Novel 2-(2-(4-aryloxybenzylidene) hydrazinyl)benzothiazole derivatives as anti-tubercular agents

Article abstract of DOI:10.1016/j.bmcl.2011.10.064

A series of structurally novel, substituted 2-(2-(4-aryloxybenzylidene) hydrazinyl)benzothiazole derivatives incorporating 2-hydrazinyl benzothiazole and 4-(aryloxy)benzaldehyde were designed and synthesized using molecular hybridization approach. All the synthesized compounds exhibited promising activity (MIC 1.5-29.00 μg/ml) against Mycobacterium tuberculosis H37Rv strains of using REMA. Five of the evaluated compounds exhibit MIC <3.0 μg/ml. Compound (E)-6-chloro-2-(2-(4-(2,4-dichlorophenoxy)benzylidene) hydrazinyl) benzothiazole showed MIC of 1.5 μg/ml. Thus, this compound could act as a potential lead for further development of new anti-tubercular drugs.

Full text of DOI:10.1016/j.bmcl.2011.10.064

Bioorganic & Medicinal Chemistry Letters 22 (2012) 649–652
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel 2-(2-(4-aryloxybenzylidene) hydrazinyl)benzothiazole derivatives
as anti-tubercular agents
⇑
Vikas N. Telvekar , Vinod Kumar Bairwa, Kalpana Satardekar, Anirudh Bellubi
Institute of Chemical Technology, Department of Pharmaceutical Sciences and Technology, Nathalal Parekh Marg, Matunga, Mumbai 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2011
Revised 28 September 2011
Accepted 19 October 2011
Available online 30 October 2011
A series of structurally novel, substituted 2-(2-(4-aryloxybenzylidene) hydrazinyl)benzothiazole deriva-
tives incorporating 2-hydrazinyl benzothiazole and 4-(aryloxy)benzaldehyde were designed and synthe-
sized using molecular hybridization approach. All the synthesized compounds exhibited promising
activity (MIC 1.5–29.00
the evaluated compounds exhibit MIC <3.0
benzylidene)hydrazinyl) benzothiazole showed MIC of 1.5
potential lead for further development of new anti-tubercular drugs.
l
g/ml) against Mycobacterium tuberculosis H37Rv strains of using REMA. Five of
g/ml. Compound (E)-6-chloro-2-(2-(4-(2,4-dichlorophenoxy)
g/ml. Thus, this compound could act as a
l
l
Keywords:
Tuberculosis
2-Hydrazinyl benzothiazole
Molecular hybridization
4-(Aryloxy)benzaldehyde
Ó 2011 Elsevier Ltd. All rights reserved.
Tuberculosis (TB) is a chronic infectious disease caused by myco-
bacteria of the ‘tuberculosis complex’, including primarily Mycobac-
terium tuberculosis, but also Mycobacterium bovis and Mycobacterium
africanum. In the last decade, TB has re-emerged as one of the leading
causes of death worldwide (nearly 3 million deaths annually).1 The
estimated 8.8 million new cases every year correspond to 52,000
deaths per week or more than 7,000 each day.2,3 These numbers
however, are only a partial depiction of the global TB threat. More
than 80% of TB patients are in the economically productive age of
15–49 years, which results in tremendous economic and social
problems. It was estimated that nearly 1 billion more people will
be infected with TB in the next 20 years. About 15% of that group
(150 million) will exhibit symptoms of the disease, and about 3.6%
(36 million) will die from TB if new disease prevention and treat-
ment measures are not developed.4 Tuberculosis is difficult to treat
due to residence of bacteria within the macrophages and its unusual
cell wall barrier. Moreover, multi-drug resistant strains of TB (MDR-
TB) and extensively drug resistant tuberculosis (XDR-TB) have
emerged recently.5,6 The dramatic increase in TB cases observed in
the recent years is a result of two major factors. First is the increased
susceptibility of people infected with Acquired Immunodeficiency
Syndrome (AIDS) to TB, which augments the risk of developing the
disease 100-fold.7 Second is the increase in resistant strains of the
disease8 with some showing cross-resistance to as many as nine
drugs.7 Although one possible long term solution to the problem is
a better vaccine, in the short term, the major reliance will be on che-
motherapy requiring the development of novel, effective and non-
toxic antitubercular agents.9
Despite numerous attempts to develop new structural proto-
type in the search for more effective antimicrobials, benzothiazole
still remain as one of the most versatile class of compounds against
microbes10–14 and therefore, are useful substructures for further
molecular exploration. Benzothiazole derivatives have attracted
continuing interest because of their varied biological activities
viz antitumour,15–18 antitubercular,19–21 antimalarial,22 anticon-
vulsant,23 antihelmintic,24 analgesic,25 anti-inflammtory26 and
antidiabetic.27
The diphenyl ether, triclosan 5-chloro-2-(2,4-dichloro-phenoxy)
phenol ether,28 is a broad-spectrum biocide that has been used for
over 30 years mainly as a component of antimicrobial wash in con-
sumer products such as toothpastes, mouthwashes, deodorant
soaps, lotions, children toys and cutting boards.29 Subsequently
extensive biochemical and structural studies have been performed
to confirm that triclosan is a specific inhibitor ofEscherichia coli ENR
Triclosan also directly inhibits ENR from M. tuberculosis and Myco-
bacterium smegmatis (encoded by InhA) and Plasmodium falciparum,
the malarial parasite. The common theme in the inhibition of ENRs
by triclosan is the requirement of the NAD+ cofactor. The interac-
tion of triclosan with ENR is stabilized by the p–p stacking interac-
tion between the hydroxyl chloro phenyl ring and the hydroxyl
group of a tyrosine from hydrogen bonding interactions with the
hydroxyl group of triclosan. Ring B of triclosan makes several
hydrophobic contacts with adenoyl acyl carrier protein reductase
(ENR). The ether oxygen of triclosan may also be critical in the for-
mation of the stable ENR–triclosan–NAD+ complex.28–32
⇑
Corresponding author. Tel.: +91 22 3361 2213; fax: +91 22 3361 1020.
E-mail address: vikastelvekar@rediffmail.com (V.N. Telvekar).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.064

650
V. N. Telvekar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 649–652
(Table 1). Most of the molecules exhibited physicochemical proper-
N
N
S
ties which fall in the range of known drugs as evidenced from
# stars for compounds being 0 or 2. Molecules also lacked known
toxicophores or reactive functional groups in all cases. The partition
coefficient exhibited by QPlogPo/w, were within range 4.14–6.09.
The next parameter of interest considered by QikProp analysis
was QPPCaco. According to QikProp analysis, value of QPPCaco
parameter <25 is considered poor and >500 is considered excellent.
It was observed that most of the designed first generation mole-
cules exhibited QPPCaco within acceptable limits. Human oral
absorption of most of compound is 100, which was considered to
be good. The designed molecules also followed the Lipinski’s rule
of five. Compounds showing good results were further considered
for synthesis.
In the present study of benzothiazole derivatives bearing diphe-
nyl ether moiety (10a–y) were synthesized as portrayed in the
Scheme 1. 2-amino benzothiazole derivatives (4a–e) required as
the starting Material was prepared according to the literature pro-
cedure.34 2-aminobenzothiazole derivatives (4a–e) which on treat-
ment with hydrazine hydrate in presence of ethylene glycol
resulted in the formation of 2-hydrazinyl benzothiazole derivatives
(6a–e). Compound (6a–e) was reacted with substituted / unsubsti-
tuted 4-phenoxy aromatic aldehydes (9a–e) in ethanol under re-
flux, to give desired products (10a–y) in good yields.35
NH
R1
R5
R2
R
O
R3
10a-y
R4
Figure 1. General Structure of 2-(2-(4-aryloxybenzylidene)hydrazinyl)benzo[d]
thiazole.
The purpose of our research is the development of new antitu-
berculotic agents with high activity using molecular hybridization
approach which is one of the most valuable structural modification
tools useful for the discovery of ligands and prototypes presenting
either optimised affinity for one bioreceptor or the ability to mod-
ulate more than one bioreceptor associated with the target disease.
The growing efforts to discover hybrid drugs resulting from the
combination of pharmacophoric moieties of different known lead.
In this light, various molecules were designed by molecular hybrid-
ization of 2-hydrazinyl benzothiazole and 4-(aryloxy) benzalde-
hyde. The design based on reason was expected at combining the
synergistic activity of 2-hydrazinyl benzothiazole and 4-(aryloxy)
benzaldehyde. In addition, the designed molecules could inhibit
the adenoyl acyl carrier protein reductase (ENR) enzyme since
the molecules contain substituted and unsubstituted diphenyl
ether moiety like triclosan. Design of 2-(2-(4-aryloxybenzylidene)
hydrazinyl) benzothiazole involved substitution 6-position of the
benzothiazole ring with various groups like halogen, methyl, meth-
oxy etc. (Fig 1).
Spectral data (IR, 1H NMR and MS) of all synthesized com-
pounds were in agreement with the proposed structures. IR(KBr)
spectrum of all the synthesized compounds had small broad N–H
absorption at 1600–1660 cmÀ1, 1100–1200 cmÀ1,which are as-
signed to C@N and C–O stretching, respectively. The 1HNMR spec-
trum exhibited singlets at 7–9 ppm, which were assigned to
azomethine –N@CH–. The Mass spectrum showed M+1 peak of
all the synthesized compounds.
From the QikProp33 analysis of designed molecules, it was ob-
served that the designed molecules exhibited good drug likeliness
The synthesized compounds (10a–y) were screened against
M. tuberculosis H37Rv in order to determine the minimum
Table 1
QikProp analysis data of 2-(2-(4-aryloxybenzylidene)hydrazinyl)benzo[d]thiazoles
Title
#Starsa
QPlogPo/wb
QPPCacoc
% Human oral absorptiond
No of violations from rule of fivee
10a
10b
10c
10d
10e
10f
10g
10h
10i
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
4.851
5.271
5.345
5.707
5.599
5.346
5.766
5.841
6.003
6.092
5.162
5.580
5.660
6.020
5.909
4.950
5.364
5.443
5.803
5.691
4.149
4.568
4.643
5.061
4.895
3942.074
3942.061
3942.008
3941.729
3941.610
3942.738
3942.930
3942.908
3942.575
3942.428
3941.549
3941.314
3941.314
3941.586
3941.076
3940.414
3940.131
3939.151
3939.171
3939.641
471.476
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
91.47
100
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
10j
10k
10l
10m
10n
10o
10p
10q
10r
10s
10t
10u
10v
10w
10x
10y
471.540
471.490
471.505
471.460
a
#Stars: #stars are MW, dipole, IP, EA, SASA, FOSA, FISA, PISA, WPSA, PSA, volume, donorHB, accptHB, QPlogPoct, QPlogPw, QPlogPo/w, logS, QPLogKhsa, QPlogBB. The
range predicted for this parameter using QikProp is 0–5; where 0–1 indicates no violation or best candidate.
b
QPlogPo/w: This gives the predicted octanol/water partition coefficient. The range predicted for this parameter using QikProp is À2.0–6.5.
c
QPPCaco: QikProp predictions are for nonactive transport, where <25 is considered poor and >500 is considered excellent.
d
% Human-Oral Absorption: This gives the predicted human oral absorption on 0–100% scale where >80% is considered high and <25% is considered poor.
Rule of Five: This property denotes the number of violations of Lipinski’s rule of five.
e

V. N. Telvekar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 649–652
651
NH2
N
S
N
b
a
NH2
.
NH2 HBr
KSCN
R
R
S
R
4a-e
1a-e
2
3
1a: R=H; 1b: R=Cl
1c: R=CH3; 1d: R=OCH3
1e: R=NO2
4a: R=H; 4b: R=Cl
4c: R=CH3; 4d: R=OCH3
4e: R=NO2
N
N
c
NH2.. H2O
NH
NH2
S
H2N
S
NH2
R
R
4a-e
6a-e
5
6a: R=H; 6b: R=Cl
6c: R=CH3; 6d: R=OCH3
6e: R=NO2
CHO
R2
OH
OHC
R5
R1
R2
R1
R3
d
R4
O
R4
R3
F
R5
9a-e
7a-e
8
9a: R1=R2=R3=R4=R5=H
7a: R1=R2=R3=R4=R5=H
7b: R1=Cl, R2=R3=R4=R5=H
7c: R3=Cl, R1=R2=R4=R5=H
9b: R1=Cl, R2=R3=R4=R5=H
9c: R3=Cl, R1=R2=R4=R5=H
9d: R1=R3=Cl, R2=R4=R5=H
9e: R2=CH3, R3=Cl, R1=R4=R5=H
7d: R1=R3=Cl, R2=R4=R5=H
7e: R2=CH3, R3=Cl, R1=R4=R5=H
OHC
N
N
N
S
e
NH
NH
S
R1
R5
R2
NH2
R
R
R5
R3
O
O
R3
10a-y
6a-e
R4
R1
R4
R2
9a-e
Scheme 1. Synthetic route of 2-(2-(4-aryloxybenzylidene)hydrazinyl)benzo[d]thiazoles.
inhibitory concentration (MIC) with Resazurin microtiter assay
(REMA).36,37 Homogenous mycobacterial (H37Rv) culture suspen-
sion was seeded in microtitre plates at density of 105 cells per well
zylidene) hydrazinyl) benzothiazole, 10f–j, showed good activity.
Further, introduction of methyl, methoxy and nitro group at
6-position on the benzothiazole ring, 10k–y, results in unfavour-
able effect on the antitubercular activity. However, 2,4-dichloro di-
phenyl ether containing benzothiazole molecules (10d, 10i, 10o
and 10x) are more active compared to other molecules. Further,
to validate the design hypothesize, the MIC’s of intermediates 2-
hydrazinyl benzothiazoles (6a, 6b and 6c) and 4-(aryloxy)benzal-
dehydes (9a, 9b and 9c), were determined. The MIC’s obtained
in 100 lL of the Middlebrook 7H9 broth (Difco laboratories, De-
troit, MI, USA) and the test compounds were serially diluted di-
rectly on the plate. The control received equivalent amount of
DMSO. The plates were incubated at 37 °C for 7 days. Freshly pre-
pared resazurin dye (0.02%) was added and plates were again incu-
bated for 48 h. MIC is the lowest concentration at which complete
inhibition was observed and was determined by visual inspection
(colour change from blue to pink) (Table 2). Isoniazid was used
as the reference drug.
for 2-hydrazinyl benzothiazoles 6a; 287.50
ml, 6c; 221.87 g/ml and 4-(aryloxy)benzaldehydes 9a;
132.81 g/ml, 9b; 123.44 g/ml, 9c; 117.19 g/ml were P15 and
P8-folds compared to their molecular hybrids 10a, 10g and 10m
which has MIC of 12.69 g/ml, 2.00 g/ml and 15.00 g/ml, respec-
lg/ml, 6b; 232.80 lg/
l
l
l
l
Structure–activity relationship reveals that compounds with
halogen substituent on benzothiazole ring of 2-(2-(4-aryloxyben-
l
l
l

652
V. N. Telvekar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 649–652
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10h
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10q
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H
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H
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H
H
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—
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H
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H
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H
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promising antitubercular activity and could serve as leads for fur-
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Acknowledgement
35. General procedure for the synthesis of 2-(2-(4-phenoxybenzylidene)
hydrazinyl)
benzo[d]thiazole
(10a–y):
A
mixture
of
2-
hydrazinylbenzothiazole (6a–e) (10 mM), 4-phenoxybenzaldehyde (9a–e),
(10 mM) were suspended in absolute ethanol (25–35 mL) and the mixture
was subjected for reflux at 80 °C for 6–10 h. The reaction mixture was then
cooled to room temperature; concentrated under reduced pressure and
partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was
separated, and the aqueous layer was extracted further with EtOAc
(2 Â 25 mL). The combined organic layers were washed with brine (50 mL),
dried over sodium sulphate (Na2SO4), and concentrated under vacuum.
Purification of compound was carried out by column chromatography (Silica
gel, 6 g, 20% EtOAc/hexane) to obtain pure 2-(2-(4-aryloxybenzylidene)
hydrazinyl)benzothiazole (10a–y) in yields ranging from 62–87%.
The author, V.N.T. is grateful to the Department of Science &
Technology (DST), Government of India, New Delhi for financial
support under the programme of SERC Fast Track Scheme for
Young Scientist (FAST).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.10.064.
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R.; Degani, M. S. Bioorg. Med. Chem. Lett. 2010, 20, 1623.
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References and notes
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1. Bloom, B. R.; Murray, C. J. L. Science 1992, 257, 1055.
2. Okada, M.; Kobayashi, K. Kekkaku Jpn. J. 2007, 82, 783.