Design, synthesis and antimycobacterial activity of novel imidazo[1,2-a]pyridine amide-cinnamamide hybrids

Article abstract of DOI:10.3390/molecules21010049

We report herein the design and synthesis of a series of novel imidazo[1,2- A]pyridine amide-cinnamamide hybrids linked via an alkyl carbon chain. All 38 new hybrids were evaluated for their antimycobacterial activity against M. tuberculosis (MTB) H37Rv ATCC 27294 using the microplate Alamar Blue assay (MABA). Although the hybrids are less active than the two reference compounds, the promising activity (MICs: 4 μg/mL) of 2,6-dimethylimidazo[1,2-a]pyridine amide-cinnamamide hybrids 11e and 11k could be a good starting point to further find new lead compounds against multi-drug-resistant tuberculosis.

Full text of DOI:10.3390/molecules21010049

Article
Design, Synthesis and Antimycobacterial
Activity of Novel Imidazo[1,2-a]pyridine
Amide-Cinnamamide Hybrids
Linhu Li 1, Zhuorong Li 1, Mingliang Liu 1,*, Weiyi Shen 2, Bin Wang 3, Huiyuan Guo 1
and Yu Lu 3,
*
Received: 2 November 2015 ; Accepted: 23 December 2015 ; Published: 30 December 2015
Academic Editor: Derek J. McPhee
1
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing 100050, China; lilinhu0627@163.com (L.L.); l-z-r@263.net (Z.L.);
guohuiyuan108@126.com (H.G.)
Zhejiang Starry Pharmaceutical Co. Ltd., Xianju 317300, China; swy109@starrypharma.com
2
3
Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology,
Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital,
Capital Medical University, Beijing 101149, China; chaofanguodu123@163.com
*
Correspondence: lmllyx@126.com (M.L.); luyu4876@hotmail.com (Y.L.); Tel./Fax: +86-10-6303-6965 (M.L.);
Tel.: +86-10-8950-9357 (Y.L.); Fax: +86-10-8050-5770 (Y.L.)
Abstract: We report herein the design and synthesis of a series of novel imidazo[1,2-a]pyridine
amide-cinnamamide hybrids linked via an alkyl carbon chain. All 38 new hybrids were evaluated for
their antimycobacterial activity against M. tuberculosis (MTB) H37Rv ATCC 27294 using the microplate
Alamar Blue assay (MABA). Although the hybrids are less active than the two reference compounds,
the promising activity (MICs: 4 µg/mL) of 2,6-dimethylimidazo[1,2-a]pyridine amide-cinnamamide
hybrids 11e and 11k could be a good starting point to further find new lead compounds against
multi-drug-resistant tuberculosis.
Keywords: imidazo[1,2-a]pyridine amide-cinnamamide hybrids; design; synthesis; antimycobacterial
activity
1. Introduction
Tuberculosis (TB), including multi-drug-resistant TB (MDR-TB) and extensively-drug-resistant
TB (XDR-TB), as well as the lethal combination represented by HIV co-infection, constitutes an
unacceptable burden of human suffering and loss [1,2]. For example, the current therapy requires at
least 20 months of treatment for MDR-TB. For these infections, several novel candidates are currently
in clinical trials [3–5], and one of them, Bedaquiline, was approved by the FDA in December 2012 for
the treatment of MDR-TB. However, its wide application may be limited because of serious adverse
effects, such as cardiac arrhythmias [6]. Therefore, there is still an urgent need for new anti-TB drugs
that target novel biological pathways in M. tuberculosis (MTB), shorten therapy and reduce the burden
of latent infection [7].
In recent years, imidazo[1,2-a]pyridine amides (IPAs) targeting the QcrB subunit of the
menaquinol cytochrome c oxidoreductase (bc1 complex), which is a critical component of mycobacterial
energy metabolism [
and -sensitive strains [
are currently in pre-clinical and phase I clinical development [11
8
], have attracted broad attention due to their potent activity against MTB-resistant
15]. Two promising drug candidates, ND-09759 (Figure 1) and Q203 (Figure 1),
16], respectively. It has been generally
9–
,
accepted that the carboxamide linker with the N-benzylic group is critical for anti-MTB activity [12],
but IPA derivatives containing a N-(2-phenoxyl)ethyl or N-(2-phenylamino)ethyl moiety, such as
Molecules 2016, 21, 49; doi:10.3390/molecules21010049
www.mdpi.com/journal/molecules

Molecules 2016, 21, 49
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IMB1502 (Figure 1), were observed to have nanomolar potency against MTB H37Rv and MDR-MTB
strains in our lab [17].
On the other hand, trans-cinnamic acid derivatives are an important class of molecules by reason
of their wide spectrum of pharmacological profiles, including antioxidative [18], antitumor [19],
antibacterial [20] and antitubercular [21] properties. It is of interest to note that cinnamic acid was used
for TB even before the current therapy was discovered [22]. Additionally, cinnamic acid was found
to act synergistically with isoniazid, rifamycin and other known anti-TB agents against MTB [23].
Additionally, rifamycin SV, a hybrid derivative of cinnamic acid and rifamycin, was observed to
show higher activity against most of the tested MTB and MDR-MTB strains than its individual
counterparts [24]. Recently, several natural products containing a cinnamic acid moiety were reported
as anti-TB agents [25–28], such as pisoniamide (Figure 1), a natural cinnamamide isolated from
Pisonia aculeate [29].
Figure 1. Structures of selected anti-tuberculosis (TB) compounds and the design of imidazo[1,2-a]
pyridine amide-cinnamamide hybrids.
In our continuous program in the search of potent and safe IMB1502 derivatives, we intended
to construct a new class of hybrids as attractive anti-TB agents by molecular hybridization between
IMB1502 and pisoniamide. A detailed structural comparison revealed that both of them are composed
of a delocalized aromatic pharmacophore (green) and a hydrophobic moiety (purple) connected via a
same ethylidyne linkage (black, Figure 1). Therefore, a series of novel hybrid structures containing
IPA and cinnamamide moieties linked via an alkyl carbon chain (ethylidyne or propylidyne) were
designed and synthesized in this study (Figure 1), with the hope that these target compounds would
exhibit improved anti-MTB activity.
2. Results and Discussion
2.1. Chemistry
Detailed synthetic pathways to cinnamamide derivatives
in Schemes 1 and 2 respectively. Commercially available cinnamic acids 1a
chloride at reflux to give the corresponding acyl chlorides 2a . Condensation of the resulting 2a
with tert-butyl (2-aminoethyl)carbamate or tert-butyl (3-aminopropyl)carbamate in the presence of
5–
6
and novel hybrids 11–14 are depicted
–
l
were treated with thionyl
–
l
–l

Molecules 2016, 21, 49
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triethylamine (NEt3) yielded 3a
–
l
and 4a
–g
, respectively, which were hydrolyzed with trifluoroacetic
acid (TFA) to afford the desired cinnamamide derivatives 5a–l and 6a–g as TFA salts (Scheme 1).
Scheme 1. Synthesis of cinnamamide derivatives 5a
–l and 6a–g. Reagents and conditions: (i) SOCl2,
DMF, relux, 4 h; (ii) Net3, CH2Cl2, rt, 2 h, 59%–75% (for two steps); (iii) TFA CHCl3, rt, 1 h, 100%.
The target Compounds 11
pyridine-3-carboxylate and ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate
hydrolysis in LiOH–EtOH and condensation with the above cinnamamide derivatives 5a
–
14 were conveniently prepared from ethyl 2,6-dimethylimidazo[1,2-a]
30 31], by
and 6a
7
8 [ ,
–
l
–g
in the presence of bis(2-oxo-3-oxazolidinyl)phosphonic chloride (BOP-Cl) and NEt3, successively
(Scheme 2).
Scheme 2. Synthesis of imidazo[1,2-a]pyridine amide-cinnamamide hybrids 11–14. Reagents and
conditions: (iv) LiOH, EtOH, rt, overnight, 78%–87%; (v) BOP-Cl, Net3, CH2Cl2, rt, 2 h, 32%–72%.
2.2. Anti-MTB Activity
The target Compounds 11
27294 using the microplate Alamar Blue assay (MABA) [32
(MIC) is defined as the lowest concentration effecting a reduction in fluorescence of
mean of replicate bacterium-only controls, and MICs of 11 14 along with IMB1502 and isoniazid (INH)
for comparison are presented in Table 1. The data reveal that all of the new synthesized hybrids 11–14
(MICs: 4–>32 g/mL) are much less active than the reference drug INH (MIC: 0.05 g/mL) and the
parent compound IMB1502 (MIC: 0.015 µg/mL), but fourteen of them have potential activity against
this strain (MICs: 4–32 g/mL). Among them, Compounds 11e and 11k display the highest activity
(MICs: 4 g/mL), and Compounds 11k and 11e have also promising activity with MICs of 8 and
–
14 were evaluated for their in vitro activity against MTB H37Rv ATCC
33]. The minimum inhibitory concentration
90% relative to the
,
ě
–
µ
µ
µ
µ
16 µg/mL, respectively, against MTB H37Rv ATCC 27294.
Variations (R1) on the benzene ring of the cinnamamide moiety in this study include methyl,
methoxy, trifluoromethyl, trifluoromethoxy, nitro, fluoro, chloro, 3,4-dichloro, 3,4,5-trimethoxyl
and hydrogen substitution (Table 1). Generally, compounds with multi-substituents (3,4-dichloro,
3,4,5-trimethoxyl) or without a substituent (hydrogen) on the benzene ring, like many mono-substituted
(fluoro, chloro, methyl, methoxy, nitro) hybrids, are inactive (MICs:
the case of the hybrids with MICs of 4–16 g/mL, the 2,6-dimethylimidazo[1,2-a]pyridineamide
moiety is more active than the responding 2,7-dimethylimidazo[1,2-a]pyridineamide one (11e vs. 12e
ě32 µg/mL) in this study. In
µ
;

Molecules 2016, 21, 49
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11k vs. 12k). On the other hand, the hybrids with an ethylidyne linker (n = 2) seem to be more potent
than the analogs containing a propylidyne one (n = 3) (11e vs. 13e 12e vs. 14e), which is consistent with
;
the structure-activity relationship (SAR) in our previous study [17]. Moreover, in the series of Hybrids
11 and 12 (n = 2), introduction of an electron-donating mono-substituted group (R1 = methyl, methoxy)
instead of an electron-withdrawing one (R1 = trifluoromethyl, trifluoromethoxy) is significantly
detrimental to the activity (11a vs. 11e
; 11d vs. 11k; 12a vs. 12e; 12d vs. 12k). Finally, representative
IMPs (5e 6e) and cinnamamide (15) were, as expected, found to have no anti-MTB activity (MICs:
,
>32 µg/mL), which highlights the design rationality of our hybrids in this study.
Table 1. Anti-M. tuberculosis (MTB) activity of imidazo[1,2-a]pyridine amide-cinnamamide Hybrids
11–14.
Compound
R1
MIC (µg/mL)
Compd.
R1
MIC (µg/mL)
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
13a
13b
13c
13d
13e
13f
13g
5e
4-CH3
3,4,5-tri-OCH3
3,4-di-Cl
4-OCH3
4-CF3
>32
>32
>32
>32
4
>32
>32
>32
>32
32
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
14a
14b
14c
14d
14e
4-CH3
3,4,5-tri-OCH3
3,4-di-Cl
4-OCH3
4-CF3
>32
>32
32
>32
16
>32
>32
>32
>32
>32
8
>32
>32
>32
>32
32
2-F
4-F
3-F
4-Cl
4-NO2
4-OCF3
H
2-F
4-F
3-F
4-Cl
4-NO2
4-OCF3
H
4
>32
32
4-CH3
3,4,5-tri-OCH3
3,4-di-Cl
4-OCH3
4-CF3
4-CH3
3,4,5-tri-OCH3
3,4-di-Cl
4-OCH3
4-CF3
32
>32
>32
32
32
32
>32
>32
>32
32
>32
32
0.05
0.015
2-F
4-F
14f
14g
2-F
4-F
isoniazid
IMB1502
6e
15
3. Materials and Methods
3.1. Chemistry
1
Melting points were determined in open capillaries and are uncorrected. H-NMR spectra were
determined on a Varian Mercury-400 spectrometer in DMSO-d6, D2O or CDCl3 using tetramethylsilane
as an internal standard (see Supplementary Materials). Electrospray ionization (ESI) mass spectra
and high resolution mass spectra (HRMS) were obtained on an MDSSCIEX Q-Tap mass spectrometer.
The reagents were all of analytical grade or chemically pure. TLC was performed on silica gel plates
(Merck, ART5554 60F254, Kenilworth, NJ, USA).

Molecules 2016, 21, 49
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3.2. Synthesis
3.2.1. General Procedure for the Synthesis of Imidazo[1,2-a]pyridine-3-carboxylic Acids 9, 10
To a solution of 7, 8 (4.0 mmol) in EtOH (30 mL) was added an aqueous solution of lithium
hydroxide (12.0 mmol in 10 mL of water), and the mixture was stirred at room temperature overnight.
The organic solvent was evaporated, and 1N HCl was added until the pH = 6. The residual was
collected by filtration, washed with water and dried to give 9, 10.
Ethyl 2,6-dimethylimidazo[1,2-a]pyridine-3-˝carboxylate acid (
9
): The title compound was obtained from
1
7
as a white solid (87%); m.p.: 173–175 C. H-NMR (500 MHz, DMSO-d6)
δ
(ppm): 12.93 (s, 1H,
-COOH), 9.08 (s, 1H, pyridine-H), 7.55 (d, J = 9.1 Hz, 1H, pyridine-H), 7.36 (dd, J = 9.1, 1.6 Hz, 1H,
pyridine-H), 2.57 (s, 3H, CH3), 2.35 (s, 3H, CH3). MS-ESI (m/z): 191 [M + H]+.
Ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate acid (10): The title compound was obtained from
˝
1
8
as a white solid (78%); m.p.: 161–163 C. H-NMR (400 MHz, DMSO-d6) δ (ppm): 12.90 (s, 1H,
-COOH), 9.12 (d, J = 7.1 Hz, 1H, pyridine-H), 7.47–7.38 (m, 1H, pyridine-H), 6.98 (dd, J = 7.1, 1.7 Hz,
1H, pyridine-H), 2.56 (s, 3H, CH3), 2.40 (s, 3H, CH3). MS-ESI (m/z): 191 [M + H]+.
3.2.2. General Procedure for the Synthesis of Cinnamamide Derivatives 5a–l and 6a–g
To a solution of 1.2 equiv of substituted cinnamic acid 1a
(3.6 mL), a catalytic amount of DMF was added. The reaction mixture was refluxed for 4 h, and
then, solvent was evaporated under vacuum to get the product 2a in the form of a solid residue in
–l (5 mmol) in 5 equiv of thionyl chloride
–l
quantitative yield. The solid residue was directly added partially to an ice-cold stirred solution of
1.0 equiv of tert-butyl (2-aminoethyl)carbamate or tert-butyl (3-aminopropyl)carbamate and 2.0 equiv
triethylamine in DCM (20 mL). After the addition, the mixture was warmed to room temperature and
stirred for 2 h. Then, DCM (20 mL) was added and washed with 0.2 M HCl (40 mL), H2O (40 mL),
5% saturated. NaHCO3 (40 mL) and brine (40 mL), then dried over anhydrous magnesium sulfate.
The solvent was removed in vacuo to give the corresponding cinnamamide derivatives 3a
–l (65%–75%,
from 1a ) and 4a (59%–70%, from 1a ) as a white solid. 3a 4a (4 mmol) in DCM/TFA
–
l
–
g
–
g
–
l,
–g
(9:1, 40 mL) were stirred at room temperature for 1 h. Solvents were removed in vacuo to yield 5a
(100%) and 6a–g (100%) as a colorless oil.
–l
3.2.3. General Procedure for the Synthesis of Imidazo[1,2-a]pyridine amide-cinnamamide
Hybrids 11–14
A mixture of imidazo[1,2-a]pyridine-3-carboxylic acids
in dry DCM (10 mL) was stirred under N2 at room temperature for 5 min at room temperature. Then,
Et3N (2.2 mmol) was added followed by 5a and 6a (1.2 mmol). The resulting suspension was
9, 10 (1.0 mmol) and BOP-Cl (1.2 mmol)
–
l
–g
allowed to continue stirring for 3 h. DCM (10 mL) was added and washed with 0.2 M HCl (20 mL), H2O
(20 mL), 5% satd. NaHCO3 (20 mL) and brine (20 mL), then dried over anhydrous magnesium sulfate.
The solvent was removed in vacuo. Silica flash column chromatography eluting with DCM/MeOH
(95:5) yielded 11–14.
(E)-2,6-Dimethyl-N-(2-(3-p-tolylacrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxamide (11a): The title
˝
9
as a white solid (61%); m.p.: 215–217 C. 1H-NMR (500 MHz,
compound was prepared from 5a and
DMSO-d6) (ppm): 8.82 (s, 1H, pyridine-H), 8.27 (d, J = 5.5 Hz, 1H, -CONH-), 7.86 (d, J = 5.0 Hz,
1H, -CONH-), 7.47–7.44 (m, 3H, Ar-H), 7.40 (d, J = 16.0 Hz, 1H, =C-H), 7.23–7.20 (m, 3H, Ar-H), 6.58
(d, J = 16.0 Hz, 1H, =C-H), 3.44–3.41 (m, 4H, 2 -CH2-), 2.54 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.28 (s, 3H,
CH3). 13C-NMR (126 MHz, DMSO-d6)
(ppm): 165.98, 161.57, 145.33, 144.25, 139.68, 139.14, 132.57,
δ
ˆ
δ
130.00, 129.63, 127.96, 125.22, 122.39, 121.53, 116.14, 115.92, 38.96, 21.41, 18.24, 16.07. MS-ESI (m/z):
377 [M + H]+.

Molecules 2016, 21, 49
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(E)-2,6-Dimethyl-N-(2-(3-(3,4,5-trimethoxyphenyl)acrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxam˝ide
11b): The title compound was obtained from 5b and 9 as a white solid (63%)’ m.p.: 224–226 C.
(
1H-NMR (500 MHz, DMSO-d6)
δ (ppm): 8.83 (s, 1H, pyridine-H), 8.24 (t, J = 5.0 Hz, 1H, -CONH-), 7.85
(t, J = 5.0 Hz, 1H, -CONH-), 7.47 (d, J = 9.0 Hz, 1H, pyridine-H), 7.38 (d, J = 15.5 Hz, 1H, =C-H), 7.23
(dd, J = 9.0, 1.5 Hz, 1H, pyridine-H), 6.90 (s, 2H, Ar-H), 6.60 (d, J = 15.5 Hz, 1H, =C-H), 3.80 (s, 6H,
-OCH3), 3.67 (s, 3H, CH3), 3.44–3.41 (m, 4H, 2
ˆ
-CH2-), 2.55 (s, 3H, CH3), 2.28 (s, 3H, CH3). 13C-NMR
(126 MHz, DMSO-d6) (ppm): 165.48, 161.13, 153.08, 144.90, 143.82, 138.93, 138.60, 130.50, 129.18,
δ
124.78, 121.95, 121.45, 115.68, 115.49, 104.91, 60.10, 55.87, 54.96, 38.58, 30.99, 17.79, 15.66. MS-ESI (m/z):
453 [M + H]+.
(E)-N-(2-(3-(3,4-Dichlorophenyl)acrylamido)ethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (11c):
The title compound was prepared from 5c and
(500 MHz, DMSO-d6) (ppm): 8.82 (s, 1H, pyridine-H), 8.37 (m, 1H, -CONH-), 7.88–7.83 (m, 2H,
9
as a white solid (57%); m.p.: 213–215 ˝C. 1H-NMR
δ
-CONH- and Ar-H), 6.65 (d, J = 8.5 Hz, 1H, Ar-H), 7.55 (dd, J = 8.0, 1.5 Hz, 1H, Ar-H), 7.46 (d, J = 9.0 Hz,
1H, pyridine-H), 7.42 (d, J = 16.0 Hz, 1H, =C-H), 7.22 (dd, J = 9.5, 2.0 Hz, 1H, Ar-H), 6.72 (d, J = 16.0 Hz,
1H, =C-H), 3.44 ( m, 4H, 2
DMSO-d6)
ˆ
-CH2-), 2.55 (s, 3H, CH3), 2.27 (s, 3H, CH3). 13C-NMR (126 MHz,
(ppm): 164.94, 161.16, 144.92, 143.82, 136.16, 135.84, 131.69, 131.61, 131.06, 129.44, 129.17,
δ
127.28, 124.78, 124.44, 121.94, 115.67, 115.46, 38.86, 38.72, 17.79, 15.66. MS-ESI (m/z): 431 [M + H]+.
(E)-N-(2-(3-(4-Methoxyphenyl)acrylamido)ethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (11d):
The title compound was prepared from 5d and
(500 MHz, CDCl3) (ppm): 9.12 (s, 1H, pyridine-H), 7.55 (d, J = 15.5 Hz, 1H, =C-H), 7.44 (d, J = 9.0 Hz,
9
as a white solid (69%); m.p.: 203–205 ˝C. 1H-NMR
δ
1H, pyridine-H), 7.40 (d, J = 9.0 Hz, 1H, pyridine-H), 7.14 (dd, J = 9.0, 1.5 Hz, 1H, Ar-H), 6.85 (d,
J = 9.0 Hz, 1H, Ar-H), 6.80 (s, 1H, -CONH-), 6.60 (s, 1H, -CONH-), 6.29 (d, J = 15.5 Hz, 1H, =C-H), 3.80
(s, 3H, OCH3), 3.69–3.67 (m, 4H, 2
ˆ
-CH2-), 2.71 (s, 3H, CH3), 2.31 (s, 3H, CH3). 13C-NMR (126 MHz,
CDCl3)
δ (ppm): 167.73, 162.64, 161.11, 145.81, 144.99, 145.37, 130.11, 129.55, 127.38, 125.96, 123.10,
117.73, 115.71, 115.21, 114.35, 55.48, 41.06, 40.12, 18.49, 16.59. MS-ESI (m/z): 393 [M + H]+.
(E)-2,6-Dimethyl-N-(2-(3-(4-(trifluoromethyl)phenyl)acrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxam˝ide
(
11e): The title compound was prepared from 5e and 9 as a white solid (72%); m.p.: 252–254 C.
1H-NMR (500 MHz, DMSO-d6)
δ (ppm): 8.82 (s, 1H, pyridine-H), 8.82–8.40 (m, 1H, Ar-H), 7.87–7.85
(m, 1H, Ar-H), 7.77 (dd, J = 9.0, 11.5 Hz, 1H, Ar-H), 7.52 (d, J = 16.0 Hz, 1H, =C-H), 7.46 (d, J = 9.0 Hz,
1H, pyridine-H), 7.22 (dd, J = 9.0, 1.5 Hz, 1H, Ar-H), 6.77 (d, J = 16.0 Hz, 1H, =C-H), 3.46–3.43 (m,
4H, 2 ˆ -CH2-), 2.55 (s, 3H, CH3), 2.26 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6)
δ (ppm): 164.91,
161.16, 144.92, 143.83, 138.98, 137.08, 129.33, 129.17, 128.17, 125.84, 125.81, 125.21, 124.95, 124.76, 121.93,
115.68, 115.49, 38.87, 38.62, 17.78, 15.65. HRMS-ESI (m/z): calcd. for C22H22O2N4F3 [M + H]+: 431.1695;
found 431.1675.
(E)-N-(2-(3-(2-Fluorophenyl)acrylamido)ethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (11f): The
˝
1
title compound was prepared from 5f and
(500 MHz, DMSO-d6) (ppm): 8.82 (s, 1H, pyridine-H), 8.42 (t, J = 5.0 Hz, 1H, -CONH-), 7.86 (t,
J = 5.0 Hz, 1H, -CONH-), 7.67–7.64 (m, 1H, Ar-H), 7.52–7.40 (m, 3H, =C-H and Ar-H), 7.30–7.21 (m,
3H, pyridine-H and Ar-H), 6.74 (d, J = 16.0 Hz, 1H, =C-H), 3.45–3.42 (m, 4H, 2 -CH2-), 2.54 (s, 3H,
CH3), 2.28 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6)
(ppm): 165.13, 161.48, 161.15, 159.49, 144.90,
9 as a white solid (70%); m.p.: 197–199 C. H-NMR
δ
ˆ
δ
143.82, 131.37, 131.30, 131.16, 129.22, 129.20, 129.18, 125.05, 124.99, 124.77, 121.94, 116.21, 116.04, 115.71,
115.49, 38.87, 38.60, 17.77, 15.62. MS-ESI (m/z): 381 [M + H]+.
(E)-N-(2-(3-(4-Fluorophenyl)acrylamido)ethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (11g): The
˝
1
title compound was prepared from 5g and
(500 MHz, DMSO-d6) (ppm): 9.14 (s, 1H, pyridine-H), 7.55 (d, J = 15.5 Hz, 1H, =C-H), 7.46–7.42
(m, 3H, pyridine-H and Ar-H), 7.04 (dd, J = 9.0, 1.5 Hz, 1H, Ar-H), 7.05–7.01 (m, 2H, Ar-H), 6.67 (s, 1H,
-CONH-), 6.60 (s, 1H, -CONH-), 6.34 (d, J = 15.5 Hz, 1H, =C-H), 3.72–3.67 (m, 4H, 2 -CH2-), 2.72 (s,
3H, CH3), 2.32 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6)
(ppm): 162.12, 159.72, 157.81, 157.73,
9 as a white solid (67%); m.p.: 208–211 C. H-NMR
δ
ˆ
δ

Molecules 2016, 21, 49
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140.98, 140.17, 135.50, 125.94, 125.92, 125.11, 124.81, 124.74, 120.97, 118.11, 114.94, 114.92, 111.16, 110.99,
110.84, 110.09, 35.81, 35.41, 13.52, 11.74. MS-ESI (m/z): 381 [M + H]+.
(E)-N-(2-(3-(3-Fluorophenyl)acrylamido)ethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (11h): The
˝
1
title compound was prepared from 5h and
(500 MHz, DMSO-d6) (ppm): 8.83 (s, 1H, pyridine-H), 8.32 (d, J = 5.5 Hz, 1H, -CONH-), 7.83 (d,
J = 5.5 Hz, 1H, -CONH-), 7.46–7.39 (m, 5H, Ar-H), 7.22–7.19 (m, 2H, Ar-H and pyridine-H), 6.34 (d,
J = 15.5 Hz, 1H, =C-H), 3.47–3.36 (m, 4H, 2
-CH2-), 2.55 (s, 3H, CH3), 2.27 (s, 3H, CH3). 13C-NMR
(126 MHz, DMSO-d6) (ppm): 165.12, 163.45, 161.51, 161.18, 144.93, 143.84, 137, 55, 137.49, 130.96,
9 as a white solid (65%); m.p.: 172–175 C. H-NMR
δ
ˆ
δ
130.89, 129.17, 124, 78, 123.71, 121.95, 116.24, 116.07, 115.69, 115.49, 114.05, 113.88, 38.91, 38.62, 17.78,
15.65. MS-ESI (m/z): 381 [M + H]+.
(E)-N-(2-(3-(4-Chlorophenyl)acrylamido)ethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (11i): The
˝
1
title compound was prepared from 5i and
(500 MHz, DMSO-d6) (ppm): 8.82 (s, 1H, pyridine-H), 8.31 (s, 1H, -CONH-), 7.83 (s, 1H, -CONH-),
7.59 (d, J = 8.5 Hz, 2H, Ar-H), 7.48–7.40 (m, 4H, Ar-H and pyridine-H), 7.23 (dd, J = 9.0, 1.5 Hz, 1H,
Ar-H), 6.64 (d, J = 16.0 Hz, 1H, =C-H), 3.45–3.41 (m, 4H, 2 -CH2-), 2.54 (s, 3H, CH3), 2.28 (s, 3H,
CH3). 13C-NMR (126 MHz, DMSO-d6)
(ppm): 165.19, 161.15, 144.91, 143.82, 137.40, 133.90, 133.86,
9 as a white solid (59%); m.p.: 252–254 C. H-NMR
δ
ˆ
δ
129.25, 129.18, 128.99, 124.77, 122.95, 121.95, 115.69, 115.48, 38.93, 38.57, 17.79, 15.64. MS-ESI (m/z):
397 [M + H]+.
(E)-2,6-Dimethyl-N-(2-(3-(4-nitrophenyl)acrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxamide (11J): The
˝
1
title compound was prepared from 5J and
(500 MHz, DMSO-d6) (ppm): 8.82 (s, 1H, pyridine-H), 8.48 (s, 1H, -CONH-), 8.24 (d, J = 9.0 Hz, 2H,
9 as a white solid (52%); m.p.: 213–215 C. H-NMR
δ
pyridine-H), 7.87–7.82 (m, 3H, -CONH- and Ar-H), 7.55 (d, J =15.5 Hz, 1H, =C-H), 7.45 (d, J = 9.0 Hz,
2H, pyridine-H) 7.21 (dd, J = 9.0, 1.5 Hz, 1H, Ar-H), 6.84 (d, J = 16.0 Hz, 1H, =C-H), 3.47–3.43 (m,
4H, 2 ˆ -CH2-), 2.55 (s, 3H, CH3), 2.27 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6)
δ (ppm): 164.70,
161.16, 147.49, 144.94, 143.83, 141.51, 136.43, 129.16, 128.59, 126.43, 124.76, 124.13, 121.94, 115.66, 115.48,
38.82, 38.68, 17.80, 15.66. MS-ESI (m/z): 408 [M + H]+.
(E)-2,6-Dimethyl-N-(2-(3-(4-(trifluoromethoxy)phenyl)acrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxamide
˝
(
11k): The title compound was prepared from 5k and
9
as a white solid (64%); m.p.: 214–217 C.
1H-NMR (500 MHz, DMSO-d6)
δ (ppm): 8.82 (s, 1H, pyridine-H), 8.81–8.42 (m, 1H, -CONH-), 7.85–7.82
(m, 1H, -CONH-), 7.70 (dd, J = 9.0, 11.5 Hz, 1H, Ar-H), 7.58 (d, J = 16.0 Hz, 1H, =C-H), 7.48 (d,
J = 9.0 Hz, 1H, pyridine-H), 7.23 (dd, J = 9.0, 1.5 Hz, 1H, Ar-H), 6.97 (d, J = 16.0 Hz, 1H, =C-H),
3.50–3.45 (m, 4H, 2
ˆ
-CH2-), 2.58 (s, 3H, CH3), 2.24 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6)
δ
(ppm): 165.90, 162.15, 145.82, 143.83, 139.92, 137.18, 129.32, 129.17, 128.18, 126.85, 125.98, 125.31, 124.85,
124.74, 122.43, 114.90, 114.49, 38.85, 37.65, 18.75, 15.65. HRMS-ESI (m/z): calcd. for C22H22O3N4F3
[M + H]+: 447.1644; found 447. 1622.
(E)-N-(2-Cinnamamidoethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (11l): The title compound
was obtained from 5l and 9 δ
as a white solid (58%); m.p.: 196–198 ˝C. 1H-NMR (500 MHz, CDCl3)
(ppm): 9.22 (s, 1H, pyridine-H), 7.65 (d, J = 16.0 Hz, 1H, =C-H), 7.52–7.47 (m, 3H, Ar-H and pyridine-H),
7.38–7.36 (m, 3H, Ar-H and pyridine-H), 7.18 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 6.89 (t, J = 6.0 Hz, 1H,
-CONH-), 6.58 (t, J = 6.0 Hz, 1H, -CONH-), 6.48 (d, J = 16.0 Hz, 1H, =C-H), 3.59 (dd, J = 12.0, 6.5 Hz, 2H,
-CH2-), 3.54 (dd, J = 12.0, 6.5 Hz, 2H, -CH2-), 2.83 (s, 3H, CH3), 2.37 (s, 3H, CH3). 13C-NMR (126 MHz,
CDCl3)
δ (ppm): 166.96, 162.28, 145.66, 145.03, 141.40, 134.81, 129.97, 129.88, 128.94, 127.93, 126.04,
123.00, 120.55, 115.76, 115.39, 36.26, 35.66, 30.53, 18.52, 16.79. MS-ESI (m/z): 363 [M + H]+.
(E)-2,7-Dimethyl-N-(2-(3-p-tolylacrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxamide (12a): The title
˝
compound was prepared from 5a and 10 as a white solid (61%); m.p.: 244–247 C. 1H-NMR (500 MHz,
DMSO-d6)
δ (ppm): 8.94 (d, J = 7.5 Hz, 1H, pyridine-H), 8.28 (d, J = 5.0 Hz, 1H, -CONH-), 7.79 (d,
J = 5.0 Hz, 1H, -CONH-), 7.45 (d, J = 8.0 Hz, 2H, Ar-H), 7.40 (d, J = 15.5 Hz, 1H, =C-H), 7.34–7.33 (m,
1H, Ar-H and pyridine-H), 7.22 (d, J = 8.0 Hz, 2H, Ar-H), 6.58 (d, J = 15.5 Hz, 1H, =C-H), 3.45–3.41 (m,

Molecules 2016, 21, 49
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4H, 2
ˆ
-CH2-), 2.55 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.32 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6)
δ
(ppm): 165.55, 161.15, 145.27, 145.16, 139.23, 138.71, 137.12, 132.12, 129.55, 127.52, 126.43, 121.08,
115.33, 115.15, 114.54, 38.52, 20.96, 20.73, 15.71. MS-ESI (m/z): 377 [M + H]+.
(E)-2,7-Dimethyl-N-(2-(3-(3,4,5-trimethoxyphenyl)acrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxam˝ide
(
12b): The title compound was obtained from 5b and 10 as a white solid (61%); m.p.: 225–227 C.
1H-NMR (500 MHz, DMSO-d6)
δ (ppm): 8.92 (d, J = 7.0 Hz, 1H, pyridine-H), 8.24 (t, J = 5.0 Hz, 1H,
-CONH-), 7.85 (t, J = 5.0 Hz, 1H, -CONH-), 7.47 (d, J = 9.0 Hz, 1H, pyridine-H), 7.38 (d, J = 15.5 Hz, 1H,
=C-H), 7.23 (dd, J = 7.0, 1.5 Hz, 1H, Ar-H), 6.90 (s, 2H, Ar-H), 6.60 (d, J = 15.5 Hz, 1H, =C-H), 3.80 (s,
6H, 2
ˆ
OCH3), 3.67 (s, 3H, OCH3), 3.44–3.41 (m, 4H, 2
ˆ
-CH2-), 2.55 (s, 3H, CH3), 2.28 (s, 3H, CH3).
13C-NMR (126 MHz, DMSO-d6)
δ
(ppm): 166.38, 162.14, 154.10, 145.12, 143.83, 138.94, 138.50, 131.40,
128.19, 124.68, 122.14, 121.45, 115.67, 115.40, 105.81, 61.15, 56.88, 53.97, 39.57, 31.87, 18.80, 15.64. MS-ESI
(m/z): 453 [M + H]+.
(E)-N-(2-(3-(3,4-Dichlorophenyl)acrylamido)ethyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (12c):
The title compound was prepared from 5c and 10 as a white solid (54%); m.p.: 201–204 ˝C. 1H-NMR
(500 MHz, DMSO-d6) δ (ppm): 8.92 (d, J = 7.5 Hz, 1H, pyridine-H), 8.34 (d, J = 5.5 Hz, 1H, -CONH-),
7.84 (d, J = 2.0 Hz, 1H, pyridine-H), 7.78 (d, J = 5.0 Hz, 1H, -CONH-), 7.66 (d, J = 8.0, 1H, pyridine-H),
7.55 (dd, J = 8.5, 2.0 Hz, 1H, Ar-H), 7.42 (d, J = 16.0 Hz, 1H, =C-H), 7.32 (s, 1H, Ar-H), 6.82 (dd, J = 7.5,
2.0 Hz, 1H, Ar-H), 6.70 (d, J = 16.0 Hz, 1H, =C-H), 3.43 ( m, 4H, 2
ˆ
-CH2-), 2.55 (s, 3H, CH3), 2.35
(s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6)
δ
(ppm): 164.93, 161.16, 145.26, 145.15, 137.15, 136.19,
135.84, 131.69, 131.61, 131.07, 129.48, 127.28, 126.44, 124.42, 115.32, 115.16, 114.53, 38.87, 38.63, 20,72,
15.72. MS-ESI (m/z): 431 [M + H]+.
(E)-N-(2-(3-(4-Methoxyphenyl)acrylamido)ethyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (12d):
The title compound was prepared from 5d and 10 as a white solid (67%); m.p.: 218–221 ˝C. 1H-NMR
(500 MHz, DMSO-d6) δ (ppm): 8.94 (d, J = 7.0 Hz, 1H, pyridine-H), 8.21 (d, J = 5.0 Hz, 1H, -CONH-),
7.78 (d, J = 5.0 Hz, 1H, -CONH-), 7.79–7.77 (m, 2H, Ar-H and pyridine-H), 7.34–7.37 (m, 2H, Ar-H and
pyridine-H), 6.98–6.95 (m, 2H, Ar-H), 6.86–6.84 (m, 2H, Ar-H), 6.48 (d, J = 16.0 Hz, 1H, =C-H), 3.78 (s,
3H, OCH3), 3.44–3.40 (m, 4H, 2
ˆ
-CH2-), 2.55 (s, 3H, CH3), 2.36 (s, 3H, CH3). 13C-NMR (126 MHz,
CDCl3)
δ (ppm): 165.72, 161.13, 160.34, 145.27, 145.15, 138.47, 137.13, 129.13, 127.43, 126.44, 119.62,
115.34, 115.16, 114.55, 114.40, 55.27, 38.49, 20.73, 15.70. MS-ESI (m/z): 393 [M + H]+.
(E)-2,7-Dimethyl-N-(2-(3-(4-(trifluoromethyl)phenyl)acrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxam˝ide
(
12e): The title compound was prepared from 5e and 10 as a white solid (72%); m.p.: 218–221 C.
1H-NMR (500 MHz, DMSO-d6)
δ (ppm): 8.83 (s, 1H, pyridine-H), 8.38 (t, J = 5.0, 1H, -CONH-), 7.83
(t, J = 5.0, 1H, -CONH-) 7.79–7.75 (m, 4H, Ar-H and pyridine-H), 7.51 (d, J = 16.0 Hz, 1H), 7.46 (d,
J = 9.0 Hz, 1H, Ar-H), 7.22 (dd, J = 9.0, 1.5 Hz, 1H, Ar-H), 6.77 (d, J = 16.0 Hz, 1H, =C-H), 3.46–3.43 (m,
4H, 2
ˆ
-CH2-), 2.55 (s, 3H, CH3), 2.27 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6)
δ (ppm): 165.71,
161.13, 160.34, 145.27, 145.15, 138.47, 137.13, 129.13, 127.43, 126.44, 119.62, 115.34, 115.16, 114.54, 114.40,
55.27, 38.49, 20.73, 15.70. MS-ESI (m/z): 431 [M + H]+.
(E)-N-(2-(3-(2-Fluorophenyl)acrylamido)ethyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (12f): The
˝
1
title compound was prepared from 5f and 10 as a white solid (61%); m.p.: 213–216 C. H-NMR
(500 MHz, DMSO-d6) (ppm): 8.92 (d, J = 7.0 Hz, 1H, pyridine-H), 8.44 (d, J = 5.0 Hz, 1H, -CONH-),
δ
7.79 (d, J = 5.0 Hz, 1H, -CONH-), 7.67–7.63 (m, 1H, Ar-H), 7.51 (d, J = 16.0 Hz, 1H, =C-H), 7.43–7.40
(m, 1H, Ar-H), 7.32 (s, 1H), 7.29–7.23 (m, 2H, Ar-H), 6.81 (dd, J = 7.5, 1.5 Hz, 1H), 6.74 (d, J = 16.0 Hz,
1H, =C-H), 3.45–3.42 (m, 4H, 2
ˆ
-CH2-), 2.55 (s, 3H, CH3), 2.35 (s, 3H, CH3). 13C-NMR (126 MHz,
CDCl3) (ppm): 165.59, 161.92, 161.60, 159.93, 145.72, 145.60, 137.56, 131.79, 131.61, 129.65, 129.63,
δ
126.87, 125.47, 125.44, 125.42, 116.64, 116.47, 115.78, 115.57, 114.98, 39.34, 39.05, 21.16, 16.14. MS-ESI
(m/z): 381 [M + H]+.
(E)-N-(2-(3-(4-Fluorophenyl)acrylamido)ethyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (12g): The
˝
1
title compound was prepared from 5g and 10 as a white solid (65%); m.p.: 246–248 C. H-NMR

Molecules 2016, 21, 49
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(500 MHz, DMSO-d6)
δ
(ppm): 8.93 (d, J = 7.5 Hz, 1H, pyridine-H), 8.30 (t, J = 5.0 Hz, 1H, -CONH-),
7.62 (t, J = 3.5 Hz, 1H, -CONH-), 7.64–7.61 (m, 1H, Ar-H), 7.43 (d, J = 16.0 Hz, 1H, =C-H), 7.33 (s, 1H,
Ar-H), 7.27–7.23 (m, 2H, Ar-H and pyridine-H), 6.83 (dd, J = 7.0, 1.5 Hz, 1H), 6.57 (d, J = 16.0 Hz, 1H,
=C-H), 3.44–3.40 (m, 4H, 2
(ppm): 165.77, 164.13, 162.17, 161.59, 145.71, 145.59, 138.02, 137.60, 131.98, 131.95, 130.19, 130.12, 126.88,
122.47, 116.47, 116.30, 115.78, 115.62, 114.98, 39.41, 38.99, 21.18, 16.15. MS-ESI (m/z): 381 [M + H]+.
ˆ
-CH2-), 2.54 (s, 3H, CH3), 2.36 (s, 3H, CH3). 13C-NMR (126 MHz, CDCl3)
δ
(E)-N-(2-(3-(3-Fluorophenyl)acrylamido)ethyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (12h): The
˝
1
title compound was prepared from 5h and 10 as a white solid (50%); m.p.: 172–175 C. H-NMR
(500 MHz, DMSO-d6) (ppm): 8.93 (d, J = 7.5 Hz, 1H, pyridine-H), 8.33 (t, J = 5.0 Hz, 1H, -CONH-),
δ
7.78 (t, J = 5.0 Hz, 1H, -CONH-), 7.48-7.40 (m, 4H, Ar-H and pyridine-H), 7.33 (s, 1H, Ar-H), 7.23–7.18
(m, 1H, Ar-H), 6.83 (dd, J = 7.0, 1.5 Hz, 1H, Ar-H), 6.58 (d, J = 16.0 Hz, 1H, =C-H), 3.44–3.41 (m, 4H,
2 ˆ -CH2-), 2.55 (s, 3H, CH3), 2.36 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6)
δ (ppm): 165.10,
163.44, 161.51, 161.16, 145.28, 145.17, 137.55, 137.48, 137.14, 130.96, 130.89, 126.44, 123.70, 116.24, 116.07,
115.33, 115.16, 114.55, 114.06, 113.89, 38.91, 38.59, 20.73, 15.71. MS-ESI (m/z): 381 [M + H]+.
(E)-N-(2-(3-(4-Chlorophenyl)acrylamido)ethyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (12i): The
˝
1
title compound was prepared from 5i and 10 as a white solid (61%); m.p.: 172–175 C. H-NMR
(500 MHz, DMSO-d6) (ppm): 8.83 (s, 1H, pyridine-H), 8.32 (d, J = 5.5 Hz, 1H, -CONH-), 7.83 (d,
J = 5.0 Hz, 1H, -CONH-), 7.46–7.39 (m, 5H, pyridine-H, Ar-H and =C-H), 7.21 (d, J = 9.0 Hz, 1H, Ar-H),
6.69 (d, J = 15.5 Hz, 1H, =C-H, Ar-H), 3.47–3.43 (m, 4H, 2 -CH2-), 2.55 (s, 3H, CH3), 2.27 (s, 3H, CH3).
13C-NMR (126 MHz, DMSO-d6)
(ppm): 165.56, 161.60, 149.25, 145.72, 145.61, 137.59, 134.72, 129.89,
δ
ˆ
δ
129.79, 126.88, 123.80, 121.91, 121.51, 119,47, 115.77, 115.61, 114.99, 39.36, 39.01, 31.17, 13.15. MS-ESI
(m/z): 397 [M + H]+.
(E)-2,7-Dimethyl-N-(2-(3-(4-nitrophenyl)acrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxamide (11j): The
˝
1
title compound was prepared from 5j and 10 as a white solid (71%); m.p.: 213–215 C. H-NMR
(500 MHz, DMSO-d6) (ppm): 8.93 (d, J = 7.0 Hz, 1H, pyridine-H), 8.45 (s, 1H, -CONH-), 8.25 (d,
J = 8.5 Hz, 1H, Ar-H), 7.83 (d, J = 8.5 Hz, 1H, Ar-H), 7.78 (d, J = 5.5 Hz, 1H, -CONH-), 7.55 (d, J = 16.0 Hz,
1H, =C-H, Ar-H), 7.33 (s, 1H, Ar-H), 6.85–6.80 (m, 2H, Ar-H), 3.44 (s, 4H, 2 -CH2-), 2.54 (s, 3H, CH3),
2.36 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6)
(ppm): 164.69, 161.17, 147.52, 145.28, 145.18, 141.51,
δ
ˆ
δ
137.15, 136.46, 128.62, 126.43, 124.16, 115.31, 115.17, 114.55, 38.83, 38.66, 20.73, 15.72. MS-ESI (m/z):
408 [M + H]+.
(E)-2,6-Dimethyl-N-(2-(3-(4-(trifluoromethoxy)phenyl)acrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxamide
(
12k): The title compound was prepared from 5k and 10 as a white solid (61%); m.p.: 214–216 ˝C.
1H-NMR (500 MHz, DMSO-d6)
δ (ppm): 8.93 (d, J = 7.0 Hz, 1H, pyridine-H), 8.33 (d, J = 5.0 Hz, 1H,
-CONH-), 7.78 (d, J = 5.0 Hz, 1H, -CONH-), 7.59 (dd, J = 7.0, 2.0 Hz, 2H, Ar-H), 7.45 (dd, J = 7.0, 2.0 Hz,
2H, Ar-H), 7.43 (d, J = 16.0 Hz, 1H, =C-H), 7.33 (s, 1H, pyridine-H), 6.83 (dd, J = 7.5, 2.0 Hz, 1H,
pyridine-H), 6.63 (d, J = 16.0 Hz, 1H, =C-H), 3.44–3.40 (m, 4H, 2
ˆ
-CH2-), 2.54 (s, 3H, CH3), 2.36 (s, 3H,
CH3). 13C-NMR (126 MHz, DMSO-d6)
δ
(ppm): 165.17, 161.15, 145.27, 145.16, 137.40, 137.14, 133.89,
133.85, 129.26, 129.00, 126.43, 122.94, 115.32, 115.16, 114.55, 54.96, 38.56, 20.73, 15.71. HRMS-ESI (m/z):
calcd. for C22H22O3N4F3 [M + H]+: 447.1644; found 447. 1631.
(E)-N-(2-Cinnamamidoethyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (12l): The title compound
˝
was obtained from 5l and 10 as a white solid (59%); m.p.: 197–200 C. 1H-NMR (500 MHz, DMSO-d6)
δ
(ppm): 8.93 (d, J = 7.0 Hz, 1H, pyridine-H), 8.30 (d, J = 5.0 Hz, 1H, -CONH-), 7.56 (d, J = 5.0 Hz, 1H,
-CONH-), 7.56–7.55 (m, 3H, Ar-H and pyridine-H), 7.42–7.34 (m, 3H, Ar-H), 6.85 (dd, J = 7.0, 2.0 Hz,
1H, pyridine-H), 6.63 (d, J = 14.5 Hz, 1H, =C-H), 3.45–3.41 (m, 4H, 2 -CH2-), 2.55 (s, 3H, CH3), 2.37 (s,
3H, CH3). 13C-NMR (126 MHz, CDCl3)
(ppm): 165.36, 161.13, 145.26, 145.14, 138.73, 137.13, 134.87,
ˆ
δ
129.49, 128.97, 127.54, 126.43,122.12, 115.33, 115.16, 114.54, 44.47, 38.53, 20.73, 15.70. MS-ESI (m/z):
363 [M + H]+.

Molecules 2016, 21, 49
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(E)-2,6-Dimethyl-N-(3-(3-p-tolylacrylamido)propyl)imidazo[1,2-a]pyridine-3-carboxamide (13a): The title
˝
compound was obtained from 6a and 9 as a white solid (52%); m.p.: 196–198 C. 1H-NMR (500 MHz,
CDCl3) (ppm): 9.15 (s, 1H, pyridine-H), 7.58 (d, J = 15.5 Hz, 1H, =C-H), 7.43 (d, J = 9.0 Hz, 2H, Ar-H),
δ
7.34 (d, J = 8.0 Hz, 1H, pyridine-H), 7.13–7.11 (m, 3H, Ar-H and pyridine-H), 6.99 (t, J = 6.0 Hz, 1H,
-CONH-), 6.81 (t, J = 6.0 Hz, 1H, -CONH-), 6.43 (d, J = 15.5 Hz, 1H, =C-H),3.55 (dd, J = 12.0, 6.0 Hz,
2H, -CH2-), 3.49 (dd, J = 12.0, 6.0 Hz, 2H, -CH2-), 2.79 (s, 3H, CH3), 2.32 (s, 6H, 2
ˆ
CH3), 1.81–1.78
(m, 2H, -CH2-). 13C-NMR (126 MHz, CDCl3)
δ
(ppm): 165.30, 160.92, 144.67, 143.79, 139.17, 138.58,
132.15, 129.54, 127.49, 124.70, 121.96, 121.12, 115.74, 115.49, 36.48, 29.56, 20.97, 17.82, 15.59. MS-ESI
(m/z): 391 [M + H]+.
(E)-2,6-Dimethyl-N-(3-(3-(3,4,5-trimethoxyphenyl)acrylamido)propyl)imidazo[1,2-a]pyridine-3-carboxam˝ide
(
13b): The title compound was obtained from 6b and 9 as a white solid (48%); m.p.: 196–199 C.
1H-NMR (500 MHz, CDCl3)
δ (ppm): 9.12 (s, 1H, pyridine-H), 7.50 (d, J =15.5 Hz, 1H, =C-H), 7.40 (d,
J =9.0 Hz, 1H, pyridine-H), 7.11 (dd, J = 9.0, 1.5 Hz, 1H, Ar-H), 6.97 (t, J = 6.0 Hz, 1H, -CONH-), 6.87 (t,
J = 6.0 Hz, 1H, -CONH-), 6.66 (s, 2H, Ar-H), 6.39 (d, J = 15.5 Hz, 1H, =C-H), 3.82 (s, 3H, OCH3), 3.80
(s, 6H, 2
ˆ
OCH3), 3.54–3.45 (m, 4H, 2
ˆ
-CH2-), 2.76 (s, 3H, CH3), 2.29 (s, 3H, CH3), 1.79–1.74 (m,
(ppm): 165.27, 160.94, 153.09, 144.70, 143.82, 138.81,
2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6)
δ
138.57, 130.56, 129.15, 124.71, 121.98, 121.52, 115.75, 115.50, 104.88, 60.10, 55.86, 36.48, 29.52, 17.82, 15.69.
MS-ESI (m/z): 467 [M + H]+.
(E)-N-(3-(3-(3,4-Dichlorophenyl)acrylamido)propyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (13c):
The title compound was prepared from 6c and
9
as a white solid (57%); m.p.: 213–215 ˝C. 1H-NMR
1
(500 MHz, CDCl3)
δ
(ppm): H-NMR (500 MHz, CDCl3)
δ
(ppm): 9.17 (s, 1H, pyridine-H), 7.55–7.54
(m, 1H, Ar-H), 7.51–7.45 (m, 2H, Ar-H and pyridine-H), 7.41 (d, J = 8.5 Hz, 1H, Ar-H), 7.30–7.27 (m,
1H, Ar-H), 7.17 (d, J = 9.0 Hz, 1H, Ar-H), 6.83 (d, J = 5.0 Hz, 1H, -CONH-), 6.76 (d, J = 5.0 Hz, 1H,
-CONH-), 6.44 (d, J = 15.5 Hz, 1H, =C-H), 3.58–3.48 (m, 4H, 2
ˆ
-CH2-), 2.78 (s, 3H, CH3), 2.35 (s, 3H,
(ppm): 164.68, 160.95, 144.69, 143.80,
CH3), 1.85–1.80 (m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6)
δ
136.07, 135.88, 131.68, 131.06, 129.44, 129.14, 127.28, 124.70, 124.47, 121.96, 115.74, 115.50, 36.59, 36.49,
29.46, 17.82, 15.69. MS-ESI (m/z): 445 [M + H]+.
(E)-N-(3-(3-(4-Methoxyphenyl)acrylamido)propyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (13d):
The title compound was prepared from 6d and
(500 MHz, CDCl3) (ppm): 9.10 (s, 1H, pyridine-H), 7.53 (d, J = 15.5 Hz, 1H, =C-H), 7.39 (d, J = 9.0 Hz,
9
as a white solid (45%); m.p.: 178–181 ˝C. 1H-NMR
δ
1H, Ar-H), 7.35 (d, J = 9.0 Hz, 1H, Ar-H), 7.10–7.05 (m, 2H, Ar-H and pyridine-H), 6.98 (t, J = 6.0 Hz,
1H, -CONH-), 6.79 (d, J = 8.5 Hz, 1H, -CONH-), 6.33 (d, J = 15.5 Hz, 1H, =C-H), 3.75 (s, 3H, OCH3),
3.53–3.44 (m, 4H, 2
(126 MHz, CDCl3)
ˆ
-CH2-), 2.76 (s, 3H, CH3), 2.83 (s, 3H, CH3), 1.79-1.74 (m, 2H, -CH2-). 13C-NMR
(ppm): 165.52, 160.94, 160.31, 144.71, 143.82, 138.38, 129.15, 129.11, 127.48, 124.73,
δ
121.98, 119.67, 115.76, 115.50, 114.39, 55.26, 36.49, 36.46, 29.61, 17.82, 15.70. MS-ESI (m/z): 407 [M + H]+.
(E)-2,6-Dimethyl-N-(3-(3-(4-(trifluoromethyl)phenyl)acrylamido)propyl)imidazo[1,2-a]pyridine-3-carboxamide
˝
(
13e): The title compound was prepared from 6e and
9
as a white solid (32%); m.p.: 162–165 C.
1H-NMR (500 MHz, CDCl3)
δ (ppm): 9.19 (s, 1H, pyridine-H), 7.66–7.57 (m, 5H, pyridine-H and Ar-H),
7.46 (d, J = 9.5 Hz, 1H), 7.17 (dd, J = 9.0, 1.5 Hz, 1H, Ar-H), 6.76 (t, J = 6.0 Hz, 1H, -CONH-), 6.67 (d,
J = 6.0 Hz, 1H, -CONH-), 6.54 (d, J = 15.5 Hz, 1H, =C-H), 3.60–3.50 (m, 4H, 2 -CH2-), 2.80 (s, 3H,
CH3), 2.35 (s, 3H, CH3), 1.86–1.81 (m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6)
(ppm): 164.67,
ˆ
δ
161.50, 144.69, 143.80, 139.03, 136.98, 129.16, 128.17, 125.84, 125.81, 125.23, 124.97, 124.70, 121.98, 115.75,
115.51, 115.49, 36.60, 36.51, 29.46, 17.81, 15.68. MS-ESI (m/z): 445 [M + H]+.
(E)-N-(3-(3-(2-Fluorophenyl)acrylamido)propyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (13f): The
˝
1
title compound was prepared from 6f and
(500 MHz, DMSO-d6) (ppm): 8.99 (s, 1H, pyridine-H), 8.42 (t, J = 5.0 Hz, 1H, -CONH-), 7.86 (t, J = 5.0
9 as a white solid (41%); m.p.: 197–199 C. H-NMR
δ
Hz, 1H, -CONH-), 7.67–7.64 (m, 1H, Ar-H), 7.53–7.41 (m, 3H, Ar-H and pyridine-H), 7.30–7.22 (m, 3H,
=C-H and Ar-H), 6.74 (d, J = 16.0 Hz, 1H, =C-H), 3.45–3.42 (m, 4H, 2 ˆ -CH2-), 2.55 (s, 3H, CH3), 2.29

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(s, 3H, CH3), 1.85–1.82 (m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6)
δ
(ppm): 165.13, 161.48, 161.15,
159.49, 144.90, 143.82, 131.37, 131.30, 131.16, 129.22, 129.20, 129.18, 125.05, 124.99, 124.77, 121.94, 116.21,
116.04, 115.71, 115.49, 38.87, 38.60, 29.44, 17.77, 15.62. MS-ESI (m/z): 395 [M + H]+.
(E)-N-(3-(3-(4-Fluorophenyl)acrylamido)propyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (13g): The
˝
1
title compound was prepared from 6g and
(500 MHz, DMSO-d6) (ppm): 8.84 (s, 1H, pyridine-H), 8.22 (t, J = 5.5 Hz, 1H, -CONH-), 7.84 (t,
9 as a white solid (67%); m.p.: 151–153 C. H-NMR
δ
J = 5.5 Hz, 1H, -CONH-), 7.64–7.61 (m, 2H, pyridine-H and Ar-H), 7.47 (d, J = 9.5 Hz, 1H, Ar-H),
7.44 (d, J = 15.5 Hz, 1H, =C-H), 7.27–7.21 (m, 3H, pyridine-H and Ar-H), 6.59 (d, J = 15.5 Hz, 1H),
3.39–3.27 (m, 4H, 2
(126 MHz, DMSO-d6)
ˆ
-CH2-), 2.58 (s, 3H, CH3), 2.30 (s, 3H, CH3), 1.79–1.73 (m, 2H, -CH2-). 13C-NMR
δ
(ppm): 165.54, 164.10, 162.14, 161.38, 145.14, 144.25, 137.90, 132.01, 130.15,
130.08, 129.58, 125.15, 122.51, 116.44, 116.27, 116.19, 115.94, 36.96, 36.94, 29.97, 18.25, 16.13. MS-ESI
(m/z): 395 [M + H]+.
(E)-2,7-Dimethyl-N-(3-(3-p-tolylacrylamido)propyl)imidazo[1,2-a]pyridine-3-carboxamide (14a): The title
˝
compound was obtained from 6a and 10 as a white solid (59%); m.p.: 197–200 C. 1H-NMR (500 MHz,
CDCl3)
1H, Ar-H), 7.10 (d, J = 8.0 Hz, 2H, Ar-H), 6.98 (s, 2H, Ar-H), 6.68 (s, 1H, -CONH-), 6.42 (d, J = 15.5 Hz,
1H, =C-H), 3.54-3.46 (m, 4H, 2 -CH2-), 2.77 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.31 (s, 3H, CH3), 1.77
(s, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6)
(ppm): 165.34, 160.96, 145.26, 144.93, 139.18, 138.61,
δ (ppm): 9.20 (d, J = 7.0 Hz, 1H, pyridine-H), 7.56 (d, J = 15.5 Hz, 1H, =C-H), 7.32 (d, J = 7.5 Hz,
ˆ
δ
137.07, 132.16, 129.54, 127.50, 126.38, 121.12, 115.44, 115.16, 114.56, 36.48, 29.59, 20.96, 20.73, 15.75.
MS-ESI (m/z): 391 [M + H]+.
(E)-2,7-Dimethyl-N-(3-(3-(3,4,5-trimethoxyphenyl)acrylamido)propyl)imidazo[1,2-a]pyridine-3-carboxam˝ide
(
14b): The title compound was obtained from 6b and 10 as a white solid (41%); m.p.: 192–195 C.
1H-NMR (500 MHz, CDCl3)
δ
(ppm): 9.19 (d, J = 7.0 Hz, 1H, pyridine-H), 7.50 (d, J = 15.5 Hz, 1H,
=C-H), 7.26 (d, J = 3.5 Hz, 1H), 6.93–6.91 (m, 2H, Ar-H), 6.69–6.67 (m, 3H, Ar-H), 6.39 (d, J = 15.5 Hz,
1H, =C-H), 3.82 (s, 3H, OCH3), 3.80 (s, 6H, 2 OCH3), 3.54–3.45 (m, 4H, 2 -CH2-), 2.76 (s, 3H, CH3),
2.35 (s, 3H, CH3), 1.77–1.73 (m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6)
(ppm): 165.27, 160.95,
ˆ
ˆ
δ
153.08, 145.25, 144.93, 138.80, 138.57, 137.08, 130.56, 126.37, 121.52, 115.42, 115.17, 114.56, 104, 88, 60.10,
55.86, 36.47, 36.44, 29.54, 20.73, 15.75. MS-ESI (m/z): 467 [M + H]+.
(E)-N-(3-(3-(3,4-Dichlorophenyl)acrylamido)propyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (14c):
The title compound was prepared from 6c and 10 as a white solid (54%); m.p.: 178–181 ˝C. 1H-NMR
(500 MHz, CDCl3)
7.52 (d, J = 15.5 Hz, 1H, =C-H), 7.44 (d, J = 8.5 Hz, 1H, Ar-H), 7.33–7.28 (m, 2H, Ar-H and -CONH-),
6.78–6.76 (m, 2H, Ar-H and -CONH-), 6.47 (d, J = 15.5 Hz, 1H, =C-H), 3.61–3.50 (m, 4H, 2 -CH2-),
2.80 (s, 3H, CH3), 2.43 (s, 3H, CH3), 1.87–1.82 (m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6)
(ppm):
δ (ppm): 9.27 (d, J = 7.0 Hz, 1H, pyridine-H), 7.57 (d, J = 1.5 Hz, 1H, pyridine-H),
ˆ
δ
165.13, 161.40, 145.68, 145.36, 137.51, 136.51, 136.32, 132.11, 132.00, 131.49, 129.88, 127.73, 126.80, 124.89,
115.86, 115.60, 114.99, 37.03, 36.92, 29.92, 21.17, 16.18. MS-ESI (m/z): 445 [M + H]+.
(E)-N-(3-(3-(4-Methoxyphenyl)acrylamido)propyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (14d):
The title compound was prepared from 6d and 10 as a white solid (67%); m.p.: 217–220 ˝C. 1H-NMR
(500 MHz, CDCl3) δ (ppm): 9.18 (d, J = 7.0 Hz, 1H, pyridine-H),7.52 (d, J = 15.5 Hz, 1H, =C-H), 7.37–7.33
(m, 2H, Ar-H and pyridine-H), 7.25 (d, J = 7.5 Hz, pyridine-H), 7.03–6.98 (m, 2H, Ar-H and -CONH-),
6.81–6.78 (m, 2H, Ar-H and -CONH-), 6.67 (dd, J = 1.5, 7.5 Hz, 1H, Ar-H), 6.48 (d, J = 16.0 Hz, 1H,
=C-H), 3.76 (s, 3H), 3.52–3.44 (m, 4H, 2
ˆ
-CH2-), 2.76 (s, 3H, CH3), 2.34 (s, 3H, CH3), 1.77–1.75 (m,
(ppm): 165.50, 160.94, 160.31, 145.25, 144.92, 138.36,
2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6)
δ
137.07, 129.10, 127.47, 119.66, 115.43, 115.17, 114.56, 114.38, 114.40, 55.20, 36.46, 36.45, 29.62, 20.73, 15.74.
MS-ESI (m/z): 407 [M + H]+.
(E)-2,7-Dimethyl-N-(3-(3-(4-(trifluoromethyl)phenyl)acrylamido)propyl)imidazo[1,2-a]pyridine-3-carboxamide
˝
(
14e): The title compound was prepared from 6e and 10 as a white solid (22%); m.p.: 222–225 C.
1H-NMR (500 MHz, DMSO-d6)
δ
(ppm): 9.26 (d, J = 7.0 Hz, 1H, pyridine-H), 8.38 (s, 1H, -CONH-),

Molecules 2016, 21, 49
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7.65–7.57 (m, 4H, c and -CONH-), 7.33 (s, 1H, pyridine-H), 6.77–6.65 (m, 3H, Ar-H), 6.52 (d, J = 15.5 Hz,
1H, =C-H), 3.59–3.51 (m, 4H, 2 -CH2-), 2.80 (s, 3H, CH3), 2.42 (s, 3H, CH3), 1.83–1.80 (m, 2H, -CH2-).
13C-NMR (126 MHz, DMSO-d6)
(ppm): 164.67, 161.50, 144.69, 143.80, 139.03, 136.98, 129.16, 128.17,
ˆ
δ
125.84, 125.81, 125.23, 124.97, 124.70, 121.98, 115.75, 115.51, 115.49, 36.60, 36.51, 29.46, 17.81, 15.68.
MS-ESI (m/z): 445 [M + H]+.
(E)-N-(3-(3-(2-Fluorophenyl)acrylamido)propyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (14f): The
˝
1
title compound was prepared from 6f and
(500 MHz, DMSO-d6) (ppm): 8.93 (d, J = 7.0 Hz, 1H, pyridine-H), 8.45 (d, J = 5.0 Hz, 1H, -CONH-),
9 as a white solid (34%); m.p.: 197–199 C. H-NMR
δ
7.78 (d, J = 5.0 Hz, 1H, -CONH-), 7.67–7.62 (m, 1H, Ar-H), 7.51 (d, J = 16.0 Hz, 1H, =C-H), 7.43–7.41 (m,
1H, Ar-H), 7.33 (s, 1H, pyridine-H), 7.29–7.23 (m, 2H, Ar-H), 6.81 (dd, J = 7.5, 1.5 Hz, 1H, Ar-H), 6.74
(d, J = 16.0 Hz, 1H, =C-H), 3.45–3.42 (m, 4H, 2
ˆ
-CH2-), 2.54 (s, 3H, CH3), 2.28 (s, 3H, CH3), 1.85–1.82
(ppm): 165.19, 161.92, 161.60, 159.93, 145.72, 145.60,
(m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6)
δ
137.55, 131.78, 131.61, 129.65, 129.63, 126.87, 125.47, 125.44, 125.42, 116.64, 116.47, 115.78, 115.57, 114.98,
38.88, 38.61, 29.44, 17.76, 15.62. MS-ESI (m/z): 395 [M + H]+.
(E)-N-(3-(3-(4-Fluorophenyl)acrylamido)propyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (14g): The
˝
1
title compound was prepared from 6g and 10 as a white solid (55%); m.p.: 203–206 C. H-NMR
(500 MHz, DMSO-d6) (ppm): 8.92 (d, J = 7.5 Hz, 1H, pyridine-H), 8.22 (d, J = 5.5 Hz, 1H, -CONH-),
δ
7.77 (d, J = 5.5 Hz, 1H, -CONH-), 7.64–7.60 (m, 1H, Ar-H), 7.42 (d, J = 16.0 Hz, 1H, =C-H), 7.41 (s, 1H,
pyridine-H), 7.26–7.22 (m, 2H, Ar-H), 6.84 (dd, J = 7.0, 1.5 Hz, 1H, Ar-H), 6.58 (d, J = 16.0 Hz, 1H,
=C-H), 3.37–3.26 (m, 4H, 2
ˆ
-CH2-), 2.57 (s, 3H, CH3), 2.35 (s, 3H, CH3), 1.78–1.72 (m, 2H, -CH2-).
(ppm): 165.10, 163.66, 161.70, 160.95, 145.25, 144.92, 137.45, 137.07,
13C-NMR (126 MHz, CDCl3)
δ
131.57, 131.55, 129.72, 129.65, 122.08, 116.00, 115.83, 115.43, 115.16, 114.56, 36.51, 36.48, 29.55, 20.73,
15.74. MS-ESI (m/z): 395 [M + H]+.
4. Conclusions
In summary, a series of novel imidazo[1,2-a]pyridine amide-cinnamamide hybrids, 11–14, linked
via an alkyl carbon chain were designed, synthesized and evaluated for their in vitro anti-MTB activity.
All of the target hybrids are less active than the two reference compounds against MTB H37Rv ATCC
27294, but the promising activity (MICs: 4 µg/mL) of two compounds, 11e and 11k, suggests that they
may be selectively targeted to MTB growths and could be a good starting point for further studies, as
well as to find new lead compounds with better anti-MTB activity. By the way, the further expansion
of the imidazo[1,2-a]pyridine amide-cinnamamide hybrids is underway to find a potent anti-TB agent
in our lab.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/
21/1/49/s1.
Acknowledgments: This work was supported by the National S&T Major Special Project on Major New Drug
Innovations (2014ZX09507009-003), NSFC (81373267-003) and Beijing Municipal Administration of Hospitals
Clinical Medicine Development of Special Funding Support (ZYLX201304).
Author Contributions: Conceived of and designed the experiments: Mingliang Liu, Yu Lu and Huiyuan Guo.
Performed the experiments: Linhu Li and Zhuorong Li. Analyzed the data: Linhu Li, Weiyi Shen and Bin Wang.
Wrote the paper: Mingliang Liu, Zhuorong Li and Linhu Li. All authors read and approved the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
References and Notes
1.
2.
WHO. WHO Report 2009 (WHO/HTM/TB/2009), Global Tuberculosis Control; WHO: Geneva, Switzerland, 2009.
Glaziou, P.; Falzon, D.; Floyd, K.; Raviglione, M. Global epidemiology of tuberculosis. Semin. Respir. Crit.
Care Med. 2013, 1, 3–16. [CrossRef] [PubMed]

Molecules 2016, 21, 49
13 of 14
3.
4.
Diacon, A.H.; Dawson, R.; Hanekom, M.; Narunsky, K.; Maritz, S.J.; Venter, A.; Donald, P.R.; van Niekerk, C.;
Whitney, K.D.; Rouse, J.; et al. Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive
tuberculosis patients. Antimicrob. Agents Chemother. 2010, 54, 3402–3407. [CrossRef] [PubMed]
Diacon, A.H.; Donald, P.R.; Pym, A.; Grobusch, M.; Patientia, R.F.; Mahanyele, R.; Bantubani, N.;
Narasimooloo, R.; de Marez, T.; van Heeswijk, R.; et al. Randomized pilot trial of eight weeks of bedaquiline
(TMC207) treatment for multidrug-resistant tuberculosis: Long-term outcome, tolerability, and effect on
emergence of drug resistance. Antimicrob. Agents Chemother. 2012, 56, 3271–3276. [CrossRef] [PubMed]
Gler, M.T.; Skripconoka, V.; Sanchez-Garavito, E.; Xiao, H.; Cabrera-Rivero, J.L.; Vargas-Vasquez, D.E.;
Gao, M.; Awad, M.; Park, S.K.; Shim, T.S.; et al. Delamanid for multidrug-resistant pulmonary tuberculosis.
N. Engl. J. Med. 2012, 366, 2151–2160. [CrossRef] [PubMed]
5.
6.
7.
8.
9.
Cohen, J. Infectious disease. Approval of novel TB drug celebrated—With restraint. Science 2013, 6116.
[CrossRef]
Mitchison, D.; Davies, G. The chemotherapy of tuberculosis: Past, present and future. Int. J. Tuberc. Lung Dis.
2012, 16, 724–732. [CrossRef] [PubMed]
Bald, D.; Koul, A. Respiratory ATP synthesis: The new generation of mycobacterial drug targets?
FEMS Microbiol. Lett. 2010, 1, 1–7. [CrossRef] [PubMed]
Moraski, G.C.; Markley, L.D.; Chang, M.; Cho, S.; Franzblau, S.G.; Hwang, C.H.; Boshoff, H.; Miller, M.J.
Generation and exploration of new classes of antitubercular agents: The optimization of oxazolines, oxazoles,
thiazolines, thiazoles to imidazo[1,2-a]pyridines and isomeric 5,6-fused scaffolds. Bioorg. Med. Chem. 2012
,
20, 2214–2220. [CrossRef] [PubMed]
10. Moraski, G.C.; Markley, L.D.; Cramer, J.; Hipskind, P.A.; Boshoff, H.; Baily, M.; Alling, T.; Ollinger, J.;
Parish, T.; Miller, M.J. Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and
Nanomolar Activity Against Mycobacterium tuberculosis. Med. Chem. Lett. 2013, 4, 675–679. [CrossRef]
[PubMed]
11. Ollinger, J.; Bailey, M.A.; Moraski, G.C.; Casey, A.; Florio, S.; Alling, T.; Miller, M.J.; Parish, T. A dual read-out
assay to evaluate the potency of compounds active against Mycobacterium tuberculosis. PLoS ONE 2013, 8.
[CrossRef] [PubMed]
12. Kang, S.; Kim, R.Y.; Seo, M.J.; Lee, S.; Kim, Y.M.; Seo, M.; Seo, J.J.; Ko, Y.; Choi, I.; Jang, J.; et al. Lead
optimization of a novel series of imidazo[1,2-a]pyridine amides leading to a clinical candidate (Q203) as a
multi- and extensively-drug-resistant anti-tuberculosis agent. J. Med. Chem. 2014, 57, 5293–5305. [CrossRef]
[PubMed]
13. Abrahams, K.A.; Cox, J.A.; Spivey, V.L.; Loman, N.J.; Pallen, M.J.; Constantinidou, C.; Fernández, R.;
Alemparte, C.; Remuiñán, M.J.; Barros, D.; et al. Identification of novel imidazo[1,2-a]pyridine inhibitors
targeting M. tuberculosis QcrB. PLoS ONE 2012, 7. [CrossRef] [PubMed]
14. Pethe, K.; Bifani, P.; Jang, J.; Kang, S.; Park, S.; Ahn, S.; Jiricek, J.; Jung, J.; Jeon, H.K.; Cechetto, J.; et al.
Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat. Med. 2013, 19, 1157–1160.
[CrossRef] [PubMed]
15. Cheng, Y.; Moraski, G.C.; Cramer, J.; Miller, M.J.; Schorey, J.S. Bactericidal activity of an
imidazo[1,2-a]pyridine using a mouse M. tuberculosis infection model. PLoS ONE 2014, 9. [CrossRef]
[PubMed]
16. Dose-Escalation Study to Evaluate Safety, Tolerability and Pharmacokinetics of Single Doses of Q203
in Normal, Healthy, Male and Female Volunteers. Available online: https://clinicaltrials.gov/show/
NCT02530710 (accessed on 18 August 2015).
17. Li, L.H.; Liu, M.L. Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Unpublished work. 2016.
18. Natella, F.; Nardini, M.; Felice, M.; Scaccini, C. Benzoic and cinnamic acid derivatives as antioxidants:
Structure-activity relation. J. Agric. Food Chem. 1999, 47, 1453–1459. [CrossRef] [PubMed]
19. De, P.; Baltas, M.; Bedos-Belval, F. Cinnamic acid derivatives as anticancer agents—A review. Curr. Med. Chem.
2011, 18, 1672–1703. [CrossRef] [PubMed]
20. Naz, S.; Ahmad, S.; Rasool, S.A.; Sayeed, S.A.; Siddiqi, R. Antibacterial activity directed isolation of
compounds from Onosma hispidum. Microbiol. Res. 2006, 161, 43–48. [CrossRef] [PubMed]

Molecules 2016, 21, 49
14 of 14
21. De, P.; Yoya, G.K.; Constant, P.; Bedos-Belval, F.; Duran, H.; Saffon, N.; Daffe, M.; Baltas, M. Design, synthesis,
and biological evaluation of new cinnamic derivatives as antituberculosis agents. J. Med. Chem. 2011, 54,
1449–1461. [CrossRef] [PubMed]
22. Patel, K.N.; Telvekar, V.N. Design, synthesis and antitubercular evaluation of novel series of
N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives. Eur. J. Med. Chem. 2014, 75, 43–56. [CrossRef]
[PubMed]
23. Rastogi, N.; Goh, K.S.; Horgen, L.; Barrow, W.W. Synergistic activities of antituberculous drugs with cerulenin
and trans-cinnamic acid against Mycobacterium tuberculosis. FEMS Immunol. Med. Microbiol. 1998, 21,
149–157. [CrossRef] [PubMed]
24. Reddy, V.M.; Nadadhur, G.; Daneluzzi, D.; Dimova, V.P.; Gangadharam, R.J. Antimycobacterial activity of a
new rifamycin derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV (T9). Antimicrob. Agents
Chemother. 1995, 39, 2320–2324. [CrossRef] [PubMed]
25. Barnes, C.C.; Smalley, M.K.; Manfredi, K.P.; Kindscher, K.; Loring, H.; Sheele, D.M. Characterization of an
anti-tuberculosis resin glycoside from the prairie medicinal plant Ipomoea leptophylla. J. Nat. Prod. 2003, 66,
1457–1462. [CrossRef] [PubMed]
26. García, A.; Bocanegra-García, V.; Palma-Nicolás, J.; Rivera, G. Recent advances in antitubercular natural
products. Eur. J. Med. Chem. 2012, 49, 1–23. [CrossRef] [PubMed]
27. Friis-Moller, A.; Chen, M.; Fuursted, K.; Christensen, S.B.; Kharazmi, A. In vitro antimycobacterial and
antilegionella activity of licochalcone A from Chinese licorice roots. Planta Med. 2002, 68, 416–419. [CrossRef]
[PubMed]
28. Yan, M.; Ma, S.T. Recent advances in the research of heterocyclic compounds as antitubercular agents.
Chem. Med. Chem. 2012, 7, 2063–2075. [CrossRef] [PubMed]
29. Wu, M.C.; Peng, C.F.; Chen, I.S.; Tsai, I.L. Antitubercular chromones and flavonoids from Pisonia aculeata.
J. Nat. Prod. 2011, 74, 976–982. [CrossRef] [PubMed]
30. Chunavala, K.C.; Joshi, G.; Suresh, E.; Adimurthy, S. Thermal and microwave-assisted rapid syntheses of
substituted imidazo [1,2-a]pyridines under solvent-and catalyst-Free conditions. Synthesis 2011, 4, 635–641.
[CrossRef]
31. Li, L.H.; Wu, Z.Y.; Li, Z.R.; Liu, M.L.; Guo, H.Y.; Zhang, Q.R. Microwave Assisted Synthesis of Disubstituted
Imidazo[1,2-a]pyridine-3-carboxylic Acid Esters. Heterocycles 2015, 11, 2087–2096. [CrossRef]
32. Collins, L.; Franzblau, S.G. Microplate alamar blue assay versus BACTEC 460 system for high-throughput
screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob. Agents
Chemother. 1997, 41, 1004–1009. [PubMed]
33. Lu, Y.; Zheng, M.Q.; Wang, B.; Fu, L.; Zhao, W.J.; Li, P.; Xu, J.; Zhu, H.; Jin, H.X.; Yin, D.L.; et al. Clofazimine
analogs with efficacy against experimental tuberculosis and reduced potential for accumulation. Antimicrob.
Agents Chemother. 2011, 55, 5185–5193. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds 11a–l, 12a–l and 13a–g, 14a–g are available from
the authors.
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