Benzo[d]thiazole-2-carbanilides as new anti-TB chemotypes: Design, synthesis, biological evaluation, and structure-activity relationship

Article abstract of DOI:10.1016/j.ejmech.2018.05.049

Tuberculosis is the second leading cause of deaths worldwide. The inadequacy of existing drugs to treat TB due to developed resistance and TB-HIV synergism urges for new anti-TB drugs. Seventy-two benzo[d]thiazole-2-carbanilides have been synthesized through CDI-mediated direct coupling of benzo[d]thiazole-2-carboxylic acids with aromatic amines using a three step methodology which includes a green protocol for synthesis of ethyl benzo[d]thiazole-2-carboxylates, precursor of the desired carboxylic acids. The compounds were evaluated in vitro for anti-tubercular activity against M. tuberculosis H₃₇Rv (ATCC27294 strain). Thirty-two compounds exhibiting MIC values in the range of 0.78–6.25 μg/mL (1.9–23 μM) were subjected to cell viability test against RAW 264.7 cell lines and thirty compounds were found to be non-toxic (<50% inhibition). The most active compounds with MIC of 0.78 μg/mL (e.g., 4i, 4n, 4s, 4w, 6f, 6h, 6u, 7e, 7h, 7p, 7r and 7w) exhibit therapeutic index of 64. The structure activity relationship of the N-arylbenzo[d]thiazole-2-carboxamides has been established for anti-mycobacterial activity. Molecular docking suggests that the compounds 7w, 4i and 4n bind to the catalytic site of the enzyme ATP Phosphoribosyltransferase (HisG) and might be attributed to their anti-TB potential. These can serve as a new starting point for the development of anti-TB agents with therapeutic potential.

Full text of DOI:10.1016/j.ejmech.2018.05.049

Accepted Manuscript
Benzo[d]thiazole-2-carbanilides as new anti-TB chemotypes: Design, synthesis,
biological evaluation, and structure-activity relationship
Tejas M. Dhameliya, Rishu Tiwari, Arkaprabha Banerjee, Sahaj Pancholia,
Dharmarajan Sriram, Dulal Panda, Asit K. Chakraborti
PII:
S0223-5234(18)30473-2
10.1016/j.ejmech.2018.05.049
EJMECH 10460
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 31 December 2017
Revised Date: 27 May 2018
Accepted Date: 28 May 2018
Please cite this article as: T.M. Dhameliya, R. Tiwari, A. Banerjee, S. Pancholia, D. Sriram, D. Panda,
A.K. Chakraborti, Benzo[d]thiazole-2-carbanilides as new anti-TB chemotypes: Design, synthesis,
biological evaluation, and structure-activity relationship, European Journal of Medicinal Chemistry
(2018), doi: 10.1016/j.ejmech.2018.05.049.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Benzo[d]thiazole-2-carbanilides as New Anti-TB
Chemotypes: Design, Synthesis and Biological
Evaluation
†
†
§
§
Tejas M. Dhameliya , Rishu Tiwari , Arkaprabha Banerjee , Sahaj Pancholia ,
‡
§
†*
Dharmarajan Sriram , Dulal Panda , and Asit K. Chakraborti
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India.
†
§
Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay,
Mumbai 400 076, India.
‡
Department of Pharmacy, Birla Institute of Technology & Science – Pilani, Hyderabad
Campus, Jawahar Nagar, Hyderabad 500 078, India.
*
Corresponding Author: Tel: 91-(0)-172 229 2027; Fax: 91-(0)-172-2214692. E-mail:
akchakraborti@niper.ac.in; akchakraborti@rediffmail.com.
The benzo[d]thiazole-2-carbanilides have been identified as new chemotypes with potent
anti-TB activities.

ACCEPTED MANUSCRIPT
Benzo[d]thiazole-2-carbanilides as New Anti-TB
Chemotypes: Design, Synthesis, Biological
Evaluation, and Structure-Activity Relationship
†
§
§
†
Tejas M. Dhameliya , Rishu Tiwari , Arkaprabha Banerjee , Sahaj Pancholia , Dharmarajan
‡
§
†*
Sriram , Dulal Panda , and Asit K. Chakraborti
†
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India.
§
Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai
4
00 076, India.
‡
Department of Pharmacy, Birla Institute of Technology & Science – Pilani, Hyderabad
Campus, Jawahar Nagar, Hyderabad 500 078, India.
*
Corresponding Author: Tel: 91-(0)-172 229 2027; Fax: 91-(0)-172-2214692. E-mail:
akchakraborti@niper.ac.in; akchakraborti@rediffmail.com.
1

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Abstract
Tuberculosis is the second leading cause of deaths worldwide. The inadequacy of existing drugs
to treat TB due to developed resistance and TB-HIV synergism urges for new anti-TB drugs.
Seventy-two benzo[d]thiazole-2-carbanilides have been synthesized through CDI-mediated
direct coupling of benzo[d]thiazole-2-carboxylic acids with aromatic amines using a three step
methodology which includes a green protocol for synthesis of ethyl benzo[d]thiazole-2-
carboxylates, precursor of the desired carboxylic acids. The compounds were evaluated in vitro
for anti-tubercular activity against M. tuberculosis H Rv (ATCC27294 strain). Thirty-two
3
7
compounds exhibiting MIC values in the range of 0.78-6.25 µg/mL (1.9-23 µM) were subjected
to cell viability test against RAW 264.7 cell lines and thirty compounds were found to be non-
toxic (< 50% inhibition). The most active compounds with MIC of 0.78 µg/mL (e.g., 4i, 4n, 4s,
4
w, 6f, 6h, 6u, 7e, 7h, 7p, 7r and 7w) exhibit therapeutic index of 64. The structure activity
relationship of the N-arylbenzo[d]thiazole-2-carboxamides has been established for anti-
mycobacterial activity. Molecular docking suggests that the compounds 7w, 4i and 4n bind to the
catalytic site of the enzyme ATP Phosphoribosyltransferase (HisG) and might be attributed to
their anti-TB potential. These can serve as a new starting point for the development of anti-TB
agents with therapeutic potential.
Keywords. Benzo[d]thiazole-2-carbanilides, new anti-TB chemotypes, anti-TB (H Rv) activity,
3
7
CDI-mediated amide coupling, molecular docking, ATP Phosphoribosyltransferase (HisG).
2

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1
. Introduction
Tuberculosis (TB), a widespread infectious disease, has been the curse to humanity for many
years. In view of the extreme alarming situation, the World Health Organization (WHO)
declared TB as a worldwide health unseen crisis in 1993. [1] The discovery of pathogenic
Mycobacterium tuberculosis (Mtb) by Robert Koch [2] that earned him the Nobel Prize in
physiology or medicine in 1905 [3] paved the way to find therapeutic agents to cope up with this
disease. However, the drive under the directly observed treatment short course (DOTS)
chemotherapy with the conventional first and second line anti-TB drugs is not sufficient to meet
the desired cure rate of TB. [4] To tackle the pandemic of TB, several therapeutic leads e.g.,
linezolid, sutezolid, gatifloxacin and moxifloxacin have been repurposed in clinical trials for the
treatment of TB (Figure 1). [5] Recently, bedaquiline (a diarylquinoline class of compound
TM
marketed as Sirturo ) [6] and delamanid (a nitro-dihydro-imidazooxazole class of compound,
Figure 1) [7] have been approved for the treatment of MDR-TB (multi-drug resistant TB) in the
United States and European countries, respectively in combination therapy with other drugs.
However, bedaquiline causes serious side effects such as QT prolongation and hepatotoxicity.
[8,9] To avoid synergistic drug-drug interaction (which also aggravate the QT prolongation) for
the use of bedaquiline special precaution is required with CYP3A4 inhibitors. [10] Delamanid
causes QT prolongation and CNS toxicity. [11] These press the need for the search of new class
of compounds as potential anti-tuberculotic agents.
Insert Figure 1 here.
1
.1 Design
3

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The design of benzo[d]thiazole-2-carbanilides (I, Figure 2) as new anti-TB chemotypes with a
wider chemical space could be derived through structural modification of the newly found anti-
TB scaffolds N-arylalkylbenzo[d]thiazole-2-carboxamide [12] and benzo[d]thiazol-2-
yl(piperazin-1-yl)methanones. [13]
Insert Figure 2 here.
2
. Results and discussion
2
.1 Chemistry
For the synthesis of the designed molecules the key intermediate ethyl benzo[d]thiazole-2-
carboxylates (2) were prepared adopting a green protocol reported [12–14] from this laboratory
which involves the cyclocondensation of 2-amino thiophenols (1) and ethyl glyoxalate in water
in the presence of catalytic amount of SDOSS as the dioxygen activator (Table 1. [15]
For the synthesis of benzo[d]thiazole-2-carbanilide (4a) we planned to adopt the NH Cl-
4
catalysed trans-amidation methodology as reported for the reaction of 2a with arylalkyl amines
[12] and alicyclic amines. [13] However, the treatment of 2a with aniline (3a) in the presence of
NH Cl (20 mol%) under neat condition at 100 °C for 12 h did not produce any significant
4
amount of 4a. The use of trifluoroacetic acid (TFA) either in catalytic amount (20 mol%) or as
solvent under heating at 100 °C (oil bath) for 12 h also did not afford 4a. The inefficiency of the
Lewis acid-catalyzed trans-anilidation of 2a with aromatic amines containing halogen (ESI:
Table S1) or electron withdrawing substituents and poor yields obtained through the base-
promoted reaction (ESI: Table S2) led us to use an alternate methodology for the preparation of
the synthetic target using 1,1’-carbonyldiimidazole (CDI) assisted coupling of carboxylic acids
with anilines. [16]
The precursor benzothiazole-2-carboxylic acid (5a), obtained through hydrolysis of 2a (98%
yield), [12] on treatment with CDI (1.5 equiv) in dry THF at rt for 12 h, followed by removal of
4

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THF under reduced pressure, and treatment of the residue with the 3a (1.1 equiv) in the presence
of (DBU, 0.5 equiv) at 60-80 °C in dry THF gave 4a in 85% yield (83% overall yield from 2a).
The ethyl 5-chloro benzo[d]thiazole-2-carboxylate 2b and ethyl 5-trifluoromethyl
benzo[d]thiazole-2-carboxylate 2c obtained from the corresponding 2-amino-4-
chlorobenzenethiol 1b and 2-amino-4-(trifluoromethyl) benzenethiol 1c, respectively, were
subjected to hydrolysis to form corresponding carboxylic acids 5b,c. The CDI-mediated direct
condensation of 5b,c with 3a-x afforded the corresponding benzo[d]thiazole-2-carbanilides 4, 6,
and 7a-x in 60-80% yields (Table 1).
Insert Table 1 here.
2
2
.2 Biological Evaluation
.2.1 Determination of MIC (H Rv)
3
7
The synthesized seventy-two benzo[d]thiazole-2-carbanilides were tested in vitro for anti-TB
activity against M. tuberculosis H37Rv (ATCC27294 strain) [17] along with a few standard anti-
TB drugs e.g., Isoniazid (INH), Rifampin (R), Ethambutol (E), Pyrazinamide (Z), and
Ciprofloxacin (Cfx) at pH 7.4 in triplicate (Table 2, Figure 3). The most active compounds (4i,
4
n, 4s, 4w, 6f, 6h, 6u, 7e, 7h, 7p, 7r and 7w) showed the Minimum Inhibitory Concentration
(MIC) of 0.78 µg/mL and were more potent than the standard drugs E, Cfx and Z. Thirteen
compounds (4j, 4u, 4x, 6b, 6k, 6f, 6m, 6n, 6q, 7b, 7c, 7f and 7g) with the MIC value of 1.56
µg/mL were equipotent to E and Cfx but more potent than Z, two compounds (4g and 4m)
having MIC of 3.125 µg/mL were more potent than Z, and five compounds (4e, 4l, 4r, 6c and
7
o) having MIC of 6.25 µg/mL showed potency similar to that of Z.
Insert Table 2 here.
Insert Figure 3 here.
2
.2.2 In vitro cell viability tests
5

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The in vitro cell viability of a few selected benzothiazole-2-anilides with MIC ≤ 6.25 µg/mL
was determined against RAW 264.7 cell lines using MTT assay at 50 µg/mL (Table 2, Figure 4)
that revealed the non-cytotoxic nature of these compounds. The most active compounds 4i, 4n,
4
s, 4w, 6f, 6h, 6u, 7e, 7h, 7p, 7r and 7w (MIC of 0.78 µg/mL) exhibited therapeutic index of 64
and emerged as the most promising anti-TB leads.
Insert Figure 4 here.
2
.2.3 Structure Activity Relationship (SAR)
The structure activity relationship (SAR) of the N-arylbenzo[d]thiazole-2-carbanilides could be
drawn by correlating the MIC (µg/mL) values of the compounds with the specific changes in the
structure made by various substitution on the core moieties. For this purpose the main structural
scaffold is segregated into two different regions: (a) the eastern region (benzenoid nucleous of
the benzo[d]thiazole moiety) and (b) western region (N-aryl part of the carbanilide moiety)
(Structure I, Figure 2).
2
.2.3.1 SAR analysis based on the modifications made on the core moieties
For the SAR analysis the various possible changes made in the western regions were
1
considered with respect to the R substituent present at the fifth position of the benzo[d]thiazole
1
(
i.e. eastern region) i.e., R = H, Cl, CF .
3
2
.2.3.2 Modifications made on the western region
1
2
.2.3.2.1 When R = H:
i. Incorporation of 4-Me on the phenyl ring of the anilide moiety increases the anti-
TB activity to 12.5 µg/mL in 4b (compared to the parent compound 4a that has
MIC of 25 µg/mL). With the 2-Me and 3-Me substitution, the activity decreased
6

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[4c, 4d; MIC of >25 µg/mL]. However, the activity increased with 2,4,6-trimethyl
substitution (4x, MIC of 1.56 µg/mL).
ii. Introduction of methoxy group increases the anti-TB activity compared to that of
the parent compound. Out of the three substitution made, the MIC values
increased (and the anti-TB potential decreased) in the order: o-OMe < p-OMe <
m-OMe [4g < 4e < 4f]. The incorporation of 3,4,5-trimenthoxy substitution
resulted into the most potent compound 4w with MIC of 0.78 µg/ml.
iii. Incorporation of the electron withdrawing chlorine at the meta position of the
phenyl ring resulted the potent compound 4i with MIC of 0.78 µg/mL than at the
para- or the ortho- position [4h, MIC of >25 µg/mL; 4j, MIC of 1.56 µg/mL].
iv. Incorporation of 2-fluoro substitution (4m, MIC of 3.125 µg/mL) increases the
anti-TB activity by two fold compared to that of the 3-fluoro substitution (4l, MIC
of 6.25 µg/mL) but with the 4-fluoro substitution the activity detoriated (4k, MIC
>
25 µg/mL)
v. The introduction of the strong electron withdrawing CF
increased the anti-TB activity. The p-CF analogue 4n showed the best activity
with the MIC value of 0.78 µg/mL. The o-CF and m-CF substitution were found
3
group in general
3
3
3
to be not so effective in improving the anti-TB potency (with 4o and 4p exhibiting
MIC of 12.5 µg/mL), though better than that of 4a.
vi. The compound with the 4-bromo substitution (4q, MIC of >25 µg/mL) showed
lesser activity compared to that of the parent compound 4a.
vii. In case of the nitro group, m-nitro derivative 4s turned out to be the the most
active compound with the MIC of 0.78 µg/mL as compared to the corresponding
7

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p-nitro analogue 4r (MIC of 6.25 µg/mL) along with an improved therapeutic
index from 8 for 4r to 64 for 4s.
viii. The activity increased by sixteen fold on incorporation of morpholine ring at the
para position (4u, MIC of 1.56 µg/mL) and by two fold at the ortho position (4v,
MIC of 12.5 µg/mL). The inferior activity of the ortho-morpholino derivative
could be due to the steric effect of the morpholine. It appears that the CF group
3
counterbalances the electronic effect of the morpholine group as the 3-fluoro-4-
morpholinyl derivative 4t exhibited poor activity (MIC of > 25 µg/mL).
1
2
.2.3.2.2 When R = Cl:
2
i. The methyl substitution (R = Me) at para- and meta- position resulted an
increase of the activity the best activity as the corresponding compounds 6b and
6
c exhibited MIC of 1.56 and 6.25 µg/mL, respectively. However, no effect on
the activity was reflected for the o-Me and 2,4,6-trimethyl derivatives 6d and 6x
that have MIC value of 25 µg/mL similar to that of the parent compound 4a.
ii. Incorporation of the OMe group at the meta position significantly improved the
activity in 6f with MIC of 0.78 µg/mL. But the anti-TB activity remained
unaffected in the corresponding para- and meta- derivatives 6a and 6d as well as
in the 3,4,5-trimenthoxy compound 6w as these showed MIC of 25 µg/mL similar
to that of the parent compound 4a.
iii. The incorporation of chlorine at the para position resulted 6h as one of the most
potent compounds with MIC of 0.78 µg/mL. No influence on the activity was
observed for the o- and m- chloro analogues 6i and 6j that have MIC value similar
(25 µg/mL) to that of 4a.
8

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iv. Substitution with fluorine, in general, increased the activity with similar extent
irrespective of being at para, meta, or ortho position with the corresponding
compounds 6k, 6l, and 6m all exhibiting MIC of 1.56 µg/mL.
v. Introduction of the trifluoromethyl group at the para position increased the
activity (6n, MIC of 1.56 µg/mL) but no effect was observed for the met and
ortho trifluoromethyl analogues 6o and 6p each of which has MIC of 25 µg/mL
similar to that of 4a.
vi. Substitution with bromine at the para position resulted in an increase of the
activity (6q, MIC of 1.56 µg/mL).
vii. For substitution with the nitro group the 3-nitro compound 6s has activity (MIC of
1
2.5 µg/mL) better than that of 4a while the 4-nitro substitution has no overall
effect on the activity as 6s has MIC of 25 µg/mL.
viii. The substitution with the morpholine ring at the para position increased the
activity giving 6u as one of the most active compounds in this study with MIC of
0
.78 µg/mL. In 6t that has the 3-fluoro substituent in addition to the 4-
morphonilyl group the anti-TB activity is less effectively increased (MIC of 12.5
µg/mL) suggesting that the electronic effect of the CF group is in dissonance
3
with that of the morpholinyl group towards the increase of the anti-TB activity.
The 2-morphonilyl substitution has no effect on the activity as the resultant
compound 6v showed anti-TB activity (MIC of 25 µg/mL) similar to that of 4a
and the lack of any influence of the ortho substitution could be due to the steric
effect.
9

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1
2
.2.3.2.3 When R = CF
3
:
2
i.
The activity increased with similar extent by substitution with methyl group (R =
Me) at the para- and meta- position and the resultant compounds 7b and 7c
showed MIC of 1.56 µg/mL. However the 2-methyl and 2,4,6-trimethyl
substitutions did not have any effect of the activity as the corresponding
compounds 7d and 7x have MIC value (25 µg/mL) similar to that of 4a.
ii.
The incorporation of methoxy substituent, in general, is associated with an
increase of activity. The most pronounced effect is exhibited by para substitution
(7e, MIC of 0.78 µg/mL) while the meta and ortho substitution increase the
activity to equally (7f and 7g both having MIC of 1.56 µg/mL), although being
inferior to the para substitution. The best activity is observed with the 4-methoxy
substituent (8e, MIC of 0.78 µg/mL). The 3,4,5-trimethoxy substituted compound
7
w also exhibited increased activity (MIC of 0.78 µg/mL) being one of the most
potent anti-TB compounds that emerged from this work.
iii.
The influence of the chloro substitution in increasing the anti-TB potential
follows the order 2-Cl < 3-Cl < 4-Cl. The compound 7h having 4-chloro
substituent appeared one amongst the most potent compounds from this study
having MIC of 0.78 µg/mL. The meta-chloro analog 7i is less effective having
MIC of 0.78 µg/mL and no improvement of the activity is noticed for the ortho-
chloro substitution as the corresponding compound 7j has anti-TB activity (25
µg/mL) similar to that of 4a.
iv.
Substitution with fluorine either at the para (7k, MIC 25 µg/mL) or the ortho
(7m, MIC 25 µg/mL) position did not have any influence on the activity as
10

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compared to the parent compound 4a. The anti-mycobacterial activity increased
by two fold with the 3-fluoro substituent (7l, MIC of 12.5 µg/mL).
Significant increase of the activity took place on incorporation of the lipophilic
trifluoromethyl group at the meta and ortho position with the corresponding
compounds 7o and 7p exhibiting the anti-TB activity with MIC of 6.25 and 0.78
µg/mL, respectively. The para-substitution has little effect on the activity as 7n
has MIC (25 µg/mL) comparable to that of 4a.
v.
vi.
The 4-bromo substitution did not show any increasing effect on the activity (7q,
MIC of 25 µg/mL).
vii.
Incorporation of the strong electron withdrawing nitro group at the para position
gave 7r as one of the most potent compounds with MIC of 0.78 µg/mL but meta-
nitro derivative was less active (7s, MIC of 25 µg/mL) being similar to 4a.
Incorporation of the morpholine ring was either ineffective (7u, MIC of 25
µg/mL) or exhibited moderate effect (7t and 7v, MIC of 12.5 µg/mL) in
increasing the activity.
viii.
2
.3 Molecular Docking
The promising anti-TB activity of the benzo[d]thiazole-2-carbanilides (Table 2) and the devoid
of cytotoxicity encouraged us further to understand the possible mode of anti-TB action of these
compounds. We were attracted by the findings on the HisG inhibitory activity of three nitro
substituted 2-amido/amino benzothiazoles. [18] However, the lack of anti-TB (whole cell)
activity and the potential mutagenicity, due to the presence of the nitro group, [19] of these
compounds encouraged us to consider these benzo[d]thiazole-2-carbanilides to be alternative and
more effective ligands of HisG and that the anti-TB activity of benzo[d]thiazole-2-carbanilides
11

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might be attributed due to HisG inhibition. The topological features of the N-
arylalkylbenzo[d]thiazole-2-carboxamide match with those of PRATP (natural ligand of HisG)
[12]. The benzo[d]thiazole-2-carbanilides are devoid of the potential mutagenic aromatic nitro
functionality and hence would represent new structural scaffold for Mtb HisG inhibition.
In this context, the molecular docking provides insight into the structure-activity correlation
that might help to optimize the lead structure and to understand the mechanism of action of
active compounds [12,20–22]. Therefore, the binding site of the potent compounds 7w, 4i, and
4
n on the ATP phosphoribosyltransferase enzyme (PDB: 1NH8) was predicted by molecular
docking using AutoDock Vina 4.2 (Figure 5) [23]. The molecular docking analysis shows that
the compounds 7w, 4i, and 4n bind to the substrate binding catalytic site of the enzyme with
differential binding energies. The compound 7w binds to the catalytic site formed by the Domain
I and Domain II of the ATP phosphoribosyl transferase enzyme [24] with a binding energy of -8
kcal/mol to the substrate binding (PRPP and ATP) pocket of the enzyme (Figure 5a) and is
involved in HB formation with the backbone nitrogen of Ala11 and Leu12. The fluorine of the
trifluoromethyl group present in 7w undergoes electrostatic interaction with the oxygen of
Asp154. The fluorine forms HB with Ala 115 and Gly138. The compound 7w also exhibits
hydrophobic interactions with Tyr116, Val155, Pro50, Leu71, Ala11, Leu12 and Gly10 in the
catalytic site. The compound 4i binds to the substrate binding site with a binding energy of -7.6
kcal/mol (Figure 5b). The chlorine of 4i forms a strong HB with Gly88 and also experiences
electrostatic interaction with oxygen of Gly88. This compound is stabilized by the hydrophobic
interactions with Gly10, Leu12, Pro50, Gly68, Leu71 and Tyr116. The compound 4n also binds
to the substrate binding pocket of the enzyme with a binding energy of -7.4 kcal/mol (Figure 5c).
The fluorine of 4n undergoes electrostatic interactions with the oxygen of Gly88 and forms
12

ACCEPTED MANUSCRIPT
strong HB with the hydroxyl (OH) group of Ser90 and the benzothiazole ring is engaged with
hydrophobic interactions with the Ala11, Leu12, Pro50 and Leu71 in the binding pocket.
Further, we also docked the 2-amido nitrobenzothiazole that has been reported [18] as the most
effective Mtb HisG inhibitor to compare its binding mode with that of the benzo[d]thiazole-2-
crbanilides. The 2-amido nitrobenzothiazole derivative binds to the catalytic site of the enzyme
(
Figure 5d) with a binding energy of -7.8 kcal/mol which is less as compared to that of 7w. The
oxygen of the nitro group of this 2-amido nitrobenzothiazole forms HB with the backbone
nitrogen of Gly157, Ser158, Gly159, Arg160, and Thr161 as well as with the Tyr116 and Asp70.
Further, this compound is also involved in stabilized hydrophobic interactions with the Pro50,
Leu10 and Leu11. We next considered the molecular docking of the next best reported HisG
inhibitor [18] that is devoid of the nitro group and the 2-amidothiazole moiety (Figure 5d) and
observed that docks onto the catalytic site of the enzyme, stabilized by the hydrophobic
interactions with Gly10, Ala11, Leu12, Pro50, Leu71, Tyr116, Val155 in the catalytic site, with
a binding energy of -7.1 kcal/mol which is inferior compared to that of the newly found anti-TB
compounds 7w, 4i, and 4n. Thus, the molecular docking studies suggest that the compound 7w
binds to the enzyme more strongly as compared to the previously reported HisG inhibitors [18],
and the compounds 4i and 4n also bind to the catalytic site of the enzyme with good affinities as
compared to the next best inhibitor that does not bear the 2-amidothazole moiety and the
mutagenic nitro aromatic group.
The compounds 7w, 4i, and 4n show a very good alignment with the PR-ATP (phosphoribosyl
pyrophosphate-adenosine triphosphate), the natural substrate of HisG where the benzothiazolyl
moiety occupies the same space of the active site which is occupied by the adenosine moiety of
PR-ATP [12] (Figure 6a). These topological features were not observed with the two reported
13

ACCEPTED MANUSCRIPT
inhibitors of Mtb HisG [18] selected for molecular docking (supporting information: Figure
S1a). The benzothizole-2-carbanilide ligands 7w, 4i, and 4n fit into the active site of HisG
(
Figures 6b, 6c; see also the supporting information: Figure S1b) better than that of the two
reported [18] Mtb HisG inhibitors suggesting HisG to be the putative target for the anti-TB
activity of these compounds.
Insert Figure 6 here.
3
. Conclusions
In this study benzo[d]thiazole-2-carbanilides have been revealed as new anti-TB chemotypes.
Seventy-two compounds have been synthesized and tested in vitro against M. tuberculosis
(
H Rv) to assess their anti-TB potential. Twenty-four compounds (e.g., 4i, 4j, 4n, 4s, 4u, 4w,
37
4
1
x, 6b, 6f, 6h, 6k, 6l, 6m, 6n, 6q, 6u, 7b, 7e, 7f, 7g, 7h, 7p, 7r and 7w) exhibited MIC values of
-10 µM. The in vitro cell viability of a few selected benzo[d]thiazole-2-carbanilides with MIC
of ≤ 6.25 µg/mL against RAW 264.7 cell lines revealed the non-cytotoxic nature of these
compounds. The structure activity relationship for the anti-mycobacterial activity of these N-
arylbenzo[d]thiazole-2-carbanilides has been analysed. Molecular docking analysis of the most
potent compounds 7w, 4i and 4n shows that these compounds bind to the substrate binding
pocket of ATP phosphoribosyl transferase enzyme (HisG) with docking energies better than that
of the reported HisG inhibitors. This reflects that these compounds might inhibit the growth of
Mycobacterium tuberculosis possibly by targeting the HisG enzyme.
14

ACCEPTED MANUSCRIPT
4
. Experimental Section
4
.1 General Chemistry
Chemicals and all solvents were commercially available, and used directly without
1
13
further purification. H NMR and C NMR spectra were determined using spectrometer at 400
and 100 MHz, respectively, with TMS (tetramethyl silane) as an internal standard and solvents
(
CDCl , DMSO and MeOD) with residual undeuterated solvent (CDCl : 7.26/77.0, DMSO-d :
3
3
6
1
3
2
.5/39.5 and MeOD: 3.31, 49.00). Coupling constants (J) were reported in hertz (Hz). The C
NMR spectra were fully decoupled. The abbreviations used to characterize the signals are as
follows: s = singlet, m = multiplet, d = doublet, dd = doublet of doublet, dt = doublet of triplet, t
=
triplet, td = triplet of doublet, q = quartet, quin = quintet, br s = broad singlet. For triplet with
the splitting pattern of 1:2:1, only one average coupling constant is reported but for doublet of
doublet with the splitting pattern of 1:2:2:1, two different coupling constants are reported. Mass
spectra were recorded in the APCI mode at an ionization potential (70 eV) with LCMS MSD and
GCMS in the EI mode mass spectrometers. Infra-red (FTIR) spectra (neat or KBr) were
-1
determined using FT-IR spectrometer (4000-600 cm ). Melting points have been determined
using digital melting point apparatus. Evaporation of solvent was done at reduced pressure, using
a rotary evaporator. HPLC of all the target compounds has been performed using C18 column
(4.6 × 250 mm, 5 micron,) and acetonitrile:water (95:50) as the mobile phase at 40 ºC (column
-1
temperature) utilizing 20 µL of the sample with flow rate of 1 mL min using binary pump.
Photo diode array detector was used for at wavelengths (254 nM and 215 nM). The intermediates
2
a-c, 5a [12] and final compounds 4a, 4b and 4i [31] are reported in the literature.
Synthetic procedure for preparation of 5-substituted benzo[d]thiazole-2-carboxylate (2a-c):
To a magnetically stirred miceller solution of SDOSS (44 mg, 10 mol %) in demineralised water
15

ACCEPTED MANUSCRIPT
(2 mL), was added 2-aminothiophenol 1a (1 mmol,) and ethyl glyoxalate (1.2 equiv) and the
mixture was stirred at rt. After completion of the reaction (5 h, TLC), the reaction mixture was
extracted with EtOAc up to four times. Combined EtOAc extracts were dried over anhydrous
Na SO , and concentrated under vacuum rotary evaporation. The crude product was purified by
2
4
passing through a column of silica gel (60-120 mesh) and eluted with hexane-EtOAc (90:10) to
afford the pure 2a.
4
.1.1 Ethyl benzo[d]thiazole-2-carboxylate (2a): Yield: 172 mg, 83% (yellow solid), mp 68-72
°
-1 1
C. IR (KBr) ν: 1750 cm . H NMR (CDCl3, 400 MHz)
δ (ppm): 8.25 (d, J = 8.16 Hz, 1H), 7.97
13
(
d, J = 7.92 Hz, 1H), 7.60-7.52 (m, 2H), 4.56 (q, J = 7.12 Hz, 2H), 1.49 (t, J = 7.12, 3H). C
NMR (100 MHz, CDCl3)
δ
(ppm): 160.68, 158.57, 153.22, 136.78, 127.54, 127.09, 125.52,
+
1
22.08, 63.13, 14.29. MS (APCI) m/z 208.21 (M + H) .
4
.1.2 Ethyl 5-chlorobenzo[d]thiazole-2-carboxylate (2b): Yield: 176 mg, 73% (yellowish
°
-1
1
solid), mp 91-93 C. IR (KBr) ν: 1743 cm . H NMR (400 MHz, CDCl
3
) δ (ppm): 8.24 (d, J =
1
1
1
.88 Hz, 1H), 7.91 (d, J = 8.68 Hz, 1H), 7.53 (dd, J = 8.64, 1.96 Hz), 4.57 (q, J = 7.16 Hz, 2H),
13
.50 (t, J = 7.12 Hz, 3H). C NMR (100 MHz, CDCl ) δ (ppm): 160.35, 160.31, 153.95, 134.98,
3
+
33.28, 128.26, 125.05, 122.89, 63.37, 14.27. MS (ESI) (m/z) 242.23 (M) .
4
.1.3 Ethyl 5-(trifluoromethyl)benzo[d]thiazole-2-carboxylate (2c): Yield: 193 mg, 70%
°
-1 1
(
white solid), mp 73-75 C. IR (KBr) ν: 1736 cm . H NMR (400 MHz, CDCl ) δ (ppm): 8.53 (s,
3
1
H), 8.13 (d, J = 8.52 Hz, 1H), 7.79 (dd, J = 8.52, 1.32 Hz, 1H), 4.60 (q, J = 7.12 Hz, 2H), 1.52
1
3
(
t, J = 7.12 Hz, 3H). C NMR (100 MHz, CDCl ) δ (ppm): 160.80, 160.01, 152.87, 139.93,
3
+
1
30.22, 129.89, 123.62, 123.59, 122.77, 122.49, 63.22, 14.05. MS (APCI) (m/z) 275.97 (M+H) .
16

ACCEPTED MANUSCRIPT
Synthesis of 5-substituted benzo[d]thiazole-2-carboxylic acid (5a): To the solution of 2 (207
mg, 1 mmol) in THF (0.5 mL) at 10 ˚C was added LiOH·H O (42 mg, 1 mmol, 1equiv) in
2
water (2 mL) and stirred magnetically for 30 min followed by drop wise addition of dil. HCl (1
N) until precipitation occurred. The precipitate was filtered and dried under rotary vacuum
evaporation (24 psi) to afford 5a in 98% yield, identical (spectral data) with an authentic sample.
[12]
4
.1.4 Benzo[d]thiazole-2-carboxylic acid (5a): Yield: 175 mg, 98% (white solid), mp 104-108
-1 1
°
C. IR (KBr) ν: 1708 cm . H NMR (400 MHz, DMSO-D ): δ (ppm): 9.43 (s, 1H), 8.19 (d, J =
6
8
.52 Hz, 1H), 8.12 (d, J = 8.44 Hz, 1H), 7.57 (dt, J = 1.16, 8.2 Hz, 1H), 7.51 (dt, J = 1.2, 8.08
1
3
Hz, 1H). C NMR (100 MHz, DMSO-D ): δ (ppm): 161.43, 159.98, 152.97, 136.26, 127.47,
6
+
1
27.15, 124.68, 122.99; MS (APCI) m/z 180 (M + H)
.
Synthesis of benzo[d]thiazole-2-carbanilides (4, 6, 7a-x): The benzothiazole-2-carboxylic
acid 5a (179 mg, 1 mmol) in dry THF (2 mL) was treated with CDI (245 mg, 1.5 mmol, 1.5
equiv). The mixture was stirred magnetically at rt overnight, concentrated under rotary vacuum
evaporation. The residue was diluted with freshly dried THF (2 mL) and treated with anilines 3
(1.1 mmol, 1.1 equiv) and DBU (76 mg, 0.5 mmol, 0.5 equiv) under magnetic stirring at 60-80
o
C for 6-8 h. After the completion of the reaction (TLC), solvent was evaporated from reaction
mixture under reduced pressure, reaction mixture was diluted with cold water (15-20 mL) and
the mixture was allowed to stir for 10 min. The solid precipitate was filtered off and air dried to
furnish the pure product (4, 6, 7a-x).
4
.1.5 N-Phenylbenzo[d]thiazole-2-carboxamide (4a): White solid (160 mg, 63%), mp 156-158
-1
1
ºC. IR (DCM, cm ) 3359, 2922, 1677, 1595, 1532, 763, 633; H NMR (400 MHz, CDCl
3
) δ
(ppm): 9.30 (s, 1H), 8.16 (d, J = 8.12 Hz, 1H), 8.04 (d, J = 7.72 Hz, 1H), 7.80 (d, J = 7.64 Hz,
17

ACCEPTED MANUSCRIPT
1
3
2
H), 7.64-7.54 (m, 2H), 7.46-7.42 (m, 2H), 7.24-7.20 (m, 1H); C NMR (100 MHz, CDCl
3
) δ
(ppm): 164.1, 157.6, 152.7, 137.5, 137.0, 129.7, 127.1, 127.0, 125.0, 124.4, 122.6, 119.8; HRMS
+
(
ESI-TOF) m/z: [M + Na] Calcd for C H N OSNa 277.0412; Found 277.0405. HPLC
1
4
10
2
analysis: retention time = 4.283 min; peak area, 99.94%.
4
.1.6 N-(p-Tolyl)benzo[d]thiazole-2-carboxamide (4b): Yield: 210 mg (78%), mp 146–148 ºC.
-1 1
IR (KBr) ν: 3365, 1684, 1543, 1029 cm . H NMR (400 MHz, CDCl ) δ (ppm): 9.22 (s, 1H),
3
8
7
1
.12 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.60-7.50 (m, 2H),
1
3
3
.21 (d, J = 8.1 Hz, 2H), 2.36 (s, 3H). C NMR (100 MHz, CDCl ) δ (ppm): 164.3, 157.5,
52.7, 137.4, 134.7, 134.5, 129.8, 127.0, 126.9, 124.3, 122.5, 119.8, 21.0. HRMS (ESI-TOF)
+
m/z: [M + Na] Calcd for C H N NaOS 291.0568; Found 291.0563. HPLC analysis: retention
1
5
12
2
time = 4.344 min; peak area, 99.94%.
4
.1.7 N-(m-Tolyl)benzo[d]thiazole-2-carboxamide (4c): Yield: 211 mg (79%), mp 115-117 ºC.
-1 1
IR (KBr) ν: 3365, 1684, 1543, 1029 cm . H NMR (400 MHz, CDCl ) δ (ppm): 9.22 (s, 1H),
3
8
7
1
.11 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.61-7.49 (m, 4H), 7.28 (t, J = 7.7 Hz, 1H),
1
3
3
.00 (d, J = 7.5 Hz, 1H), 2.39 (s, 3H). C NMR (100 MHz, CDCl ) δ (ppm): 164.3, 157.5,
52.7, 139.2, 137.5, 136.9, 129.1, 127.0, 126.9, 125.8, 124.4, 122.5, 120.5, 116.9, 21.5. HRMS
+
(
ESI-TOF) m/z: [M + Na] Calcd for C H N OSNa 291.0568; Found 291.0563. HPLC
1
5
12
2
analysis: retention time = 4.228 min; peak area, 99.90%.
4
.1.8 N-(o-Tolyl)benzo[d]thiazole-2-carboxamide (4d): Yield: 192 mg (72%), mp 106–109 ºC.
-1 1
IR (KBr) ν: 3365, 1684, 1543, 1029 cm . H NMR (400 MHz, CDCl ) δ (ppm): 9.26 (s, 1H),
3
8
7
.18 (d, J = 8.1 Hz, 1H), 8.14 (d, J = 8.0 Hz ,1H), 8.00 (d, J = 7.7 Hz, 1H), 7.61-7.50 (m, 2H),
13
3
.31-7.25 (m, 2H), 7.13 (t, J = 7.5 Hz, 1H), 2.46 (s, 3H). C NMR (100 MHz, CDCl ) δ (ppm):
18

ACCEPTED MANUSCRIPT
1
1
64.3, 157.6, 152.8, 137.5, 135.1, 130.6, 128.4, 127.0, 127.0, 126.9, 125.4, 124.5, 122.5, 121.8,
+
7.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H N OSNa 291.0568; Found 291.0563.
1
5
12
2
HPLC analysis: retention time = 4.470 min; peak area, 95.92%.
4
1
9
2
1
.1.9 N-(4-Methoxyphenyl)benzo[d]thiazole-2-carboxamide (4e): Yield: 220 mg (75%), mp
-1 1
35-139 ºC. IR (KBr) ν: 3372, 1687, 1524, 1251 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.17 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.71-7.67 (m, 2H), 7.61-7.49 (m,
1
3
3
H), 6.96-6.92 (m, 2H), 3.83 (s, 3H). C NMR (100 MHz, CDCl ) δ (ppm): 164.4, 157.3, 156.9,
52.8, 137.4, 130.2, 127.0, 126.9, 124.3, 122.5, 121.4, 114.4, 55.5. HRMS (ESI-TOF) m/z: [M +
+
Na] Calcd for C H N O SNa 307.0517; Found 307.0507. HPLC analysis: retention time =
1
5
12
2
2
4
.897 min; peak area, 99.91%.
4
1
9
2
1
.1.10 N-(3-Methoxyphenyl)benzo[d]thiazole-2-carboxamide (4f): Yield: 233 mg (82%), mp
-1 1
25-128 ºC. IR (KBr) ν: 3365, 1674, 1544, 1261 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.26 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.61-7.50 (m, 3H), 7.32-7.22 (m,
1
3
3
H), 6.74-6.74 (m, 1H), 3.86 (s, 3H). C NMR (100 MHz, CDCl ) δ (ppm): 164.1, 160.3, 157.6,
52.7, 138.2, 137.5, 129.9, 127.1, 127.0, 124.4, 122.5, 112.0, 111.2, 105.3, 55.4.HRMS (ESI-
+
TOF) m/z: [M + Na] Calcd for C H N O SNa 307.0517; Found 307.0507. HPLC analysis:
1
5
12
2
2
retention time = 3.818 min; peak area, 97.30%.
4
1
9
7
8
.1.11 N-(2-Methoxyphenyl)benzo[d]thiazole-2-carboxamide (4g): Yield: 213 mg (75%), mp
-1 1
17-120 ºC. IR (KBr) ν: 3370, 1684, 1534, 1251 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.88 (s, 1H), 8.54 (dd, J = 1.6, 8.0 Hz, 1H), 8.17 (d, J = 8.1 Hz 1H), 7.99 (d, J = 8.0 Hz, 1H),
.60-7.49 (m, 2H), 7.13 (dt, J = 1.6, 7.7 Hz, 1H), 7.04 (dt, J = 1.2, 7.8 Hz, 1H), 6.96 (dd, J = 1.2,
1
3
3
.1 Hz, 1H), 4.00 (s, 3H). C NMR (100 MHz, CDCl ) δ (ppm): 164.5, 157.5, 152.9, 148.7,
19

ACCEPTED MANUSCRIPT
1
37.4, 124.7, 124.6, 126.9, 126.8, 124.7, 124.6, 122.4, 121.9, 121.1, 120.0, 110.2, 56.3. HRMS
+
(
ESI-TOF) m/z: [M + Na] Calcd for C H N O SNa 307.0517; Found 307.0507. HPLC
1
5
12
2
2
analysis: retention time = 4.893 min; peak area, 99.91%.
4
1
9
2
1
.1.12 N-(4-Chlorophenyl)benzo[d]thiazole-2-carboxamide (4h): Yield: 250 mg (87%), mp
-1 1
45-150 ºC. IR (KBr) ν: 3338, 1689, 1590, 1538 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.30 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.74-7.71 (m, 2H), 7.62-7.51 (m,
1
3
H), 7.39-7.35 (m, 2H). C NMR (100 MHz, CDCl ) δ (ppm): 163.7, 157.6, 152.6, 137.4, 135.6,
3
+
30.0, 129.3, 127.2, 127.1, 124.4, 122.6, 121.0. HRMS (ESI-TOF) m/z: [M + Na] Calcd for
C H ClN OSNa 311.0022; Found 311.0015. HPLC analysis: retention time = 7.235 min; peak
14
9
2
area, 99.54%.
4
1
9
7
1
.1.13 N-(3-Chlorophenyl)benzo[d]thiazole-2-carboxamide (4i): Yield: 219 mg (76%), mp
-1 1
31-133 ºC. IR (KBr) ν: 3338, 1689, 1590, 1538 cm . H NMR (400 MHz, CDCl
3
) δ (ppm):
.28 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.63-
1
3
.51 (m, 3H), 7.32 (t, J = 8.0 Hz, 1H), 7.17-7.15 (m, 1H). C NMR (100 MHz, CDCl ) δ (ppm):
3
63.5, 157.7, 152.6, 138.1, 137.5, 135.0, 130.2, 127.1, 125.0, 124.5, 122.5, 121.9, 119.9, 117.8.
+
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C14
H
9
ClN
2
OSNa 311.0022; Found 311.0015.
HPLC analysis: retention time = 7.203 min; peak area, 99.72%.
4
1
9
7
.1.14 N-(2-Chlorophenyl)benzo[d]thiazole-2-carboxamide (4j): Yield: 192 mg (67%), mp
-1 1
41–144 ºC. IR (KBr) ν: 3338, 1689, 1590, 1538 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.92 (s, 1H), 8.58 (dd, J = 1.3, 8.2 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H),
.61-7.51 (m, 2H), 7.45 (dd, J = 1.2, 8.0 Hz,1H), 7.35 (t, J = 8.2 Hz 1H), 7.12 (dt, J = 1.2, 7.8
1
3
Hz, 1H). C NMR (100 MHz, CDCl
3
) δ (ppm): 163.5, 157.8, 152.8, 137.5, 134.0, 129.3, 127.4,
+
1
27.1, 127.1, 125.3, 124.8, 123.5, 122.4, 121.3. HRMS (ESI-TOF) m/z: [M + Na] Calcd for
20

ACCEPTED MANUSCRIPT
C
14
H
9
ClN
2
OSNa 311.0022; Found 311.0015. HPLC analysis: retention time =5.203 min; peak
area, 98.23%.
4
1
9
2
1
.1.15 N-(4-Fluorophenyl)benzo[d]thiazole-2-carboxamide (4k): Yield: 212 mg (78%), mp
-1 1
42–145 ºC. IR (KBr) ν: 3373, 1690, 1544, 1275 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.25 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.77-7.71 (m, 2H), 7.61-7.51 (m,
1
3
3
H), 7.13-7.07 (m, 2H). C NMR (100 MHz, CDCl ) δ (ppm): 163.9, 161.0, 158.5, 157.6, 152.7,
37.4, 133.1, 133.1, 127.1, 127.0, 124.4, 122.5, 121.6, 121.5, 116.1, 115.9. HRMS (ESI-TOF)
+
m/z: [M + Na] Calcd for C H FN OSNa 295.0371; Found 295.0311. HPLC analysis: retention
1
4
9
2
time = 4.269 min; peak area, 99.06%.
.1.16 N-(3-Fluorophenyl)benzo[d]thiazole-2-carboxamide (4l): Yield: 206 mg (76%), mp
4
1
9
7
1
1
2
4
1
9
7
1
1
2
-
1 1
08–110 ºC. IR (KBr) ν: 3373, 1690, 1544, 1275 cm . H NMR (400 MHz, CDCl
3
) δ (ppm):
.32 (s, 1H), 8.13 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.72 (td, J = 2.2, 10.7 Hz, 1H),
1
3
.62-7.51 (m, 2H), 7.43-7.32 (m, 2H), 6.92-6.87 (m, 1H). C NMR (100 MHz, CDCl ) δ (ppm):
3
64.3, 163.6, 161.9, 157.7, 152.6, 138.5, 138.4, 137.5, 130.4, 130.3, 127.1, 124.5, 122.6, 115.2,
+
15.17, 111.9, 111.6, 107.5, 107.2. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H FN OSNa
1
4
9
2
95.0371; Found 295.0311. HPLC analysis: retention time = 3.856 min; peak area, 96.22%.
.1.17 N-(2-Fluorophenyl)benzo[d]thiazole-2-carboxamide (4m): Yield: 184 mg (68%), mp
-1 1
32–135 ºC. IR (KBr) ν: 3378, 1685, 1544, 1285 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.55 (s, 1H), 8.51 (dt, J = 1.8, 8.1 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H),
1
3
.62-7.51 (m, 2H), 7.24-7.11 (m, 3H). C NMR (100 MHz, CDCl ) δ (ppm):165.4, 157.7, 154.0,
3
52.7, 151.5, 137.5, 127.1, 127.1, 125.7, 125.6, 125.2, 125.1, 124.8, 124.8, 124.7, 122.5, 121.5,
+
15.2, 115.0. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C14
H
9
FN
2
OSNa 295.0371; Found
95.0311. HPLC analysis: retention time = 4.422 min; peak area, 96.65%.
21

ACCEPTED MANUSCRIPT
4
.1.18 N-(4-(Trifluoromethyl)phenyl)benzo[d]thiazole-2-carboxamide (4n): Yield: 174 mg
-1 1
(
54%), mp 150-153 ºC. IR (KBr) ν: 3372, 1687, 1548, 1334 cm . H NMR (400 MHz, CDCl ) δ
3
(ppm): 9.43 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H),
1
3
7
1
1
3
4
3
.67 (d, J = 8.6 Hz, 2H), 7.61-7.53 (m, 2H). C NMR (100 MHz, CDCl ) δ (ppm): 163.3, 157.9,
52.6, 140.0, 137.5, 127.3, 127.2, 126.9, 126.7, 126.6, 126.6, 126.5, 126.5, 124.5, 122.6, 119.5,
+
19.0, 114.2. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C15
H
9
F
3
N
2
OSNa 345.0285; Found
45.0283. HPLC analysis: retention time = 4.516 min; peak area, 96.03%.
.1.19 N-(3-(Trifluoromethyl)phenyl)benzo[d]thiazole-2-carboxamide (4o): Yield: 183
-1
1
mg(53%), mp 148-151 ºC. IR (KBr) ν: 3362, 1697, 1558, 1314 cm . H NMR (400 MHz,
CDCl ) δ (ppm): 9.40 (s, 1H), 8.15-8.12 (m, 1H), 8.08 (s, 1H), 8.02-7.97 (m, 2H), 7.63-7.52 (m,
3
1
3
3
1
1
H), 7.45 (d, J = 7.8 Hz, 1H). C NMR (100 MHz, CDCl ) δ (ppm): 163.3, 157.9, 152.6, 137.6,
3
37.5, 132.2, 131.9, 131.6, 131.2, 130.9, 129.8, 128.9, 127.2, 127.2, 125.1, 124.5, 122.8, 122.6,
+
22.4, 121.5, 121.5, 121.5, 116.6, 116.6, 116.6, 116.5. HRMS (ESI-TOF) m/z: [M + Na] Calcd
for C H F N OSNa 345.0285; Found 345.0283. HPLC analysis: retention time = 4.393 min;
1
5
9
3
2
peak area, 97.62%.
.1.20 N-(2-(Trifluoromethyl)phenyl)benzo[d]thiazole-2-carboxamide (4p): Yield: 184 mg
4
-1 1
(
59%), mp 116–119 ºC. IR (KBr) ν: 3372, 1687, 1548, 1334 cm . H NMR (400 MHz, CDCl )
3
δ (ppm): 9.82 (s, 1H), 8.51 (d, J = 8.3 Hz, 1H), 8.19-8.17 (m, 1H), 8.02-7.99 (m, 1H), 7.71-7.51
1
3
(
m, 4H), 7.30 (t, J = 7.6 Hz, 1H). C NMR (100 MHz, CDCl ) δ (ppm): 163.1, 158.1, 152.7,
3
1
1
37.5, 134.6, 133.1, 127.2, 127.1, 126.4, 126.4, 126.3, 126.3, 125.4, 124.9, 124.8, 123.4, 122.7,
+
22.4, 120.4, 120.1. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C15
H F
9 3
N
2
OSNa 345.0285;
Found 345.0283. HPLC analysis: retention time = 4.388 min; peak area, 98.31%.
22

ACCEPTED MANUSCRIPT
4
1
8
.1.21 N-(4-Bromophenyl)benzo[d]thiazole-2-carboxamide (4q): Yield: 261 mg (79%), mp
-1 1
49-152 ºC. IR (KBr) ν: 3328, 1648 cm . H NMR (400 MHz, CDCl ) δ (ppm): 9.28 (s, 1H),
3
1
3
.12 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 7.9 Hz 1H), 7.69-7.66 (m, 2H), 7.62-7.50 (m, 4H). C
NMR (100 MHz, CDCl
3
) δ (ppm): 163.7, 157.6, 152.6, 137.5, 136.1, 132.3, 127.1, 127.1, 124.4,
+
1
22.6, 121.4, 117.7. HRMS (ESI): m/z for C14
observed: 354.9510. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C16
Found 271.0846. HPLC analysis: retention time = 4.397 min; peak area, 97.99%.
H
9
BrN
2
OSNa [M + Na] , calc.: 354.9517;
+
12 2
H N ONa 271.0847;
4
1
8
2
1
.1.22 N-(4-Nitrophenyl)benzo[d]thiazole-2-carboxamide (4r): Yield: 245 mg (82%), mp
-1 1
51-155 ºC. IR (KBr) ν: 3398, 1668 cm . H NMR (400 MHz, CDCl ) δ (ppm): 9.58 (s, 1H),
3
.31 (d, J = 9.1 Hz, 2H), 8.16 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 9.1 Hz,
1
3
H), 7.65-7.55 (m, 2H). C NMR (100 MHz, CDCl ) δ (ppm): 162.7, 152.5, 150.1, 144.3, 142.7,
3
+
36.3, 132.9, 127.5, 127.4, 125.3, 124.6, 122.6, 121.0, 119.4. HRMS (ESI-TOF) m/z: [M + Na]
Calcd for C H N O SNa 322.0262; Found 322.0267. HPLC analysis: retention time = 3.713
1
4
9
3
3
min; peak area, 97.56%.
4
2
8
.1.23 N-(3-Nitrophenyl)benzo[d]thiazole-2-carboxamide (4s): Yield: 250 mg (84%), mp
-1 1
00–202 ºC. IR (KBr) ν: 3398, 1668 cm . H NMR (400 MHz, CDCl
3
) δ (ppm): 9.50 (s, 1H),
1
3
.65 (t, J = 2.1 Hz, 1H), 8.19-8.15 (m, 2H), 8.07-8.02 (m, 2H), 7.65-7.55 (m, 3H). C NMR
(
100 MHz, CDCl ) δ (ppm): 163.0, 158.0, 152.5, 138.1, 137.5, 130.2, 127.4, 127.3, 125.3, 124.6,
3
+
1
3
4
22.6, 119.5, 114.6, 107.0. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H N O SNa
1
4
9
3
3
22.0262; Found 322.0267. HPLC analysis: retention time = 3.658 min; peak area, 96.88%.
.1.24 N-(3-Fluoro-4-morpholinophenyl)benzo[d]thiazole-2-carboxamide (4t): Yield: 239
-1 1
mg (67%), mp 186–188 ºC. IR (KBr) ν: 3373, 1164, 1532, 1260 cm . H NMR (400 MHz,
CDCl ) δ (ppm): 9.21 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.69 (dd, J =
3
23

ACCEPTED MANUSCRIPT
2
3
1
1
3
4
.4, 14.0 Hz, 1H), 7.61-7.47 (m, 2H), 7.37 (dd, J = 1.4, 8.6 Hz, 1H), 6.96 (t, J = 9.0 Hz, 2H),
1
3
.88 (t, J = 4.5 Hz, 4H), 3.09 (t, J = 4.6 Hz, 4H). C NMR (100 MHz, CDCl ) δ (ppm): 163.8,
3
57.4, 156.6, 154.2, 152.67, 137.4, 137.1, 137.0, 132.1, 132.0, 127.1, 127.0, 124.4, 122.5, 118.9,
+
18.9, 115.7, 109.0, 108.7, 67.0, 51.0. HRMS (ESI-TOF) m/z: [M] Calcd for C H FN O SNa
18
16
3
2
80.0845; Found 380.0835. HPLC analysis: retention time = 4.337 min; peak area, 96.98%.
.1.25 N-(4-Morpholinophenyl)benzo[d]thiazole-2-carboxamide (4u): Yield: 210 mg (62%),
-
1 1
mp 220-230 ºC. IR (KBr) ν: 3373, 1164, 1532, 1260 cm . H NMR (400 MHz, CDCl
3
) δ (ppm):
.17 (s, 1H), 8.11 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 7.9 Hz 1H), 7.69 (td, J = 3.2, 9.0 Hz, 2H),
.60-7.49 (m, 2H), 6.95 (td, J = 3.2, 9.0 Hz, 2H), 3.88 (t, J = 4.7 Hz, 4H), 3.17 (t, J = 4.8 Hz,
9
7
4
1
1
3
H). C NMR (100 MHz, CDCl ) δ (ppm): 165.6, 159.4, 153.6, 137.2, 135.4, 133.0, 128.9,
3
+
28.0, 127.9, 127.4, 124.0, 123.2, 44.0. HRMS (ESI-TOF) m/z: [M + Na] Calcd for
C
18
H
17
N
3
O
2
SNa 362.0939; Found 362.0936. HPLC analysis: retention time = 3.997 min; peak
area, 99.61%.
.1.26 N-(2-Morpholinophenyl)benzo[d]thiazole-2-carboxamide (4v): Yield: 200 mg (59%),
4
-1 1
mp 190-193 ºC. IR (KBr) ν: 3373, 1664, 1532, 1260 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
1
7
0.64 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.62-
1
3
.50 (m, 2H), 7.25-7.16 (m, 3H), 4.04 (t, J = 4.5 Hz 4H), 2.99 (t, J = 4.6 Hz 4H). C NMR (100
MHz, CDCl
3
) δ (ppm): 164.6, 157.4, 152.9, 141.8, 137.4, 132.5, 127.0, 126.9, 125.7, 124.7,
+
1
24.5, 122.5, 120.5, 119.6, 67.7, 52.6. HRMS (ESI-TOF) m/z: [M + Na] Calcd for
C H N O SNa 362.0939; Found 362.0936. HPLC analysis: retention time = 5.074 min; peak
18
17
3
2
area, 98.60%.
.1.27 N-(3,4,5-Trimethoxyphenyl)benzo[d]thiazole-2-carboxamide (4w): Yield: 189 mg
4
-1 1
(
3
55%), mp 160-162 ºC. IR (KBr) ν: 3368, 1665, 1510, 1319 cm . H NMR (400 MHz, CDCl ) δ
24

ACCEPTED MANUSCRIPT
(ppm): 9.21 (s, 1H), 8.13 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.62-7.54 (m, 2H), 7.10
1
3
(
s, 2H), 3.92 (s, 6H), 3.86 (s, 3H). C NMR (100 MHz, CDCl ) δ (ppm): 164.1, 157.5, 153.5,
3
1
52.7, 137.4, 135.2, 133.0, 127.1, 127.0, 124.3, 122.6, 97.4, 61.0, 56.2. HRMS (ESI-TOF) m/z:
+
[
M + Na] Calcd for C H N O SNa 367.0728; Found 367.0723. HPLC analysis: retention time
1
7
16
2
4
=
4.232 min; peak area, 96.56%.
4
.1.28 N-Mesitylbenzo[d]thiazole-2-carboxamide (4x): Yield: 177 mg (60%), mp 155-157 ºC.
-1 1
IR (KBr) ν: 3369, 1672, 1515, 1320 cm . H NMR (400 MHz, CDCl
3
) δ (ppm): 8.72 (s, 1H),
8
2
1
.13 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.59-7.52 (m, 2H), 6.96 (s, 2H), 2.31 (s, 3H),
1
3
.29 (s, 6H). C NMR (100 MHz, CDCl ) δ (ppm): 163.8, 158.2, 152.9, 137.5, 137.4, 135.2,
3
+
30.1, 129.1, 126.9, 126.9, 124.4, 122.5, 21.0, 18.5. HRMS (ESI-TOF) m/z: [M + Na] Calcd for
C H N OSNa 319.0881; Found 319.0877. HPLC analysis: retention time = 4.283 min; peak
17
16
2
area, 97.48%.
4
1
9
.1.29 5-Chloro-N-phenylbenzo[d]thiazole-2-carboxamide (6a): Yield: 216 mg (75%), mp
-1 1
60-162 ºC. IR (KBr) ν: 3366, 1681, 1536, 1308 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.22 (s, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.52
1
3
(
dd, J = 1.8, 8.6 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H). C NMR (100 MHz,
CDCl
3
) δ (ppm): 166.0, 157.2, 153.5, 136.8, 135.7, 133.2, 129.3, 127.6, 125.2, 124.1, 123.3,
+
1
19.9. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C17
H
16
N
2
OSNa 311.0022; Found 311.0011.
HPLC analysis: retention time = 4.345 min; peak area, 99.39%.
4
1
9
.1.30 5-Chloro-N-(p-tolyl)benzo[d]thiazole-2-carboxamide (6b): Yield: 247 mg, (82%), mp
-1 1
40-142 ºC. IR (KBr) ν: 3365, 1684, 1543, 1029 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.15 (s, 1H), 8.09 (s, J = 1.8 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.49 (dd,
1
3
J = 1.9, 8.6 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 2.36 (s, 3H). C NMR (100 MHz, CDCl ) δ
3
25

ACCEPTED MANUSCRIPT
(ppm): 166.2, 157.0, 153.5, 135.6, 134.9, 134.3, 133.1, 129.8, 127.5, 124.0, 123.3, 119.9, 21.0.
+
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H ClN OSNa 325.0178; Found 325.0172.
15
11
2
HPLC analysis: retention time = 4.771 min; peak area, 96.12%.
4
1
9
1
.1.31 5-Chloro-N-(m-tolyl)benzo[d]thiazole-2-carboxamide (6c): Yield: 229 mg (76%), mp
-1 1
38-142 ºC. IR (KBr) ν: 3365, 1684, 1543, 1029 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.17 (s, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.60 (s, 1H), 7.56 (d, J = 8.3 Hz,
H), 7.5 (dd, J = 1.9, 8.6 Hz, 2H), 7.29 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 2.40 (s, 3H).
1
3
C NMR (100 MHz, CDCl ) δ (ppm): 166.2, 157.1, 153.5, 139.3, 136.7, 135.6, 133.1, 129.1,
3
+
1
27.6, 126.0, 124.0, 123.3, 120.5, 117.0, 21.5. HRMS (ESI-TOF) m/z: [M + Na] Calcd for
C H ClN OSNa 325.0178; Found 325.0172. HPLC analysis: retention time = 4.613 min; peak
15
11
2
area, 98.55%.
4
1
9
7
1
.1.32 5-Chloro-N-(o-tolyl)benzo[d]thiazole-2-carboxamide (6d): Yield: 225 mg (74%), mp
-1 1
79-181 ºC. IR (KBr) ν: 3365, 1684, 1543, 1029 cm . H NMR (400 MHz, CDCl ) δ (ppm):
3
.20 (s, 1H), 8.18-8.14 (m, 2H), 7.92 (d, J = 8.6 Hz, 1H), 7.50 (dd, J = 1.6, 8.6 Hz, 1H), 7.31-
1
3
.25 (m, 2H), 7.14 (t, J = 7.4 Hz, 1H), 2.45 (s, 3H). C NMR (100 MHz, CDCl ) δ (ppm): 166.2,
3
57.2, 153.5, 135.7, 134.9, 133.1, 130.7, 128.3, 127.6, 127.1, 125.5, 124.2, 1233, 121.8, 17.7.
+
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C15
H11ClN
2
OSNa 325.0178; Found 325.0172.
HPLC analysis: retention time = 4.500 min; peak area, 96.45%.
.1.33 5-Chloro-N-(4-methoxyphenyl)benzo[d]thiazole-2-carboxamide (6e): Yield: 248 mg
4
-1 1
(
78%), mp 160-163 ºC. IR (KBr) ν: 3370, 1684, 1534, 1251 cm . H NMR (400 MHz, CDCl ) δ
3
(ppm): 9.12 (s, 1H), 8.09 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 8.9 Hz, 2H),
1
3
7
.49 (dd, J = 1.8, 8.6 Hz, 1H), 6.94 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H). C NMR (100 MHz,
CDCl ) δ (ppm): 166.3, 157.0, 156.9, 153.5, 135.6, 133.1, 130.0, 127.5, 124.0, 123.3, 121.5,
3
26

ACCEPTED MANUSCRIPT
+
1
3
4
14.4, 55.5. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C15
H11ClN
2
2
O SNa 341.0127; Found
41.0119. HPLC analysis: retention time = 4.697 min; peak area, 96.46%.
.1.34 5-Chloro-N-(3-methoxyphenyl)benzo[d]thiazole-2-carboxamide (6f): Yield: 252 mg
-1 1
(
79%), mp 139-142 ºC. IR (KBr) ν: 3370, 1684, 1534, 1251 cm . H NMR (400 MHz, CDCl ) δ
3
(ppm): 9.22 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.55-7.51 (m, 2H), 7.33 (t,
1
3
J = 8.1 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 6.78 (dd, J = 2.1, 8.1 Hz, 1H), 3.88 (s, 3H). C NMR
(
100 MHz, CDCl ) δ (ppm): 165.0, 159.3, 156.2, 152.4, 137.0, 134.6, 132.2, 129.9, 126.6, 123.1,
3
+
1
3
4
22.3, 111.1, 110.3, 104.4, 54.4. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H ClN O SNa
1
5
11
2
2
41.0127; Found 341.0119. HPLC analysis: retention time = 4.927 min; peak area, 96.04%.
.1.35 5-Chloro-N-(2-methoxyphenyl)benzo[d]thiazole-2-carboxamide (6g): Yield: 216 mg
-
1 1
(
69%), mp 163-167 ºC. IR (KBr) ν: 3370, 1684, 1534, 1251 cm . H NMR (400 MHz, CDCl
ppm): 9.84 (s, 1H), 8.51 (dd, J = 1.2, 8.0 Hz, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 8.6 Hz,
H), 7.49 (dd, J = 1.8, 8.6 Hz, 1H), 7.14 (dt, J = 1.4, 8.0 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 6.97
3
) δ
(
1
1
3
(
d, J = 8.1 Hz, 1H), 4.00 (s, 3H). C NMR (100 MHz, CDCl ) δ (ppm): 166.3, 157.1, 153.7,
3
1
48.6, 135.6, 133.0, 127.4, 126.6, 124.9, 124.3, 123.2, 121.2, 120.0, 110.2, 55.9. HRMS (ESI-
+
TOF) m/z: [M + Na] Calcd for C15
H11ClN
2
O
2
SNa 341.0127; Found 341.0119. HPLC analysis:
retention time = 5.030 min; peak area, 95.03%.
.1.36 5-Chloro-N-(4-chlorophenyl)benzo[d]thiazole-2-carboxamide (6h): Yield: 270 mg
4
-
1 1
(
(
(
84%), mp 170-181 ºC. IR (KBr) ν: 3338, 1689, 1590, 1538 cm . H NMR (400 MHz, CDCl ) δ
3
ppm): 9.21 (s, 1H), 8.09 (d, J = 1.88 Hz, 1H), 7.91 (d, J = 8.64 Hz, 1H), 7.64-7.70 (m, 2H), 7.50
1
3
dd, J = 2.0, 8.6 Hz, 1H), 7.39-7.36 (m, 2H). C NMR (100 MHz, CDCl
3
) δ (ppm): 165.6, 157.2,
1
53.4, 135.6, 135.4, 133.3, 130.2, 129.3, 127.8, 124.1, 123.3, 121.1. HRMS (ESI-TOF) m/z: [M
27

ACCEPTED MANUSCRIPT
+
+
Na] Calcd for C14
.025 min; peak area, 99.03%.
.1.37 5-Chloro-N-(3-chlorophenyl)benzo[d]thiazole-2-carboxamide (6i): Yield: 279 mg
H
8
Cl
2
N
2
OSNa 344.9632; Found 344.9651. HPLC analysis: retention time =
7
4
-1 1
(
86%), mp 168-170 ºC. IR (KBr) ν: 3338, 1689, 1590, 1538 cm . H NMR (400 MHz, CDCl ) δ
3
(ppm): 9.24 (s, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.90 (t, J = 1.9 Hz, 1H),
7
.63 (dd, J = 1.2, 8.2 Hz, 1H), 7.53 (dd, J = 1.9, 8.6 Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H) 7.20 (dd, J
1
3
=
1.0, 8.0 Hz, 1H). C NMR (100 MHz, CDCl ) δ (ppm): 165.4, 157.2, 153.4, 137.9, 135.7,
3
+
1
35.0, 133.3, 130.3, 127.8, 125.2, 124.1, 123.3, 120.0, 117.9. HRMS (ESI-TOF) m/z: [M + Na]
Calcd for C H Cl N OSNa 344.9632; Found 344.9651. HPLC analysis: retention time = 5.027
1
4
8
2
2
min; peak area, 98.06%.
.1.38 5-Chloro-N-(2-chlorophenyl)benzo[d]thiazole-2-carboxamide (6j): Yield: 250 mg
4
-1 1
(
74%), mp 195-197 ºC. IR (KBr) ν: 3338, 1689, 1590, 1538 cm . H NMR (400 MHz, CDCl
3
) δ
(ppm): 9.90 (s, 1H), 8.58 (dd, J = 1.4, 8.3 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.6 Hz,
1
H), 7.53 (dd, J = 2.0, 8.6 Hz, 1H), 7.48 (dd, J = 1.4, 8.0 Hz, 1H), 7.40-7.36 (m, 1H), 7.16 (dt, J
1
3
=
1.5, 7.8 Hz, 1H). C NMR (100 MHz, CDCl ) δ (ppm): 165.4, 157.3, 153.5, 135.7, 133.8,
3
+
1
33.2, 129.4, 127.9, 127.7, 125.5, 124.4, 123.5, 123.2, 121.3. HRMS (ESI-TOF) m/z: [M + Na]
Calcd for C14 Cl
min; peak area, 99.68%.
.1.39 5-Chloro-N-(4-fluorophenyl)benzo[d]thiazole-2-carboxamide (6k): Yield: 220 mg
H
8
2 2
N OSNa 344.9632; Found 344.9651. HPLC analysis: retention time = 7.232
4
-1 1
(
72%), mp 163-165 ºC. IR (KBr) ν: 3373, 1690, 1544, 1275 cm . H NMR (400 MHz, CDCl ) δ
3
(ppm): 9.50 (s, 1H), 8.49 (dt, J = 1.6, 8.1 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.93 (t, J = 8.7 Hz,
1
3
1
1
H), 7.51 (dd, J = 2.0, 8.6 Hz, 1H), 7.24-7.14 (m, 3H). C NMR (100 MHz, CDCl
3
) δ (ppm):
65.2, 157.3, 154.0, 153.5, 151.6, 135.7, 133.3, 127.8, 125.6, 125.5, 125.4, 125.3, 124.8, 124.8,
28