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Article

Design, Synthesis and Antimycobacterial Activity of Novel Imidazo[1,2-a]pyridine Amide-Cinnamamide Hybrids

by
Linhu Li
1,
Zhuorong Li
1,
Mingliang Liu
1,*,
Weiyi Shen
2,
Bin Wang
3,
Huiyuan Guo
1 and
Yu Lu
3,*
1
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2
Zhejiang Starry Pharmaceutical Co. Ltd., Xianju 317300, China
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
*
Authors to whom correspondence should be addressed.
Molecules 2016, 21(1), 49; https://doi.org/10.3390/molecules21010049
Submission received: 2 November 2015 / Revised: 22 December 2015 / Accepted: 23 December 2015 / Published: 30 December 2015
(This article belongs to the Section Medicinal Chemistry)
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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.

Graphical Abstract

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 [3,4,5], 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 [8], have attracted broad attention due to their potent activity against MTB-resistant and -sensitive strains [9,10,11,12,13,14,15]. Two promising drug candidates, ND-09759 (Figure 1) and Q203 (Figure 1), are currently in pre-clinical and phase I clinical development [11,16], respectively. It has been generally 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 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 [25,26,27,28], such as pisoniamide (Figure 1), a natural cinnamamide isolated from Pisonia aculeate [29].
Molecules 21 00049 g001 550
Figure 1. Structures of selected anti-tuberculosis (TB) compounds and the design of imidazo[1,2-a]pyridine amide-cinnamamide hybrids.
Figure 1. Structures of selected anti-tuberculosis (TB) compounds and the design of imidazo[1,2-a]pyridine amide-cinnamamide hybrids.
Molecules 21 00049 g001
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 5–6 and novel hybrids 11–14 are depicted in Scheme 1 and Scheme 2, respectively. Commercially available cinnamic acids 1a–l were treated with thionyl chloride at reflux to give the corresponding acyl chlorides 2a–l. Condensation of the resulting 2a–l with tert-butyl (2-aminoethyl)carbamate or tert-butyl (3-aminopropyl)carbamate in the presence of 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).
Molecules 21 00049 g002 550
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%.
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%.
Molecules 21 00049 g002
The target Compounds 11–14 were conveniently prepared from ethyl 2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate 7 and ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate 8 [30,31], by hydrolysis in LiOH–EtOH and condensation with the above cinnamamide derivatives 5a–l and 6a–g in the presence of bis(2-oxo-3-oxazolidinyl)phosphonic chloride (BOP-Cl) and NEt3, successively (Scheme 2).
Molecules 21 00049 g003 550
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%.
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%.
Molecules 21 00049 g003

2.2. Anti-MTB Activity

The target Compounds 11–14 were evaluated for their in vitro activity against MTB H37Rv ATCC 27294 using the microplate Alamar Blue assay (MABA) [32,33]. The minimum inhibitory concentration (MIC) is defined as the lowest concentration effecting a reduction in fluorescence of ≥90% relative to the 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 μg/mL) are much less active than the reference drug INH (MIC: 0.05 μg/mL) and the parent compound IMB1502 (MIC: 0.015 μg/mL), but fourteen of them have potential activity against this strain (MICs: 4–32 μg/mL). Among them, Compounds 11e and 11k display the highest activity (MICs: 4 μg/mL), and Compounds 11k and 11e have also promising activity with MICs of 8 and 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: ≥32 μg/mL) in this study. In the case of the hybrids with MICs of 4–16 μg/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; 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
Table 1. Anti-M. tuberculosis (MTB) activity of imidazo[1,2-a]pyridine amide-cinnamamide Hybrids 11–14. Molecules 21 00049 i001
Table 1. Anti-M. tuberculosis (MTB) activity of imidazo[1,2-a]pyridine amide-cinnamamide Hybrids 11–14. Molecules 21 00049 i001
CompoundR1MIC (μg/mL)Compd.R1MIC (μg/mL)
11a4-CH3>3212a4-CH3>32
11b3,4,5-tri-OCH3>3212b3,4,5-tri-OCH3>32
11c3,4-di-Cl>3212c3,4-di-Cl32
11d4-OCH3>3212d4-OCH3>32
11e4-CF3412e4-CF316
11f2-F>3212f2-F>32
11g4-F>3212g4-F>32
11h3-F>3212h3-F>32
11i4-Cl>3212i4-Cl>32
11j4-NO23212j4-NO2>32
11k4-OCF3412k4-OCF38
11lH>3212lH>32
13a4-CH33214a4-CH3>32
13b3,4,5-tri-OCH33214b3,4,5-tri-OCH3>32
13c3,4-di-Cl>3214c3,4-di-Cl>32
13d4-OCH3>3214d4-OCH332
13e4-CF33214e4-CF332
13f2-F3214f2-F>32
13g4-F3214g4-F32
5e >32isoniazid 0.05
6e >32IMB1502 0.015
15 >32

3. Materials and Methods

3.1. Chemistry

Melting points were determined in open capillaries and are uncorrected. 1H-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).

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 7 as a white solid (87%); m.p.: 173–175 °C. 1H-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 8 as a white solid (78%); m.p.: 161–163 °C. 1H-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–l (5 mmol) in 5 equiv of thionyl chloride (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–l in the form of a solid residue in 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–l) and 4a–g (59%–70%, from 1a–g) as a white solid. 3a–l, 4a–g (4 mmol) in DCM/TFA (9:1, 40 mL) were stirred at room temperature for 1 h. Solvents were removed in vacuo to yield 5a–l (100%) and 6a–g (100%) as a colorless oil.

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 9, 10 (1.0 mmol) and BOP-Cl (1.2 mmol) 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–l and 6a–g (1.2 mmol). The resulting suspension was 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 compound was prepared from 5a and 9 as a white solid (61%); m.p.: 215–217 °C. 1H-NMR (500 MHz, DMSO-d6) δ (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) δ (ppm): 165.98, 161.57, 145.33, 144.25, 139.68, 139.14, 132.57, 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]+.
(E)-2,6-Dimethyl-N-(2-(3-(3,4,5-trimethoxyphenyl)acrylamido)ethyl)imidazo[1,2-a]pyridine-3-carboxamide (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 × -CH2-), 2.55 (s, 3H, CH3), 2.28 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6) δ (ppm): 165.48, 161.13, 153.08, 144.90, 143.82, 138.93, 138.60, 130.50, 129.18, 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 9 as a white solid (57%); m.p.: 213–215 °C. 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 8.82 (s, 1H, pyridine-H), 8.37 (m, 1H, -CONH-), 7.88–7.83 (m, 2H, -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 × -CH2-), 2.55 (s, 3H, CH3), 2.27 (s, 3H, CH3). 13C-NMR (126 MHz, DMSO-d6) δ (ppm): 164.94, 161.16, 144.92, 143.82, 136.16, 135.84, 131.69, 131.61, 131.06, 129.44, 129.17, 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 9 as a white solid (69%); m.p.: 203–205 °C. 1H-NMR (500 MHz, CDCl3) δ (ppm): 9.12 (s, 1H, pyridine-H), 7.55 (d, J = 15.5 Hz, 1H, =C-H), 7.44 (d, J = 9.0 Hz, 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 × -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-carboxamide (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 × -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 title compound was prepared from 5f and 9 as a white solid (70%); m.p.: 197–199 °C. 1H-NMR (500 MHz, DMSO-d6) δ (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) 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, 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 title compound was prepared from 5g and 9 as a white solid (67%); m.p.: 208–211 °C. 1H-NMR (500 MHz, DMSO-d6) δ (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) δ (ppm): 162.12, 159.72, 157.81, 157.73, 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 title compound was prepared from 5h and 9 as a white solid (65%); m.p.: 172–175 °C. 1H-NMR (500 MHz, DMSO-d6) δ (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) δ (ppm): 165.12, 163.45, 161.51, 161.18, 144.93, 143.84, 137, 55, 137.49, 130.96, 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 title compound was prepared from 5i and 9 as a white solid (59%); m.p.: 252–254 °C. 1H-NMR (500 MHz, DMSO-d6) δ (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) δ (ppm): 165.19, 161.15, 144.91, 143.82, 137.40, 133.90, 133.86, 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 title compound was prepared from 5J and 9 as a white solid (52%); m.p.: 213–215 °C. 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 8.82 (s, 1H, pyridine-H), 8.48 (s, 1H, -CONH-), 8.24 (d, J = 9.0 Hz, 2H, 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 × -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 × -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 as a white solid (58%); m.p.: 196–198 °C. 1H-NMR (500 MHz, CDCl3) δ (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, 4H, 2 × -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-carboxamide (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 × OCH3), 3.67 (s, 3H, OCH3), 3.44–3.41 (m, 4H, 2 × -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 × -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 × -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-carboxamide (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 × -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 title compound was prepared from 5f and 10 as a white solid (61%); m.p.: 213–216 °C. 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 8.92 (d, J = 7.0 Hz, 1H, pyridine-H), 8.44 (d, J = 5.0 Hz, 1H, -CONH-), 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 × -CH2-), 2.55 (s, 3H, CH3), 2.35 (s, 3H, CH3). 13C-NMR (126 MHz, CDCl3) δ (ppm): 165.59, 161.92, 161.60, 159.93, 145.72, 145.60, 137.56, 131.79, 131.61, 129.65, 129.63, 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 title compound was prepared from 5g and 10 as a white solid (65%); m.p.: 246–248 °C. 1H-NMR (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 × -CH2-), 2.54 (s, 3H, CH3), 2.36 (s, 3H, CH3). 13C-NMR (126 MHz, CDCl3) δ (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]+.
(E)-N-(2-(3-(3-Fluorophenyl)acrylamido)ethyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (12h): The title compound was prepared from 5h and 10 as a white solid (50%); m.p.: 172–175 °C. 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 8.93 (d, J = 7.5 Hz, 1H, pyridine-H), 8.33 (t, J = 5.0 Hz, 1H, -CONH-), 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 × -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 title compound was prepared from 5i and 10 as a white solid (61%); m.p.: 172–175 °C. 1H-NMR (500 MHz, DMSO-d6) δ (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) δ (ppm): 165.56, 161.60, 149.25, 145.72, 145.61, 137.59, 134.72, 129.89, 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 title compound was prepared from 5j and 10 as a white solid (71%); m.p.: 213–215 °C. 1H-NMR (500 MHz, DMSO-d6) δ (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) δ (ppm): 164.69, 161.17, 147.52, 145.28, 145.18, 141.51, 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 × -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) δ (ppm): 165.36, 161.13, 145.26, 145.14, 138.73, 137.13, 134.87, 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]+.
(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) δ (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), 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 × 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-carboxamide (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 × OCH3), 3.54–3.45 (m, 4H, 2 × -CH2-), 2.76 (s, 3H, CH3), 2.29 (s, 3H, CH3), 1.79–1.74 (m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6) δ (ppm): 165.27, 160.94, 153.09, 144.70, 143.82, 138.81, 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 (500 MHz, CDCl3) δ (ppm): 1H-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 × -CH2-), 2.78 (s, 3H, CH3), 2.35 (s, 3H, CH3), 1.85–1.80 (m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6) δ (ppm): 164.68, 160.95, 144.69, 143.80, 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 9 as a white solid (45%); m.p.: 178–181 °C. 1H-NMR (500 MHz, CDCl3) δ (ppm): 9.10 (s, 1H, pyridine-H), 7.53 (d, J = 15.5 Hz, 1H, =C-H), 7.39 (d, J = 9.0 Hz, 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 × -CH2-), 2.76 (s, 3H, CH3), 2.83 (s, 3H, CH3), 1.79-1.74 (m, 2H, -CH2-). 13C-NMR (126 MHz, CDCl3) δ (ppm): 165.52, 160.94, 160.31, 144.71, 143.82, 138.38, 129.15, 129.11, 127.48, 124.73, 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) δ (ppm): 164.67, 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 title compound was prepared from 6f and 9 as a white solid (41%); m.p.: 197–199 °C. 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 8.99 (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), 7.53–7.41 (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 × -CH2-), 2.55 (s, 3H, CH3), 2.29 (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 title compound was prepared from 6g and 9 as a white solid (67%); m.p.: 151–153 °C. 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 8.84 (s, 1H, pyridine-H), 8.22 (t, J = 5.5 Hz, 1H, -CONH-), 7.84 (t, 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 × -CH2-), 2.58 (s, 3H, CH3), 2.30 (s, 3H, CH3), 1.79–1.73 (m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6) 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) 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, 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) δ (ppm): 165.34, 160.96, 145.26, 144.93, 139.18, 138.61, 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-carboxamide (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) δ (ppm): 165.27, 160.95, 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) δ (ppm): 9.27 (d, J = 7.0 Hz, 1H, pyridine-H), 7.57 (d, J = 1.5 Hz, 1H, pyridine-H), 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) δ (ppm): 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 × -CH2-), 2.76 (s, 3H, CH3), 2.34 (s, 3H, CH3), 1.77–1.75 (m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6) δ (ppm): 165.50, 160.94, 160.31, 145.25, 144.92, 138.36, 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-), 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) δ (ppm): 164.67, 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)-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide (14f): The title compound was prepared from 6f and 9 as a white solid (34%); m.p.: 197–199 °C. 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 8.93 (d, J = 7.0 Hz, 1H, pyridine-H), 8.45 (d, J = 5.0 Hz, 1H, -CONH-), 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 × -CH2-), 2.54 (s, 3H, CH3), 2.28 (s, 3H, CH3), 1.85–1.82 (m, 2H, -CH2-). 13C-NMR (126 MHz, DMSO-d6) δ (ppm): 165.19, 161.92, 161.60, 159.93, 145.72, 145.60, 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 title compound was prepared from 6g and 10 as a white solid (55%); m.p.: 203–206 °C. 1H-NMR (500 MHz, DMSO-d6) δ (ppm): 8.92 (d, J = 7.5 Hz, 1H, pyridine-H), 8.22 (d, J = 5.5 Hz, 1H, -CONH-), 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 × -CH2-), 2.57 (s, 3H, CH3), 2.35 (s, 3H, CH3), 1.78–1.72 (m, 2H, -CH2-). 13C-NMR (126 MHz, CDCl3) δ (ppm): 165.10, 163.66, 161.70, 160.95, 145.25, 144.92, 137.45, 137.07, 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: https://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

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  • Sample Availability: Samples of the compounds 11a–l, 12a–l and 13a–g, 14a–g are available from the authors.

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MDPI and ACS Style

Li, L.; Li, Z.; Liu, M.; Shen, W.; Wang, B.; Guo, H.; Lu, Y. Design, Synthesis and Antimycobacterial Activity of Novel Imidazo[1,2-a]pyridine Amide-Cinnamamide Hybrids. Molecules 2016, 21, 49. https://doi.org/10.3390/molecules21010049

AMA Style

Li L, Li Z, Liu M, Shen W, Wang B, Guo H, Lu Y. Design, Synthesis and Antimycobacterial Activity of Novel Imidazo[1,2-a]pyridine Amide-Cinnamamide Hybrids. Molecules. 2016; 21(1):49. https://doi.org/10.3390/molecules21010049

Chicago/Turabian Style

Li, Linhu, Zhuorong Li, Mingliang Liu, Weiyi Shen, Bin Wang, Huiyuan Guo, and Yu Lu. 2016. "Design, Synthesis and Antimycobacterial Activity of Novel Imidazo[1,2-a]pyridine Amide-Cinnamamide Hybrids" Molecules 21, no. 1: 49. https://doi.org/10.3390/molecules21010049

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