds 1a–g in dry benzene (50 mL), thio-
glycolic acid (0.02 mol) was added dropwise and the reaction
mixture was refluxed on a water bath for 12–15 h. The excess of
solvent was distilled off under reduced pressure. The cooled
residual mass was filtered, washed with dilute sodium bicarbon-
ate solution, and dried. Recrystallization from suitable solvents
afforded the title compounds 2a–g. The physicochemical, spec-
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

730
S. Jaju et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 723–731
Table 5. The in-vitro antimycobacterial activity of compounds
2a–g and 3a–g against M. tuberculosis H37Rv strain.
the lowest drug concentration, which prevented a color change
from blue to pink.
Compound
MICa)
2a
2b
2c
2d
2e
2f
2g
3a
3b
3c
3d
3e
3f
3g
resistant
0.62
1.25
3.12
5.0
1.25
0.31
resistant
0.62
1.25
5.0
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