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Research Article
Syntheses and evaluation of novel 3-hydroxy-1,3-diaryl-2,3,5,6,7,8-hexahydro-imidazo[1,2-a]pyridine-1-ium bromides as potential anticancer agents
expand article infoSergii Demchenko‡, Sergii Yarmoluk‡, Volodymyr Sukhovieiev§|, Oleksandr Golovchenko|, Oleksandr Sukhovieiev|, Anatolii Demchenko§
‡ Institute of Molecular Biology and Genetics of National Academy of Sciences Ukraine, Kyiv, Ukraine
§ Nizhyn Mykola Gogol State University, Nizhyn, Ukraine
| V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Kyiv, Ukraine
¶ Institute of Pharmacology and Toxicology, National Academy of Medical Sciences, Kyiv, Ukraine

Corresponding author: Sergii Demchenko ( demcha.chem@gmail.com )

Academic editor: Emiliya Cherneva
© 2024 Sergii Demchenko, Sergii Yarmoluk, Volodymyr Sukhovieiev, Oleksandr Golovchenko, Oleksandr Sukhovieiev, Anatolii Demchenko.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation: Demchenko S, Yarmoluk S, Sukhovieiev V, Golovchenko O, Sukhovieiev O, Demchenko A (2024) Syntheses and evaluation of novel 3-hydroxy-1,3-diaryl-2,3,5,6,7,8-hexahydro-imidazo[1,2-a]pyridine-1-ium bromides as potential anticancer agents. Pharmacia 71: 1-10. https://doi.org/10.3897/pharmacia.71.e135992
Open Access

Abstract

New 3-hydroxy-1,3-diaryl-2,3,5,6,7,8-hexahydro-imidazo[1,2-a]pyridine-1-ium bromides have been designed, synthesized, and characterized by 1Н NMR, 13C NMR, and LCMS. The cyclic structure of the condensation products of aryl-(3,4,5,6-tetahydropyridin-2-yl)amines with α-bromoketones has been proven. It has been shown that heating 3-hydroxy-1,3-bis-(41-methoxyphenyl)-2,3,5,6,7,8-hexahydro-imidazo[1,2-a]pyridine-1-ium bromide in acetic anhydride accompanied by elimination of water to form 1,3-bis-(41-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-1-ium bromide. Antitumor activity of 1,3-bis-(41-ethoxyphenyl)-3-hydroxy-2,3,5,6,7,8-hexahydro-imidazo[1,2-a]pyridine-1-ium bromide and 1,3-bis-(41-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-1-ium bromide have been studied. The fully aromatic imidazo[1,2-a]pyridine-1-ium bromide system was shown to have a higher antitumor effect. According to the screening results, the tested compound showed a significant level of anticancer effect on cancer cells of colon COLO 205 (lgGI50 = -5.35, lgTGI = –4.70 and lgLC50 = –4.19) and melanoma SK-MEL-5 (lgGI50 = –5.57, lgTGI = –4.81 and lgLC50 = –4.17).

Keywords

arylamidines, 1,3-diaryl-3-hydroxy-2,3,5,6,7,8-hexahydro-imidazo[1,2-a]pyridine-1-ium bromides, anticancer activity

Introduction

The heterocyclic system of imidazo[1,2-a]pyridine is a part of a number of natural biologically active substances and drugs (Nisha et al. 2016). This group reveals a wide range of pharmacological activity (Fig. 1). Thus, for example, Olprinone, which contains the fragment of imidazo[1,2-a]pyridine, is a cardiotonic (Mizushige et al. 2002); Fadrozol has antitumor activity against breast cancer cells (Bonnefoi et al. 1996); Zolpidem has hypnotic properties (Arbilla et al. 1986; Crestani et al. 2000); Alpidem has anxiolytic properties (Sanger and Zivkovic 1994; Zivkovic et al. 1996); Miroprofen is an analgesic and NSAID (Sakaizumi et al. 1983); Zolmidine has antiulcer properties (Belohlavek and Malfertheiner 1979); Necopidem and Saripidem have sedative, anxiolytic properties (Santos et al. 2019). Compound HS-173 on the proliferation of human non-small cell lung cancer (NSCLC) cells. The cytotoxic effects of HS-173 on human NSCLC cell lines (A549, H1299, and NCI-H596) (Lee et al. 2013).

Figure 1. 

Some selected models of imidazo[1,2-a]pyridine derivatives possessing different biological activity.

Thus, the synthesis of new derivatives of imidazo[1,2-a]pyridine and the search for antitumor agents among them has not only theoretical but also practical interest.

Materials and methods

Chemicals and anticancer activity

All solvents were purified before use.

The reactions were monitored by thin-layer chromatography (TLC) using Fluka silica gel (60 F 254) plates (0.25 mm). The visualization was made with UV light. Melting points of the compounds synthesized were taken on a melting point tube. Elemental analysis was performed on a EuroEA 3000 elemental analyzer. The mass spectra were recorded on an Agilent LC/MSD SL 1100 instrument (USA).

1Н NMR spectra were recorded on a Varian Gemini device with 400 MHz (Germany) in DMSO-d6 using tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported in ppm units using the d scale.

All the chemicals used were of analytical grade (AR). The melting points of the synthesized compounds were determined by open capillaries and are uncorrected. 1H NMR spectra in DMSO-d6 on a Varian NMR mercury-300 instrument,

The structures of all the synthesized derivatives were elucidated by 1H NMR and 13CNMR spectroscopical analysis. The steps included in the synthesis are described below.

Chemistry

The general procedure for the synthesis of 1,3-diaryl-3-hydroxy-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromides 10 a–k and 11 a–f, i, l

A mixture of (0.01 mol) (4-methoxyphenyl)-(3,4,5,6-tetrahydropyridin-2-yl)amine 7 or (0.01 mol) (4-ethoxyphenyl)-(3,4,5,6-tetrahydropyridin-2-yl)amine 8 and appropriate 2-bromo-1-arylethanones 9 a–k or 9 a–f, i, l were placed in a round bottom flask. Further add 50 ml of ethyl acetate and reflux it in a water bath for 2 h at ambient temperature for a specified time. After completion of the reaction, the solid separates out; this was then filtered, dried, and recrystallized by propanol-2.

10 a. 3-Hydroxy-1-(41-methoxyphenyl)-3-phenyl-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 69%. M.p. = 236–238 °C. 1H NMR (DMSO-d6): 1.76–1.81 (m, 4Н, CH2СН2), 2.65 and 2.71 (m+m, 2Н, 8-СН2), 2.89 and 3.37 (m+m, 2Н, 5-СН2), 3.81 (s, 3H, ОCH3), 4.31 and 4.39 (d-d, 2Н, 2-СН2, J=12.6 Hertz), 7.11 and 7.60 (d-d, 4Н, С6Н4, J=9.3 Hertz), 7.46–7.54 (m, 3Н, С6Н3), 7.72–7.74 (m, 2Н, С6Н2), 7.99 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 17.97, 21.05, 23.61, 56.10, 66.29, 92.57, 115.4, 126.9, 128.0, 128.3, 129.1, 129.6, 138.5, 159.9, 164.7. Anal. calcd. for C20H23BrN2O2: N, 6.94; Br, 19.8. Found: N, 7.09; Br, 19.6. MS m/z: 323.2 [(M+H)+].

10 b. 3-Hydroxy-1-(41-methoxyphenyl)-3-(32-nitrophenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 84%. M.p.= 233–234 °C. 1H NMR (DMSO-d6): 1.78–1.82 (m, 4Н, CH2СН2), 2.68 and 2.72 (m+m, 2Н, 8-СН2), 2.91 and 3.37 (m+m, 2Н, 5-СН2), 3.82 (s, 3H, ОCH3), 4.35 and 4.47 (d-d, 2Н, 2-СН2, J=13.0 Hertz), 7.13 and 7.62 (d-d, 4Н, С6Н4, J=9.1 Hertz), 8.35 (s, 1Н, ОН), 7.81–8.56 (m, 4Н, С6Н4). 13C NMR (125 MHz, DMSO-d6) δ: 17.92, 21.06, 23.80, 56.11, 65.84, 91.84, 115.4, 122.0, 124.7, 128.0, 131.0, 134.0, 140.6, 148.5, 160.0, 165.4. Anal. calcd. for C20H22BrN3O4: N, 9.37; Br, 17.8. Found: N, 9.53; Br, 17.6. MS m/z: 369.2 [(M+H)+].

10 c. 3-Hydroxy-1,3-bis-(41-methoxyphenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium

Yield 65%. M.p. = 211–212 °C. 1H NMR (DMSO-d6): 1.79 (m, 4Н, CH2СН2), 2.63 and 2.71 (m+m, 2Н, 8-СН2), 2.88 and 3.32 (m+m, 2Н, 5-СН2), 3.81 (s, 3H, ОCH3), 3.82 (s, 3H, ОCH3), 4.28 and 4.36 (d-d, 2Н, 2-СН2, J=12.6 Hertz), 7.04 and 7.64 (d-d, 4Н, С6Н4, J=8.7 Hertz), 7.11 and 7.67 (d-d, 4Н, С6Н4, J=9.0 Hertz), 7.92 (с, 1Н, ОН). Anal. calcd. for C21H25BrN2O3: N, 6.46; Br, 18.5. Found: N, 6.37; Br, 18.3.

10 d. 3-Hydroxy-1-(41-methoxyphenyl)-3-(42-fluorophenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 72%. M.p. = 231–233 °C. 1H NMR (DMSO-d6): 1.88–1.97 (m, 4Н, CH2СН2), 2.62 and 2.80 (m+m, 2Н, 8-СН2), 2.95 and 3.50 (m+m, 2Н, 5-СН2), 3.83 (s, 3H, ОCH3), 4.27 and 4.37 (d-d, 2Н, 2-СН2, J=12.2 Hertz), 7.00 and 7.81 (d-d, 4Н, С6Н4, J=8.6 Hertz), 7.15–7.89 (m+m, 4Н, С6Н4), 8.02 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 17.94, 21.04, 23.65, 56.10, 66.16, 92.20, 115.4, 115.8, 116.0, 128.1, 128.2, 129.4, 129.5, 134.8, 160.0, 162.0, 163.9, 164.8. Anal. calcd. for C20H22BrFN2O2: N, 6.65. Found: N, 6.77. MS m/z: 341.2 [(M+H)+].

10 e. 3-Hydroxy-1-(41-methoxyphenyl)-3-(42-difluoromethoxyphenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 76%. M.p. = 193–194 °C. 1H NMR (DMSO-d6): 1.78–1.82 (m, 4Н, CH2СН2), 2.64 and 2.71 (m+m, 2Н, 8-СН2), 2.89 and 3.33 (m+m, 2Н, 5-СН2), 3.82 (s, 3H, ОCH3), 4.31 and 4.39 (d-d, 2Н, 2-СН2, J=12.7 Hertz), 7.11 and 7.64 (d-d, 4Н, С6Н4, J=9.0 Hertz), 7.31 and 7.82 (d-d, 4Н, С6Н4, J=8.7 Hertz), 7.36 (t, 1H, OCHF2, J=73.8 Hertz) , 8.06 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 17.95, 21.05, 23.64, 56.10, 66.11, 92.23, 114.6, 115.4, 116.7, 118.7, 119.1, 128.0, 128.2, 129.0, 135.3, 160.0, 164.8. Anal. calcd. for C21H23BrF2N2O3: N, 5.97. Found: N, 6.12. MS m/z: 389.2 [(M+H)+].

10 f. 3-Hydroxy-1-(41-methoxyphenyl)-3-(32,42-dimethoxyphenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 60%. M.p. = 223–225 °C. 1H NMR (DMSO-d6): 1.75–1.80 (m, 4Н, CH2СН2), 2.67 and 2.72 (m+m, 2Н, 8-СН2), 2.93 and 3.33 (m+m, 2Н, 5-СН2), 3.80 (s, 3H, ОCH3), 3.82 (s, 3H, ОCH3), 3.83 (s, 3H, ОCH3), 4.25 and 4.40 (d-d, 2Н, 2-СН2, J=12.8 Hertz), 7.04 - 7.27 (m, 3Н, С6Н3), 7.12 and 7.57 (d-d, 4Н, С6Н4, J=9.1 Hertz), 7.92 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 18.00, 21.07, 23.69, 56.10, 56.45, 66.12, 92.46, 110.7, 112.0, 115.3, 119.6, 128.0, 128.4, 130.5, 149.2, 149.8, 159.9, 165.4. Anal. calcd. For. C22H27BrN2O2: N, 6.04; Br, 17.2. Found: N, 6.21; Br, 17.5. MS m/z: 383.2 [(M+H)+].

10 g. 3-Hydroxy-1-(41-methoxyphenyl)-3-(42-diphenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 78%. M.p. = 273–275 °C. 1H NMR (DMSO-d6): 1.80–1.84 (m, 4Н, CH2СН2), 2.66 and 2.74 (m+m, 2Н, 8-СН2), 2.97 and 3.41 (m+m, 2Н, 5-СН2), 3.83 (s, 3H, ОCH3), 4.35 and 4.44 (d-d, 2Н, 2-СН2, J=12.8 Hertz), 7.12 and 7.64 (d-d, 4Н, С6Н4, J=9.0 Hertz), 7.79 and 7.84 (d-d, 4Н, С6Н4, J=8.4 Hertz), 7.41-7.73 (m, 5Н, С6Н5), 8.04 (s, 1Н, ОН). 13C NMR (100 MHz, CDCl3) δ: 22.9, 26.8, 27.3, 30.0, 44.4, 55.7, 67.8, 92.5, 115.3, 126.2, 127.1, 127.6, 127.9, 128.2, 128.8, 129.0, 138.4, 140.0, 142.3, 160.5, 169.6. Anal. calcd. for C26H27BrN2O2: N, 5.84; Br, 16.7. Found: N, 5.71; Br, 16.9. MS m/z: 400.2 [(M+H)+].

10 h. 3-Hydroxy-1-(41-methoxyphenyl)-3-(42-bromophenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 81%. M.p. = 245–246 °C. 1H NMR (DMSO-d6): 1.75–1.80 (m, 4Н, CH2СН2), 2.64 and 2.69 (m+m, 2Н, 8-СН2), 2.90 and 3.33 (m+m, 2Н, 5-СН2), 3.81 (s, 3H, ОCH3), 4.30 and 4.39 (d-d, 2Н, 2-СН2, J=13.1 Hertz), 7.11 and 7.57 (d-d, 4Н, С6Н4, J=9.3 Hertz), 7.67 and 7.77 (d-d, 4Н, С6Н4, J=9.0 Hertz), 8.10 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 17.93, 21.06, 23.64, 56.10, 65.98, 92.25, 115.4, 123.2, 128.0, 128.2, 129.4, 132.0, 138.0, 160.0, 164.9. Anal. calcd. for C20H22Br2N2O2: N, 5.81; Br, 33.1. Found: N, 5.94; Br, 29.8. MS m/z: 389.2 [(M+H)+].

10 i. 3-Hydroxy-1-(41-methoxyphenyl)-3-(42-ethoxyphenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 73%. M.p. = 211–213 °C. 1H NMR (DMSO-d6): 1.34 (t, 3H, OCH2CH3), 1.74–1.79 (m, 4Н, CH2СН2), 2.63 and 2.70 (m+m, 2Н, 8-СН2), 2.9 and 3.32 (m+m, 2Н, 5-СН2), 3.81 (s, 3H, ОCH3), 4.01 (q, 2H, OCH2CH3), 4.26 and 4.36 (d-d, 2Н, 2-СН2, J=12.8 Hertz), 7.03 and 7.57 (d-d, 4Н, С6Н4, J=8.7 Hertz), 7.11 and 7.63 (d-d, 4Н, С6Н4, J=8.7 Hertz), 7.90 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 15.13, 17.99, 21.07, 23.57, 56.09, 63.73, 66.18, 92.49, 114.8, 115.4, 128.0, 128.4, 130.1, 159.5, 159.9, 164.4. Anal. calcd. for C22H27BrN2O3: N, 5.36; Br, 17.9. Found: N, 5.51; Br, 18.2. MS m/z: 367.9 [(M+H)+].

10 j. 3-Hydroxy-1-(41-methoxyphenyl)-3-(22-fluoro-42-methoxyphenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 70%. M.p. = 195–196 °C. 1H NMR (DMSO-d6): 1.72–1.82 (m, 4Н, CH2СН2), 2.69 and 2.72 (m+m, 2Н, 8-СН2), 2.87 and 3.41 (m+m, 2Н, 5-СН2), 3.82 (s, 3H, ОCH3), 3.83 (s, 3H, ОCH3), 4.31 and 4.48 (d-d, 2Н, 2-СН2, J=13.0 Hertz), 6.91-7.71 (m, 3Н, С6Н3), 7.12 and 7.51 (d-d, 4Н, С6Н4, J=9.0 Hertz), 8.16 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 17.99, 21.07, 23.20, 56.14, 56.45, 64.77, 90.08, 103.0, 103.2, 110.6, 115.6, 117.1, 117.2, 127.8, 128.0, 129.7, 159.7, 160.1, 161.6, 162.4, 162.5, 163.7. Anal. calcd. for C21H24BrFN2O3: N, 6.20. Found: N, 6.05. MS m/z: 371.2 [(M+H)+].

10 k. 3-Hydroxy-1-(41-methoxyphenyl)-3-(22,32-dihydrobenzo[1,4]dioxin-6-yl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 79%. M.p. = 226–228 °C. 1H NMR (DMSO-d6): 1.76–1.81 (m, 4Н, CH2СН2), 2.62 and 2.68 (m+m, 2Н, 8-СН2), 2.92 and 3.33 (m+m, 2Н, 5-СН2), 3.81 (s, 3H, ОCH3), 4.28 (m, 6Н, 2-СН2 + -OCH2CH2O-), 6.95-7.24 (m, 3Н, С6Н3), 7.11 and 7.60 (d-d, 4Н, С6Н4, J=8.1 Hertz), 7.90 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 17.94, 21.03, 23.49, 56.04, 64.56, 66.07, 92.23, 115.3, 115.9, 117.5, 119.8, 127.8, 128.3, 131.3, 143.8, 144.5, 159.8, 164.4. Anal. calcd. for C22H25BrN2O4: N, 6.07; Br, 17.3. Found: N, 6.21; Br, 17.0. MS m/z: 381.2 [(M+H)+].

11 a. 3-Hydroxy-1-(41-ethoxyphenyl)-3-phenyl-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 65%. M.p. = 177–179 °C. 1H NMR (DMSO-d6): 1.35 (t, 3H, OCH2CH3), 1.76–1.80 (m, 4Н, CH2СН2), 2.65 and 2.71 (m+m, 2Н, 8-СН2), 2.89 and 3.33 (m+m, 2Н, 5-СН2), 4.09 (q, 2H, OCH2CH3), 4.30 and 4.38 (d-d, 2Н, 2-СН2, J=12.8 Hertz), 7.09 and 7.58 (d-d, 4Н, С6Н4, J=8.7 Hertz), 7.46-7.55 (m, 3Н, С6Н3), 7.72-7.75 (m, 2Н, С6Н2), 8.00 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 15.07, 17.97, 21.04, 23.62, 64.06, 66.32, 95.55, 115.8, 126.9, 128.0, 128.1, 129.1, 129.6, 138.5, 159.2, 164.8. Anal. calcd. for C21H24BrN2O2: N, 6.71; Br, 19.1. Found: N, 6.84; Br, 19.4. MS m/z: 338.2 [(M+H)+].

11 b. 3-Hydroxy-1-(41-ethoxyphenyl)-3-(32-nitrophenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 80%. M.p. = 163–164 °C. 1H NMR (DMSO-d6): 1.35 (t, 3H, OCH2CH3), 1.77–1.81 (m, 4Н, CH2СН2), 2.67 and 2.70 (m+m, 2Н, 8-СН2), 2.90 and 3.34 (m+m, 2Н, 5-СН2), 4.09 (q, 2H, OCH2CH3), 4.34 and 4.48 (d-d, 2Н, 2-СН2, J=13.0 Hertz), 7.11 and 7.58 (d-d, 4Н, С6Н4, J=8.7 Hertz), 8.35 (s, 1Н, ОН), 7.81-8.56 (m, 4Н, С6Н4). 13C NMR (125 MHz, DMSO-d6) δ: 15.06 17.92 21.06 23.79, 64.07, 65.81, 91.84, 115.8, 122.0, 124.7, 128.0, 131.0, 134.0, 140.6, 148.5, 159.3, 165.3. Anal. calcd. for C21H24BrN3O4: N, 9.09; Br, 17.3. Found: N, 9.31; Br, 17.0. MS m/z: 383.1 [(M+H)+].

11 c. 3-Hydroxy-1-(41-ethoxyphenyl)-3-(42-methoxyphenyl)-2,3,5,6,7,8-hexahydro-imidazo[1,2-a]pyridine-1-ium bromide

Yield 65%. M.p.=197–199 °C. 1H NMR (DMSO-d6): 1.35 (t, 3H, OCH2CH3), 1.74–1.79 (m, 4Н, CH2СН2), 2.64 and 2.69 (m+m, 2Н, 8-СН2), 2.88 and 3.31 (m+m, 2Н, 5-СН2), 3.80 (s, 3H, ОCH3), 4.08 (q, 2H, OCH2CH3), 4.27 and 4.35 (d-d, 2Н, 2-СН2, J=13.0 Hertz), 7.04 and 7.56 (d-d, 4Н, С6Н4, J=8.7 Hertz), 7.09 and 7.64 (d-d, 4Н, С6Н4, J=9.0 Hertz), 7.90 (с, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 15.07, 17.98, 21.04, 23.59, 55.81, 64.05, 66.22, 92.44, 114.4, 115.7, 128.0, 128.2, 128.4, 130.3, 159.2, 160.2, 164.5. Anal. calcd. for C22H27BrN2O3: N, 6.26; Br, 17.9. Found: N, 6.09; Br, 17.5. MS m/z: 367.2 [(M+H)+].

11 d. 3-Hydroxy-1-(41-ethoxyphenyl)-3-(42-fluorophenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 72%. M.p. = 183–185 °C. 1H NMR (DMSO-d6): 1.35 (t, 3H, OCH2CH3), 1.76–1.80 (m, 4Н, CH2СН2), 2.64 and 2.69 (m+m, 2Н, 8-СН2), 2.88 and 3.32 (m+m, 2Н, 5-СН2), 4.09 (q, 2H, OCH2CH3), 4.30 and 4.39 (d-d, 2Н, 2-СН2, J=13.1 Hertz), 7.10 and 7.57 (d-d, 4Н, С6Н4, J=9.0 Hertz), 7.32-7.82 (m, 4H, С6Н4), 8.05 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 15.06, 17.93, 21.02, 23.64, 64.06, 66.14, 92.19, 115.7, 115.8, 116.0, 128.0, 128.1, 129.4, 129.5, 134.8, 159.2, 161.9, 163.9, 164.8. Anal. calcd. for C21H24BrFN2O2: N, 6.43. Found: N, 6.57. MS m/z: 355.2 [(M+H)+].

11 e. 3-Hydroxy-1-(41-ethoxyphenyl)-3-(42-difluoromethoxyphenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 77%. M.p. = 197–198 °C. 1H NMR (DMSO-d6): 1.35 (t, 3H, OCH2CH3), 1.75–1.80 (m, 4Н, CH2СН2), 2.65 and 2.69 (m+m, 2Н, 8-СН2), 2.88 and 3.32 (m+m, 2Н, 5-СН2), 4.08 (q, 2H, OCH2CH3), 4.29 and 4.39 (d-d, 2Н, 2-СН2, J=12.8 Hertz), 7.09 and 7.56 (d-d, 4Н, С6Н4, J=9.0 Hertz), 7.31 and 7.79 (d-d, 4Н, С6Н4, J=8.8 Hertz), 7.35 (t, 1H, OCHF2, J=73.7 Hertz), 8.05 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 15.06, 17.94, 21.03, 23.67, 64.06, 66.16, 92.19, 114.6, 115.8, 116.7, 118.7, 119.0, 128.1, 129.0, 135.3, 151.9, 159.2, 164.8. Anal. calcd. for C22H25BrF2N2O3: N, 5.79. Found: N, 5.92. MS m/z: 404.1 [(M+H)+].

11 f. 3-Hydroxy-1-(41-ethoxyphenyl)-3-(32,42-dimethoxyphenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 61%. M.p. = 229–231 °C. 1H NMR (DMSO-d6): 1.35 (t, 3H, OCH2CH3), 1.75–1.80 (m, 4Н, CH2СН2), 2.67 and 2.70 (m+m, 2Н, 8-СН2), 2.92 and 3.32 (m+m, 2Н, 5-СН2), 3.80 (s, 3H, ОCH3), 3.82 (s, 3H, ОCH3), 4.08 (q, 2H, OCH2CH3), 4.25 and 4.40 (d-d, 2Н, 2-СН2, J=12.8 Hertz), 7.09 and 7.56 (d-d, 4Н, С6Н4, J=9.1 Hertz), 7.04–7.27 (m, 3Н, С6Н3), 7.91 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 15.07, 18.00, 21.07, 23.69, 56.14, 56.44, 64.05, 66.07, 92.46, 110.7, 112.0, 115.7, 119.6, 127.9, 128.2, 130.5, 149.2, 149.9, 159.1, 164.4. Anal. calcd. for C23H29BrN2O4: N, 5.87; Br, 16.7. Found: N, 5.95; Br, 16.9. MS m/z: 397.2 [(M+H)+].

11 i. 3-Hydroxy-1,3-bis-(41-ethoxyphenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]-pyridine-1-ium bromide

Yield 71%. M.p. = 203–205 °C. 1H NMR (DMSO-d6): 1.35 (t, 6H, 2OCH2CH3), 1.75–1.79 (m, 4Н, CH2СН2), 2.64 and 2.68 (m+m, 2Н, 8-СН2), 2.87 and 3.30 (m+m, 2Н, 5-СН2), 4.08 (q+q, 4H, 2OCH2CH3), 4.26 and 4.36 (d-d, 2Н, 2-СН2, J=12.8 Hertz), 7.02 and 7.55 (d-d, 4Н, С6Н4, J=9.1 Hertz), 7.09 and 7.62 (d-d, 4Н, С6Н4, J=9.1 Hertz), 7.89 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 15.08, 17.94, 21.02, 23.51, 63.67, 64.00, 66.09, 92.43, 92.85, 114.8, 115.7, 127.9, 128.0, 128.3, 130.0, 159.1, 159.5, 164.4. Anal. calcd. for C23H29BrN2O3: N, 6.07; Br, 17.3. Found: N, 5.94; Br, 17.4. MS m/z: 381.3 [(M+H)+].

11 l. 3-Hydroxy-1-(41-ethoxyphenyl)-3-(42-chlorophenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide

Yield 79%. M.p. = 211–213 °C. 1H NMR (DMSO-d6): 1.35 (t, 3H, OCH2CH3), 1.75–1.80 (m, 4Н, CH2СН2), 2.64 and 2.69 (m+m, 2Н, 8-СН2), 2.88 and 3.32 (m+m, 2Н, 5-СН2), 4.08 (q, 2H, OCH2CH3), 4.30 and 4.38 (d-d, 2Н, 2-СН2, J=13.1 Hertz), 7.09 and 7.56 (d-d, 4Н, С6Н4, J=9.0 Hertz), 7.59 and 7.77 (d-d, 4Н, С6Н4, J=8.7 Hertz), 8.09 (s, 1Н, ОН). 13C NMR (125 MHz, DMSO-d6) δ: 15.06, 17.93, 21.03, 23.68, 64.06, 66.08, 92.15, 115.8, 128.7, 129.1, 134.5, 137.6, 159.2, 164.9. Anal. calcd. for C21H24BrClN2O2: N, 6.20. Found: N, 6.38. MS m/z: 371.1 [(M+H)+].

Synthesis of 1,3-bis-(41-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-1-ium bromide 12 c

0.01 mole of 3-hydroxy-1,3-bis-(41-methoxyphenyl)-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide 11 c was refluxed in acetic anhydride (20 ml) for 5 h and left overnight at room temperature. The obtained solution was concentrated under reduced pressure, and the purified by recrystallized from the propanol-2.

12 c. 1,3-bis-(41-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-1-ium bromide

Yield 85%. M.p. = 233–234 °C. 1H NMR (DMSO-d6): 1.90-2.80 (m, 4Н, CH2СН2), 2.94 (m, 2Н, СН2), 2.88 and 3.32 (m+m, 2Н, 5-СН2), 3.82 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.13 (s, 2Н, СН2), 7.13 and 7.59 (d-d, 4Н, С6Н4, J=8.7 Hertz), 7.18 and 7.62 (d-d, 4Н, С6Н4, J=8.8 Hertz), 8.04 (s, 1Н, 2-CН). 13C NMR (125 MHz, DMSO-d6) δ: 18.01, 21.40, 22.30, 45.70, 55.92, 56.22, 115.1, 115.5, 118.0, 120.0, 127.4, 127.5, 131.2, 133.2, 145.3, 160.7, 160.9. Anal. calcd. for C21H23BrN2O2: N, 6.72. Found: N, 6.68. MS m/z: 336.2 [(M+H)+].

Results

The synthesis of oxime cyclopentanone 2 as starting material from commercially available cyclopentanone 1 was achieved by simply grinding these hydroxylamine hydrochloride and sodium hydroxide without solvent by method (Damljanovice et al. 2006) (95% yields). 2-Piperidone (valerolactam) 3 was achieved by Beckmann rearrangement of oxime cyclopentanone 2 neat no solvent 6 hours, T = 120 °C by method (Mona et al. 2011) (80% yields). 6-Methoxy-2,3,4,5-tetrahydropyridine 4 was obtained by alkylation of valerolactam 3 with dimethyl sulfate using the method (Granik 1992) (Fig. 2). A mixture of 4-methoxyphenylamine 5 or 4-ethoxyphenylamine 6 and O-methylvalerolactim 4 was heated at 140–150 °C for 3 h under the simultaneous distillation of methanol. After cooling the mixture to room temperature, crystalline products 7 or 8 were obtained (Javorsky et al. 1992). Compounds 10 a–k and 11 a–f, i, l were obtained by condensation of equimolar amounts of (4-methoxyphenyl or 4-ethoxyphenyl)-3,4,5,6-tetrahydro-pyridin-2-yl)-amines 7 or 8 with different α-bromoketones 9 a–k or 9 a–f, l in ethyl acetate. The conclusion about the direction of alkylation of (4-methoxyphenyl or 4-ethoxyphenyl)-3,4,5,6-tetrahydro-pyridin-2-yl)-amines 7 or 8 and the structure of the resulting products 10 a–k and 11 a–f, i, l (Fig. 3) were made based on results of our previous works (Demchenko 2000; Demchenko et al. 2001, 2003, 2020, 2021; Demchenko and Lozinskii 2002). Refluxing of salt 10 c in acetic anhydride yields elimination of water molecules and formation of the corresponding 1,3-di(4-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-1-ium bromide 12 c (Fig. 4).

Figure 2. 

Schematic representation of the reaction process for the synthesis of O-methylvalerolactim 4.

Figure 3. 

Schematic representation of the reaction process for the synthesis of 3-hydroxy-1-(41-methoxyphenyl)-3-aryl-2,3,5,6,7,8-hexahydro-imidazo[1,2-a]pyridine-1-ium bromides 10 a-k and 11 a-f, i, l.

Figure 4. 

Schematic representation of the reaction process for the synthesis 1,3-bis-(41-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-1-ium bromide 12 c.

Anticancer effect of 1,3-bis-(41-ethoxyphenyl)-3-hydroxy-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide 11 i and 1,3-bis-(41-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-1-ium bromide 12 c was investigated in the National Cancer Institute (National Cancer Institute of Health, USA) within the Therapeutic Development Program.

The first stage of the pharmacological screening (pre-screening) was aimed to analyze the antitumor effect of compounds in vitro within cancer cell lines (leukemia, melanoma, lung, colon, CNS, ovarian, kidney, prostate, and breast cancer). The substance operated in the concentration of 10–5 mol/l according to the standard procedure (Alley et al. 1988; Teicher and Andrews 2004) of mitotic activity evaluation of new potential biologically active compounds by fluorescent staining (the stainer is sulforhodamine B). The research results are compared with the control, 5-fluorouracil; the growth of cancer cells is expressed in percent. The table indexes show how much the studied compounds are more effective in inhibiting cancer cell growth in comparison with the control.

Calculation was carried out by the high-resolution fluorometric method, quantitatively evaluating the color intensity of fluorescent light (the stainer is sulforodamin B) in 48 hours of irradiation of the cell with the tested compound. The selection and study system of potential antitumor activity compounds in vitro is based on the percentage of tumor cell growth (PG) under the test compound influence.

In the experiment, the compounds 11 i and 12 с in the concentration of 10–5 M were able to inhibit the growth of cancer cells, covering virtually the entire spectrum of human cancers (Table 1).

Table 1.
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Antitumor activity of the compounds 11 i and 12 с in vitro within cancer cell lines, reagent concentration of 10–5 M, and in-depth in vitro screening in the concentration gradient 10–4–10–8 M.

Cancer Types Cancer Cell Lines Parameters of Antitumor Activity
12 с 11 i
Mitotic Activity, % lgGI50 lg TGI lg LC50 Mitotic Activity, %
Leukemia CCRF-CEM 63.76 –5.02 > –4.00 > –4.00 99.89
HL-60(TB) 16.71 –5.77 –4.68 > –4.00 92.65
K-562 40.17 –5.58 –4.00 > –4.00 90.44
MOLT-4 58.43 –4.92 –4.00 > –4.00 73.47
RPMI-8226 22.27 –6.00 –4.22 > –4.00 101.56
SR 61.13 –5.38 –4.00 > –4.00 97.16
Small Cell Lung Cancer A549/ATCC 55.40 –5.22 –4.00 > –4.00 96.90
HOP-62 91.75 –4.32 –4.00 > –4.00 97.49
HOP-92 74.28 –6.07 –4.74 > –4.00 92.49
NCI-H226 80.12 –4.63 –4.00 > –4.00 99.48
NCI-H23 39.72 –5.48 –4.00 > –4.00 105.00
NCI-H322M 97.79 –4.53 –4.00 > –4.00 95.31
NCI-H460 82.24 –4.92 –4.00 > –4.00 105.18
NCI-H522 53.46 –5.09 –4.02 > –4.00 102.87
Colon Cancer COLO 205 49.78 –5.35 –4.70 –4.19 106.47
HCС2998 69.09 –5.55 > –4.00 > –4.00 106.67
HCT-116 57.59 –5.32 > –4.00 > –4.00 102.16
HCT-15 102.64 > –4.00 > –4.00 > –4.00 95.22
HT-29 70.38 –4.87 > –4.00 > –4.00 92.37
KM12 51.76 –5.53 > –4.00 > –4.00 100.66
SW-620 100.11 –4.73 > –4.00 > –4.00 102.87
Brain Cancer SF-268 81.05 –4.76 > –4.00 > –4.00 90.37
SF-295 – –4.81 –4.21 > –4.00 –
SF-539 89.65 –4.96 > –4.00 > –4.00 109.92
SNB-19 – –5.04 > –4.00 > –4.00 –
SNB-75 64.15 –5.24 > –4.00 > –4.00 95.70
U251 54.82 –5.38 > –4.00 > –4.00 96.84
Melanoma LOX IMVI 71.52 –4.95 > –4.00 > –4.00 95.97
MALME-3M – –5.11 –4.08 > –4.00 –
M14 84.05 –4.74 > –4.00 > –4.00 105.14
MDA-MB-435 65.49 –5.42 –4.26 > –4.00 102.56
SK-MEL-2 64.50 –4.92 –4.22 > –4.00 98.73
SK-MEL-28 68.92 –4.69 > –4.00 > –4.00 105.57
SK-MEL-5 28.97 –5.57 –4.81 –4.17 100.05
UACC-257 35.51 –5.67 –4.72 > –4.00 108.90
UACC-62 61.82 –5.31 > –4.00 > –4.00 108.46
Ovarian Cancer IGROV1 67.55 –4.96 > –4.00 > –4.00 93.82
OVCAR-3 51.07 –5.43 > –4.00 > –4.00 104.04
OVCAR-4 66.30 –5.84 > –4.00 > –4.00 104.44
OVCAR-5 99.10 –4.36 > –4.00 > –4.00 87.30
OVCAR-8 83.71 –4.96 > –4.00 > –4.00 105.28
NCI/ADR-RES 106.01 > –4.00 > –4.00 > –4.00 111.06
SK-OV-3 82.78 –4.48 > –4.00 > –4.00 95.46
Kidney Cancer 786-0 87.41 –4.38 > –4.00 > –4.00 96.68
A498 83.28 –5.20 > –4.00 > –4.00 91.95
ACHN 91.92 –4.15 > –4.00 > –4.00 95.73
CAKI-1 103.09 > –4.00 > –4.00 > –4.00 95.14
RXF 393 107.39 –4.71 > –4.00 > –4.00 115.53
SN12C 73.35 –4.89 > –4.00 > –4.00 90.06
TK-10 93.68 –4.37 > –4.00 > –4.00 100.73
UO-31 98.55 > –4.00 > –4.00 > –4.00 80.97
Prostate Cancer РС-3 74.87 –5.09 > –4.00 > –4.00 97.74
DU-145 95.77 –5.54 > –4.00 > –4.00 118.96
Breast Cancer MCF7 37.78 –5.38 > –4.00 > –4.00 96.00
MDA-MB-231/ATCC 86.26 –4.73 > –4.00 > –4.00 104.55
HS 578T 90.51 –4.58 > –4.00 > –4.00 109.99
ВТ-549 57.61 –5.36 > –4.00 > –4.00 99.79
Т47D 29.28 –5.59 > –4.00 > –4.00 84.72
MDA-MB-468 10.26 –6.44 –5.16 > –4.00 94.35

Discussion

According to Table 1, the compound 12 c exceeds the standard within 55 cancer cell lines out of 60 surveyed. The most effective it was relatively leukemia cells HL-60 (TB) and RPMI-8226 (higher than the effect of 5-fluorouracil up to 83.29% and 77.73%, respectively), small cell lung cancer NCI-H23 (higher than the effect of 5-fluorouracil up to 60,28%), colon cancer COLO 205 (exceeds the standard up to 50.22%), melanoma SK-MEL-5 and UACC-257 (exceed the effect of 5-fluorouracil up to 71.03% and 64.49%, respectively), and breast cancer cells MCF7, T47D, and MDA-MB-468 exceed the effect of 5-fluorouracil up to 62.22%, 70.72%, and 89.74%, respectively.

At the second phase of the research, or in vitro in-depth screening, the compound 12 c was tested at five concentrations and at 10-fold dilution (100 μM, 10 μM, 1 μM, 0.1 μM, and 01 μM) within the listed lines of human cancer cells. In the experiment, three dose-dependent parameters were calculated, namely: GI50 – concentration of the compound that causes growth inhibition of up to 50% cells within the line; TGI-concentration causes a complete inhibition of cell growth; LC50-concentration causes death in 50% of tumor cells. GI50 is interpreted as an effective level of inhibition; TGI makes a cytostatic effect; and LC50 is the lethal concentration that characterizes a cytotoxic action. If logarithmic values of researched parameters (lgGI50, lgTGI, and lgLC50) are under -4.00, the compound is considered active (Grever et al. 1998; Carter et al. 2001).

According to the screening results, the tested compound showed a significant level of anticancer effect on cancer cells of colon COLO 205 (lgGI50 = -5.35, lgTGI = –4.70 and lgLC50 = –4.19) and melanoma SK-MEL-5 (lgGI50 = –5.57, lgTGI, = –4.81 and lgLC50 = –4.17).

Conclusion

The synthesis of 19 compounds of 1,3-diaryl-3-hydroxy-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromides 10 a–k and 11 a–f, i, l was carried out. Their cyclic structure was proved using 1H NMR and 13C NMR spectroscopical analysis. It was demonstrated that refluxing of salt 10 c in acetic anhydride yields elimination of water molecules and formation of the corresponding 1,3-di(4-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-1-ium bromide 12 c. The antitumor activity of compounds 1,3-bis-(41-ethoxyphenyl)-3-hydroxy-2,3,5,6,7,8-hexahydroimidazo[1,2-a]pyridine-1-ium bromide 11 i and 1,3-bis-(41-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-1-ium bromide 12 c was studied. It was demonstrated that compound 12 c with a fully aromatized imidazolium ring is more active than compound 11 i.

Acknowledgements

The authors would like to thank all the brave defenders of Ukraine who made the finalization of this article possible.

The authors sincerely thank the Krzysztof Skubiszewski Foundation for financial support of this study.

Additional information

Conflict of interest

The authors have declared that no competing interests exist.

Ethical statements

The authors declared that no clinical trials were used in the present study.

The authors declared that no experiments on humans or human tissues were performed for the present study.

The authors declared that no informed consent was obtained from the humans, donors or donors’ representatives participating in the study.

This study does not involve experiments on animals or human subjects.

The authors declared that no commercially available immortalised human and animal cell lines were used in the present study.

Funding

No funding was reported.

Author contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.

Author ORCIDs

Sergii Demchenko https://orcid.org/0000-0003-2242-0471

Sergii Yarmoluk https://orcid.org/0000-0002-5898-6103

Volodymyr Sukhovieiev https://orcid.org/0000-0002-1590-1675

Oleksandr Golovchenko https://orcid.org/0000-0001-7756-6019

Oleksandr Sukhovieiev https://orcid.org/0000-0001-9949-2188

Anatolii Demchenko https://orcid.org/0000-0002-2173-3356

Data availability

All data generated and analyzed are included within this research article.

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