N-Arylalkylbenzo[d]thiazole-2-carboxamides as anti-mycobacterial agents: Design, new methods of synthesis and biological evaluation

Article abstract of DOI:10.1039/c4md00224e

Benzothiazole-2-carboxyarylalkylamides are reported as a new class of potent anti-mycobacterial agents. Forty-one target compounds have been synthesized following a green synthetic strategy using water as the reaction medium to construct the benzothiazole scaffold followed by (i) microwave-assisted catalyst-free and (ii) ammonium chloride-catalyzed solvent-free amide coupling. The anti-mycobacterial potency of the compounds was determined against H₃₇Rv strain. Twelve compounds exhibited promising anti-TB activity in the range of 0.78-6.25 μg mL^-1 and were found to be non-toxic (<50% inhibition at 50 μg mL^-1) to HEK 293T cell lines with therapeutic index (TI) of 8-64. The most promising anti-TB compound 5bf showed MIC of 0.78 μg mL^-1 (TI > 64). The molecular docking studies of 5bf predict it to be a ligand for the M. tuberculosis HisG, the putative drug target for tuberculosis and could serve as a guiding principle for lead optimization.

Full text of DOI:10.1039/c4md00224e

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D. Sriram, Med. Chem. Commun., 2014, DOI: 10.1039/C4MD00224E.
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Medicinal Chemistry Communications
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DOI: 10.1039/C4MD00224E
Cite this: DOI: 10.1039/c0xx00000x
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ARTICLE TYPE
NꢀArylalkylbenzo[d]thiazoleꢀ2ꢀcarboxamides as antiꢀmycobacterial
agents: Design, new methods of synthesis and biological evaluation
a
a
a
a
a
Parth Shah, Tejas M. Dhameliya, Rohit Bansal, Manesh Nautiyal, Damodara N. Kommi, Pradeep S.
a
b
b
b
Jadhavar, Jonnalagadda Padma Sridevi, Perumal Yogeeswari, Dharmarajan Sriram, and Asit K.
a,
5
Chakraborti *
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Abstract:
Benzothiazoleꢀ2ꢀcarboxyarylalkylamides
are
(lpm/Cln), clarithromycin (Clr) (Group 5). The rise of drug
resistance Mtb strains is a severe obstacle for the treatment
against TB with about 440,000 cases of multidrugꢀresistant TB
(MDRꢀTB) (resistance to at least R and INH) responsible for
most of deaths for TB, extensively drugꢀresistance TB (XDRꢀTB)
1
1
2
2
0
5
0
5
reported as new class of potent antiꢀmycobacterial agents.
Forty one target compounds have been synthesized following
a green synthetic strategy using water as the reaction medium
to construct the benzothiazole scaffold followed by (i)
microwaveꢀassisted catalystꢀfree, and (ii) ammonium
chlorideꢀcatalysed solventꢀfree amide coupling. The antiꢀ
mycobacterial potency of the compounds was determined
5
5
5
6
6
0
5
0
5
(MDRꢀTB plus resistance to a fluoroquinolone and at least one
second line injectable agent i.e. Amk, Km and/or Cm) reported in
6
8
4 countries and the recent reports on totally drugꢀresistant TB
(TDRꢀTB) that are resistant to all firstꢀ and secondꢀline TB
against H Rv strain. Twelve compounds exhibited promising
3
7
7
drugs. Treatment of drug sensitive TB requires 6 months with
antiꢀTB activity in the range of 0.78ꢀ6.25 µg/mL and were
found to be nonꢀtoxic (< 50% inhibition at 50 µg/mL) to HEK
293T cell lines with the therapeutic index (TI) of 8ꢀ64. The
most promising antiꢀTB compound 5bf showed MIC 0.78
µg/mL (TI > 64). The molecular docking studies of 5bf
predicts it to be a ligand for the M. tuberculosis HisG, the
putative drug target for tuberculosis, and could serve as
guiding principle for lead optimization.
firstꢀline therapy involving 2 months of four drugs (INH, R, Z,
and E) followed by 4 months of INH plus R through directly
observed treatment short course strategy (DOTS) with a cure rate
of > 95%. The treatment of drugꢀresistant TB requires 18ꢀ24
months or longer, involving the use of the secondꢀline drugs
which are more toxic and expensive. The dual pandemics of TB
and human immunodeficiency virusꢀ1 (HIV) compound the
8
problem causing morbidity and mortality. The major challenges
associated with the available therapy are: drug intolerance and
toxicities, drugꢀdrug interaction particularly with the antiꢀ
retroviral therapy (ART) drugs to treat patients coꢀinfected with
Introduction
2,8,9
TB and HIV.
All these press the need to develop novel, more
1
0,11
effective and well tolerated drugs to curb the TB pandemic.
The human tuberculosis (TB), caused by infection with
Mycobacterium tuberculosis (Mtb), is world’s most debilitating
1
3
3
4
4
0
5
0
5
disease accounting for the death of 1.3 million people in 2012
and 8.6 million new cases. The majority of Mtb infected people
2
contain the pathogen as asymptomatic latent TB infection (LTBI)
and about 2 billion people with LTBI are in the risk zone of
1
,3
disease reꢀactivation. The options for treating TB is limited to
4
the following therapeutic regimen: (i) first –line drugs isoniazid
(INH), rifampicin (R), pyrazinamide (Z), ethambutol (E), and
rifapentine (P) or rifabutin (Rfb) (Group 1), (ii) secondꢀline drugs
aminoglycosides streptomycin (S), kanamycin (Km), amikacin
(Amk), the polypeptides capreomycin (Cm), viomycin (Vim)
(Group 2), the fluoroquinolones (e.g., ciprofloxacin (Cfx),
levofloxacin (Lfx), moxifloxacin (Mfx), ofloxacin (Ofx),
gatifloxacin (Gfx) (Group 3), and paraꢀamino salicylic acid (Pas),
cycloserine (Dcs), teridizone (Trd), ethionamide (Eto),
prothionamide (Pto), thioacetazone (Thz), and linezolid (Lzd)
(Group 4), and (iii) thirdꢀline drugs clofazimine (Cfz),
amoxicillin plus clavulanate (Amx/Clv), imipenem plus cilastatin
70
Figure 1 1. Various benzothiazole scaffolds with antiꢀtuberculosis
2ꢀ19
activity.
The benzothiazole scaffold has been recognized as an essential
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12ꢀ19
pharmacophoric feature for antiꢀtuberculosis activity.
45 with ethyl glyoxalate in water in the presence of SDOSS (10
However, the design of the target compounds in these reports is
focused on the Cꢀ2 heteroatom (predominantly nitrogen)
substitution of the benzothiazole moiety (Motifs A, C, D, FꢀH;
Figure 1). The finding on the Mtb growth inhibitory potential of
mol%) afforded 2a in 83% yield after 5 h (route a, Scheme 1).
Hydrolysis of 2a with LiOH·H O in aqueous THF at 10°C for 30
2
min afforded 3a in 97% yield (route b, Scheme 1).
5
2
ꢀmethylbenzothiazoles (Motif E; Figure 1) is the lone example
of Cꢀ2 carbo substitution which however focused on functional
1
6
building through the benzenoid nucleus. Most of these cases the
nitro aryl containing fragments is a predominant structural feature
(Motifs BꢀD, G and H). The nitro aromatic group is involved in
DNA adduct formation, methaemoglobinemia and are potentially
10
20
mutagenic.
50
Scheme 1. Synthetic strategies for the synthesis of Nꢀ
arylmethylbenzo[d]thiazoleꢀ2ꢀcarboxamides.
Results and Discussion
21
In the present study we adopted scaffold hopping strategy and
designed the Cꢀ2 carboxamide (reverse amide) substituted
benzothiazole scaffold (Figure 2).
2
2
15
In order to avoid the twoꢀstep synthesis for 3a a direct one pot
preparation from oxalic acid was planned. Benzazoles can be
prepared in oneꢀpot directly from carboxylic acids through in situ
5
6
6
5
0
5
2
9,30
carboxyl activation by thionyl chloride
assisted direct condensation
but the microwaveꢀ
31,32
with carboxylic acids appears to
be more appealing in the context of green synthesis. However, the
treatment of 1a with oxalic acid (1.4 equiv, route c) under
microwave irradiation afforded 3a in moderate yield (60%).
Therefore, the two stage process of waterꢀSDOSS mediated
condensation of ethyl glyoxalate with 1a followed by hydrolysis
(routes a and b) was preferred and 3a was obtained in 80.5%
yield. The desired amides 5aaꢀaz were formed by DCCꢀassisted
coupling of 3a with various substituted arylalkyl amines 4aꢀz
(Scheme 2).
Figure 2. New benzothiazole scaffold with Cꢀ2 reverse amide
20
substitution (present work).
The design for the new scaffold (Nꢀarylalkylbenzo[d]thiazoleꢀ2ꢀ
carboxamides) is devoid of the nitroaryl moiety thus would be
free from nitroarylꢀderived toxicity and gains boost from the
recent pharmaceutical use of benzothiazoles for treating the
proliferation of the HIV virus, treating AIDS or delaying the
onset of AIDS or ARC symptoms as it would augment the antiꢀ
tubercular potency of the newly designed 2ꢀcarboxamido
benzothiazoles in view of the MtbꢀHIV coꢀinfection.
25
2
3
70
Scheme 2. Synthesis of 5aaꢀaz via DCCꢀassisted coupling of 3a with the
amines 4aꢀz (Method A).
Reagents and condition: (i) LiOH·H
0°C, 30 min, 97%. (ii) Oxalic acid (1.4 equiv), neat, 100°C, 4 h, 60%.
iii) DCC (1.2 equiv), DCM, Et N (4 equiv), rt, 12 h.
2
O (1 equiv), Water (2 mL), THF,
1
(
3
Chemistry
30
35
40
The synthetic design of the target compounds is depicted in 75 Although the DCCꢀassisted amide formation (Scheme 2) afforded
Scheme 1. The key intermediate ethyl benzothiazoleꢀ2ꢀ
carboxylate 2a can be prepared by the reaction of 2ꢀ
aminothiophenol 1a with (i) ethyl carboethoxyformidate in
the synthetic targets, in view of the longer reaction time and the
generation of waste it was planned to develop a better
3
3
methodology to comply with the timely compound supply for
24
refluxing ethanol and (ii) ethyl triethoxyacetate at 130°C for 18
biological evaluation and enrich the medicinal chemists’ tool
2
5
34
h. The lack of commercial availability of the coupling agents 80 box.
Microwaveꢀassisted activation would enable the
35
(ethyl carboethoxyformidate and ethyl triethoxyacetate)
condensation of 2a with an amine. The reported microwaveꢀ
necessitates a more convenient method of preparation. The acidꢀ
catalyzed condensation of 1a with commercially available diethyl
oxalate in 1:2 molar ratio followed by thermal decomposition of
assisted amide formation requires stoichiometric amount of
KOBu . Herein we describe a baseꢀfree protocol by the
treatment of 2a with the amines 4aꢀz in MeCN at 100°C under
t 36
the intermediate at 225°C under nitrogen forms 2a in moderate 85 microwave irradiation (Scheme 3) to afford the desired amides
26
yield. Earlier we reported that benzothiazoles are conveniently
5aaꢀaz in 51ꢀ97% yields in 15 min (Table 1) (Method B).
synthesized by condensation of 1a with aldehydes in water under
27
heating or even at rt in the presence of catalytic amount of
28
SDOSS that constitute a green protocol. The treatment of 1a
2
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Table 1. Synthesis of the Nꢀarylalkyl benzo[d]thiazoleꢀ2ꢀcarboxamides
a
b
5
5aaꢀaz by the newly developed methods A and B (Schemes 2 and 3,
respectively).
c
Entry
Amine
Compd
No.
Yield (%)
Method A Method B
Scheme 3. Microwaveꢀassisted synthesis of 5aaꢀaz by direct
condensation of the amines 4aꢀz with 2a (Method B).
1
2
5aa
78
85
5ab
66
83
3
4
5ac
5ad
55
70
87
87
5
6
5ae
5af
54
60
95
96
7
8
9
5ag
5ah
58
68
97
68
Cl
NH2
NH2
Cl
5ai
5aj
71
73
85
84
1
1
0
1
5ak
5al
49
65
63
75
1
2
1
1
3
4
5am
5an
51
75
79
85
1
1
1
5
6
7
5ao
5ap
5aq
76
48
51
80
64
74
1
1
8
9
5ar
5as
58
58
58
60
2
2
2
2
0
1
2
3
5at
5au
5av
5aw
61
55
51
55
64
64
51
55
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d
d
30 diversity through structural modification in the benzenoid moiety
of the benzothiazole scaffold. Thus, we explored the potential of
the Nꢀarylalkylbenzo[d]thiazoleꢀ2ꢀcarboxamides having Cl and
2
2
4
5
5ax
5ay
65
53
72
65
CF group in the benzenoid nucleous of the benzothiazole ring.
3
The desired starting materials chloro/trifluoromethyl substituted
35 2ꢀcarboethoxybenzothiazoles 2b and 2c were prepared following
the similar green protocol of SDOSSꢀwater promoted
cyclocondensation of ethyl glyoxalate with 1b and 1c
respectively, as mentioned above for the synthesis of 2a (route a,
Scheme 1)
d
2
6
5az
58
70
a
3
a was treated with the amine (1.3 equiv) in the presence of DCC (1.2
b
equiv) and Et
3
N (4 equiv) in DCM at rt for 12 h. 2a was treated with the
amine (1.2 equiv) in MeCN (except for entries 24ꢀ26) under microwave
irradiation (100 °C) for 15 min. Isolated yield. MeOH was used as the
solvent instead of MeCN.
c
d
SH
O
S
O
OEt
SDOSS (10 mol%)
5
H
O
Water, rt, 8-12 h
R
N
OEt
R
NH2
All of the synthesized twenty six benzo[d]thiazoleꢀ2ꢀ
carboxamide 5aaꢀaz were subjected to in vitro antiꢀTB activity
1b: R = Cl
2b: R = Cl, 73%
1c: R = CF3
2c: R = CF , 70%
3
40
37
Scheme 4. Synthesis of the chloro/trifluoromethyl substituted 2ꢀ
carboethoxybenzothiazoles 2b and 2c, respectively.
against M.tuberculosis H Rv
(ATCC
27294
strain).
3
7
The minimum inhibitory concentration (MIC), the minimum
concentration in µg/mL of the compound required for 99%
inhibition of bacterial growth, of 5aaꢀaz and those of the standard
drugs (INH, R, E, Z and Cfx) determined in triplicate at pH 7.4,
are provided in Table 2. All of these synthesized compounds
showed MIC values in micromolar range (3.125ꢀ50 µg/mL). Out
of these, seven compounds (5aa, 5ac, 5ad, 5af, 5ah, 5aw and
10
During the preparation of the 5Cl/CF3 substituted Nꢀ
arylalkylbenzo[d]thiazoleꢀ2ꢀcarboxamides we revisited the earlier
method of microwaveꢀassisted amide formation (Method B, table
) and realized the dependence on the use of organic solvents
MeCN/MeOH). In an attempt to avoid the use of volatile organic
solvent, to comply with the green chemistry principle, a new
synthetic protocol (Method C) for the preparation of the desired
chloro/trifluoromethyl substituted Nꢀarylmethyl benzo[d]thiazoleꢀ
ꢀcarboxamides was developed under solventꢀfree condition in
the presence of catalytic amount (20 mol%) of NH Cl at 100 °C
45
1
(
15
39
5
ax) exhibited MIC in the range of 3.125–6.25 µg/mL with 5aa
and 5ax being the most active (MIC 3.125 µg/mL) in the series
50
and was found to be more potent than the standard drug Z (MIC
2
38
6
.25 µg/mL).
4
20
Table 2. Antimycobaterial activity of 5aaꢀaz, and a few standard antiꢀTB
(Scheme 5).
drugs.
a
a
a
Compound
MIC (µg/mL)
Compound
MIC (µg/mL)
5
aa
ab
3.125
25
5aq
5ar
5as
5at
5au
5av
5aw
5ax
5ay
5az
INH
R
50
25
5
5
5
Scheme 5. Synthesis of the chloro/trifluoromethyl substituted Nꢀ
arylmethyl benzo[d]thiazoleꢀ2ꢀcarboxamides by NH Clꢀcatalysed direct
4
condensation of 2b and 2c with the corresponding amines under solventꢀ
free condition (Method C).
5
ac
ad
ae
af
6.25
6.25
25
50
5
12.5
12.5
12.5
6.25
3.125
25
5
5
6.25
25
60 This method was found to be more advantageous compared to
Method A and Method B. The product was isolated by diluting
the reaction mixture with cold water followed by filtration of the
solid precipitate to furnish the final product that did not require
any further purification (Table 3).
5
ag
ah
5
6.25
50
5
ai
aj
5
50
25
65
5
ak
al
am
50
0.098
0.197
1.56
6.25
1.56
5
12.5
50
5
E
5
an
ao
ap
25
Z
5
50
Cfx
5
12.5
a
9
9% inhibition of growth of M.tuberculosis H37Rv (ATCC 27294
strain).
While establishing the structure activity relationship (SAR) of the
amides 5aaꢀaz with respect to their antiꢀTB activity it was
realized that the unsubstituted amides 5aa and 5ax are more
potent compared to their substituted analogues and this leaves
little scope for further optimization of the lead. To further
improve the antiꢀTB activity it became apparent to increase the
25
4
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Table 3. Synthesis of the additional Nꢀarylmethyl benzo[d]thiazoleꢀ2ꢀ
carboxamides with chloro/trifluoromethyl substitution in the benzene ring
counterpart 5af. However, the CF substituted derivatives (5ca,
3
5
cd, 5cy and 5cz) did not show any improvement in antiꢀTB
of the benzothiazole scaffold by the newly developed method C (Scheme
a
potency.
5
).
20
Table 4. Antimycobaterial activity of the additional Nꢀarylmethyl
benzo[d]thiazoleꢀ2ꢀcarboxamides with chloro/trifluoromethyl substitution
in the benzene ring of the benzothiazole scaffold.
b
Amine
R
Compd no.
Yield (%)
79
1
Cl
5ba
a
a
Compound
MIC (µg/mL)
Compound
MIC (µg/mL)
2
3
Cl
Cl
5bd
5bf
75
52
5
ba
bd
6.25
25
5bw
5by
5bz
5ca
25
5
1.56
12.5
5
bf
0.78
12.5
25
6.25
Cl
5bh
5bi
4
5
6
NH2
NH2
Cl
Cl
Cl
5bh
5bi
5bj
62
59
56
5cd
5cy
5cz
12.5
50
5
bj
25
Cl
5
bo
bp
12.5
6.25
25
5
a
9
9% inhibition of growth of M.tuberculosis H37Rv (ATCC 27294 strain.
The in vitro cell viability of the compounds with MIC ≤ 12.5
ꢁg/mL was evaluated against HEKꢀ293T (Human Embryonic
Kidney) cell lines at 50 ꢁg/mL concentration by using [(3ꢀ(4,5ꢀ
dimethylthiazolꢀ2ꢀyl)ꢀ2,5ꢀdiphenyl tetrazolium bromide)] MTT
assay. The % inhibitory cytotoxicity data are summarized in
Table 5 and graphically represented in Figure 3 along with the
MIC values of the respective compounds. In general, all of these
eleven compounds were found to be nonꢀtoxic (< 50% inhibition)
and 5bf the most active compound has therapeutic index greater
than 64. The compound 5bf emerged as the most promising antiꢀ
TB lead compound from this series.
2
5
7
Cl
Cl
5bo
5bp
63
63
8
9
30
Cl
Cl
5bw
5by
5bz
5ca
65
73
86
83
78
54
70
1
0
1
2
3
4
5
35
Table 5. In vitro cell viability of compounds with MIC ≤ 12.5 ꢁg/mL.
Compound
HEK 293T
Mtb
MIC (µg/ mL)
3.125
6.25
1
1
1
1
Cl
a
b
%
Inhibition
41.21
44.56
50.34
52.12
35.62
42.6
5
aa
ac
CF3
5
5
ad
af
ah
5al
ap
6.25
CF3
5cd
5cy
5cz
5
6.25
5
6.25
CF3
12.5
5
19.12
36.70
36.00
38.12
16.12
21.98
40.12
32.16
35.97
38.92
30.95
36.13
25.9
12.5
5
at
12.5
1
CF3
5
au
12.5
a
5av
aw
5ax
ba
bf
bh
5bo
bz
12.5
5
4
2b/2c was treated with the amine (1.0 equiv) in the presence of NH Cl
b
(
20 mol%) under neat condition at100 °C for 1ꢀ2 h. Isolated yield.
6.25
5
These newly synthesized fifteen compounds (Table 3) were
subjected to in vitro biological evaluation and were found to have
significant improvement in their antiꢀTB activity with MIC
ranging from 0.78ꢀ50 µg/mL (Table 4) compared to the MIC
ranges of 3.125ꢀ50 µg/mL for the 2ꢀcarboxamido benzothiazoles
without any substitution in the benzene ring of the benzothiazole
scaffold (Table 2). Among the eleven chloro substituted
derivatives, five compounds showed improved potency (0.78ꢀ
6.25 µg/mL). The most active compound 5bf (MIC 0.78 µg/mL)
turned out to be eight fold more potent than its unsubstituted
3.125
6.25
5
5
0.78
1
0
5
12.5
12.5
5
12.5
5
bp
by
6.25
1
5
5
1.56
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40
5bz
5ca
5cd
30.94
40.08
38.74
12.5
6.25
12.5
a
%
inhibition at 50 µg/mL concentration determined against HEK 293T
b
cells lines. Against Mycobacterium tuberculosis H37Rv strain.
a
Figure 3. Graphical representation of the antitubercular activity and
cytotoxicity profile of the compounds with MIC ≤ 12.5 ꢁg/mL in
comparison with the standard drugs.
5
A complete SAR can be drawn taking into account the MIC
values (Tables 2 and 4) and the cytotoxicity data of the selected
compounds (Table 5). The presence of the chloro group in the
benzene ring of the benzothiazole scaffold increases the potency.
Better antiꢀTB activity is exhibited by the benzylamides than the
corresponding phenethyl amides (5ap vs 5az and 5bp vs 5bz).
The detrimental effect of the increase in the amide chain length
on the antiꢀTB activity was also observed for compounds that did
not have the chloro substitution in the benzene ring of the
benzothiazole scaffold.
10
15
20
25
30
35
b
The antimycobacterial activity of Cꢀ2 Nꢀcarboxamide substituted
benzothiazoles have been demonstrated due to their interaction
with ATP phosphoribosyl transferase (HisG) that catalyzes the
1
5
first step in the biosynthesis of histidine, the putative drug
target. As the designed molecules resemble the reverse amide
scaffold we planned to correlate/rationalise the biological activity
of the best active compound (5bf) on its binding affinity with
HisG through molecular docking (PDB structure 1NH8).
To obtain an inꢀdepth understanding on the interaction of 5bf on
to the HisG active site, we docked compound 5bf utilizing PDB
c
1
NH8, centered about Tyr116. An automated docking analysis of
all compounds was performed into the crystallographic structure
4
0
of HisG, using AutoDock Vina 4.2. These molecules were
found to fit reasonably well into the catalytic site, with the ligand
mainly locating into the ATP binding site. The predicted binding
mode for compound 5bf is shown in (Figure 4a). The
benzothiazole ring was found to interact with the same
hydrophobic pocket next to Leu12, Leu71 and Pro50 as observed
Figure 4. (a) Docking pose of 5bf with HisG PDB:1NH8 as determined
using Autodock Vina 4.2. Structure is represented using Pymol. (b)
Ligandꢀprotein surface docking pose (c) Docked structures of two
4
5
1
5
reported HisG inhibitors.
1
5
The literature report
reveals that the nitrobenzothiazole
16
fragment is the essential feature for inhibitory potential against
HisG. A careful analysis of this benzothiazole scaffold (Figure 5)
lead to derive a topological model (common pharmacophoric
feature) that includes the presence of aryl groups at either end of
the molecule and a hydrophobic aryl group in the middle. This
topology mimics the natural ligand phosphoribosyl ATP
(PRATP) of HisG. In the newly found 5bf the benzothiazole
moiety represents the adenosine ring system of ATP and the
benzylamine moiety resembles the ribose ring of PRATP.
suggesting HisG as putative target in Mtb for the compound 5bf.
by Huang et. al. The Hꢀbond interactions is formed between
carbonyl oxygen of the amide and the backbone amide of Ala11.
Figure 4b shows the favourable lock and key model of the 5bf
into the active cavity. Figure 4c shows two previously identified
HisG inhibitors in complex with 1NH8 as taken from ref 15.
50
55
6
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DOI: 10.1039/C4MD00224E
Thus, this modelling study suggests that the compounds of the
benzothiazoleꢀ2ꢀcarboxamide series might be acting on Mtb
HisG.
2. World Health Organization (WHO), Global tuberculosis report
2013,http://www.who.int/tb/publications/global_report/gtbr13
main_text.pdf
4
5
5
6
6
7
5
0
5
0
5
0
3
.
R. Diel, R. Loddenkemper, J. P. Zellweger, G. Sotgiu, L.
D'Ambrosio, R. Centis, M. J. van der Werf, M. Dara, A.
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4
.
M. Raviglione, B. Marais, K. Floyd, K. Lönnroth, H. Getahun,
G. B. Migliori, A. D. Harries, P. Nunn, C. Lienhardt, S.
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5
1
1
2. L. Katz, J. Am. Chem. Soc., 1953, 75, 712.
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Figure 5. Comparative analysis of pharmacophoric features between
natural ligand of HisG: Phosphoribosyl ATP (PRATP) and literature
reported Mtb inhibitors.
14. K. P. Bhusari, N. D. Amnerkar, P. B. Khedekar, M. K. Kale
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Conclusion
15. Y. Cho, T. R. Ioerger and J. C. Sacchettini, J. Med. Chem.,
2
008, 51, 5984.
1
1
2
2
0
5
0
5
The present work reveals Nꢀarylmethylbenzo[d]thiazoleꢀ2ꢀ
carboxamide as a new antiꢀTB scaffold. Forty one compounds in
the series have been prepared by three newly developed synthetic
methods and evaluated in vitro for their potential as antiꢀTB drug
candidate. Twelve compounds displayed good in vitro
antimycobacterial activity, with MIC in low micromolar range
against replicating TB and are, in general, nonꢀtoxic to HEK
1
1
6. Q. Huang, J. Mao, B. Wan, Y. Wang, R. Brun, S. G. Franzblau
and A. P. Kozikowski, J. Med. Chem., 2009, 52, 6757.
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80
2
010, 45, 4293.
1
1
8. K. Hazra et al. Arch. Pharm. Chem. Life Sci., 2012, 345, 137.
9. A. Kamal, R. V. Shetti, P. Swapna, A. Shaik, A. M. Reddy, I.
A. Khan, T. A. Sheikh, S. Sharma and N. P. Kalia, US
2012/0095021 A1, 2012.
2
2
0. V. Purohit and A. K. Basu, Chem. Res. Toxicol., 2000, 13,
2
93T cell lines (< 50% inhibition at 50 µg/mL). The most potent
compound 5bf exhibits MIC of 0.78 µg/mL (therapeutic index >
0), more than that of the standard drugs E, Z and Cfx. The
6
73.
1. a) S. Bhagat, P. Shah, S. K. Garg, S. Mishra, P. K. Kaur,S
Singh and A. K. Chakraborti, Med. Chem. Commun., 2014, 5,
665. (b) K. Seth, S. K. Garg, R. Kumar, P. Purohit, V. S.
Meena, R. Goyal, U. C. Banerjee and A. K. Chakraborti, ACS
Med Chem. Lett. 2014, 5, 512. For review (c) H. Sun, G. Tawa
and A. Wallqvist, Drug Discov. Today, 2012, 17, 310.
6
8
9
9
5
0
5
significant increase in antiꢀTB activity with the 5ꢀCl substituted
benzothiazole derivatives shows further scope for improvement
in antiꢀTB activity. The molecular docking study with 5bf
suggests that the antiꢀTB benzothiazoleꢀ2ꢀcarboxamides might be
acting on Mtb HisG. The docking information may provide
valuable guiding principle for future design to evolve more potent
antiꢀTB molecules. In fine, this study has provided novel antiꢀTB
lead and can be a useful starting point for further exploration in
this area.
22. Scaffold hopping through the reverse amide staretgy generated
more potent COXꢀ2 selective agents [A. S. Kalgutkar, B. C.
Crews, S. Saleh, D. Prudhomme and L. J. Marnett, Bioorg.
Med. Chem., 2005, 13, 6810].
2
3. M. L Mitchell, P. A. Roethle, L. Xu, H. Yang, R. McFadden,
and K. Babaoglu, WO Patent 2012/145728 A1, 2012.
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2
Notes and references
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1
3
3
0
5
* Corresponding author
1
00
a
Department of Medicinal Chemistry, National Institute of
1
Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S.
Nagar 160 062, Punjab, India.
2
7. A. K. Chakraborti, S. Rudrawar, K. B. Jadhav, G. Kaur and S.
V. Chankeshwara, Green Chem., 2007, 9, 1335.
28. N. Parikh, D. Kumar, S. R. Roy and A. K. Chakraborti, Chem.
Comm., 2011, 47, 1797.
29. S. Rudrawar, A. Kondaskar and A. K. Chakraborti, Synthesis,
2005, 2521.
Fax: 91-(0)-172 2214692; Tel: 91-(0)-172 2214683;
E-mail: akchakraborti@niper.ac.in; akchakraborti@rediffmail.com.
105
b
Department of Pharmacy, Birla Institute of Technology & Science –
Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, India.
3
0. D. Kumar, S. Rudrawar and A. K. Chakraborti, Aust. J. Chem.,
2008, 61, 881.
†
Electronic Supplementary Information (ESI) available: [Procedure for
4
0
the synthesis, molecular modelling, spectral characterization and 110
31. A. K. Chakraborti, C. Selvam, G. Kaur and S. Bhagat, Synlett,
biological evaluation is described ]. See DOI: 10.1039/b000000x/
2004, 851.
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A. Zumla, M. Raviglione, R. Hafner and C. F. von Reyn, New
Engl. J. Med., 2013, 368, 745.
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3. J. Potoski, Drug Disc. Today, 2005, 10, 115.
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3
4. S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54,
451.
5. Microwaveꢀassisted aromatic nucleophilic substitution has
been earlier demonstrated from this laboratory [H. F.
Motiwala, R. Kumar and A. K Chakraborti, Aust. J. Chem.,
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007, 60, 369].
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3
3
6
7. National Committee for Clinical Laboratory Standards.
Antimycobacterial susceptibility testing for Mycobacterium
tuberculosis, tentative standard M24ꢀT. Wayne, PA: NCCLS,
1
1
2
1
995.
3
8. At the time of completion of this work we came across a
patent application on the antimycobacterial activity of Nꢀ
arylethyl benzothiazoleꢀ2ꢀcarboxamides [A. Pellet, WO Patent
2
012/069743, 2012].
3
4
9. J. H. Clark, Green Chem., 1999, 1, G1.
0. O. Trott and A. S. Olson, J. Comp. Chem., 2010, 31, 455.
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DOI: 10.1039/C4MD00224E
Graphical Abstract
N-Arylalkylbenzo[d]thiazole-2-carboxamides as anti-mycobacterial
agents: Design, new methods of synthesis and biological evaluation
a
a
a
a
a
Parth Shah, Tejas M. Dhameliya, Rohit Bansal, Manesh Nautiyal, Damodara N. Kommi, Pradeep S.
a
b
b
b
Jadhavar, Jonnalagadda Padma Sridevi, Perumal Yogeeswari, Dharmarajan Sriram, and Asit K.
a,
Chakraborti *
a
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062,
Punjab, India.
b
Department of Pharmacy, Birla Institute of Technology & Science – Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, India.