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Article

Synthesis and Cytotoxic Activity of Some Novel N-Pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide Derivatives

by
Huaiwei Ding
1,2,
Zhe Chen
2,
Cunlong Zhang
2,
Tian Xin
2,
Yini Wang
2,
Hongrui Song
1,
Yuyang Jiang
2,
Yuzong Chen
3,
Yongnan Xu
1,* and
Chunyan Tan
2,*
1
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
2
The Key Laboratory of Chemical Biology, Guangdong Province, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China
3
Bioinformatics and Drug Design Group, Department of Computational Science, National University of Singapore, Blk SOC1, Level 7, 3 Science Drive 2, Singapore 117543, Singapore
*
Authors to whom correspondence should be addressed.
Molecules 2012, 17(4), 4703-4716; https://doi.org/10.3390/molecules17044703
Submission received: 29 February 2012 / Revised: 1 April 2012 / Accepted: 13 April 2012 / Published: 23 April 2012
(This article belongs to the Section Medicinal Chemistry)
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Versions Notes

Abstract

:
A series of novel compounds bearing imidazo[2,1-b]thiazole scaffolds were designed and synthesized based on the optimization of the virtual screening hit compound N-(6-morpholinopyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5a), and tested for their cytotoxicity against human cancer cell lines, including HepG2 and MDA-MB-231. The results indicated that the compound 2-(6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-(4-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)acetamide (5l), with slightly higher inhibition on VEGFR2 than 5a (5.72% and 3.76% inhibitory rate at 20 μM, respectively), was a potential inhibitor against MDA-MB-231 (IC50 = 1.4 μM) compared with sorafenib (IC50 = 5.2 μM), and showed more selectivity against MDA-MB-231 than HepG2 cell line (IC50 = 22.6 μM).

1. Introduction

During the last few decades, anticancer therapy has made significantly progress, especially after the approval of a few small-molecule inhibitors, but the management of malignancies in humans is still one major concern. Extensive interest is being focused on exploring newly functional scaffolds capable of being further developed as anticancer agents. Recently, considerable attention has been paid to the design and the biological activity of compounds bearing imidazo[2,1-b]thiazole scaffolds due to their broad spectrum of pharmacological activities, such as antifungal [1,2,3], antibacterial [3,4,5,6] anti-inflammatory [7] and antihypertensive properties [8], as well as being used as cystic fibrosis transmembrane conductance regulator (CFTR)-selective potentiators [9]. In particular, many imidazo[2,1-b]thiazole derivatives have been reported to display potential antitumor activities against a variety of human cancer cell lines [10,11,12,13,14,15,16]. The recent studies demonstrated that pyrimidinyl-substituted imidazo[2,1-b]thiazole derivatives could inhibit Raf kinases [17], and appropriately substituted imidazo[2,1-b]thiazoles could be developed as dual inhibitors of IGF-IR (insulin-like growth factor receptor) and EGFR (epidermal growth factor receptor) [18] or P38 kinase inhibitors [19]. However, there is no report about imidazo[2,1-b]thiazole derivatives as vascular endothelial growth factor receptor (VEGFR) inhibitors. These observations elicited much interest in this fused ring system and prompted us to attempt to develop VEGFR inhibitors possessing the imidazo[2,1-b]thiazole core.
Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a central role in the process of tumor growth and metastasis [20]. Blockade of VEGF/VEGFR signaling pathways, which regulates proliferation and migration of endothelial cells, has been explored as a highly successful clinical strategy in cancer treatment [21]. Several VEGFR inhibitors have been approved and many are under development in clinic. Based on our interest in searching for novel biologically active molecules as VEGFR inhibitors and consideration of the potent bioactivities of compounds that possess an imidazo[2,1-b]thiazole scaffold, we searched Ambinter and ChemSpider chemical database using a SVM (support vector machine) screening model [22,23], and found one hit compound 5a (ChemSpider ID: 11102329) (Figure 1) bearing an imidazo[2,1-b]thiazole core with potential anticancer activity. As follow-up to this observation, we have now designed and synthesized a series of novel imidazo[2,1-b]thiazole acetamide derivatives and assessed their in vitro activities.

2. Results and Discussion

2.1. Chemistry

All the agents, unless mentioned otherwise, are commercially available and were directly used without further purification. Synthesis of the intermediates and target compounds was accomplished according to the steps illustrated in Scheme 1. Ethyl 2-(2-aminothiazol-4-yl)acetate (2) reacted with substituted or nonsubstituted 2-bromoacetophenones 1 to give the crude products 1a–c [12], which without further purification were refluxed in EtOH-H2O-NaOH (1.5 mol/L), acidified by 2M HCl, to afford 2a–c in good yields (62%–80%) [24]. Compounds 3a–d were prepared by the reaction of 2-chloro-5-nitropyridine (3) with various R2groups in high yield (96%–99%) [25]. Compounds 4a–d which were obtained by the reduction of 3a–d [26], along with commercial agents 4e–h, were coupled with 2a–c to afford the target compounds 5a–p.
Molecules 17 04703 g001 550
Figure 1. Structures of hit compound 5a and modification position of target compounds.
Figure 1. Structures of hit compound 5a and modification position of target compounds.
Molecules 17 04703 g001
Molecules 17 04703 g002 550
Scheme 1. The Synthesis Route of Compounds 5a–p.
Scheme 1. The Synthesis Route of Compounds 5a–p.
Molecules 17 04703 g002

2.2. In Vitro Bioactivity

Compound 5a acquired by the SVM screening model was first evaluated for its inhibitory activity on VEGFR2 kinase and against HepG2 and MDA-MB-231 cell lines. Although 5a at 20 µM exhibited only a 3.76% inhibitory rate on VEGFR2 kinase, it displayed moderate cytotoxic activity against the HepG2 and MDA-MB-231 cell lines (IC50 = 74.2 and 27.1 μM, respectively), which made it a potential hit compound for further investigation. The other 15 compounds were also evaluated against HepG2 and MDA-MB-231 cell lines with sorafenib as the positive control. The IC50 value results are summarized in Table 1.
Table
Table 1. The substituents and in vitro cytotoxicity of synthesized compounds against HepG2 and MDA-MB-231 cell lines. Molecules 17 04703 i001
Table 1. The substituents and in vitro cytotoxicity of synthesized compounds against HepG2 and MDA-MB-231 cell lines. Molecules 17 04703 i001
CompoundR1R2IC50* (µM)
HepG2MDA-MB-231
5aH Molecules 17 04703 i00274.2 ± 2.527.1 ± 0.4
5bHOCH3>100>100
5cClOCH363.7 ± 0.440.1 ± 1.3
5dHCl62.0 ± 3.722.8 ± 4.6
5eHF>10079.0 ± 3.8
5fClCl50.0 ± 1.413.0 ± 0.2
5gClF53.4 ± 0.522.3 ± 1.3
5hOCH3Cl>10051.8 ± 0.8
5iH Molecules 17 04703 i00371.5 ± 1.7>100
5jCl Molecules 17 04703 i00428.2 ± 0.6>100
5kH Molecules 17 04703 i00539.4 ± 1.96.0 ± 0.7
5lCl Molecules 17 04703 i00622.6 ± 1.51.4 ± 0.1
5mH Molecules 17 04703 i00755.2 ± 1.519.8 ± 2.2
5nCl Molecules 17 04703 i00834.7 ± 0.412.9 ± 0.2
5oH >10062.6 ± 3.7
5pCl 48.9 ± 1.435.1 ± 0.5
sorafenib 33.7 ± 1.35.2 ± 0.2
* The IC50 values were reported as the average of three independent determinations and expressed as the mean ± SD.
As shown in Table 1, some of the modified compounds showed tantamount or better cytotoxicity against either HepG2 or MDA-MB-231 cell line compared with hit compound 5a. In particular, 5l exhibited potent activity against MDA-MB-231 cell line, slightly better than sorafenib, with IC50 values of 1.4 µM and 5.2 µM, respectively, though it displayed only a little increased inhibition on VEGFR2 kinase (5.72%, inhibitory rate at 20 µM) compared with 5a (3.76%, inhibitory rate at 20 µM); Compared to the positive control sorafenib, whose activity against the MDA-MB-231 cell line was 7-fold stronger than HepG2, our synthesized compound 5l demonstrated 16-fold stronger inhibition against MDA-MB-231 than HepG2. Moreover, 5l showed much lower toxicity towards the HL7702 cell line (normal liver cell) with an IC50 value of more than 100 µM, indicating that it may be considered a lead structure for the design of novel useful anticancer agents with low toxicity. Besides 5l, 5k with an IC50 value of 6.0 µM also displayed good activity which is equivalent to that of sorafenib.
The structure-activity relationships (SARs) suggested that all of compounds with Cl substituents at the R1 position displayed better cytotoxic activities than those substituted by H atom or OCH3 groups on the same position, including 5c vs. 5b, 5f vs. 5d or 5h, 5g vs. 5e, 5j vs. 5i, 5l vs. 5k, 5n vs. 5m and 5p vs. 5o. When R1 is H atom, morpholine on R2 position replaced by smaller groups, methoxyl or F, decreased the cytotoxicity against both cell lines, but Cl atom showed similar activity to 5a. Trying 1-methylpiperazine on this position to produce 5j increased the cytotoxic activity against the HepG2 cell line but considerably decreased cytotoxicity against the MDA-MB-231 cell line, with IC50 values of 28.2 μM and >100 μM, respectively. Compounds 5k and 5m with further substituted piperazine groups slightly increased the cytotoxic activity, especially 5k increased much more against MDA-MB-231 cell line. The above observation indicates that pyridine substituted by bulk groups is beneficial for the antitumor activity. Compounds 5o and 5p with N-(6-aminopyridin-2-yl) moieties displayed lower or similar cytotoxic activity against both cell lines, compared with most of other compounds, which may indicate that the N position on the pyridine ring is important for the cytotoxic activity, or that aminopyridine groups with much larger hydrophilicity hamper the activity. More studies need to be carried out for confirmation of this conjecture.

3. Experimental

3.1. Materials and Reagents

1H-NMR, and 13C-NMR spectra were determined on a Bruker ARX-400 400 MHz spectrometer with tetramethylsilane (TMS) as the internal standard and DMSO-d6 or CDCl3 as the solvents (chemical shifts in ppm). Splitting patterns were designated as follows: s: singlet; d: doublet; t: triplet; m: multiplet. Mass spectra were carried out using a Waters Micromass Q-TOF Premier Mass Spectrometer. Melting points were determined in open glass capillaries with a SGW X-4 digital apparatus and were uncorrected. Follow-up of the reactions and checking the homogeneity of the compounds were made by TLC (thin layer chromatography) on silica gel-protected glass plates and the spots were detected by exposure to UV-lamp at λ254 and λ365. Unless otherwise noted, all solvents and reagents were commercially available and used without further purification.

3.2. Chemical Synthesis

3.2.1. General Procedure for Preparation of 2-(6-Phenylimidazo[2,1-b]thiazol-3-yl)acetic Acid Derivatives 2a–c

Ethyl 2-(2-aminothiazol-4-yl) acetate (20 mmol) was dissolved in acetone (50 mL) and treated with the substituted 2-bromoacetophenone (20 mmol, 1 eq.), the mixture was refluxed for 8 h. and then concentrated to 20 mL. The resulting solution was cautiously basified with 15% NH4OH to pH 8–9, then poured into CH2Cl2, separated, washed and concentrated. The crude product was dissolved in EtOH-H2O-NaOH (1.5 mol/L) and refluxed for another 0.5 h, then acidified to pH 3–4 with 2M HCl to afford white solid precipitate, following by wash and dry, to afford the desired compounds 2a–c.
2-(6-Phenylimidazo[2,1-b]thiazol-3-yl)acetic acid (2a, C13H10N2O2S; M.W.: 258.0463). Yield: 79%; mp: 221–223 °C; 1H-NMR (DMSO-d6) δ: 8.72 (s, 1H, imidazole H), 7.91 (d, J = 7.6 Hz, 2H, Ar-H), 7.55–7.41 (m, 4H, Ar-H and thiazole H), 4.12 (s, 2H, CH2); 13C-NMR (DMSO-d6) δ: 169.3, 147.4, 139.3, 129.1, 128.9, 128.7, 127.6, 125.0, 114.5, 110.0, 32.2.
2-(6-(4-Chlorophenyl)imidazo[2,1-b]thiazol-3-yl)acetic acid (2b, C13H9ClN2O2S; M.W.: 292.0073). Yield: 80%; mp: 236–238 °C; 1H-NMR (DMSO-d6) δ: 8.50 (s, 1H, imidazole H), 7.89 (d, J = 8.4 Hz, 2H, Ar-H), 7.52 (d, J = 8.4 Hz, 2H, Ar-H), 7.30 (s, 1H, thiazole H), 4.04 (s, 2H, CH2); 13C-NMR (DMSO-d6) δ: 169.4, 148.2, 141.8, 132.3, 130.6, 128.8, 126.7, 126.5, 112.3, 109.6, 32.6.
2-(6-(4-Methoxyphenyl)imidazo[2,1-b]thiazol-3-yl)acetic acid (2c, C14H12N2O3S; M.W.: 288.0569). Yield: 62%; mp: 231–233 °C; 1H-NMR (DMSO-d6)δ: 8.57 (s, 1H, imidazole H), 7.83 (d, J = 8.4 Hz, 2H, Ar-H), 7.46 (s, 1H, thiazole H), 7.09 (d, J = 8.4 Hz, 2H, Ar-H), 4.10 (s, 2H, CH2), 3.82 (s, 3H, CH3); 13C-NMR (DMSO-d6) δ: 169.2, 159.7, 147.0, 139.7, 127.5, 126.6, 121.3, 114.6, 114.0, 108.7, 55.3, 32.2.

3.2.2. General Procedure for Preparation of Compounds 3a–d

A mixture of morpholine (100 mmol), 2-chloro-5-nitropyridine (50 mmol), and K2CO3 (100 mmol) in THF (50 mL) were stirred at 80 °C for 4 h, and then concentrated to 20 mL, poured into water (100 mL), whereby a yellow solid precipitate formed. The precipitate was washed, dried and recrystallized with CH2Cl2 to afford yellow crystals of 3a. Compounds 3b–d were obtained as the same procedure as 3a.
4-(5-Nitropyridin-2-yl)morpholine (3a, C9H11N3O3; M.W.: 209.0800). Yield: 99%; mp: 141–143 °C; 1H-NMR (CDCl3) δ: 9.04 (d, J = 2.8 Hz, 1H, pyridine H), 8.23 (dd, J = 2.8, 9.6 Hz, 1H, pyridine H), 6.57 (d, J = 9.6 Hz, 1H, pyridine H), 3.82 (t, J = 4.8 Hz, 4H, CH2), 3.75 (t, J = 4.8 Hz, 4H, CH2); 13C-NMR (CDCl3) δ: 160.6, 146.3, 135.5, 133.1, 104.5, 66.5, 45.1.
1-Methyl-4-(5-nitropyridin-2-yl)piperazine (3b, C10H14N4O2; M.W.: 222.1117). Yield: 97%; mp: 97–99 °C; 1H-NMR (DMSO-d6) δ: 9.02 (d, J = 2.4 Hz, 1H, pyridine H), 8.19 (dd, J = 2.4, 9.6 Hz, 1H, pyridine H), 6.57 (d, J = 9.6 Hz, 1H, pyridine H), 3.79 (t, J = 4.8 Hz, 4H, CH2), 2.52 (t, J = 4.8 Hz, 4H, CH2), 2.36 (s, 3H, CH3); 13C-NMR (DMSO-d6) δ: 160.4, 146.5, 135.1, 133.0, 104.5, 54.6, 46.5, 44.9.
1-(4-Methoxybenzyl)-4-(5-nitropyridin-2-yl)piperazine (3c, C17H20N4O3; M.W.: 328.1535). Yield: 96%; mp: 110–112 °C; 1H-NMR (DMSO-d6) δ: 8.94 (d, J = 2.8 Hz, 1H, pyridine H), 8.20 (dd, J = 2.8, 9.6 Hz, 1H, pyridine H), 7.24 (d, J = 8.4 Hz, 2H, Ar-H), 6.92 (d, J = 9.6 Hz, 1H, pyridine H), 6.90 (d, J = 8.8 Hz, 2H, Ar-H), 3.74 (brs, 7H, CH2 and CH3), 3.47 (brs, 2H, CH2), 2.45 (brs, 4H, CH2); 13C-NMR (DMSO-d6) δ: 160.0, 158.3, 146.0, 134.1, 132.7, 130.1, 113.5, 105.5, 61.0, 54.9, 51.9, 44.4.
1-(4-Fluorobenzyl)-4-(5-nitropyridin-2-yl)piperazine (3d, C16H17FN4O2; M.W.: 316.1336). Yield: 98%; mp: 99–101 °C; 1H-NMR (CDCl3) δ: 9.00 (d, J = 2.4 Hz, 1H, pyridine H), 8.18–8.15 (m, 1H, pyridine H), 7.31 (dd, J = 5.2, 8.8 Hz, 2H, Ar-H), 7.03 (d, J = 8.8 Hz, 2H, Ar-H), 6.54 (d, J = 9.6 Hz, 1H, pyridine H), 3.77 (t, J = 5.2 Hz, 4H, CH2), 3.52 (s, 2H, CH2), 2.53 (t, J = 5.2 Hz, 4H, CH2); 13C-NMR (CDCl3) δ: 162.2, 160.4, 146.5, 134.9, 133.3, 132.9, 130.6, 115.2, 104.5, 62.0, 52.5, 44.9.

3.2.3. General Procedure for Preparation of Compounds 4a–d

The mixture of 3a–d (20 mmol) and Pd/C (20%, 500 mg) in methanol was hydrogenated at atmosphere at r.t. for 12 h, followed by filtration and concentration, to afford crude residue 4a–d, which was purified by recrystallization (ethanol).
6-Morpholinopyridin-3-amine (4a, C9H13N3O; M.W.: 179.1059). Yield: 70%; mp: 119–121 °C; 1H-NMR (CDCl3) δ: 7.79 (d, J = 2.8 Hz, 1H, pyridine H), 7.00 (dd, J = 2.8, 8.8 Hz, 1H, pyridine H), 6.56 (d, J = 8.8 Hz, 1H, pyridine H), 3.83 (t, J = 4.8 Hz, 4H, CH2), 3.33 (t, J = 4.8 Hz, 4H, CH2), 3.26 (brs, H, NH2); 13C-NMR (CDCl3) δ: 154.4, 135.2, 135.1, 126.0, 108.3, 66.8, 47.1.
6-(4-Methylpiperazin-1-yl)pyridin-3-amine (4b, C10H16N4; M.W.: 192.1375). Yield: 76%; mp: 91–93 °C; 1H-NMR (CDCl3) δ: 7.78 (d, J = 2.8 Hz, 1H, pyridine H), 6.98 (dd, J = 2.8, 8.8 Hz, 1H, pyridine H), 6.57 (d, J = 8.8 Hz, 1H, pyridine H), 3.39 (t, J = 4.8 Hz, 4H, CH2), 3.29 (brs, 2H, NH2), 2.54 (t, J = 4.8 Hz, 4H, CH2), 2.34 (s, 3H, CH3); 13C-NMR (CDCl3) δ: 154.4, 135.2, 134.7, 126.1, 108.5, 55.0, 46.7, 46.2.
6-(4-(4-Methoxybenzyl)piperazin-1-yl)pyridin-3-amine (4c, C17H22N4O; M.W.: 298.1794). Yield: 74%; mp: 104–106 °C; 1H-NMR (CDCl3) δ: 7.78 (d, J = 2.8 Hz, 1H, pyridine H), 7.25 (d, J = 8.4 Hz, 2H, Ar-H), 6.96 (dd, J = 2.8, 8.8 Hz, 1H, pyridine H), 6.87 (dd, J = 2.8, 8.8 Hz, 2H, Ar-H), 6.54 (d, J = 8.8 Hz, 1H, pyridine H), 3.84 (brs, 2H, NH2), 3.80 (s, 3H, CH3), 3.52 (s, 2H, CH2), 3.37 (t, J = 4.8 Hz, 4H, CH2), 2.58 (t, J = 4.8 Hz, 4H, CH2); 13C-NMR (CDCl3) δ: 158.9, 154.6, 135.4, 134.6, 130.5, 129.7, 126.2, 113.7, 108.4, 62.3, 55.3, 52.7, 46.6.
6-(4-(4-Fluorobenzyl)piperazin-1-yl)pyridin-3-amine (4d, C16H19FN4; M.W.: 286.1594). Yield: 80%; mp: 94–96 °C; 1H-NMR (CDCl3) δ: 7.76 (d, J = 2.8 Hz, 1H, pyridine H), 7.29 (t, J = 6.8 Hz, 2H, Ar-H), 6.99 (t, J = 8.8 Hz, 2H, Ar-H), 6.92 (dd, J = 2.8, 8.8 Hz, 1H, pyridine H), 6.52 (d, J = 8.8 Hz, 1H, pyridine H), 3.48 (s, 2H, NH2), 3.35 (t, J = 4.8 Hz, 6H, CH2), 2.53 (t, J = 4.8 Hz, 4H, CH2); 13C-NMR (CDCl3) δ: 161.9, 154.3, 135.1, 134.8, 133.8, 130.5, 126.0, 115.0, 108.4, 62.2, 52.8, 46.7.

3.2.4. General Procedure for Preparation of Compounds 5a–p

A solution of the 2a (1 mmol), 4a (1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1 mmol), N-hydroxybenzotrizole (HOBt, 1 mmol), and N-diisopropylethylamine (DIPEA, 3 mmol) in anhydrous THF (10 mL) was stirred for 24 h. The reaction was quenched with 1M NaOH (20 mL) and extracted with ethyl acetate (3 × 20 mL), the organic layer was washed with 1M HCl (3 × 20 mL), water (20 mL), dried with Na2SO4 and evaporated to give compound 5a as a white solid. Other title compounds 5b–p were synthesized using the same procedure.
N-(6-Morpholinopyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5a). Yield: 72%; mp: 212–214 °C; 1H-NMR (DMSO-d6) δ: 10.23 (s, 1H, NH), 8.33 (d, J = 2.4 Hz, 1H, pyridine H), 8.24 (s, 1H, imidazole H), 7.84–7.81 (m, 3H, Ar-H and pyridine H), 7.39 (t, J = 7.6 Hz, 2H, Ar-H), 7.25 (t, J = 7.6 Hz, 1H, Ar-H), 7.08 (s, 1H, thiazole H), 6.83 (d, J = 9.2 Hz, 1H, pyridine H), 3.99 (s, 2H, CH2), 3.69 (t, J = 4.8 Hz, 4H), 3.36 (t, J = 4.8 Hz, 4H); 13C-NMR (DMSO-d6) δ: 165.4, 156.0, 148.5, 145.9, 139.1, 134.2, 130.0, 128.5, 126.9, 126.7, 126.6, 124.6, 109.9, 108.3, 106.8, 65.8, 45.5, 34.9; MS (Q-TOF) m/z: 420.1491 [M+H]+ (calc. for C22H21N5O2S, 419.1416).
N-(6-Methoxypyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5b). Yield: 76%; mp: 184–186 °C; 1H-NMR (DMSO-d6) δ: 10.48 (s, 1H, NH), 8.42 (s, 1H, pyridine H), 8.31 (s, 1H, imidazole H), 7.96 (d, J = 1.6 Hz, 1H, Ar-H), 7.94 (s, 1H, Ar-H), 7.86 (d, J = 7.6 Hz, 1H, pyridine H), 7.41 (t, J = 7.2 Hz, 2H, Ar-H), 7.27 (t, J = 7.2 Hz, 1H, Ar-H), 7.14 (s, 1H, thiazole H), 6.83 (d, J = 8.8 Hz, 1H, pyridine H), 4.06 (s, 2H, CH2), 3.83 (s, 3H, CH3); 13C-NMR (DMSO-d6)δ: 165.6, 159.8, 148.5, 145.6, 137.8, 33.9, 131.5, 129.7, 128.6, 127.1, 126.6, 124.7, 110.4, 110.1, 108.5, 53.1, 34.9; MS (Q-TOF) m/z: 365.1066 [M+H]+ (calc. for C19H16N4O2S, 364.0994).
2-(6-(4-Chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-methoxypyridin-3-yl)acetamide (5c). Yield: 75%; mp: 247–249 °C; 1H-NMR (DMSO-d6) δ: 10.39 (s, 1H, NH), 8.39 (d, J = 2.8 Hz, 1H, pyridine H), 8.31 (s, 1H, imidazole H), 7.94 (dd, J = 2.8, 8.8 Hz, 1H, pyridine H), 7.87 (d, J = 8.8 Hz, 2H, Ar-H), 7.45 (d, J = 8.4 Hz, 2H, Ar-H), 7.12 (s, 1H, thiazole H), 6.82 (d, J = 8.8 Hz, 1H, pyridine H), 4.03 (s, 2H, CH2), 3.83 (s, 3H, CH3); 13C-NMR (DMSO-d6)δ: 165.6, 159.8, 148.8, 144.8, 137.7, 133.2, 131.5, 131.3, 129.7, 128.6, 126.5, 126.3, 110.4, 110.1, 108.9, 53.1, 34.9; MS (Q-TOF) m/z: 399.0683 [M+H]+ (calc. for C19H15ClN4O2S, 398.0604).
N-(6-Chloropyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5d). Yield: 70%; mp: 161–163 °C; 1H-NMR (DMSO-d6) δ: 11.21 (s, 1H, NH), 8.73 (d, J = 4.0 Hz, 1H, imidazole H), 8.70 (d, J = 2.8 Hz, 1H, pyridine H), 8.14 (dd, J = 2.8, 8.8 Hz, 1H, pyridine H), 7.88 (d, J = 7.2 Hz, 2H, Ar-H), 7.53–7.48 (m, 4H, Ar-H and thiazole H and pyridine H), 7.41 (t, J = 7.2 Hz, 1H, Ar-H), 4.26 (s, 2H, CH2); 13C-NMR (DMSO-d6)δ: 166.1, 147.7, 143.8, 140.7, 140.4, 135.1, 129.8, 129.0, 128.6, 127.5, 127.4, 125.0, 124.1, 113.9, 109.9, 34.4; MS (Q-TOF) m/z: 369.0573 [M+H]+ (calc. for C18H13ClN4OS, 368.0499).
N-(6-Fluoropyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5e). Yield: 77%; mp: 98–100 °C; 1H NMR (DMSO-d6) δ: 10.13 (s, 1H, NH), 8.32 (d, J = 1.6 Hz, 1H, imidazole H), 8.22–8.18 (m, 1H, pyridine H), 7.69 (d, J = 7.2 Hz, 2H, Ar-H), 7.57 (s, 1H, pyridine H), 7.34 (t, J = 7.2 Hz, 2H, Ar-H), 7.26 (dd, J = 1.6, 7.2 Hz, 1H, Ar-H), 6.87 (dd, J = 2.8, 8.8 Hz, 1H, pyridine H), 6.45 (s, 1H, thiazole H), 3.68 (s, 2H, CH2); 13C-NMR (DMSO-d6)δ: 165.5, 160.0, 149.7, 147.5, 138.7, 133.5, 133.4, 132.9, 129.0, 128.0, 125.3, 125.2, 110.2, 109.6, 107.3, 36.1; MS (Q-TOF) m/z: 353.0876 [M+H]+ (calc. for C18H13FN4OS, 352.0794).
2-(6-(4-Chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-chloropyridin-3-yl)acetamide (5f). Yield: 72%; mp: 215–217 °C; 1H-NMR (DMSO-d6) δ: 10.73 (s, 1H, NH), 8.62 (d, J = 2.0 Hz, 1H, pyridine H), 8.31 (s, 1H, imidazole H), 8.10 (dd, J = 2.8, 8.4 Hz, 1H, pyridine H), 7.85 (d, J = 8.4 Hz, 2H, Ar-H), 7.50 (d, J = 8.4 Hz, 1H, pyridine H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 7.13 (s, 1H, thiazole H), 4.08 (s, 2H, CH2); 13C-NMR (DMSO-d6)δ: 166.3, 148.8, 144.8, 143.8, 140.4, 135.1, 133.1, 131.2, 129.9, 128.5, 126.3, 126.1, 124.2, 110.6, 108.9, 35.0; MS (Q-TOF) m/z: 403.0188 [M+H]+ (calc. for C18H12Cl2N4OS, 402.0109).
2-(6-(4-Chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-fluoropyridin-3-yl)acetamide (5g). Yield: 74%; mp: 211–213 °C; 1H–NMR (DMSO-d6) δ: 10.66 (s, 1H, NH), 8.45 (brs, 1H, pyridine H), 8.31 (s, 1H, imidazole H), 8.21–8.17 (m, 1H, pyridine H), 7.86 (dd, J = 2.0, 6.8 Hz, 2H, Ar-H), 7.45 (dd, J = 2.0, 6.8 Hz, 2H, Ar-H), 7.19 (dd, J = 3.2, 8.8 Hz, 2H, pyridine H), 7.14 (s, 1H, thiazole H), 4.07 (s, 2H, CH2); 13C-NMR (DMSO-d6)δ: 166.1, 158.7, 148.8, 144.8, 137.8, 133.8, 133.2, 132.9, 131.3, 128.6, 126.3, 126.2, 110.6, 109.3, 108.9, 34.9; MS (Q-TOF) m/z: 387.0480 [M+H]+ (calc. for C18H12ClFN4OS, 386.04040.
N-(6-Chloropyridin-3-yl)-2-(6-(4-methoxyphenyl)imidazo[2,1-b]thiazol-3-yl)acetamide (5h). Yield: 81%; mp: 108–110 °C; 1H-NMR (CDCl3) δ: 10.24 (s, 1H, NH), 8.52 (d, J = 2.8 Hz, 1H, pyridine H), 8.16 (dd, J = 2.8, 8.8 Hz, 1H, pyridine H), 7.61 (d, J = 8.8 Hz, 2H, Ar-H), 7.43 (s, 1H, imidazole H), 7.25 (d, J = 7.6 Hz, 1H, pyridine H), 6.89 (d, J = 8.8 Hz, 2H, Ar-H), 6.45 (s, 1H, thiazole H), 3.80 (s, 3H, CH3), 3.66 (s, 2H, CH2); 13C-NMR (CDCl3)δ: 165.6, 159.6, 149.5, 147.5, 146.2, 140.8, 134.3, 130.3, 126.5, 126.1, 125.2, 124.5, 114.4, 109.8, 106.2, 55.4, 36.4; MS (Q-TOF) m/z: 399.0683 [M+H]+ (calc. for C19H15ClN4O2S, 398.0604).
N-(6-(4-Methylpiperazin-1-yl)pyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5i). Yield: 71%; mp: 132–134 °C; 1H-NMR (DMSO-d6) δ: 10.27 (s, 1H, NH), 8.31 (d, J = 2.4 Hz, 1H, pyridine H), 8.24 (s, 1H, imidazole H), 7.83 (d, J = 7.6 Hz, 2H, Ar-H), 7.79 (dd, J = 2.4, 9.2 Hz, 1H, pyridine H), 7.39 (t, J = 7.6 Hz, 2H, Ar-H), 7.25 (t, J = 7.6 Hz, 1H, Ar-H), 7.08 (s, 1H, thiazole H), 6.82 (d, J = 9.2 Hz, 1H, pyridine H), 3.99 (s, 2H, CH2), 3.40 (t, J = 4.8 Hz, 4H, CH2), 2.37 (t, J = 4.8 Hz, 4H, CH2), 2.20 (s, 3H, CH3); 13C-NMR (DMSO-d6) δ: 165.3, 155.9, 148.6, 146.0, 139.2, 134.2, 130.1, 128.5, 126.9, 126.6, 126.3, 124.6, 109.9, 108.3, 106.8, 54.3, 45.7, 44.9, 34.9; MS (Q-TOF) m/z: 433.1808 [M+H]+ (calc. for C23H24N6OS, 432.1732).
2-(6-(4-Chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-acetamide (5j). Yield: 71%; mp: 118–120 °C; 1H-NMR (DMSO-d6) δ: 10.22 (s, 1H, NH), 8.31 (d, J = 2.4 Hz, 1H, pyridine H), 8.29 (s, 1H, imidazole H), 7.85(d, J = 8.4 Hz, 2H, Ar-H), 7.79 (dd, J = 2.4, 9.2 Hz, 1H, pyridine H), 7.45 (d, J = 8.8 Hz, 2H, Ar-H), 7.10 (s,1H, thiazole H), 6.82 (d, J = 9.2 Hz, 1H, pyridine H), 3.98 (s, 2H, CH2), 3.41 (t, J = 4.8 Hz, 4H, CH2), 2.39 (t, J = 4.8 Hz, 4H, CH2), 2.21(s, 3H, CH3); 13C-NMR (DMSO-d6)δ: 165.3, 155.9, 148.8, 144.7, 139.2, 133.1, 131.2, 130.0, 128.6, 126.6, 126.3, 126.2, 110.2, 108.8, 106.8, 54.2, 45.7, 44.9, 34.9; MS (Q-TOF) m/z: 467.1423 [M+H]+ (calc. for C23H23ClN6OS, 466.1343).
N-(6-(4-(4-Methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5k). Yield: 78%; mp: 92–94 °C; 1H-NMR (DMSO-d6) δ: 9.26 (s, 1H, NH), 8.19 (d, J = 2.4 Hz, 1H, pyridine H), 7.75–7.71 (m, 3H, Ar-H and pyridine H), 7.58 (s, 1H, imidazole H), 7.34 (t, J = 7.6 Hz, 2H, Ar-H), 7.24 (t, J = 8.4 Hz, 3H, Ar-H), 6.85 (d, J = 8.4 Hz, 2H, Ar-H), 6.51 (d, J = 9.2 Hz, 1H, pyridine H), 6.42 (s, 1H, thiazole H), 3.79 (s, 3H, CH3), 3.60 (s, 2H, CH2), 3.45 (s, 2H, CH2), 3.43 (t, J = 4.8 Hz, 4H, CH2), 2.47 (t, J = 4.8 Hz, 4H, CH2); 13C-NMR (DMSO-d6)δ: 165.2, 158.8, 157.2, 149.7, 147.6, 140.6, 133.8, 131.4, 130.3, 129.9, 128.8, 127.7, 125.5, 125.2, 125.0, 113.7, 110.0, 107.1, 106.9, 62.4, 55.3, 52.7, 45.5, 36.2; MS (Q-TOF) m/z: 539.2231 [M+H]+ (calc. for C30H30N6O2S, 538.2151).
2-(6-(4-Chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-(4-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)acetamide (5l). Yield: 72%; mp: 116–118 °C; 1H-NMR (DMSO-d6) δ: 8.68 (s, 1H, NH), 8.14 (d, J = 2.4 Hz, 1H, pyridine H), 7.71 (dd, J = 2.4, 9.2 Hz,1H, pyridine H), 7.66 (s, 1H, imidazole H), 7.63 (d, J = 3.6 Hz, 2H, Ar-H), 7.30 (d, J = 8.4 Hz, 2H, Ar-H), 7.23 (d, J = 8.4 Hz, 2H, Ar-H), 6.86 (d, J = 8.4 Hz, 2H, Ar-H), 6.53 (s, 1H, thiazole H), 6.52 (d, J = 8.8 Hz, 1H, pyridine H), 3.79 (s, 3H, CH3), 3.67 (s, 2H, CH2), 3.46 (s, 2H, CH2), 3.44 (t, J = 4.8 Hz, 4H, CH2), 2.48 (t, J = 4.8 Hz, 4H, CH2); 13C-NMR (DMSO-d6)δ: 164.9, 158.9, 157.4, 149.9, 146.8, 140.7, 133.3, 132.4, 131.6, 130.4, 129.9, 128.9, 126.5, 125.3, 124.5, 113.7, 110.4, 107.1, 106.8, 62.5, 55.3, 52.7, 45.5, 36.4; MS (Q-TOF) m/z: 573.1841 [M+H]+ (calc. for C30H29ClN6O2S, 572.1761).
N-(6-(4-(4-Fluorobenzyl)piperazin-1-yl)pyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5m). Yield: 75%; mp: 80–82 °C; 1H-NMR (DMSO-d6) δ: 10.22 (s, 1H, NH), 8.32 (d, J = 2.4 Hz, 1H, pyridine H), 8.24 (s, 1H, imidazole H), 7.84 (d, J = 7.6 Hz, 2H, Ar-H), 7.80 (dd, J = 2.4, 8.8 Hz, 1H, pyridine H), 7.41–7.34 (m, 4H, Ar-H), 7.25 (t, J = 7.2 Hz, 1H, Ar-H), 7.15 (t, J = 9.2 Hz, 2H, Ar-H), 7.09 (s, 1H, thiazole H), 6.80 (d, J = 9.2 Hz, 1H, pyridine H), 3.99 (s, 3H, CH3), 3.48 (s, 2H, CH2), 3.41 (t, J = 4.4 Hz, 4H, CH2), 2.43 (t, J = 4.4 Hz, 4H, CH2); 13C-NMR (DMSO-d6)δ: 165.3, 161.2, 155.9, 148.6, 146.0, 139.2, 134.2, 134.1, 130.6, 130.1, 128.5, 126.9, 126.6, 126.3, 124.6, 114.8, 109.9, 108.3, 106.8, 61.1, 52.2, 45.1, 34.9; MS (Q-TOF) m/z: 527.2030 [M+H]+ (calc. for C29H27FN6OS, 526.1915).
2-(6-(4-Chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-(4-fluorobenzyl)piperazin-1-yl)pyridin-3-yl)acetamide (5n). Yield: 73%; mp: 86–88 °C; 1H-NMR (CDCl3) δ: 9.09 (s, 1H, NH), 8.16 (d, J = 2.4 Hz, 1H, pyridine H), 7.69 (dd, J = 2.4, 8.8 Hz, 1H, pyridine H), 7.61 (d, J = 8.4 Hz, 2H, Ar-H), 7.60 (s, 1H, imidazole H), 7.29–7.26 (m, 4H, Ar-H), 6.99 (t, J = 8.8 Hz, 2H, Ar-H), 6.49 (d, J = 9.2 Hz, 1H, pyridine H), 6.47 (s, 1H, thiazole H), 3.63 (s, 2H, CH2), 3.47 (s, 2H, CH2), 3.42 (t, J = 4.8 Hz, 4H, CH2), 2.46 (t, J = 4.8Hz, 4H, CH2); 13C-NMR (CDCl3)δ: 165.2, 162.1, 157.2, 149.8, 146.6, 140.6, 133.6, 133.2, 132.3, 131.4, 130.6, 128.9, 126.4, 125.5, 124.9, 115.1, 110.3, 107.3, 106.9, 62.2, 52.7, 45.5, 36.1; MS (Q-TOF) m/z: 561.1640 [M+H]+ (calc. for C29H26ClFN6OS, 560.1561).
N-(6-Aminopyridin-2-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5o). Yield: 70%; mp: 216–218 °C; 1H-NMR (DMSO-d6) δ: 10.30 (s, 1H, NH), 8.22 (s, 1H, imidazole H), 7.83 (d, J = 7.6 Hz, 2H, Ar-H), 7.41–7.32 (m, 3H, pyridine H and Ar-H), 7.27–7.19 (m, 2H, pyridine H and Ar-H), 7.08 (s, 1H, thiazole H), 6.20 (d, J = 8.0 Hz, 1H, pyridine H), 5.82 (s, 2H, NH2), 4.03 (s, 2H, CH2); 13C-NMR (DMSO-d6)δ: 165.9, 158.5, 150.0,148.6, 145.9, 138.8, 134.2, 128.5, 126.9, 126.6, 124.6, 109.9, 108.3, 103.7, 35.2; MS (Q-TOF) m/z: 350.1075 [M+H]+ (calc. for C18H15ClN5OS, 349.0997).
N-(6-Aminopyridin-2-yl)-2-(6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl)acetamide (5p). Yield: 72%; mp: 228–230 °C; 1H-NMR (DMSO-d6) δ: 10.29 (s, 1H, NH), 8.27 (s, 1H, imidazole H), 7.84 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 7.34 (t, J = 8.0 Hz, 1H, pyridine H), 7.18 (brd, J = 0.8 Hz, 1H, pyridine H), 7.09 (s, 1H, thiazole H), 6.19 (d, J = 8.4 Hz, 1H, pyridine H), 5.81 (s, 2H, NH2), 4.02 (s, 2H, CH2); 13C-NMR (DMSO-d6)δ: 165.9, 158.5, 150.0, 148.8, 144.7, 138.8, 133.1, 131.2, 128.6, 126.6, 126.2, 110.2, 108.8, 103.7, 100.8, 35.2; MS (Q-TOF) m/z: 384.0690 [M+H]+ (calc. for C18H14ClN5OS, 383.0608).

3.3. Biological Methods

3.3.1. In Vitro Cytotoxic Assay

The cytotoxic activities of compounds 5a–p were evaluated with HepG2 (liver cancer cell) and MDA-MB-231(breast cancer cell), as well as the toxicity of 5l towards HL7702 cell line (normal liver cell) by the MTT (3-(4,5-dimethylthiahiazol-2-y1)-2,5-diphenyltetrazolium bromide) method in vitro, with sorafenib as positive control. All the cell lines were purchased from the Type Culture Collection of the Chinese Academy of Sciences, Shanghai, China. Two cancer cell lines were cultured in DMEM (Dulbecco’s modified Eagle medium), 10% fetal bovine serum (FBS), 100 μg/mL penicillin, and 100 μg/mL streptomycin in humidified air at 37 °C, 5% CO2. HL7702 cell line cultured in RPMI-1640 (Roswell Park Memorial Institute-1640), 10% FBS, and 100 μg/mL streptomycin in humidified air at 37 °C, 5% CO2. The cells were then seeded in 96-well tissue culture plate and treated with the synthesized compounds at different concentrations. 48 h later, 15 μL of MTT solution (5 mg/mL) was added to each well and incubated for another 4 h at 37 °C, 5% CO2. The formazan precipitate was dissolved in 100 μL DMSO and the absorbance at 495 nm of each well was measured by Multimode Detector DTX880 (Beckman Coulter). Each assay condition was prepared in triplicate, and the experiments were carried out three times. IC50 values were obtained by nonlinear regression (Origin 7.5) and represent the concentration at which cell growth was inhibited by 50% and the SD (standard deviation) were derived.

3.3.2. In Vitro VEGFR Inhibitory Activity Assay

The assay was tested by HD Biosciences Co., Ltd. (Shanghai, China). General procedures are as followed: Kinase was incubated with substrate (5-FAM-KKKKEEIYFFF-CONH2), compounds and ATP (adenosine triphosphate) in a final buffer of 25 mM 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (HEPES, pH 7.4), 10 mM MgCl2, 0.01% Triton X-100, 100 µg/mL albumin from bovine serum (BSA), 2.5 mM DL-dithiothreitol (DTT) in 384-well plate with the total volume of 10 µL. The assay plate was incubated at 30 °C for 1 h and stopped with the addition of equal volume of kinase-glo plus reagent. The luminescence was read at envision. The signal was correlated with the amount of ATP present in the reaction and was inversely correlated with the kinase activity [27].

4. Conclusions

In summary, based on the virtual screening hit compound 5a, we designed and synthesized a series of novel compounds possessing an imidazo[2,1-b]thiazole scaffold, and evaluated them for their anticancer activity. The results showed that some of the synthesized compounds displayed better activity than 5a, against either the HepG2 or MDA-MB-231 cell lines. Of these compounds, 5l with lower inhibition on VEGFR2 kinase was a potent, selective inhibitor against the MDA-MB-231 cell line compared with the HepG2 cell line. This study may provide valuable information for further design of imidazo[2,1-b]thiazole derivatives as potential antitumor agents which could specifically target VEGFR kinase.

Acknowledgments

Authors wish to thank to the National High Technology Research and Development Program of China (863 Program) (No. 2012AA020305).

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  • Sample Availability: Samples of the compounds 5a–p are available from the authors.

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MDPI and ACS Style

Ding, H.; Chen, Z.; Zhang, C.; Xin, T.; Wang, Y.; Song, H.; Jiang, Y.; Chen, Y.; Xu, Y.; Tan, C. Synthesis and Cytotoxic Activity of Some Novel N-Pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide Derivatives. Molecules 2012, 17, 4703-4716. https://doi.org/10.3390/molecules17044703

AMA Style

Ding H, Chen Z, Zhang C, Xin T, Wang Y, Song H, Jiang Y, Chen Y, Xu Y, Tan C. Synthesis and Cytotoxic Activity of Some Novel N-Pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide Derivatives. Molecules. 2012; 17(4):4703-4716. https://doi.org/10.3390/molecules17044703

Chicago/Turabian Style

Ding, Huaiwei, Zhe Chen, Cunlong Zhang, Tian Xin, Yini Wang, Hongrui Song, Yuyang Jiang, Yuzong Chen, Yongnan Xu, and Chunyan Tan. 2012. "Synthesis and Cytotoxic Activity of Some Novel N-Pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide Derivatives" Molecules 17, no. 4: 4703-4716. https://doi.org/10.3390/molecules17044703

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