Journal Information

Journal ID (publisher-id): chemical

Title: Journal of the Korean Chemical Society

Translated Title (ko): 대한화학회지

ISSN (print): 1017-2548

ISSN (electronic): 2234-8530

Publisher: Korean Chemical Society대한화학회

Article Information

Copyright statement: Copyright © 2020, Korean Chemical Society

Copyright: 2020

Date received: 19 September 2019

Date accepted: 18 November 2019

Publication date (print): 20 February 2020

Volume: 64

Issue: 1

Pages: 7-18

Publisher ID: jkcs-64-7

DOI: 10.5012/jkcs.2020.64.1.7

Synthesis and Antiproliferative Potency within Anticonvulsant of Novel Bichalcone Derivatives

Eman Mansour[*]

Yaser A. El-Badry[†][‡]

Afaf El-Tokhy

Rezed Ayyad[§][#]

Ahmed A. Abd-Rabou[][＄]

Organic Chemistry Dep., Faculty of Women's for Arts, Science and Education, Ain Shams University, Cairo 11767, Egypt.

[†] Organic Chemistry Lab., Faculty of Specific Education, Ain Shams University, Abbasseya 11566, Cairo, Egypt.

[‡] Organic Chemistry Dep., Faculty of Science, Taif University, Khurma 21985, Kingdom of Saudi Arabia.

[§] Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

[#] Medicinal Chemistry Department, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Addakahlia, Egypt.

[] Hormones Department, Medical Research Division, National Research Centre, Giza, Egypt.

[＄] Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Giza, Egypt.

Author notes:

Correspondence to: [*] E-mail: emanmansour211@yahoo.com

Abstract

An efficient and facile procedure has been developed for the synthesis of novel bichalcone derivatives (4a, 4b). The key step contains the solvent-free aldol synthesis of bichalcones based on quinones. Bichalcones (4a, 4b) were used as precursors for the synthesis of some interesting heterocyclic compounds like, diazepines (5a, 5b), pyrazolo-pyrimidines (7a, 7b), and pyrazoline derivatives (8a, 8b). Moreover, new thioxopyrimidine derivatives (9a, 9b) were furnished and used as a functionalizing agent to produce the triazole-pyrimidines (11, 12) and the carbonitrile derivative (14). All the synthesized compounds were fully characterized using physical and spectral data like, FT-IR, 1H NMR, 13C NMR, and MS. Bichalcones (4a, 4b) and diazepines (5a, 5b) were screened for their anticonvulsant activity, where compounds (4a, 5a, and 5b) revealed potent anticonvulsant activity compared to diazepam. On the other hand, some of the prepared compounds were screened for their antiproliferative activity and they showed significant cytotoxic effects on most of the cancer cell lines with regard to broad spectrum antitumor activity.

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INTRODUCTION▼

Quinones are the class of natural and synthetic compounds that have several beneficial effects.1 They represent a class of molecules preventing and treating several anti-oxidant activities, and so improve general health conditions. Many drugs clinically approved or still in clinical trials against cancer are quinone-related compounds. In addition, chalcones and their derivatives were recognized as biologically active compounds.2−4 Benzodiazepine compounds are widely used as anticonvulsant,5 anti-cancer,6-8 and anti-anxiety agents.9

The combination of pharmacophores on the same scaffold is a well-established approach to the synthesis of more potent drugs.10,11 A perusal of literature has shown that chalcones are proved as potential building blocks for the synthesis of various interesting heterocyclic systems.12,13 We decided to incorporate chalcone system into cyclic products through Michael addition reactions.

In this work, we synthesized new classes of compounds containing seventeen heterocyclic systems quinone moiety bearing chalcone as an important class of heterocyclic or diazepine ring system that may result in enhanced biological activity due to their synergistic effect.

EXPERIMENTAL▼

General

All reagents and solvents were dried and purified before use by the usual procedures. M.p.: Büchi® melting point apparatus; uncorrected. TLC: Merck TLC aluminum sheets, silica gel 60 F254 with detection by UV quenching at 254 nm. IR spectra: FT-IR Nicolet Impact 400D; KBr pellets; ν in cm-1. 1H and 13C NMR spectra: Bruker at 400 and 100 MHz, respectively; in DMSO-d6; δ in ppm relative to Me4Si as internal standard, J in Hz. DEPT135 NMR spectroscopy: used where appropriate, to aid the assignment of signals in the 1H and 13C NMR spectra. EIMS were recorded on a gas chromatographic GCMS–HP model MS5988. Elemental analyses were carried out at the Technical University of Dortmund.

2,5-Dichloro-3,6-bis-(4-acetylphenylamino)-[1,4]benzoquinone (3). To a solution of chloranil 1 (10 mmol) in 30 mL of acetonitrile, 4-aminoacetophenone 2 (20 mmol) and few drops of piperidine were added. The reaction mixture was heated under reflux for 6 h. The solid that separated after cooling was filtered and recrystallized from acetonitrile to give 3. Brown crystals (yield 89%) m.p. > 300 ºC. IR (KBr): νmax/cm-1 3207(NH), 1682, 1663(C=O). 1H NMR (DMSO): δ 2.43(s, 6H, 2 Me), 7.31(d, J=8.6Hz, 2H, Ar-H), 7.37(d, J=8.6Hz, 2H, Ar-H), 7.90−7.95(m, 4H, Ar-H), 8.76(brs, 2H, D2O Exch., NH’s).13C NMR (DMSO): δ 26.5(2CH3), 118.3(4CH), 123.2(2C), 127.8(2C), 132.6(4CH), 141.4(2C), 150.7(2C), 177.4(2C), 193.8(2C). MS: m/z(%) 443(M+, 22.3). Anal. Calcd. for C22H16Cl2N2O4(443.28): C, 59.61; H, 3.64; Cl, 16.00; N, 6.32. Found: C, 59.86; H, 3.50; Cl, 15.76; N, 6.58.

Synthesis of Bichalcone Compounds 4a,b

A mixture of 3 (10 mmol), 4-chlorobenzaldehyde and/or 2-furaldehyde (10 mmol), and KOH (6 pellets) was grounded in a porcelain mortar at room temperature. After 10 min, the mixture was treated with water (50 mL) and filtered to give bichalcones 4a, and 4b, respectively.

2,5-Dichloro-3,6-bis-{4-[3-(4-chlorophenyl)acryloyl] phenylamino}-[1,4]benzoquinone (4a). Green crystals (yield 95%) m.p. > 300 ºC. IR (KBr): νmax/cm-1 3210(NH), 1660, 1611(C=O). 1H NMR (DMSO): δ 6.54(d, J=12.6Hz, 2H, =CHCO), 7.06(d, J=8.8Hz, 4H, Ar-H), 7.48–7.70(m, 8H, Ar-H),7.85(d, J=12.6Hz, 2 H, =CHAr), 7.90(d, J=8.6Hz, 4H, Ar-H), 9.06(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 118.9(4CH), 121.4(2C), 123.2(2C), 128.9(4CH), 129.4(4CH), 131.5(4CH), 135.3(2C), 136.1(2C), 138.9(2C), 142.1(2CH), 143.7(2C), 150.7(2C), 177.4(2C), 191.8(2C). MS: m/z (%) 688 (M+, 2). Anal. Calcd. for C36H22Cl4N2O4 (688.38): C, 62.81; H, 3.22; Cl, 20.60; N, 4.07. Found: C, 62.62; H, 3.04; Cl, 20.25; N, 3.91.

2,5-Dichloro-3,6-bis-[4-(3-furan-2-yl-acryloyl)-phenylamino]-[1,4] benzoquinone (4b). Brown crystals (yield 97%) m.p. > 300 ºC. IR (KBr): νmax/cm-1 3205(NH), 1656, 1609(C=O). 1H NMR (DMSO): δ 6.13(d, J=3.7Hz, 2H, furyl-H), 6.41(dd, J1=1.8Hz, J2=3.7Hz, 2H, furyl-H), 6.62 (d, J=12.7Hz, 2H, =CHCO), 6.98(d, J=8.8Hz, 4H, Ar-H), 7.20–7.27(m, 4H, Ar-H), 7. 52(d, J=1.8Hz, 2H, furyl-H), 7.85(d, J=12.7Hz, 2H, =CHAr), 9.82(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 111.9(2CH), 116.3(2CH), 118.8(4CH), 121.7(2C), 123.2(2C), 131.2(4CH), 136.0(2C), 137.8(2C), 142.3(2C), 145.1(2CH), 148.8(2C), 150.7(2C), 177.4(2C), 189.3(2C). MS: m/z(%) 599(M+, 4.3), 601 ([M+2]+, 12). Anal. Calcd. for C32H20Cl2N2O6(599.42): C, 64.12; H, 3.36; Cl, 11.83; N, 4.67. Found: C, 64.39; H, 3.21; Cl, 11.55; N, 4.82.

Synthesis of Diazepines 5a, and 5b

Bichalcone compounds 4a, and/or 4b (10 mmol) were dissolved in acetonitrile and added to a solution of 2,3-diaminomaleonitrile (10 mmol) in acetonitrile. The reaction mixture was catalyzed with 5 drops of acetic acid anhydride and subjected to ultrasound radiation for 2h. The reaction mixture was left at room temperature overnight and the obtained precipitate was recrystallized from absolute ethanol to give the diazepine compounds (5a and 5b), respectively.

7,7'-(((2,5-Dichloro-3,6-dioxocyclohexa-1,4-diene-1,4-diylbis(azanediyl))bis(4,1-phenylene))bis(5-(4-chlorophenyl)-4,5-dihydro-1H-1,4-diazepine-2,3-dicarbonitrile) (5a). Brown crystals(yield 64%) m.p.175−176 ºC. IR (KBr): νmax/cm-1 3407, 3318, 3212(NH), 2248, 2210(CN), 1669 (C=O). 1H NMR (DMSO): δ 5.46(d, J=8.7 Hz, 2H, diazepine-H), 5.88(d, J=8.7Hz, 2H, =CH diazepine), 7.16(d, J=8.8Hz, 4H, Ar–H), 7.38(s, 4H, D2O Exch., NH’s diazepine), 7.72−7.91(m, 8H, Ar-H), 8.16(d, J=8.6 Hz, 4H, Ar-H), 9.16 (brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 59.7(2CH), 97.0(2C), 97.8(2C), 99.3(2CH), 118.4(4CH), 119.6(4C), 123.2(2C), 128.5(4CH), 129.7(4CH), 131.0(2C), 132.6(2C), 133.2(2C), 133.9(4CH), 136.7(2C), 142.3(2C), 150.7(2C), 177.4(2C). MS: m/z(%) 870 ([M+2]+, 20). Anal. Calcd. for C44H26Cl4N10O2 (868.55): C, 60.84; H, 3.02; Cl, 16.33; N, 16.13. Found: C, 61.14; H, 3.19; Cl, 16.10; N, 15.95.

7,7'-(((2,5-Dichloro-3,6-dioxocyclohexa-1,4-diene-1,4-diyl)bis(azanediyl))bis(4,1-phenylene))bis(5-(furan-2-yl)-4,5-dihydro-1H-1,4-diazepine-2,3-dicarbonitrile) (5b). Yellow crystals(yield 68%) m.p. 150−152 ºC. IR (KBr): νmax/cm-1 3407, 3332, 3213(NH), 2243, 2206(CN), 1671 (C=O). 1H NMR (DMSO): δ 5.48 (d, J=8.7Hz, 2H, diazepine-H), 5.83(d, J=8.7Hz, 2H, =CH diazepine), 6.38(d, J=3.7Hz, 2H, furyl-H), 6.67(dd, J1=1.8Hz, J2=3.7Hz, 2H, furyl -H), 7.16(d, J=8.8Hz, 4H, Ar-H), 7.54(brs, 4H, D2O Exch., NH’s diazepine), 7.74(d, J=1.8Hz, 2H, furyl-H), 7.90–8.06 (m, 4H, Ar-H), 9.19(brs, 2 H, D2O Exch., NH’s). 13C NMR (DMSO): δ 56.7(2CH), 97.1(4C), 99.4(2CH), 112.1 (2CH), 114.5(2CH), 118.7(4CH), 119.4(4C), 123.2(2C), 129.3 (4CH), 130.7(2C), 131.5(2C), 136.3(2C), 144.1(2CH), 144.8(2C), 150.7(2C), 177.4(2C). MS: m/z(%): 779(M+, 3). Anal. Calcd. for C40 H24Cl2N10O4 (779.59): C, 61.63; H, 3.10; Cl, 9.16; N, 17.97. Found: C, 61.93; H, 3.25; Cl, 8.85; N, 18.28.

Synthesis of Pyrazolopyrimidines 7a, and 7b

An equimolar mixture of bichalcone 4a (10 mmol) and 3-aminopyrazoles 6a and/or 6b (10 mmol) in DMF (30 mL) and 5mL of 10% KOH was heated under reflux at 110 ºC for 1 h. The reaction mixture was left overnight then poured into ice water. The solid that separated was filtered off, washed with H2O, and crystallized from the proper solvent to give 7a and 7b, respectively.

2,5-Dichloro-3,6-bis-{4-[7-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidin-5-yl]-phenylamino}-[1,4]benzoquinone (7a). Brown crystals (yield 58%) (n-BuOH) m.p.178−179 ºC. IR (KBr): νmax/cm-1 3217(NH), 1663(C=O). 1H NMR (DMSO): δ 6.82 (d, J=2.4Hz, 2H, pyrazole-H), 7.14(d, J=8.8Hz, 4H, Ar-H), 7.33(d, J=8.2Hz, 4H, Ar–H), 7.48(s, 2H, pyrimidine-H), 7.69−7.92(m, 4H, Ar-H), 8.14(d, J=8.2Hz, 4H, Ar-H), 9.08(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 104.9(2CH), 107.3(2CH), 118.7(4CH), 123.2(2C), 129.5 (4CH), 129.8(4CH), 131.4(2CH), 133.0(4CH), 133.8(2C), 137.1(2C), 138.2(2C), 139.7(2C), 140.6(2C), 149.3(2C), 150.7(2C), 164.2(2C), 177.4(2C). MS: m/z(%) 814 (M+, 4.1), 816 ([M+2]+, 13.2). Anal. Calcd. for C42H24Cl4N8O2 (814.50): C, 61.93; H, 2.97; Cl, 17.41; N, 13.76. Found: C, 62.30; H, 3.16; Cl, 17.03; N, 13.98.

2,5-Dichloro-3,6-bis-{4-[7-(4-chloro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenylamino}-[1,4]benzoquinone (7b). Yellow crystals (yield 63%) (EtOH) m.p. 191−193 ºC. IR (KBr): νmax/cm-1 3209(NH), 1668(C=O). 1H NMR (DMSO): δ 2.36(s, 6H, 2Me), 6.67(s, 2H, pyrazole-H), 7.17(d, J=8.8Hz, 4H, Ar-H), 7.32(d, J=8.2Hz, 4H, Ar-H), 7.51(s, 2H, pyrimidine-H), 7.83(d, J=8.8Hz, 4H, Ar-H), 8.22(d, J=8.2Hz, 4H, Ar-H), 9.12(brs, 2H, D2O Exch., NH’s).13CNMR(DMSO): δ 13.6(2CH3), 105.3(2CH), 110.8 (2CH), 118.1(4CH), 123.2(2C), 129.3(4CH), 129.7(4CH), 132.8(4CH), 133.8(2C), 137.1(2C), 137.8(2C), 139.1(2C), 139.4(2C), 139.9(2C), 149.3(2C), 150.7(2C), 164.3(2C), 177.4(2C). MS: m/z (%) 842 (M+, 13). Anal. Calcd. for C44H28Cl4N8O2 (842.56): C, 62.72; H, 3.35; Cl, 16.83; N, 13.30. Found: C, 62.36; H, 3.21; Cl, 16.54; N, 13.08.

Synthesis of Pyrazole Derivatives 8a, and 8b

To a solution of bichalcones 4a, and/or 4b (10 mmol) in 30 mL of ethanol, hydrazine hydrate (15 mmol) and a catalytic amount of glacial acetic acid (5 drops) were added. The reaction mixture was refluxed for 6 h. The solid that formed after cooling was filtered off, dried, and recrystallized from ethanol to give compounds (8a, and 8b), respectively.

2,5-Dichloro-3,6-bis-{4-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]-phenylamino}-[1,4]benzoquinone (8a). Brown crystals (yield 79%) m.p. 167−168 ºC. IR (KBr): νmax/cm-1 3362, 3214(NH), 1660(C=O). 1H NMR (DMSO): δ 6.53(s, 2H, pyrazole-H), 7.28−7.45(m, 8H, Ar-H), 7.64(d, J=8.8Hz, 4H, Ar–H), 7.86(d, J=8.2Hz, 4H, Ar-H), 8.47(brs, 2H, D2O Exch., pyrazole NH’), 9.04(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 102.3(2CH), 118.4(4CH), 123.2(2C), 128.1(4CH), 128.8(4CH), 130.7(4CH), 131.9(2C), 134.0(2C), 134.5(2C), 139.8(2C), 146.6(2C), 148.1(2C), 150.7(2C), 177.4(2C). MS: m/z(%) 712 (M+, 27). Anal. Calcd. for C36H22Cl4N6O2 (712.41): C, 60.69; H, 3.11; Cl, 19.91; N, 11.80. Found: C, 61.07; H, 3.32; Cl, 20.24; N, 12.05.

2,5-Dichloro-3,6-bis-[4-(5-furan-2-yl-1H-pyrazol-3-yl]-phenylamino}-[1,4] benzoquinone (8b). Yellow crystals (yield 83%) m.p. 201−203 ºC. IR (KBr): νmax/cm-1 3218, 3100(NH), 1684(C=O). 1H NMR (DMSO): δ 6.34(d, J=3.7Hz, 2H, furyl-H), 6.48(s, 2H, pyrazole-H), 6.77(dd, J1=1.8Hz, J2=3.7Hz, 2H, furyl-H), 7.08(d, J=8.8Hz, 4H, Ar-H), 7.19−7.37(m, 4H, Ar-H), 7.86(d, J=1.8Hz, 2H, furyl-H), 8.27(brs, 2H, D2O Exch., pyraole NH’s), 9.13 (brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 102.8(2CH), 110.8(2CH), 115.6(2CH), 118.7(4CH), 123.2(2C), 129.1(4CH), 132.9(2C), 133.4(2C), 141.5(2C), 144.3(2CH), 149.0(2C), 149.2(2C), 150.7(2C), 177.4(2C). MS: m/z(%) 623 (M+, 8), 625 ([M+2]+, 21). Anal. Calcd. for C32H20Cl2N6O4 (623.44): C, 61.65; H, 3.23; Cl, 11.37; N, 13.48. Found: C, 61.92; H, 3.06; Cl, 11.09; N, 13.73.

Synthesis of Thioxopyrimidines 9a, and 9b

To a solution of bichalcone 4a ,and/or 4b (10 mmol) in 50 mL of ethanol, 1.0 g of sodium hydroxide (25 mmol) and 1.2 g of thiourea (12 mmol) were added. The reaction mixture was refluxed for 6 h, then left to cool overnight and the formed solid product was filtered off, dried, and crystallized from ethanol to give compounds 9a and 9b, respectively.

2,5-Dichloro-3,6-bis-{4-[6-(4-chlorophenyl)-2-mercapto-pyrimidin-4-yl]-phenylamino}-[1,4]benzoquinone (9a). Brown crystals (yield 74%) m.p. 184−186 ºC. IR (KBr): νmax/cm-1 3425(SH), 3214(NH), 1659(C=O), 1592(C=N). 1H NMR (DMSO): δ 3.82(s, 2H, D2O Exch., SH), 7.19(d, J=8.8Hz, 4H, Ar-H), 7.53−7.64(m, 10H, pyrimidine-H, 8Ar-H), 7.89 (m, 4H, Ar-H), 9.03(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 108.5(2CH), 117.1(4CH), 123.2(2C), 129.6(4CH), 132.8(2C), 134.9(2C), 135.3(2C), 136.8(2C), 138.7(4CH), 140.5(4CH), 150.7(2C), 155.1(2C), 155.7(2C), 177.4(2C), 179.9(2C). MS: m/z (%) 800 (M+, 7), 802 ([M+2]+, 23). Anal. Calcd. for C38H22Cl4N6O2S2 (800.56): C, 57.01; H, 2.77; Cl, 17.71; N, 10.50; S, 8.01. Found: C, 57.27; H, 2.86; Cl, 17.39; N, 10.34; S, 7.73.

2,5-Dichloro-3,6-bis-[4-(6-(furan-2-yl)-2-mercapto-pyrimidin-4-yl)-phenylamino)-[1,4]bezoquinone (9b). Red crystals (yield 53%) m.p. > 300 ºC. IR (KBr): νmax/cm-1 3349(SH), 3220(NH), 1649(C=O), 1594(C=N). 1H NMR (DMSO): δ 3.87(s, 2H, D2O Exch., SH), 6.08(d, J=3.7Hz, 2H, furyl-H), 6.89(dd, J1=1.8Hz, J2=3.7Hz, 2H, furyl-H), 7.19(d, J=8.8Hz, 4H, Ar-H), 7.43(d, J=8.6Hz, 4H, Ar-H), 7.65(s, 2H, pyrimidine-H), 7.79(d, J=1.8Hz, 2H, furyl-H), 8.94(brs, 2 H, D2O Exch., NH’s). 13C NMR (DMSO): δ 109.8(2CH), 111.3(2CH), 116.5(2CH), 117.9(4CH), 123.2(2C), 135.7(2C), 136.2(2C), 141.1(4CH), 147.4(2C), 148.8(2CH), 150.7(2C), 155.6(2C), 157.3(2C), 177.4(2C), 183.8(2C). MS: m/z(%) 711(M+, 3), 713([M+2]+, 11). Anal. Calcd. for C34H20Cl2N6O4S2 (711.60): C, 57.39; H, 2.83; Cl, 9.96; N, 11.81; S, 9.01. Found: C, 57.06; H, 2.69; Cl, 9.73; N, 12.14; S, 8.77.

Synthesis of Hydrazinopyrimidine 10a, and 10b

A mixture of compounds 9a, and/or 9b (10 mmol), hydrazine hydrate (10 mmol), and a catalytic amount of glacial acetic acid (5 drops) in ethanol (30mL) was refluxed for 6 h. Evaporation of excess alcohol and recrystallization from ethanol gave compounds 10a, and 10b, respectively.

2,5-Dichloro-3,6-bis-{4-[6-(4-chlorophenyl)-2-hydrazino-pyrimidin-4-yl]-phenylamin}-[1,4] benzoqinone (10a). Yellow crystals (yield 82%) m.p. 221−223 ºC. IR (KBr): νmax/cm-1 3336, 3203(NH), 1658(C=O), 1556(C=N). 1H NMR(DMSO): δ 7.13(d, J=8.8Hz, 4H, Ar-H), 7.48(d, J=8.6Hz, 4H, Ar-H), 7.56−7.65(m, 6H, pyrimidine-H, Ar-H), 8.47(brs, 6H, D2O Exch., NH’s), 9.21(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 102.4(2CH), 112.6(4CH), 123.2(2C), 128.9(4CH), 130.5(4CH), 133.1(2C), 134.3(4CH), 134.9(2C), 135.4(2C), 136.7(2C), 150.7(2C), 153.8(2C), 156.2(2C), 157.0(2C), 177.4(2C). MS: m/z (%) 796 (M+, 8). Anal. Calcd. for C38H26Cl4N10O2 (796.49): C, 57.30; H, 3.29; Cl, 17.80; N, 17.59. Found: C, 57.71; H, 3.15; Cl, 17.98; N, 17.80.

2,5-Dichloro-3,6-bis-[4-(6-(furan-2-yl)-2-hydrazinopyrimidin-4-yl)-phenylamino]-[1,4]benzoqinone (10b). Brown crystals (yield 76%) m.p. 218−219 ºC. IR (KBr): νmax/cm-1 3372, 3176(NH), 1648(C=O), 1566(C=N). 1H NMR (DMSO): δ 6.11(d, J=3.7Hz, 2H, furyl-H), 6.92(dd, J1=1.8Hz, J2=3.7Hz, 2H, furyl-H), 7.22(d, J=8.8Hz, 4H, Ar-H), 7.48(d, J=8.6Hz, 4H, Ar-H),7.63(s, 2H, pyrimidine-H), 7.78(d, J=1.8Hz, 2H, furyl-H), 8.53(brs, 2H, D2O Exch., NH’s), 9.06(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ102.9 (2CH), 106.8(2CH), 113.1(4CH), 114.4(2CH), 123.2(2C), 134.0(4CH), 135.5(2C), 137.1(2C), 144.8(2C), 145.3(2C), 150.4(2CH), 150.7(2C), 158.7(2C), 159.9(2C), 177.4(2C). MS: m/z(%) 707 (M+, 17), 709 ([M+2]+, 39). Anal. Calcd. for C34H24Cl2N10O4 (707.52): C, 57.72; H, 3.42; Cl, 10.02; N, 19.80. Found: C, 58.02; H, 3.59; Cl, 9.71; N, 19.63.

2,5-Dichloro-3,6-bis-{4-[5-(4-chlorophenyl)-3-methyl-[1,2,4]triazzolo[4,3-a]pyrimidin-7-yl]-phenylamino}-[1,4] benzoqinone (11). A solution of compound 10a (10 mmol) in 10 mL freshly distilled acetic acid anhydride was heated under reflux for 1 h. The solid that formed after concentration and cooling was filtered off and crystallized from EtOH to give 11. Reddish brown crystals (yield 79%)m.p. 207−208 ºC. IR (KBr): νmax/cm-1 3213(NH), 1658(C=O). 1H NMR (DMSO): δ 2.37(s, 6H, 2Me), 7.16 (d, J=8.8Hz, 4H, Ar-H), 7.43(d, J=8.6Hz, 4H, Ar-H), 7.52(s, 2H, pyrimidine-H), 7.61−7.82(m, 8H, Ar-H), 9.17(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 13.7(2CH3), 104.8(2CH), 118.5(4CH), 123.2(2C), 128.7(4CH), 132.6(4CH), 133.3(4CH), 136.2(2C), 137.5(2C), 139.8(2C), 141.3(2C), 141.9(2C), 149.8(2C), 150.7(2C), 158.6(2C), 165.0(2C), 177.4(2C). MS: m/z (%) 844 (M+, 3). Anal. Calcd. for C42H26Cl4N10O2(844.53): C, 59.73; H, 3.10; Cl, 16.79; N, 16.59. Found: C, 59.94; H, 2.91; Cl, 16.46; N, 16.26.

2,5-Dichloro-3,6-bis-{4-[5-(4-chlorophenyl)-3-thioxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-yl]-phenylamino}-[1,4]benzoqinone (12). To a solution of 10a (10 mmol) in dry pyridine (30 mL), CS2 (20 mmol) was added and the reaction mixture was heated under reflux for 10 h. After cooling the reaction mixture was poured into ice/HCl mixture and the solid that separated was washed with cold water, filtered off, and crystallized from EtOH/H2O to give 12. Reddish brown crystals (yield 71%) m.p. 248−250 ºC. IR (KBr): νmax/cm-1 3309, 3217(NH), 1658(C=O), 1451(C=S). 1H NMR (DMSO): δ 7.06 (d, J=8.8Hz, 4H, Ar-H), 7.48−7.68(m, 10H, pyrimidine-H, Ar-H), 7.92(d, J=8.8Hz, 4H, Ar-H), 9.22(brs, 2H, D2O Exch., NH’s), 9.84(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 104.7(2CH), 118.6(4CH), 123.2(2C), 128.5(4CH), 132.8(4CH), 133.2(4CH), 135.9(2C), 137.3(2C), 140.0(2C), 141.2(2C), 150.7(2C), 152.6(2C), 154.9(2C), 164.8(2C), 168.1(2C), 177.4(2C). MS: m/z(%) 880 (M+, 4), 882 ([M+2]+, 17).Anal. Calcd. for C40H22Cl4N10O2S2 (880.61): C, 54.56; H, 2.52; Cl, 16.10; N, 15.91; S, 7.28. Found: C, 54.90; H, 2.83; Cl, 15.75; N, 16.17; S, 7.03.

Synthesis of Pyrimidines 13a, and 13b

A mixture of 10a (10 mmol), piperonal and/or 2-furaldehyde (10 mmol), in 1,4-dioxane (20 mL) was refluxed for 6h. The solid that separated after concentration and cooling was filtered off and crystallized from EtOH/H2O to give 13a, and 13b, respectively.

2,5-Dichloro-3,6-bis-{4-2-(N-benzo[1,3]dioxol-4-yl-methylene-hydrazino)-6-(4-chloro-phenyl-pyrimidin-4-yl]-phenylamino}-[1,4]benzoquinone (13a). Brown crystals (yield 57%) m.p. > 300 ºC. IR (KBr): νmax/cm-1 3366, 3224(NH), 1641(C=O). 1H NMR(DMSO): δ 5.68(s, 4H, 2OCH2O), 6.78(d, J=8.1Hz, 2H, Ar-H), 7.08−7.17(m, 8H, Ar-H),7.38(s, 2H, pyrimidine-H), 7.43−7.65(m, 8H, Ar-H), 7.84(d, J=8.6Hz, 4H, Ar-H), 8.12(s, 2H, =CHN), 9.13(brs, 2H, D2O Exch., NH’s), 9.37(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 99.4(2CH2), 104.7(2CH), 107.9(2CH), 110.2(2CH), 115.6(4CH), 123.2(2C), 123.7(2CH), 128.1(2C), 130.4(4CH), 132.0(4CH), 132.3(2C), 132.8(2C), 134.6(4CH), 135.9(2C), 136.3(2C), 137.8(2C), 147.1(2C), 150.7(2C), 150.9(2C), 152.3(2C), 156.8(2C), 157.6(2C), 177.4(2C). MS: m/z (%) 1060 (M+, 2). Anal. Calcd. for C54H34Cl4N10O6 (1060.72): C, 61.14; H, 3.23; Cl, 13.37; N, 13.20. Found: C, 61.46; H, 3.39; Cl, 13.08; N, 12.90.

2,5-Dichloro-3,6-bis-{4-[6-(4-chlorophenyl)-2-(N-furn-2-yl-methylene-hydrazino)-pyrimidin-4-yl]phenylamino}-[1,4]benzoquinone (13b). Brown crystals (yield 47%) m.p. > 300 ºC. IR (KBr): νmax/cm-1 3309, 3226(NH), 1654(C=O). 1H NMR (DMSO): δ 6.31(d, J=4Hz, 2H, furyl-H), 6.56(dd, J1=1.8Hz, J2=4Hz, 2H, furyl-H), 7.12(d, J=8.6Hz, 4H, Ar-H), 7.28(d, J=8.3Hz, 4H, Ar-H), 7.43(s, 2H, pyrimidine-H), 7.57(s, 2H, =CHN), 7.62(d, J=1.8Hz, 2H, furyl-H), 7.81−7.94(m, 8H, Ar-H), 9.17(brs, 2H, D2O Exch., NH’s), 9.48(brs, 2H, D2O Exch., NH’s). 13C NMR (DMSO): δ 105.8(2CH), 114.6(2CH), 115.7(2CH), 123.2(2C), 125.1(2CH), 128.4(4CH), 130.7 (4CH), 131.9 (2C), 133.5 (4CH), 133.8(2C), 134.9(2C), 136.1(2C), 137.7(2C), 140.4(2CH), 144.6(2C), 150.7(2C), 154.9(2C), 158.2(4C), 177.4(C). MS:m/z(%) 878 ([M+-1]+, 47). Anal. Calcd. for C45H32Cl2N10O6 (879.70): C, 61.44; H, 3.67; Cl, 8.06; N, 15.92. Found: C, 61.42; H, 3.69; Cl, 8.07; N, 15.94.

1,1'-(6,6'-(((2,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,4-diyl)bis(azanediyl))bis(4,1-phenylene))bis(4-(4-chlorophenyl)pyrimidine-6,2-diyl))bis(5-amino-1H-pyrazole-4-carbonitrile) (14a). To a solution of compound 10a (10 mmol) in absolute ethanol (30 mL), methoxy methylene malononitrile (10 mmol) was added. The reaction mixture was heated under reflux for 8h. The formed precipitate was filtered off and recrystallized from ethanol to give compound 14a. Yellowish brown crystals (yield 64%) m.p. > 300 ºC. IR (KBr): νmax/cm-1 3346, 3916(NH), 2221(C=N), 1633(C=O), 1593(C=N). 1H NMR (DMSO): δ 7.12(d, J=8.8Hz, 4H, Ar-H), 7.30(s, 2H, pyrazole-H), 7.34−7.46(m, 10H, pyrimidine-H, Ar-H), 7.78(d, J=8.8Hz, 4H, Ar-H), 8.89(brs, 4H, D2O Exch., NH’s), 9.21(brs, 2H, D2O Exch., NH’s). 13CNMR (DMSO): δ 97.8(2C), 108.3(2CH), 109.5(2C), 116.6(4CH), 123.2(2C), 129.1(4CH), 131.0(4CH), 132.7(4CH), 134.8(2C), 135.2(2CH), 135.8(2C), 136.4(2C), 137.9(2C), 150.7(2C), 151.5(2C), 156.8(4C), 160.3(2C), 177.4(2C). MS: m/z(%) 948 (M+, 17). Anal. Calcd. for C46H26Cl4N14O2 (948.60): C, 58.24; H, 2.76; Cl, 14.95; N, 20.67.Found: C, 58.03; H, 3.05; Cl, 15.18; N, 20.45.

Biological

Anticonvulsant Activity

Bichalcone compounds (4a, 4b) and diazepines (5a, and 5b) were screened for their anticonvulsant activity via pentylenetetrazole metrazole induced convulsions test. The results were compared with diazepam as a standard anticonvulsant.

Swiss albino adult male mice, weighing 20−25g were used. They were obtained from an animal facility (Animal House, Department of pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University). Mice were housed in stainless steel wire-floored cages without any stressful stimuli and kept under well-ventilated conditions at room temperature (25−30 ℃). They were fed on an adequate standard laboratory chow (El-Nasr Co., Abou Zabal, Egypt) and allowed to acclimatize with free access to food and water for 24 h before testing.

The study was approved by the Institutional Animal Ethical Committee (IAEC) and was in accordance with the guideline of the Committee for the purpose of control and Supervision of Experimental Animal (PCSEA). Pentylenetetrazole was used to induce convulsions, the tested compounds were solubilized in DMSO and orally administered in dose ranging from 500−200 mg/kg animal weight using the same dosing volume of a 2 mL per 20g pentylenetetrazole (PTZ, Sigma) was dissolved in normal saline at 2% concentration and was given intraperitoneally in a dose of 60 mg/kg body weight (dose that could induce convulsions in at least 80% of the animals without death during the following 24 h.) Diazepam (sigma, USA) was dissolved in normal saline at 2% concentration and was given in doses of 62.50, 125, 250 mg/kg using the same dosing volume. All drugs were freshly prepared according to the desired concentration just before use.

Mice were administered as the graded doses of the test compounds and diazepam orally. Control animals received an equal volume of saline (10 mL/kg). After one hour the animals were subcutaneously injected with the convulsive dose of (PTZ) (60 mg/kg). The criterion of anticonvulsant activity is complete protection against convulsions of any kind. Observations were made at least 60 minutes after the administration of (PTZ).

Anti-proliferative Activity

The newly synthesized compounds 4a, 4b, 5a, 5b, 8a, 8b, 9a, and 9b were tested for their in vitro anti-proliferative activities in the National Cancer Institute (NCI), where a single dose (10 μM) of the test compounds was used against 60 cell lines panel assay.29−33 All cells were cultured using Dulbecco’s modified Eagle’s medium (DMEM) and Roswell Park Memorial Institute (RPMI-1640) medium. All media were supplemented with 4.5 g/L Glucose with L-Glutamine and 10% fetal bovine serum (FBS). The cells were incubated in 5% CO2 humidified at 37 ℃ for growth maintenance. All compounds were evaluated by MTT assay. Briefly, the cells were cultured in 96-well plates at a density of 1×104 cells/well. Culture media without compound administration was used as a negative control and doxorubicin (a standard anticancer drug) administration was used as a positive control. After 24 h incubation, MTT dissolved in PBS was added to each well at a final concentration of 5 mg/mL, and the samples were incubated at 37 ℃ for 4 h. Water-insoluble dark blue formazan crystals that formed during MTT cleavage in actively metabolizing cells were then dissolved in dimethyl sulfoxide (DMSO). Absorbance was measured at 540 nm, using a microplate reader (BMG Labtech, Germany). The cell viability (%) was calculated and compared with the controls.

The data reported as mean-graph of the percent of the growth of the treated cells, as percentage growth of the treated cells and as a percentage of growth inhibition (GI%) caused by the tested compounds.

RESULTS and DISCUSSIONS▼

Chemistry

Preparation of bichalcone derivatives was initiated by reaction of 2,3,5,6-tetrachloro-[1,4]benzoquinone (1) and a solution of 4-aminoacetophenone (2) in acetonitrile with a few drops of piperidine, according to the recently published procedure.14 This rection afforded 2,5-bis(4-acetylphenylamino)-3,6-dichloro-[1,4]benzoquinone (3) in 89% yield (Scheme 1).

The synthesis of bichalcone derivatives 4a, and 4b was shown in Scheme 1. Chalcone formation is usually accomplished using Claisen-Schmidt reaction under basic medium in a polar solvent.15 The condensation was carried out with equimolar quantities of 2,5-bis(4-acetylphenylamino)-3,6-dichloro-[1,4]benzoquinone (3), and 4-chlorobenzaldehyde, (or 2-furaldehyde) in methanolic KOH solution, according to the reported procedure,16 furnishing 4a, and 4b in 68% and 73% yield, respectively. Remarkable improvement in yields (95−97%) was obtained by carrying out the Aldol condensation under solvent-free conditions.17,18 In this respect, solvent-free aldol condensation, by grinding a mixture of equimolar quantities of compound 3 and 4-chlorobenzaldehyde (or 2-furaldehyde) with KOH, in a porcelain mortar, furnished bichalcone derivatives 4a (95%) and 4b (97%), respectively (Scheme 1). The IR spectra of the new compounds displayed the characteristic absorption bands for conjugated carbonyl group at νmax: 1660-1656 cm-1. The 1H NMR spectra revealed the olefinic H in the aromatic region beside the other signals at their expected positions. The MS spectra showed their exact molecular ion peak.

Scheme1.

Synthesis of bichalcones 4a, and 4b.

jkcs-64-7-f001.tif
Scheme2.

Reactions of bichalcone derivatives 4a, and 4b.

jkcs-64-7-f002.tif

We began our investigation of utilities of the prepared bichalcone derivatives 4a, and 4b by considering 1,4-cycloaddition reactions to α,β-unsaturated carbonyl compounds (chalcones). They are versatile tools for building heterocycles, so we aimed to synthesize new diazepine derivatives 5a, and 5b by reacting the bichalcone derivatives 4a, and 4b with 2,3-diaminomaleonitrile in acetonitrile under ultrasonic conditions. The structures of the new diazepines 5a, and 5b were deduced from their analytical and spectral data, where IR spectra showed two absorption bands at νmax ranging from 3407 to 3212 cm-1, assignable for two NH groups; and two bands ranging from 2248 to 2206 cm-1, assignable for two C≡N groups. The 1H NMR spectra showed two NH singlets (D2O exchangeable) in the region 9.17−9.21 ppm. MS data of the diazepines 5a, and 5b were found to be in full agreement with the proposed structures.

There are a few reports with bichalcones or even chalcones as precursors for the synthesis of pyrazolo[1,5-a]pyrimidines. For example, Elnagdi and Erian synthesized analogs of tetrasubstituted pyrazolo[1,5-a]pyrimidines with chalcones as precursors in moderate yields.19−22 We achieved the synthesis of pyrazolo[1,5-a]pyrimidines (7a, and 7b) through the tandem reaction of 3-amino pyrazoles (6a, and 6b) and bichalcone derivative 4a in the presence of catalytic amounts of KOH.23 The 1H NMR spectra of 7a, and 7b displayed two doublets of pyrazole protons at δ = 6.82 and 6.67 ppm. Cyclocondensation of 4a, and 4b with hydrazine hydrate in refluxing ethanol gave the corresponding pyrazoline derivatives 8a, and 8b. The structures of these products were ascertained by their elemental and spectral data, where their IR spectra of 8a showed absorption bands at 3362 and 3214 cm-1 characteristic for (NH groups).

Furthermore, the new pyrimidine-2-thiol derivatives 9a, and 9b were prepared via the condensation reactions of the bichalcone derivatives 4a, and 4b with thiourea in the presence of a catalytic amount of sodium ethoxide. The reaction possibly takes place via Aza-Michael addition to the unsaturated carbonyl moiety of the chalcone followed by cyclo-condensation reaction with the loss of water to give thioxopyrimidines 9a, and 9b. The structures of the obtained new pyrimidines were substantiated by their spectral and analytical data.

The behavior of the thioxopyrimidines 9a, and 9b towards nitrogen nucleophiles have been studied; its reaction with hydrazine hydrate was chosen as a model reaction. The reaction of compounds 9a, and 9b with hydrazine hydrate in ethanol afforded the hydrazino-pyrimidine derivatives 10a, and 10b. The disappearance of the absorption bands characteristic of the SH group, which are present in the starting compounds 9a, and 9b, are confirmatory from their IR and 1H NMR spectra of compounds 10a, and 10b, in addition to their exact molecular weights given by the mass spectra for their structures.

The chemistry of pyrimidines has become a subject of great interest in the last few years because they display some interesting properties in functionalization of other heterocycles.24−26 Considering the importance of pyrimidines, and the uses of bichalcones as key precursors we have successfully attempted to use hydrazino-pyrimidine based on bichalcones as a key starting material for the synthesis of some interesting nitrogen bridgehead compounds. Indeed, the hydrazino-pyrimidine derivative 10a was allowed to react with Ac2O, and the bis 3-methyl-1,2,4-triazolo[4,3-a]pyrimidine derivative 11 was afforded. When compound 10a was reacted with CS2 in pyridine, the bis 3-thioxo-1,2,4-triazolo[4,3-a]pyrimidine derivative 12 was obtained. Moreover, compound 10a was condensed with piperonal or 2-furaldehyde in 1,4-dioxane to afford the corresponding hydrazone derivatives 13a, and 13b, respectively (Scheme 3). The structures of compounds 11, 12, 13a, and 13b were deduced from their analytical and spectral data, which were in full agreement with the proposed structure.

Scheme3.

Reactions of hydrazinopyrimidines 10a.

jkcs-64-7-f003.tif

Finally, the hydrazino-pyrimidine derivative 10a was used as an assorted precursor for the synthesis of some biologically active heterocycles, where the amino pyrazole carbonitrile compound 14 was synthesized by refluxing an equimolar mixture of compounds 10a and methoxy methylene malononitrile in boiling absolute ethanol. The structure of compound 14 was confirmed by spectral and elemental analysis, where its IR spectrum gave the absorption bands at νmax= 3346 and 2221 cm-1 for NH2 and CN groups, respectively. Its 1H NMR substantiated the signal for NH2 as a broad singlet (D2O exchangeable) at δ = 8.89 ppm.

Biological

Anticonvulsant Activity

Doses that gave full protection against the induced convulsions and that which exhibited 50% protection in addition to the relative potencies of the test compounds to diazepam were recorded. The ED50 of each compound (mg/kg and mmol.) and the relative potencies of the test compounds to Diazepam were calculated and presented in Table 1.

Table1.

Anticonvulsant activity of compounds 4a, 4b, 5a, 5b, and diazepam

Compd. Dose mg/kg No. of protected animal % protection ED50 mcg/kg MWt ED50 mol/kg Relative potincy
Diazepam 82.5 1 16.66 125 284 0.44 1
125 3 50
250 6 100
4a 500 4 66.66 250 688 0.36 0.73
1000 5 83.33
2000 6 100
4b 500 3 50 500 599 0.83 0.34
1000 4 66.66
2000 6 100
5a 500 6 100 250 868 0.29 0.67
1000 4 66.66
2000 5 83.33
5b 500 4 66.66 250 764 0.33 0.63
1000 5 83.33
2000 6 100

ED50 (Median effective dose = the effective that protects 50% of the animal against PTZ induced convulsion.

RP = Relative potencies.

The tested compounds revealed good anticonvulsant activity compared to that of Diazepam, but the bichalcone 4b was the less reactive one.

Anti-proliferative Activity

The tested compounds displayed significant in vitro screening on the tested cell lines and showed cytotoxic effects on most of the cancer cell lines with regard to broad spectrum antitumor activity. Close examination of the data presented in Table 2 revealed that compounds 5a, 5b, and 8a were the most active members of this study showing effectiveness towards numerous cell lines within different tumor subpanels.

Figure1.

Anticonvulsant activity of compounds 4a, 4b, 5a, 5b, and diazepam.

jkcs-64-7-f004.tif
Table2.

Percentage growth inhibitor (GI %) of in vitro subpanel tumor cell lines at 10 μM concentration

Subpanel tumor cell lines % Growth inhibition (GI%)
4a 4b 5a 5b 6a 6b 7a 7b
Melanoma
LOX IMVI - - 26 18 39 - 32 29
MALME-3M - 17 39 19 51 16 55 67
M14 - 22 27 - 35 25 61 13
MDA-MB-435 - - 22 11 33 12 24 -
SK-MEL-2 - - 23 16 43 27 55 48
SK-MEL-28 - - 22 - 25 30 40 27
SK-MEL-5 - - 55 13 61 26 33 10
UACC-257 - - 31 11 39 39 80 43
UACC-62 - - 57 34 47 47 24 15
Ovarian Cancer
IGROVI - - 16 - 26 - 25 -
OVCAR-3 - - 23 12 57 - 31 33
OVCAR-4 11 - 19 37 77 39 52 L
OVCAR-5 - - 15 - - 12 - -
OVCAR-8 - 55 32 21 59 27 L 71
NCI/ADR-RES - - 33 18 34 16 nt 17
SK-OV-3 - 28 28 - 61 19 53 70
Renal Cancer
786-o - - 42 17 57 - L 28
A498 - 17 89 36 86 65 L 33
ACHN - - 43 22 63 55 34 47
CAKI-1 - 12 24 28 18 37 16 35
RXF 393 - 29 70 - 76 43 64 64
SN12C - - 12 18 17 21 31 11
TK-10 - - 28 - 45 - L -
UO-31 - 23 38 55 29 26 52 29
Prostate Cancer
PC-3 10 - 29 34 26 57 65 17
DU-145 - - 28 - 20 - 46 17
Breast Cancer
MCF7 21 - 30 16 30 30 18 23
MDA-MB-231/TCC - 15 56 36 65 49 59 48
HS 578T - 45 53 23 56 60 76 94
BT-549 - 28 69 12 47 27 87 -
T-47D - - 45 22 88 36 27 65
MDA-MB-468 - nt nt - nt - nt 32

Consequently, compounds 5a, 5b, and 8a were tested against a panel of 32 different tumor cell lines at a 5-log dose range. Three response parameters GI50, TGI, and LC50 were calculated for each cell line using the known drug 5-fluorouracil (5-FU) as a positive control (Table 3). Compounds 5a, 5b, and 8a exhibited remarkable growth inhibitory activity pattern against renal cancer (GI50 = 4.26, 3.47 and 12.30 μM), breast cancer (GI50 = 4.16, 4.16 and 6.16 μM), ovarian cancer (GI50 = 9.54, 6.30 and 10.23 μM), melanoma cancer (GI50 = 6.58, 4.24 and 3.70 μM), and prostate cancer (GI50 = 27.22, 4.89 and 18.8 μM), respectively.29−33

Table3.

Compounds 5a, 5b, and 6a medium growth inhibitory (GI50, μM), total Growth inhibitory (TGI, μM), and medium lethal concentration (LC50, μM) of in vitro subpanel cell lines

Activity Melanoma Ovarian cancer Renal cancer Prostate cancer Breast cancer MG-MIDa
GI50 6.56 9.54 4.26 27.22 4.16 10.5
TGI 19.85 60.25 39.8 b 67.1 58.8
LC50 b b b b b b
GI50 4.24 6.3 3.47 4.89 4.16 7.24
TGI 45.47 26.0 26.7 b 27.3 36.3
LC50 b 93.11 98.0 b 70.8 87.9
GI50 3.7 10.23 12.3 18.8 6.16 14.1
TGI 79.03 87.09 45.5 b 57.3 60.3
LC0 b b 97.72 B b 95.5
GI50 70.6 61.4 45.6 22.7 76.4 22.6
TGI b b b B b b
LC50 b b b B b b

Comparing with the antitumor activities of Gefitinib and Erlotinib, compounds 5a, 5b, and 8b (Table 4) possess activities almost equal to or higher than those of Gefitinib and Erlotinib against most cell lines except melanoma (SK-MEL-28), ovarian (IGROVI and SK-OV-3), renal (ACHN and TK-10), and breast cancer (MDA-MB-435).

Table4.

GI50 values (μM) of compounds 5a, 5b, 6a, gefitinib and erlotinib over the most cell lines of non-small lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, and breast cancer

Subpanel tumor cell lines GI50 (μM)
5a 5b 6a Erlotinib Gefitinib
Melanoma
LOX IMVI 55.0 4.71 6.4 5.01 7.94
MALME-3M 4.07 3.3 4.73 5.01 3.16
M14 8.38 16.1 24.4 6.30 5.01
MDA-MB-435 9.55 4.91 >100 15.84 3.16
SK-MEL-2 3.38 3.41 4.40 12.58 12.58
SK-MEL-28 7.04 3.02 6.30 31.62 0.31
SK-MEL-5 3.67 - 32.4 15.84 3.98
UACC-257 4.86 3.55 4.96 100.00 6.30
UACC-62 2.93 2.35 15.7 1.25 5.01
Ovarian Cancer
IGROVI 32.5 7.34 27.7 0.25 0.20
OVCAR-3 9.36 7.68 5.05 3.16 5.01
OVCAR-4 3.41 2.11 3.95 19.95 7.94
OVCAR-5 58.0 >100 >100 19.95 10.00
OVCAR-8 4.42 3.46 5.01 7.94 10.00
NCI/ADR-RES 8.97 3.30 9.25 6.30 12.58
SK-OV-3 3.06 2.91 4.75 0.39 0.63
Renal Cancer
786-O 3.2 3.51 4.17 5.01 7.94
A498 1.01 1.75 15.8 1.58 0.4
ACHN 3.49 4.63 3.72 0.15 0.2
CAKI-1 5.08 3.05 >100 0.10 0.16
RXF 393 2.24 2.55 3.48 6.3 5.01
SN12C 5.24 4.70 78.0 6.3 6.3
TK-10 5.58 4.06 7.43 0.10 0.10
UO-31 5.97 1.95 11.6 1.99 1.25
Breast Cancer
MCF7 9.98 7.93 32.0 10.0 10.0
MDA-MB-231/ATCC 3.42 3.73 4.2 1.99 12.58
HS 578T 3.23 2.46 2.18 6.3 10.0
BT-549 2.98 2.02 5.02 39.81 7.94
T-47D 4.01 6.57 7.04 3. 16 6.3
MDA-MB-468 4.11 5.72 5.39 0.2 0.01

The 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide is based on the conversion of MTT into formazan crystals by living cells,which reflects cytotoxicity based on mitochondrial activity. Thus, the pathway of cancerous cell death may be through mitoptosis, a de novo mitochondrial death mechanism. The detailed mechanism of action may be further investigated in an in vivo study that we are proposing to approach.

CONCLUSION▼

We successfully endeavor to design, synthesize, and evaluated new anticonvulsant bichalcone derivatives 4a, and 4b and their utilization for producing more interesting functionalized heterocycles like pyrazoles, diazepines, and pyrimidine-based compounds. We hereby highlighted the potential of such new heterocycles as anti-proliferative agents.

Notes▼

[1] Conflicts of interest Conflict of Interest. The authors declare no conflict of interest.

Acknowledgements▼

The publication cost of this paper was supported by the Korean Chemical Society.

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