Synthesis and antitubercular evaluation of novel dibenzo[b,d]thiophene tethered imidazo[1,2-a]pyridine-3-carboxamides

Article abstract of DOI:10.1016/j.bmcl.2016.04.088

A series of novel dibenzo[b,d]thiophene tethered imidazo[1,2-a]pyridine carboxamides 7a-s were designed and synthesized. The required building block, 2-dibenzo[b,d]thiophenyl imidazo[1,2-a]pyridine carboxylic acid (5) was synthesized from commercial dibenzo[b,d]thiophene in good yields following five-step reaction sequence. The desired carboxamides 7a-s was prepared through coupling of acid 5 with various benzyl amines. All the new analogues 7a-s was characterized by their NMR and mass spectral analysis. Among nineteen new compounds 7a-s screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv, three compounds 7k (MIC: 0.78 μg/mL); 7e and 7n (MIC: 1.56 μg/mL) were identified as potent analogues with low cytotoxicity. The results reported here will help global efforts for identification of potential lead antimycobacterial agents.

Full text of DOI:10.1016/j.bmcl.2016.04.088

Accepted Manuscript
Synthesis and antitubercular evaluation of novel dibenzo[b,d]thiophene tethered
imidazo[1,2-a]pyridine-3-carboxamides
Lokesh Pulipati, Jonnalagadda Padma Sridevi, Perumal Yogeeswari,
Dharmarajan Sriram, Srinivas Kantevari
PII:
S0960-894X(16)30476-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.04.088
BMCL 23850
Reference:
Bioorganic & Medicinal Chemistry Letters
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27 April 2016
29 April 2016
Please cite this article as: Pulipati, L., Sridevi, J.P., Yogeeswari, P., Sriram, D., Kantevari, S., Synthesis and
antitubercular evaluation of novel dibenzo[b,d]thiophene tethered imidazo[1,2-a]pyridine-3-carboxamides,
Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.04.088
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Bioorganic & Medicinal Chemistry Letters
Synthesis and antitubercular evaluation of novel dibenzo[b,d]thiophene tethered
imidazo[1,2-a]pyridine-3-carboxamides
Lokesh Pulipatia, Jonnalagadda Padma Sridevib, Perumal Yogeeswari b, Dharmarajan Sriramb and Srinivas
Kantevaria,c
a Organic Chemistry Division-II (C P C Division), CSIR- Indian Institute of Chemical Technology, Hyderabad-500 007, Telangana, INDIA.
bMedicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus,
Jawahar Nagar, Hyderabad-500078, Telangana, INDIA.
cAcademy of Scientific and innovative Research, CSIR- Indian Institute of Chemical Technology, Hyderabad-500 007, Telangana, INDIA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of novel dibenzo[b,d]thiophene tethered imidazo[1,2-a]pyridine carboxamides 7a-s
were designed and synthesized. The required building block, 2-dibenzo[b,d]thiophenyl imidazo
[1,2-a]pyridine carboxylic acid (5) was synthesized from commercial dibenzo[b,d]thiophene in
good yields following five-step reaction sequence. The desired carboxamides 7a-s was prepared
through coupling of acid 5 with various benzyl amines. All the new analogues 7a-s was
characterized by their NMR and mass spectral analysis. Among nineteen new compounds 7a-s
screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv,
three compounds 7k (MIC: 0.78 µg/mL); 7e and 7n (MIC: 1.56 µg/mL) were identified as
potent analogues with low cytotoxicity. The results reported here will help global efforts for
identification of potential lead antimycobacterial agents.
Keywords:
Dibenzothiophene
Imidazole
Pyridine
Antitubercular agents
Carboxamide
2009 Elsevier Ltd All rights reserved.
Tuberculosis (TB), caused by intracellular bacterial pathogen
Mycobacterium tuberculosis (Mtb) is one of the most prevalent
and deadliest pandemic diseases worldwide.1 World Health
Organization (WHO) Global tuberculosis report 2015 estimated
that TB killed 890,000 men, 480,000 women and 140,000
children in 2014 alone and ranked alongside HIV as a leading
killer in infectious diseases.2 Also, TB is more frequent and
rampant in immune-compromised individuals suffering from
human immune deficiency virus (HIV).3 In fact, the significant
proportion of TB cases and deaths occurred in HIV positive
people.4 This disease was further aggravated by the emergence of
multi-drug resistant (MDR) and extensively drug resistant (XDR)
TB.5 These resistant strains, in turn, requires prolonged treatment
up to 24 months with the use of a cocktail of 6-8 first and second-
line drugs, which are more toxic, less effective and expensive.5
More recently totally-drug-resistant (TDR) TB also reported.6
With someone dying of TB nearly every 20s, and continuous
increase in number of drug-resistant cases, there is an urgent need
for development of fast and long acting antitubercular agents with
high potency against TB and other latent infections.7
M. tuberculosis, they are not active against other mycobacteria,
other gram-positive or gram-negative bacteria.9d Owing that IPAs
are inexpensive and readily synthesized, they have ideally suited
to structure-activity-relationship (SAR) studies with MIC values
ranging in low micro molar levels.8,9 Interestingly, some of the
IPs III-VII showed Mtb inhibition activities comparable to the
first-line anti-TB drugs.8b
Recently Kim,8 Miller9 and other groups10 used imidazo[1,2-a]
pyridine-3-acetamide of anti-insomnia drugs Zolpidem (I) and
Alpidem (II) as core skeleton for the development of newer anti-
tubercular agents. Among the several imidazo[1,2-a]pyridine
amides (IPAs) reported, two potent analogues Q-2038b & PA-
82411 (Figure 1) progressed to preclinical and Phase-II clinical
evaluations respectively. Moreover, IPAs seems to be remarkably
Figure 1: Clinical anti-insomnia drugs I & II and antitubercular agents III-
VII possessing imidazo[1,2-a]pyridine (IP) core.
selective since while they are potently active against
———
Corresponding author; Tel.: +91-4027191437; fax: +91-4027198933; e-mail: kantevari@yahoo.com, kantevari@gmail.com.
1

We recently reported12 antimycobacterial activity of various di
benzo[b,d]furan, dibenzo[b,d]thiophene and N-methyl carbazole
tethered substituted heterocycles. Structure-activity relationships
(SAR) studies suggested that dibenzo[b,d]thiophene tethered
heterocycles (VIII & IX, Figure 2) exhibited M. tuberculosis
inhibition at lower concentrations compared to the corresponding
dibenzo[b,d]furan and N-methylcarbazole derivatives.13 Apart
from antitubercular activity, dibenzo[b,d]thiophene derivatives
X-XIII (Figure 2) exhibited DNA-dependent protein kinase
(DNA-PK) inhibition.14 These observations led us to focus on
further development of dibenzo[b,d]thiophene derived newer
scaffolds for improving antitubercular activity. We, therefore,
envisaged that combining dibenzo[b,d]thiophene with IPA core
could lead to the more modern framework to evaluate as
inhibitors of Mycobacterium tuberculosis.
Table 1: Synthesis of novel dibenzo[b,d]thiophene tethered imidazo[1,2-a]
pyridine-3-carboxamide analogues 7a-s.a
Amine
(6a-s)
6a
Product Yield
(7a-s)
S.No
1.
CLogPb
7.21
7.36
7.93
7.71
9.04
7.13
8.10
8.24
R
(%)a
86
7a
-H
2.
71
72
78
63
72
74
73
6b
6c
6d
6e
6f
7b
7c
7d
7e
7f
-F
3.
-Cl
4.
-CH3
-tBu
5.
6.
-OCH3
-CF3
-OCF3
7.
6g
6h
6i
7g
7h
8.
9.
55
60
61
53
6.67
7.50
9.99
8.95
7i
7j
7k
7l
6j
10.
11.
12.
6k
Figure 2: Dibenzo[b,d]thiophene derived anti-tubercular agents VIII & and
IX DNA-PK inhibitors X-XIII.
6l
6m
13.
14.
45
37
8.98
9.55
7m
7n
6n
15.
16.
58
55
9.31
9.46
7o
7p
6o
6p
Figure 3: Design strategy for synthesis of dibenzothiophene tethered imidazo
[1,2-a] pyridine-3-carboxamide analogues
6q
6r
17.
18.
50
68
10.03
11.14
7q
7r
19.
62
10.34
7s
6s
aIsolated yield.
bCalculated using Chembiodraw 12.0 programme.
Continuing our work on the development of novel
antitubercular agents,12,13,15 we herein report the synthesis and
antitubercular evaluation of novel dibenzo[b,d]thiophene tethered
imidazo[1,2-a]pyridine-3-carboxamide analogues 7a-s. In vitro
screening of all nineteen new analogs 7a-s against
Mycobacterium tuberculosis H37Rv (Mtb) resulted in 7k (MIC:
Scheme 1: Synthesis of 2-(dibenzo[b,d]thiophen-2-yl)imidazo[1,2-a]pyridine-
3-carboxylic acid (5)
2

0.78 µg/mL), 7e and 7n (MIC: 1.56 µg/mL) as promising IPA
analogs with lower cytotoxicity profile.
standard drugs ethambutol and pyrazinamide. Two compounds
7a and 7b (MIC 3.13 µg/mL) is equipotent to standard drug
ethambutol and more potent than pyrazinamide. Among other
derivatives, two compounds 7f and 7o exhibited MIC 6.25 µg/
mL, and another three derivatives 7d, 7g and 7s showed MIC
12.5 µg/mL and were more potent than pyrazinamide.
The safety profile of antitubercular active dibenzo[b,d]
thiophene tethered imidazo[1,2-a]pyridine-3-carboxamides with
MIC ≤ 6.25 µg/mL were assessed for in vitro cytotoxicity against
Human Embryonic Kidney (HEK-293T) cells using 3-(4,5-di
methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assay.24 The promising antitubercular compounds 7a-b, 7e-f, 7k,
7n and 7o exhibited 34.6%, 25.8%, 18.76%, 36.98%, 34.78%,
24.36% and 38.4% growth inhibition of HEK-293T cells at 50.0
μg/mL concentration (Figure 5). The results indicated that potent
analogs 7e, 7k and 7n are less toxic compared to other
derivatives 7a-b, 7f and 7o.
Broadly, the designer scaffold contains three segments (Figure
3). First segment is imidazo[1,2-a]pyridine, an active
pharmacophore from clinical antitubercular TB drug Q-203
(Figure 1). Bioactive dibenzo[b,d]thiophene is the second
segment tethered to imidazo[1,2-a]pyridine core for desired
pharmacological behavior. Anti-TB activity profile of the
proposed scaffold was tuned with the choice of appended
substituted benzyl amines in the third segment.
To start synthesis, commercially available dibenzo[b,d]
thiophene was acetylated using acetyl chloride and anhydrous
AlCl3 in chloroform by following literature procedure13,16 to yield
2-acetyl dibenzo[b,d]thiophene (1), in 70% yield. Compound 1
was reacted with sodium hydride in diethyl carbonate heated at
130oC for 1.5 h to give Ethyl 3-(dibenzo[b,d]thiophen-2-yl)-3-
oxopropanoate (2) in 69% yield.17 Reaction of 2 with equimolar
NH4Br/ Oxone, refluxing in methanol for 1.5 h gave ethyl 2-
bromo-3-(dibenzo[b,d]thiophen-2-yl)-3-oxopropanoate (3) in
74% yield.18 Mono brominated β-keto ester 3 was further
condensed with 2-aminopyridine at 55oC to give 4 in excellent
yield via formation of imine-enamine.19 Saponification with
lithium hydroxide followed by acidic work up gave the desired
imidazo[1,2-a] pyridine-3-carboxylic acid 5 in 82% yield.20
Further to built the desired amide analogues, 2-(dibenzo[b,d]
thiophen-2-yl)imidazo[1,2-a]pyridine-3-carboxylic acid 5 was
coupled with various benzyl amines 6a-s using classical EDCI-
HOBT protocol21 (Table 1). For example, compound 5 was
reacted with 4-Fluoro benzyl amine 6b using EDCI/ HOBT in
o
presence of triethyl amine in DMF at 80 C to give 2-(dibenzo
[b,d]thiophen-2-yl)-N-(4-fluorobenzyl)imidazo[1,2-a] pyridine-3-
carboxamide (7b) in 71% yield. Similarly, all the compounds 7a-
s were prepared in excellent yields and were fully characterized
Figure 5: Percentage growth inhibition of HEK-293Tcells in the presence of
dibenzothiophene tethered imidazo [1,2-a] pyridine-3-carboxamides
at a concentration of 50 μg/mL.
1
by their H & 13C NMR, IR and Mass spectral data.22 ClogP
required assessing the lipophilic character of new analogs was
calculated using Chembiodraw 12.0 programme (Table 1).
On structure-activity relationship (SAR), we have not found
the best correlation in SAR among the synthesized analogues 7a-
s but indicated some unusual patterns. To describe SAR in
general; Mtb inhibition activity for all the dibenzo[b,d]thiophene
tethered imidazo[1,2-a]pyridine-3-carboxamides is varied large
extent with substituent appended in the benzyl amine unit. For
example, 4-benzyl piperidine analogue 7k exhibited best M.
tuberculosis inhibition activity (MIC: 0.78 µg/mL) among all the
synthesized compounds. Interestingly, Mtb inhibition activity
was reduced to half (MIC 1.56 µg/mL) when replaced 4-benzyl
piperidine unit of 7k with 4-chlorophenyl piperazine 7n, or with
simple tert-butyl group in 7e. Further changing substitutions on
benzyl group with phenyl ethers reduced Mtb inhibition activity
to the large extent with MIC up to 25.0 µg/mL (7p-s; Table 1).
All the newly synthesized dibenzo[b,d]thiophene tethered
imidazo[1,2-a]pyridine-3-carboxamide analogues 7a-s were
screened for in vitro antimycobacterial activity against M.
tuberculosis H37Rv (ATCC27294) by agar dilution method.23
The minimum inhibitory concentration (MIC) is defined as the
minimum concentration of compound required for complete
inhibition of the bacterial growth. The MIC values (µg/mL) of
7a-s determined in triplicate along with the standard drugs for
comparison are listed in figure 4. All nineteen new compounds
were screened showed in vitro activity against Mtb with MIC
ranging from 0.78-25.0 µg/mL. When compared to first line anti-
TB drugs all the compounds are less potent than isoniazid (0.1
µg/mL). Three compounds 7k (MIC 0.78 µg/mL) and 7e, 7n
(MIC 1.56 µg/mL) exhibited greater in vitro potency than
Figure 4. Antitubercular activity of dibenzo[b,d]thiophene tethered imidazo[1,2-a]pyridine-3-carboxamide analogues 7a-s.
3

We thank CSIR for research fellowship to LP and IICT-CSIR for
research facilities, encouragement and financial support to SK as part of
CSIR-12th FYP projects [ORIGIN, CSC 0108; DENOVA, CSC0205].
Structure-activity correlation of potent analogs 7e, 7k and 7n
was made with recently reported preclinical IPA derivatives VII,
XIV and XV (Figure 6).8b Compound 7k exhibited Mtb inhibition
activity (MIC100:1.3 µM) comparable to the reported XIV
(MIC50:1.86 µM) and XV (MIC50:2.63 µM).8 These results
indicate that dibenzo[b,d]thiophene tethered imidazo[1,2-a]
pyridine-3-carboxamide analogues 7e, 7k and 7n could be lead
analogues for further development as antitubercular drugs. The
results described here demonstrate the potential utility of
dibenzo[b,d] thiophene as pharmacophore tethered to
imidazo[1,2-a]pyridine-3-carboxamide unit for the development
of lead antitubercular agents.
References and notes
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Figure 6: SAR of preclinical IPA derivatives VII, XIV and XV, with
synthesized potent IPAs 7e, 7k and 7n
In conclusion, we have synthesized a series of novel dibenzo
[b,d]thiophene tethered imidazo[1,2-a]pyridine-3-carboxamides
7a-s via acid-amine coupling in the penultimate step. The
required building block, 2-(dibenzo[b,d]thiophen-2-yl)imidazo
[1,2-a]pyridine-3-carboxylic acid (5) was synthesized from
commercial dibenzo[b,d]thiophene in excellent yields following
five step reaction sequence described in scheme-1. All the new
analogues were fully characterized by their NMR and mass
spectral data. Among nineteen new compounds 7a-s screened for
in vitro antimycobacterial activity against Mycobacterium
tuberculosis H37Rv, three compounds 7k (MIC: 0.78 µg/mL); 7e
and 7n (MIC: 1.56 µg/mL) were identified as potent analogues
with low cytotoxicity. SAR study and Mtb inhibition activity
profile indicated that dibenzo[b,d]thiophene tethered imidazo
[1,2-a]pyridine-3-carboxamide analogues 7e, 7k and 7n could be
lead analogues for further development as antitubercular drugs.
With new anti-TB agents desperately needed, we believe that the
analogues reported in this work will help global efforts for
identification of potential lead antimycobacterial agents for
further development.
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4

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MHz, CDCl3) δ 9.49-9.46 (m, 1H), 8.62-8.59 (m, 1H), 8.24-8.18 (m, 1H),
7.94-7.86 (m, 3H), 7.82-7.76 (m, 1H), 7.51-7.44 (m, 1H), 7.08 (td, J= 6.8,
1.0 Hz, 1H), 4.32 (q, J= 7.1 Hz, 2H), 1.19 (t, J= 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 161.0, 153.3, 147.1, 139.9, 139.6, 135.5, 135.0,
130.7, 128.9, 128.3, 128.0, 126.6, 124.4, 123.3, 122.7, 121.7, 121.6,
117.3, 114.0, 60.4, 14.0; IR (KBr) 2978, 1688, 1469, 1217, 1043, 756 cm-
1; MS (ESI) m/z 373 [M+H]+; HR-MS (ESI) Calcd for C22H17N2O2S
[M+H]+: 373.10053, found: 373.09961.
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Kmentova, I.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W.
A.; Thompson, A. M. J. Med. Chem. 2015, 58(7), 3036.
12. (a) Surineni, G.; Yogeeswari, P.; Sriram, D.; Kantevari, S. Bioorg. Med.
Chem. Lett. 2014, 25, 485. (b) Yempala, T.; Sridevi, J. P.; Yogeeswari,
P.; Sriram, D.; Kantevari, S.; Eur. J. Med. Chem. 2014, 71, 160. (c)
Yempala, T.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D.; Kantevari, S.
Bioorg. Med. Chem. Lett. 2013, 23, 5393. (d) Yempala, T.; Sriram, D.;
Yogeeswari, P.; Kantevari, S. Bioorg Med Chem Lett., 2012, 22, 7426. (e)
Kantevari, S.; Yempala, T.; Yogeeswari, P.; Sriram, D.; Sridhar, B.;
Bioorg. Med. Chem. Lett. 2011, 21, 4316. (f) Kantevari, S.; Patpi, S. R.;
Addla, D.; Putapatri, S. R.; Sridhar, B.; Yogeeswari, P.; Sriram, D. ACS
Comb. Sci., 2011, 13, 427. (g) Kantevari, S.; Yempala, T.; Surineni, G.;
Sridhar, B.; Yogeeswari, P.; Sriram, D. Eur. J. Med. Chem. 2011, 46,
4827. (h) Addla, D.; Jallapally, A.; Gurram, D.; Yogeeswari, P.; Sriram,
D.; Kantevari, S. Bioorg. Med. Chem. Lett. 2014, 24, 1974. (i) Addla,
D.; Jallapally, A.; Gurram, D.; Yogeeswari, P.; Sriram, D.; Kantevari, S.
Bioorg Med Chem Lett. 2014, 24, 233.
20. 2-(Dibenzo[b,d]thiophen-2-yl)imidazo[1,2-a]pyridine-3-carboxylic
acid (5): To a solution of 4 (5.0 g, 13.4 mmol) in MeOH and THF (1:1,
20 mL) was added lithium hydroxide (27 mmol in 10 mL of water), and
stirred at room temperature overnight. The organic solvent was
evaporated and 1 N HCl was added until the pH reached 4. The pale solid
was collected by filtration, washed with water, and dried to give 5 as a
light brown solid. Yield: 3.80 g, 82%; m.p: 169-171 °C; 1H NMR (300
MHz, DMSO-d6) δ 13.14 (brs, 1H), 9.45 (d, J= 7.1 Hz, 1H), 8.76 (d, J=
1.1 Hz, 1H), 8.46-8.39 (m, 1H), 8.14-8.04 (m, 2H), 7.93 (dd, J= 8.2, 1.6
Hz, 1H), 7.85 (d, J= 9.0 Hz, 1H), 7.66-7.52 (m, 3H), 7.25 (td, J= 6.8, 1.1
Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 161.7, 151.9, 146.2, 138.7,
138.6, 134.9, 134.3, 131.1, 129.0, 128.2, 128.1, 127.0, 124.7, 123.4,
123.3, 123.0, 121.8, 116.9, 114.3, 112.0; IR (KBr) 3378, 2980, 1678,
1520, 1446, 1132, 758 cm-1; MS (ESI) m/z 345 [M+H]+; HR-MS (ESI)
Calcd for C20H13N2O2S [M+H]+: 345.06904, found: 345.06859.
21. General Procedure for synthesis of N-substituted 2-(dibenzo[b,d]thio-
phen-2-yl)imidazo[1,2-a]pyridine-3-carboxamides 7a-s. To a solution
of2-(dibenzo[b,d]thiophen-2-yl)imidazo[1,2-a]pyridine-3-carboxylic acid
5 (2.83 mmol) in anhydrous DMF (10 mL) were added 1-[3-(dimethyl
amino)propyl]-3-ethylcarbodiimide (EDCI, 3.84 mmol), 1-hydroxybenzo
triazole (HOBt, 1.54 mmol), triethyl amine (TEA, 5.12 mmol) and 6a-s
(2.56 mmol) at room temperature, and the resulting solution was heated at
70°C with stirring. After 12 h, the reaction mixture was cooled to room
temperature and evaporated. Water (50 mL) was added into the crude
residue, the resulting solid was collected by filtration, and the filtered
cake was washed with water (50 mL) and dried to afford crude product.
The resulting crude compound was purified by column chromatography
over silica gel (n hexane / EtOAc = 1:1) to give 7a-s as a white solid.
22. N-Benzyl-2-(dibenzo[b,d]thiophen-2-yl)imidazo[1,2-a]pyridine-3-
carboxamide (7a): Yield: 0.32 g, 86%; m.p. 247-249 °C; 1H NMR (300
MHz, DMSO-d6) δ 8.88 (d, J= 6.8 Hz, 1H), 8.71 (d, J= 1.1 Hz, 1H), 8.63
(t, J= 5.7 Hz, 1H), 8.32-8.24 (m, 1H), 7.85 (dd, J= 8.2, 1.6 Hz, 1H), 7.74
(d, J= 8.8 Hz, 1H), 7.60-7.42 (m, 3H), 7.36-7.18 (m, 5H), 7.10 (td, J= 6.8,
1.1 Hz, 1H), 4.48 (d, J= 6.0 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ
160.8, 145.0, 144.6, 138.7, 138.6, 138.5, 135.0, 134.7, 130.3, 128.1,
127.6, 127.5, 127.1, 126.7, 126.6, 124.8, 122.9, 122.7, 121.9, 121.8,
116.7, 115.8, 113.3, 42.6; IR (KBr) 3136, 2923, 1632, 1548, 1498, 748,
727 cm-1; MS (ESI) m/z 434 [M+H]+; HR-MS (ESI) Calcd for
C27H20N3OS [M+H]+: 434.13216, found: 434.13100. 2-(Dibenzo[b,d]
thiophen-2-yl)-N-(4-fluorobenzyl)imidazo[1,2-a]pyridine-3-
13. Patpi, S. R.; Pulipati, L.; Yogeeswari, P.; Sriram, D.; Jain, N.; Sridhar,
B.; Murthy, R.; Anjana devi, T.; Kalivendi S. V.; Kantevari, S. J. Med.
Chem. 2012, 55, 3911.
14. Finlay, M. R.; Griffin, R. J. Bioorg. Med. Chem Lett. 2012, 22(17), 5352.
15. (a) Surineni, G.; Yogeeswari, P.; Sriram, D.; Kantevari, S. Med. Chem.
Res. 2015, 24,1298. (b) Jallapally, A.; Addla, D.; Yogeeswari, P.; Sriram,
D.; Kantevari, S. Bioorg. Med. Chem. Lett. 2014, 24, 5520.
16. Grisar, M. J.; Claxton, G. P.; MacKenzie, R. D. J. Med. Chem. 1976, 19,
503.
17. Synthesis of Ethyl 3-(dibenzo[b,d]thiophen-2-yl)-3-oxopropanoate
(2): To a mixture of 1 (5.0 g, 22 mmol) and diethyl carbonate (50 mL)
was added NaH (60% in mineral oil, 1.59 g, 66 mmol) at room
temperature under N2. The mixture was heated at 130°C for 1.5 h. After
quenching the reaction with H2O, the organic materials were extracted
with CHCl3, organic layer was washed with brine, dried over anhyd.
Na2SO4, and concentrated in vacuum. The crude residue was purified
over silica gel column eluting with hexane/ethyl acetate (1:9) to give
Ethyl 3-(dibenzo[b,d]thiophen-2-yl)-3-oxopropanoate (2) as colorless
crystals. Yield: 4.6 g, 69%; m.p: 107-109 °C; 1H NMR (500 MHz,
CDCl3) δ 8.73 (d, J= 1.5 Hz, 1H), 8.25-8.20 (m, 1H), 8.01 (dd, J= 8.3, 1.6
Hz, 1H), 7.94-7.83 (m, 1H), 7.54-7.48 (m, 2H), 4.24 (q, J= 7.1 Hz, 2H),
4.11 (s, 2H), 1.27 (t, J= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
191.8, 167.4, 144.9, 139.4, 135.3, 134.6, 132.2, 127.3, 125.9, 124.7,
122.6, 121.6, 61.3, 45.9, 13.9; IR (KBr) 3059, 2980, 1733, 1676, 1229,
1022, 761 cm-1; MS (ESI) m/z 299 [M+H]+; HR-MS (ESI) Calcd for
C17H14O3NaS [M+Na]+: 321.05559, found: 321.05345.
1
carboxamide (7b) Yield: 0.28 g, 71%; m.p. 243-245 °C; H NMR (300
MHz, CDCl3) δ 9.50 (d, J= 6.9 Hz, 1H), 8.38 (d, J= 1.1 Hz, 1H), 8.07-
7.99 (m, 1H), 7.94-7.86 (m, 1H), 7.82 (d, J= 8.3 Hz, 1H), 7.70-7.59 (m,
1H), 7.57-7.42 (m, 2H), 7.41-7.31 (m, 1H), 7.09-6.92 (m, 3H), 6.81-6.69
(m, 2H), 6.27 (t, J= 5.6 Hz, 1H), 4.41 (d, J= 5.6 Hz, 2H); 13C NMR (75
MHz, DMSO-d6) δ 160.7, 145.1, 144.7, 138.7, 138.5, 134.9, 134.8, 134.7,
130.3, 129.6, 129.5, 127.6, 127.1, 126.7, 126.6, 124.7, 122.9, 122.7,
121.9, 121.8, 116.7, 114.9, 114.6, 113.3, 41.9; IR (KBr) 3168, 2922,
1639, 1549, 1504, 1219, 729 cm-1; MS (ESI) m/z 452 [M+H]+; HR-MS
(ESI) Calcd for C27H19FN3OS [M+H]+: 452.12274, found: 452.12144. N-
(4-Chlorobenzyl)-2-(dibenzo[b,d]thiophen-2-yl)imidazo[1,2-a]
18. Ethyl 2-bromo-3-(dibenzo[b,d]thiophen-2-yl)-3-oxo propanoate (3):
Oxone (6.8 g, 11 mmol) was added to the well stirred solution of 2 (3.0 g,
10 mmol) and NH4Br (1.0 g, 11 mmol) in methanol (10 ml) and the
reaction mixture was allowed to stir at reflux for 1.5 h. After completion
(monitored by TLC), the reaction mixture was quenched with saturated
aqueous sodium thiosulphate, extracted with CHCl3 (3x25 mL),
combined organic layer was washed with water, dried over anhydrous
sodium sulfate, filtered and concentrated in vacuum. Crude residue thus
obtained was purified over silica gel column chromatography to afford
pure product 3 as colorless crystals. Yield: 2.8 g, 74%; m.p: 115-117 °C;
1H NMR (500 MHz, CDCl3) δ 8.79 (d, J= 1.6 Hz, 1H), 8.25-8.21 (m,
1H), 8.05 (dd, J= 8.3, 1.6 Hz, 1H), 7.94 (d, J= 8.3 Hz, 1H), 7.55-7.51 (m,
pyridine-3-carboxamide (7c): Yield: 0.29 g, 72%; m.p. 238-240 °C; 1H
NMR (300 MHz, DMSO-d6) δ 8.90 (d, J= 6.8 Hz, 1H), 8.68 (d, J= 1.1
Hz, 1H), 8.62 (t, J= 5.7 Hz, 1H), 8.28-8.21 (m, 1H), 8.10-8.03 (m, 2H),
7.85 (dd, J= 8.5, 1.6 Hz, 1H), 7.74 (d, J= 8.8 Hz, 1H), 7.60-7.43 (m, 3H),
7.29 (q, J= 8.5 Hz, 4H), 7.10 (td, J= 6.8, 1.1 Hz, 1H), 4.45 (d, J= 5.7 Hz,
2H); 13C NMR (100 MHz, DMSO-d6) δ 160.8, 145.2, 144.7, 138.7, 138.5,
137.7, 135.0, 134.7, 131.3, 130.3, 129.4, 128.0, 127.7, 127.1, 126.8,
126.6, 124.7, 123.2, 122.8, 121.9, 116.7, 115.6, 113.4, 41.9; IR (KBr)
3138, 2922, 1632, 1542, 1494, 752, 728 cm-1; MS (ESI) m/z 468 [M+H]+;
HR-MS (ESI) Calcd for C27H19ClN3OS [M+H]+: 468.09319, found:
468.09098. 2-(Dibenzo[b,d]thiophen-2-yl)-N-(4-methylbenzyl)imidazo
[1,2-a]pyridine-3-carboxamide (7d): Yield: 0.30 g, 78%; m.p. 214-216
°C; 1H NMR (300 MHz, CDCl3) δ 9.52 (d, J= 6.9 Hz, 1H), 8.40 (d, J= 1.1
Hz, 1H), 8.09-8.02 (m, 1H), 7.92-7.86 (m, 1H), 7.79 (d, J= 8.3 Hz, 1H),
7.69-7.62 (m, 2H), 7.55-7.43 (m, 2H), 7.41-7.33 (m, 1H), 7.01-6.82 (m,
5H), 6.21 (t, J= 4.9 Hz, 1H), 4.41 (d, J= 5.4 Hz, 2H), 2.21 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.8, 147.9, 146.1, 140.3, 139.7, 137.0,
135.8, 134.9, 134.2, 129.8, 129.1, 128.1, 127.7, 127.5, 127.1, 124.5,
123.0, 122.7, 122.5, 121.9, 116.9, 114.7, 113.5, 43.1, 20.9; IR (KBr)
3132, 2925, 1632, 1544, 1496, 754 cm-1; MS (ESI) m/z 448 [M+H]+;
2H), 5.79 (s, 1H), 4.31 (q, J= 7.1, 1.2 Hz, 2H), 1.27 (t, J= 7.1 H, 3H); 13
C
NMR (75 MHz, CDCl3) δ 187.6, 165.1, 145.8, 139.5, 135.7, 134.7, 129.6,
127.6, 126.5, 125.0, 122.9, 122.8, 122.6, 121.8, 63.3, 46.5, 13.8; IR (KBr)
3059, 2981, 1733, 1675, 1498, 1227, 1081, 761 cm-1; MS (ESI) m/z 376
[M+H]+; HR-MS (ESI) Calcd for C17H14BrO3S [M+H]+: 376.98415,
found: 376.98376.
19. Ethyl
2-(dibenzo[b,d]thiophen-2-yl)imidazo[1,2-a]pyridine-3-
carboxylate (4): Mixture of Ethyl 2-bromo-3-oxo proanoate 3 (3.0 g, 10
mmol) and 2-aminopyridine (1.13 g, 12 mmol) was heated at 55°C for 3
h. After completion, the mixture was made basic (pH 8–9) by addition of
saturated Na2SO3 solution. The product was extracted with EtOAc (3×10
mL), combined organic layers washed with saturated Na2SO3 (2×10 mL),
dried over anhydrous Na2SO4, filtered and the combined organic solvent
was removed under reduced pressure. Crude residue thus obtained was
subjected to column chromatography over silica gel to afford pure Ethyl
2-(dibenzo[b,d]thiophen-2-yl)imidazo[1,2-a]pyridine-3-carboxylate (4) as
colorless crystals. Yield: 2.80 g, 74%; m.p: 147-149°C; 1H NMR (500
5

HR-MS (ESI) Calcd for C28H22N3OS [M+H]+: 448.14781, found:
448.14664. N-(4-(tert-Butyl)benzyl)-2-(dibenzo[b,d]thiophen-2-yl)
144.6, 140.1, 138.7, 138.4, 134.9, 134.8, 130.3, 128.9, 128.3, 128.0,
127.6, 127.0, 126.6, 126.5, 125.6, 124.8, 122.9, 122.7, 122.0, 121.8,
116.7, 115.9, 115.3, 113.2, 48.7, 42.2, 42.1, 37.1, 31.0; IR (KBr) 3420,
2924, 1634, 1552, 1515, 754 cm-1; MS (ESI) m/z 607 [M+H]+; HR-MS
(ESI) Calcd for C39H35N4OS [M+H]+: 607.25261, found: 607.25225. N-
(4-(4-Benzylpiperazin-1-yl)benzyl)-2-(dibenzo[b,d]thiophen-2-yl)
imidazo[1,2-a]pyridine-3-carboxamide (7l): Yield: 0.28 g, 53%; m.p.
221-223 °C; 1H NMR (500 MHz, CDCl3) δ 9.49 (d, J= 7.0 Hz, 1H), 8.42
(s, 1H), 8.12-8.08 (m, 1H), 7.89-7.85 (m, 1H), 7.78 (d, J= 8.2 Hz, 1H),
7.66-7.60 (m, 2H), 7.51-7.45 (m, 2H), 7.38-7.32 (m, 5H), 6.98-6.89 (m,
3H), 6.54 (d, J= 8.6 Hz, 2H), 6.17 (t, J= 5.1 Hz, 1H), 4.37 (d, J= 5.4 Hz,
2H), 3.57 (s, 2H), 3.05 (t, J= 4.8 Hz, 4H), 2.57 (t, J= 4.8 Hz, 4H); 13C
NMR (100 MHz, CDCl3) δ 160.7, 150.4, 147.7, 146.0, 140.1, 139.6,
137.7, 135.7, 135.0, 129.8, 129.1, 128.5, 128.1, 127.9(x2), 127.7, 127.0,
124.6, 122.9, 122.6, 122.4, 121.9, 116.8, 115.6, 114.8, 113.3, 62.9, 52.8,
48.7, 42.8; IR (KBr) 3418, 2935, 1633, 1549, 1518, 747 cm-1; MS (ESI)
m/z 608 [M+H]+; HR-MS (ESI) Calcd for C38H34N5OS [M+H]+:
608.24786, found: 608.24691. 2-(Dibenzo[b,d]thiophen-2-yl)-N-(4-(4-
(2-fluorophenyl)piperazin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-
carboxamide (7m): Yield: 0.24 g, 45%; m.p. 198-200 °C; 1H NMR (500
MHz, CDCl3) δ 9.49 (d, J= 7.0 Hz, 1H), 8.42 (s, 1H), 8.12-8.08 (m, 1H),
7.89-7.85 (m, 1H), 7.78 (d, J= 8.2 Hz, 1H), 7.66-7.60 (m, 2H), 7.51-7.45
(m, 2H), 7.38-7.32 (m, 5H), 6.98-6.89 (m, 3H), 6.54 (d, J= 8.6 Hz, 2H),
6.17 (t, J= 5.1 Hz, 1H), 4.37 (d, J= 5.4 Hz, 2H), 3.57 (s, 2H), 3.05 (t, J=
4.8 Hz, 4H), 2.57 (t, J= 4.8 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 160.7,
156.6, 154.7, 150.4, 147.8, 146.1, 140.2, 139.9, 139.7, 135.8, 135.0,
129.8, 128.6, 128.4, 128.1, 127.8, 127.2, 127.1, 124.6, 124.4, 123.0,
122.7, 122.6, 121.9, 118.9, 116.9, 116.2, 116.0, 114.8, 113.5, 50.4, 49.1,
42.9; IR (KBr) 3449, 2923, 1658, 1635, 1499, 1229, 1084, 737 cm-1; MS
(ESI) m/z 612 [M+H]+; HR-MS (ESI) Calcd for C37H31FN5OS [M+H]+:
612.22279, found: 612.22186. N-(4-(4-(4-Chlorophenyl)piperazin-1-yl)
benzyl)-2-(dibenzo[b,d]thiophen-2-yl)imidazo[1,2-a]pyridine-3-
imidazo[1,2-a]pyridine-3-carboxamide (7e): Yield: 0.31 g, 63%; m.p.
1
234-236 °C; H NMR (300 MHz, CDCl3) δ 9.57 (dt, J= 7.0, 1.0 Hz, 1H),
8.49 (d, J= 1.2 Hz, 1H), 8.19-8.15 (m, 1H), 7.93-7.88 (m, 1H), 7.80 (d, J=
8.0 Hz, 1H), 7.73-7.65 (m, 2H), 7.56-7.47 (m, 2H), 7.44-7.38 (m, 1H),
7.08-7.04 (m, 2H), 7.01 (dt, J= 7.0, 1.2 Hz, 1H), 6.99-6.95 (m, 2H), 6.10
(t, J= 5.4 Hz, 1H), 4.45 (d, J= 5.6 Hz, 2H), 1.21 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 160.8, 150.2, 147.7, 145.9, 140.1, 139.6, 135.7, 134.9,
134.2, 129.7, 127.9, 127.7, 127.4, 127.0, 125.3, 124.6, 122.8, 122.7,
122.4, 121.9, 116.7, 114.7, 113.3, 43.0, 34.3, 31.1; IR (KBr) 3135, 2924,
1635, 1544, 1495, 753 cm-1; MS (ESI) m/z 490 [M+H]+ HR-MS (ESI)
Calcd for C31H28N3OS [M+H]+: 490.19476 found: 490.19031. 2-
(Dibenzo[b,d]thiophen-2-yl)-N-(4-methoxybenzyl)imidazo[1,2-a]
1
pyridine-3-carboxamide (7f): Yield: 0.29 g, 72%; m.p. 228-230 °C; H
NMR (500 MHz, CDCl3) δ 9.53 (d, J= 7.0 Hz, 1H), 8.41 (d, J= 1.3 Hz,
1H), 8.07-8.05 (m, 1H), 7.90-7.87 (m, 1H), 7.81 (d, J= 8.0 Hz, 1H), 7.68-
7.65 (m, 2H), 7.53-7.45 (m, 2H), 7.40-7.36 (m, 1H), 7.00-6.94 (m, 3H),
6.58-6.55 (m, 2H), 6.14 (br t, 1H), 4.39 (d, J= 5.4 Hz, 2H), 3.68 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 160.8, 158.8, 148.0, 146.2, 140.4, 139.7,
135.9, 135.0, 129.8, 129.4, 128.9, 128.2, 127.8, 127.3, 127.1, 124.6,
123.1, 122.7(x2), 121.9, 117.0, 114.8, 113.8, 113.6, 55.1, 42.8; IR (KBr)
3134, 2924, 1630, 1545, 1492, 753 cm-1; MS (ESI) m/z 464 [M+H]+;
HR-MS (ESI) Calcd for C28H22N3O2S [M+H]+: 464.14272, found:
464.14045.
2-(Dibenzo[b,d]thiophen-2-yl)-N-(4-(trifluoromethyl)
benzyl)imidazo[1,2-a]pyridine-3-carboxamide (7g): Yield: 0.32 g,
74%; m.p. 240-242 °C; 1H NMR (500 MHz, CDCl3) δ 9.50 (d, J= 7.0 Hz,
1H), 8.40 (d, J= 1.0 Hz, 1H), 8.04 (d, J= 7.6 Hz, 1H), 7.89 (d, J= 7.7 Hz,
1H), 7.83 (d, J= 8.2 Hz, 1H), 7.68-7.61 (m, 2H), 7.54-7.45 (m, 2H), 7.40-
7.33 (m, 3H), 7.20 (d, J= 7.9 Hz, 1H), 6.97 (td, J= 7.0, 0.9 Hz, 1H), 6.34
(t, J= 5.6 Hz, 1H), 4.49 (d, J= 5.8 Hz, 2H); 13C NMR (125 MHz, CDCl3)
δ 161.0, 148.5, 146.4, 141.7, 140.6, 139.8, 136.0, 134.8, 129.9, 128.3,
127.8, 127.7, 127.5, 127.3, 125.4(x2), 124.7, 123.2, 122.9, 122.6, 121.7,
117.1, 114.4, 113.8, 42.8; IR (KBr) 3142, 2924, 1637, 1550, 1326, 1119,
753 cm-1; MS (ESI) m/z 502 [M+H]+; HR-MS (ESI) Calcd for
C28H19F3N3OS [M+H]+: 502.11954, found: 502.11819. 2-(Dibenzo[b,d]
thiophen-2-yl)-N-(4-(trifluoromethoxy)benzyl)imidazo[1,2-a]
1
carboxamide (7n): Yield: 0.20 g, 37%; m.p. 228-230 °C; H NMR (500
MHz, CDCl3) δ 9.54 (d, J= 7.0 Hz, 1H), 8.44 (d, J= 1.2 Hz, 1H), 8.13-
8.10 (m, 1H), 7.89-7.86 (m, 1H), 7.81 (d, J= 8.2 Hz, 1H), 7.70-7.66 (m,
2H), 7.53-7.46 (m, 2H), 7.41-7.37 (m, 6H), 6.60 (d, J= 8.6 Hz, 2H), 6.12
(br t, 1H), 4.39 (d, J= 5.4 Hz, 2H), 3.28-3.24 (m, 4H), 3.20-3.15 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 160.6, 150.2, 149.7, 145.9, 140.5, 139.7,
135.9, 135.0, 129.0, 128.7, 128.2, 127.8, 127.6, 127.1, 124.9, 124.7,
123.2, 122.7, 122.0, 117.5, 116.8, 116.2, 114.9, 113.8, 49.2, 49.0, 42.9;
IR (KBr) 3338, 2917, 1619, 1520, 1495, 1227, 759 cm-1; MS (ESI) m/z
pyridine-3-carboxamide (7h): Yield: 0.33 g, 73%; m.p. 203-205 °C; 1H
NMR (400 MHz, CDCl3) δ 9.51 (d, J= 6.9 Hz, 1H), 8.41 (d, J= 1.2 Hz,
1H), 8.09-8.05 (m, 1H), 7.91-7.88 (m, 1H), 7.82 (d, J= 8.1 Hz, 1H), 7.67-
7.62 (m, 2H), 7.54-7.45 (m, 2H), 7.40-7.35 (m, 1H), 7.13-7.09 (m, 2H),
7.00-6.92 (m, 3H), 6.28 (t, J= 5.6 Hz, 1H), 4.45 (d, J= 5.8 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 160.9, 148.3, 148.1, 146.2, 140.4, 139.7, 136.4,
135.8, 134.8, 129.7, 129.0, 128.0, 127.6, 127.2, 124.6, 122.9, 122.8,
121.7, 120.9, 116.8, 114.5, 113.5, 42.5; IR (KBr) 3144, 2925, 1635, 1554,
1325, 1112, 759 cm-1; MS (ESI) m/z 518 [M+H]+; HR-MS (ESI) Calcd
for C28H18F3N3O2S [M+H]+: 518.11446, found: 518.11347. 2-(Dibenzo
[b,d]thiophen-2-yl)-N-(4-morpholinobenzyl)imidazo[1,2-a]pyridine-3-
628 [M+H]+; HR-MS (ESI) Calcd for
628.19324, found: 628.19171. 2-(Dibenzo[b,d]thiophen-2-yl)-N-(4-(4-
fluorophenoxy)benzyl)imidazo[1,2-a]pyridine-3-carboxamide (7p):
C37H31ClN5OS [M+H]+:
Yield: 0.26 g, 55%; m.p. 230-232 °C; 1H NMR (400 MHz, CDCl3) δ 9.52
(d, J= 6.9 Hz, 1H), 8.45 (d, J= 0.9 Hz, 1H), 8.12-8.07 (m, 1H), 7.88-7.81
(m, 2H), 7.71-7.64 (m, 2H), 7.52-7.34 (m, 3H), 7.06-6.95 (m, 5H), 6.92-
6.85 (m, 2H), 6.66 (d, J= 8.5 Hz, 2H), 6.25 (br t, 1H), 4.43 (d, J= 5.6 Hz,
2H); 13C NMR (125 MHz, CDCl3) δ 160.9, 159.7, 157.8, 156.9, 152.5,
148.0, 146.2, 140.5, 139.7, 135.9, 134.9, 132.0, 129.8, 129.1, 128.2,
127.8, 127.5, 127.2, 124.7, 123.2, 122.8, 122.7, 121.8, 120.5, 118.0,
117.0, 116.3, 114.6, 113.7, 42.8; IR (KBr) 3152, 2928, 1634, 1550, 1498,
1251, 748 cm-1; MS (ESI) m/z 544 [M+H]+; HR-MS (ESI) Calcd for
C33H23FN3O2S [M+H]+: 544.14895, found: 544.14747. N-(4-(4-(tert-
Butyl)phenoxy)benzyl)-2-(dibenzo[b,d]thiophen-2-yl)imidazo[1,2-a]
pyridine-3-carboxamide (7r): Yield: 0.34 g, 68%; m.p. 216-218 °C; 1H
NMR (500 MHz, CDCl3) δ 9.52 (d, J= 6.8 Hz, 1H), 8.44 (d, J= 1.2 Hz,
1H), 8.11-8.06 (m, 1H), 7.87-7.81 (m, 2H), 7.70-7.62 (m, 2H), 7.51-7.42
(m, 2H), 7.40-7.31 (m, 2H), 7.06-7.01 (m, 2H), 6.96 (dt, J= 7.1, 1.2 Hz,
1H), 6.89-6.84 (m, 2H), 6.75-6.69 (m, 2H), 6.26 (t, J= 5.6 Hz, 1H), 4.43
(d, J= 5.6 Hz, 2H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 160.8,
156.8, 154.3, 147.7, 146.1, 146.0, 140.1, 139.5, 135.7, 134.8, 131.9,
129.7, 129.1, 127.9, 127.6, 127.0(x2), 126.4, 124.6, 122.8, 122.6, 122.3,
121.8, 118.4, 118.3, 116.7, 114.6, 113.3, 42.7, 34.2, 31.4; IR (KBr) 3154,
2957, 1638, 1551, 1500, 1241, 753 cm-1; MS (ESI) m/z 582 [M+H]+; HR-
MS (ESI) Calcd for C37H32N3O2S [M+H]+: 582.22097, found: 582.21978.
2-(Dibenzo[b,d]thiophen-2-yl)-N-(4-(4-(trifluoromethoxy)phenoxy)
benzyl)imidazo[1,2-a]pyridine-3-carboxamide (7s): Yield: 0.33 g,
62%; m.p.216-218 °C; 1H NMR (500 MHz, CDCl3) δ 9.51 (td, J= 7.0, 1.0
Hz, 1H), 8.43 (d, J= 1.2 Hz, 1H), 8.10-8.07 (m, 1H), 7.87-7.82 (m, 2H),
7.68 (dd, J= 8.2, 1.6 Hz, 1H), 7.64 (td, J= 9.0, 1.0 Hz, 1H), 7.50-7.43 (m,
2H), 7.37 (dq, J= 6.8, 1.2 Hz, 1H), 7.19-7.14 (m, 2H), 7.06 (d, J= 8.5 Hz,
1H), 6.97 (dt, J= 7.0, 1.2 Hz, 1H), 6.92-6.88 (m, 2H), 6.72-6.68 (m, 2H),
6.26 (t, J= 5.6 Hz, 1H), 4.44 (d, J= 5.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 160.9, 155.9, 155.4, 147.8, 146.1, 144.3, 140.2, 139.5, 135.7,
134.8, 132.9, 129.8, 129.2, 127.9, 127.7, 127.1, 124.6, 122.9, 122.7,
122.4, 121.7, 119.4, 118.8, 116.7, 114.5, 113.4, 42.7; IR (KBr) 3143,
2923, 1636, 1549, 1497, 1246, 1163, 753 cm-1; MS (ESI) m/z 610
1
carboxamide (7i): Yield: 0.25 g, 55%; m.p. 200-202 °C; H NMR (500
MHz, CDCl3) δ 9.50 (dt, J= 7.0, 1.0 Hz, 1H), 8.41 (d, J= 1.2 Hz, 1H),
8.11-8.07 (m, 1H), 7.90-7.86 (m, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.67-7.60
(m, 2H), 7.54-7.45 (m, 2H), 7.38-7.33 (m, 1H), 6.99-6.91 (m, 2H), 6.56-
6.51 (m, 2H), 6.17 (t, J= 5.4 Hz, 1H), 4.38 (d, J= 5.4 Hz, 2H), 3.82 (t, J=
4.8 Hz, 4H), 2.99 (t, J= 4.8 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 160.7,
150.4, 147.7, 146.0, 140.1, 139.6, 135.7, 135.0, 129.8, 128.6, 128.4,
128.0, 127.7, 127.1, 127.0, 124.6, 122.9, 122.6, 122.5, 121.9, 116.8,
115.4, 114.8, 113.4, 66.7, 49.0, 42.8; IR (KBr) 3218, 2958, 1637, 1514,
1225, 759 cm-1; MS (ESI) m/z 519 [M+H]+; HR-MS (ESI) Calcd for
C31H27N4O2S [M+H]+: 519.18492, found: 519.18417. 2-(Dibenzo[b,d]
thiophen-2-yl)-N-(4-thiomorpholinobenzyl)imidazo[1,2-a] pyridine-3-
1
carboxamide (7j): Yield: 0.28 g, 60%; m.p. 213-215 °C; H NMR (500
MHz, CDCl3) δ 9.56 (dt, J= 7.0, 1.0 Hz, 1H), 8.45 (d, J= 1.2 Hz, 1H),
8.15-8.11 (m, 1H), 7.92-7.88 (m, 1H), 7.82 (d, J= 8.2 Hz, 1H), 7.71-7.66
(m, 2H), 7.55-7.46 (m, 2H), 7.43-7.38 (m, 1H), 7.00 (td, J= 7.0, 1.2 Hz,
1H), 6.93-6.89 (m, 2H), 6.53-6.47 (m, 2H), 6.06 (t, J= 5.3 Hz, 1H), 4.38
(d, J= 5.4 Hz, 2H), 3.41-3.36 (m, 4H), 2.70-2.65 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 160.7, 150.3, 147.7, 146.1, 140.3, 139.7, 135.9, 135.0,
129.7, 128.7, 128.2, 127.8, 127.4, 127.1, 124.7, 123.1, 122.7, 121.9,
116.9, 116.8, 114.8, 113.6, 51.8, 42.9, 26.5; IR (KBr) 3216, 29235, 1638,
1520, 1224, 761 cm-1; MS (ESI) m/z 535 [M+H]+; HR-MS (ESI) Calcd
for C31H27N4O2S [M+H]+: 535.16208, found: 535.16169. N-(4-(4-Benzyl
piperidin-1-yl)benzyl)-2-(dibenzo[b,d]thiophen-2-yl)imidazo[1,2-a]
pyridine-3-carboxamide (7k): Yield: 0.32 g, 61%; m.p. 212-214 °C; 1H
NMR (500 MHz, CDCl3) δ 8.87 (d, J= 6.8 Hz, 1H), 8.70 (d, J= 1.1 Hz,
1H), 8.45 (d, J= 5.7 Hz, 1H), 8.32-8.26 (m, 1H), 8.09-7.96 (m, 2H), 7.84-
7.79 (m, 1H), 7.72 (d, J= 9.0 Hz, 1H), 7.57-7.40 (m, 3H), 7.34-7.26 (m,
2H), 7.23-7.15 (m, 3H), 6.66 (d, J= 8.8 Hz, 2H), 4.35 (d, J= 5.5 Hz, 2H),
3.52 (d, J= 12.3 Hz, 2H), 2.55-2.48 (m, 5H), 1.61 (d, J= 12.1 Hz, 2H),
1.31-1.14 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 160.5, 150.0, 144.9,
6

[M+H]+; HR-MS (ESI) Calcd for C34H23F3N3O3S [M+H]+: 610.14067,
found: 610.13693.
23. Antitubercular evaluation assay: Two-fold serial dilutions (50.0, 25.0,
12.5, 6.25, 3.13, 1.56, 0.78 and 0.4 µg/mL) of each test compounds 7a-s,
and drugs were prepared and incorporated into Middlebrook 7H11 agar
medium with OADC Growth Supplement. Inoculum of M. tuberculosis
H37Rv (ATCC 27294) was prepared from fresh Middlebrook 7H11 agar
slants with OADC (oleic acid, albumin, dextrose and catalase; Difco)
Growth Supplement adjusted to 1 mg/mL (wet weight) in Tween 80
(0.05%) saline diluted to 10−2 to give a concentration of ~ 107 cfu/mL. A
5 μL amount of bacterial suspension was spotted into 7H11 agar tubes
containing two-fold serial dilutions of drugs per mL. The tubes were
incubated at 37 °C, and final readings were recorded after 28 days. This
method is similar to that recommended by the National Committee for
Clinical Laboratory Standards for the determination of MIC in triplicate.
24. Evaluation of cytotoxicity: Antitubercular active compounds with MIC
≤ 12.5μg/mL were further examined for toxicity in a HEK-293T cell line
at the concentration of 50 µg/mL. After 72 h of exposure, viability of
HEK-293T cells were assessed based on cellular conversion of MTT into
a formazan product using the Promega Cell Titer 96 non-radioactive cell
proliferation assay.
Supplementary Material
Copies of 1H, 13C NMR and mass spectra of all the compounds 7a-s can
be obtained free of charge from the internet.
7

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Synthesis and antitubercular evaluation of novel dibenzo[b,d]
thiophene tethered imidazo[1,2-a]pyridine-3-carboxamides.
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Lokesh Pulipati, Jonnalagadda Padma Sridevi , Perumal Yogeeswari, Darmarajan Sriram and Srinivas Kantevari*
R
MIC (μg/mL)
Entry
7e
t-Butyl
1.56
0.78
1.56
7k
7n
8