One-Pot Synthesis of Novel Furochromone and Oxazocine Derivatives as Promising Antitumor Agents with Their Molecular Docking Studies

Borik, Rita M.

doi:https://doi.org/10.1155/2020/1474050

Journal of Chemistry

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Abstract Introduction Experimental Results and Discussion Conclusion Data Availability Conflicts of Interest Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2020 | Article ID 1474050 | https://doi.org/10.1155/2020/1474050

One-Pot Synthesis of Novel Furochromone and Oxazocine Derivatives as Promising Antitumor Agents with Their Molecular Docking Studies

Rita M. Borik¹

Academic Editor: Artur M. S. Silva

Received14 Jan 2020

Revised17 Mar 2020

Accepted20 Mar 2020

Published29 Apr 2020

Abstract

One-pot efficient synthesis of novel chromone derivatives 4a–h and that of 5a–h were described in a simple method via four-component reaction between furochromone carbaldehyde, amine, isocyanate derivatives, and benzoic acid derivatives or nicotinic acid, respectively. Also, oxazocine derivatives 7a, b were prepared via reaction of visnagine carbaldehyde, ethyl acetoacetate and isocyanate derivatives 2a, b. The obtained derivatives of novel furochromone and oxazocine derivatives were evaluated as promising antitumor agents against panel of two human cell lines, hepatocellular carcinoma (HEPG2) and breast carcinoma (MCF7). The antitumor results suggested that furochromone derivatives 5a–h have activity against MCF7 in comparison with doxorubicin as the standard drug. Furthermore, the molecular docking studies of these novel derivatives of furochromone and oxazocine showed good agreement with the biological results when their binding pattern and affinity towards the active site of EGFR was investigate.

1. Introduction

Cancer is uncontrolled growth of abnormal cells, one of the most widespread serious diseases and its growth and metastasis depends on angiogenesis [1–4]. So, targeting of angiogenesis is a great goal for inhibition of tumor growth, invasion, and metastasis [5, 6].

Treatment of cancer using cytotoxic drugs (antineoplastics that preventing replication of cells) has many side effects [7, 8] although they are toxic to cancer cells. However, they all tend to work by interfering with some aspect of how the cells divide and multiply. For example, some work by affecting the cells’ genetic “makeup” (material which controls specific cell characteristics) and others work by blocking cells from using nutrients needed to divide and multiply. The choice of cytotoxic drugs depends on the type and stage of cancer [9]. Survey and research to get safe novel drugs with less side effects are still in continuation [10, 11].

In point of this view, heterocyclic organic compounds play an important and vital role in synthesis and preparation of novel pharmacological compounds that may have a good manner in treatment of various types of tumors [12] and the human immunodeficiency virus (HIV) [13]. Our initial studies focused on the chromone and its derivatives which are important class of heterocyclic compounds. These heterocyclic compounds show a variety of pharmacological properties [14]. The tricycle-heterocyclic compounds especially dibenzooxazocine and furochromone or visnagine derivatives are used for the treatment of pain and/or inflammation [15], and also they have efficient activity against tumor cells [16–18].

Imidazole derivatives are an important class of heterocyclic compounds [19, 20] that exhibiting biological and pharmacological properties [21–23]. Also, oxazocine heterocyclic compounds are active compounds against CNS disorders and are used for the treatment of pain and/or inflammation [24].

So, according to this survey and in continuation of our heterocyclic synthesis of novel active compounds against some carcinoma cell lines [25], we aim to synthesize novel derivatives of furochromone and oxazocine as promising antitumor agents towards hepatic and breast cell lines (HEPG2 and MFC7) as well as the normal cell line (human normal melanocyte, HFB4) using the MTT colorimetric test [26–29] depending on their molecular docking studies via one-pot reaction of three or four components of carbaldehyde, amine, isocyanate, and benzoic acid derivatives.

2. Experimental

All chemicals were provided by Fluka or Aldrich companies and were used without additional purification. Elemental microanalyses were carried out at Microanalytical Unit, Central Services Laboratory, National Research Centre, Dokki, Giza, Egypt, using Vario Elementar and were found within ± 0.4% of the theoretical values. All melting points were uncorrected and were taken in open capillary tubes using electrothermal apparatus 9100. FT-IR spectra were recorded with a Perkin-Elmer Frontier. Routine NMR spectra were recorded at room temperature on a Bruker Avance TM 400 (or 300) spectrometer as solutions in dimethyl sulfoxide (DMSO-d₆) or chloroform (CDCl₃). All chemical shifts are quoted in δ relative to the trace resonance of protonated dimethyl sulfoxide (δ2.50 ppm), DMSO (δ39.51 ppm) or CDCl₃ (δ7.28 ppm), (δ77.28 ppm), and external 85% aqueous H₃PO₄ (δ0.0 ppm). The mass spectra were measured with a GC Finnigan MAT SSQ-7000 mass spectrometer. The reactions were followed, the purity of the compounds was checked using TLC on silica gel-precoated aluminum sheets (Type 60, F 254, Merck, Darmstadt, Germany), and the spots were detected by exposure to UV lamp at λ_{254 nm}. The chemical names given for the prepared compounds are according to the IUPAC system. The reported yields are based upon pure materials isolated by column chromatography. Solvents were dried/purified according to conventional procedures.

2.1. General Procedure for the Preparation of Compounds 4a–h and 5a–h

The desired compounds were synthesized utilizing a 25 ml round bottom flask. Mixture A, aniline/or benzyl amine (1.1 mmol), was added to furochromone carbaldehyde 1 (1.1 mmol) in methanol (20.0 ml); then the mixture A was stirred for 15–30 min at room temperature. Mixture B, benzoic acid/or p-amino benzoic acid/or p-nitro benzoic acid/or nicotinic acid, respectively, (1.1 mmol) and phenyl isocyanate/or cyclohexyl isocyanate, respectively, (1.1 mmol) in methanol were stirred for 5 minutes. Then, Mixture B was poured on Mixture A. Finally, the resultant mixture was stirred at room temperature for 23–68 h, and solid K₂CO₃ (0.38 mmol) was added and refluxed for 76–100 h. After the reaction was completed, the crude material was concentrated and redissolved in dichloromethane. The resulting organic solution was then washed with 1 M HCl (aq). This was followed by adding a saturated aqueous solution of NaHCO₃ (aq) combined with brine. The resulting organic layer was collected, dried by MgSO₄, and then concentrated in vacuum at 40°C for 8 h to afford the crude material. The crude material was purified by ethanol to give the desired products 4a–h.

2.1.1. N-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl) (Phenylimino) Methyl)-N-phenyl Benzamide (4a)

Product 4a was separated as orange crystals, yield 59%. m.p. 210–212°C. IR (KBr, cm⁻¹) 1674, 1656 (2C=O), 1623 (C=N). ¹H NMR (500 MHz, DMSO-d₆): δ = 3.99, 4.00 (s, 6H, 2OCH₃); 6.22, 6.60 (dd, 2H, J = 2.01 Hz, furan ring), 7.10 (s, 1H, H₇), 7.00–7.31 (m, 15H, CH arom) ppm. ¹³C NMR (100 MHz, DMSO-d₆): δ176.2 (CO), 173.7 (CO), 164.0 (CN), 155.8, 152.9, 150.1, 147.0, 146.5, 146.1, 134.1, 133.5, 132.1, 130.0, 128.9, 128.0, 127.6, 127.1, 123.1 124,0, 122.1, 121.6 (aromatic C-H), 118.2, 111.3, 106.3, 55.0 (OCH₃), 54.5 (OCH₃) ppm. MS (m/z): M⁺ 543 (31%), 542 (17%), 541(55%). Anal. for C₃₃H₂₄N₂O₆ (544.55): Calcd. C, 72.78; H, 4.44; N, 5.14. Found C, 72.21; H, 4.02; N, 4.82.

2.1.2. N-(Cyclohexylimino) (4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)methyl)-N-phenyl Benzamide (4b)

Product 4b was separated as brown solid, yield: 52%, m.p. 182°C. IR (KBr, cm⁻¹) 1674, 1646 (2C=O), 1621(C=N). ¹H-NMR (500 MHz, DMSO-d₆): δ = 1.25–1.64 (m, 10H, 5CH₂ cyclohexane); 3.10 (dd, H, CH-N cyclohexane); 3.88 (s, 6H, 2OCH₃); 6.64, 6.56 (dd, 2H, J=2.0 Hz 1, furan ring); 7.21–7.10 (m 10H, CH armo.); 8.00 (s, 1H, H₇). MS (m/z): M⁺ 550.6, m/e: 549 (13%), 548 (36%), 547 (64%). Anal. for C₃₃H₃₀N₂O₆ (550.21): Calcd: C, 71.99; H, 5.49; N, 5.09, Found: C, 71.42; H, 5.02; N, 4.64.

2.1.3. 4-Amino-N-((4,9-dimethoxy-5-oxo-5H-furo [3,2-g] Chromen-6-yl) (Phenylimino) Methyl)-N-phenyl Benzamide (4c)

Product 4c was separated as yellow solid, yield: 55%. m.p. 177°C. IR (KBr, cm⁻¹) 1622 (C=N), 1686, 1645 (2CO) and 3347 (NH₂). ¹H-NMR (500 MHz, DMSO-d₆): δ = 3.89 (s, 6H, 2OCH₃); 6.92–6.24 (m, 14H, arom.), 6.73, 6.36 (dd, 2H, J=2.01 Hz, furan ring); 7.89 (s, 1H, H₇) and 8.82 (s, 2H, NH₂, exchangeable D₂O). ¹³C NMR (100 MHz, DMSO-d₆): δ, 177.6 (CO), 174.1 (CO), 164.1 (CN), 156.1, 155.3, 153.8, 151,1, 147.5, 147.0, 146.3, 134.0, 133,2, 132.4, 129.0, 128.7, 127.6, 124.8, 124.3 123.1, 122.3, 121.6 (aromatic C-H), 113.0, 112,1, 56.6 (OCH₃), 56.3 (OCH₃). MS (m/z): M⁺: 558 (9%), 557 (35%), 556 (43%). Anal. for C₃₃H₂₅N₃O₆ (559.57): Calcd: C, 70.83; H, 4.50; N, 7.51, Found: C, 70.43; H, 4.24; N, 7.24.

2.1.4. 4-Amino-N-(cyclohexylimino) (4,9-Dimethoxy-5-oxo-5H-furo [3,2-g] Chromen-6-yl) Methyl)-N-phenylbenzamide (4d)

Product 4d was separated as brown solid, yield: 56%. m.p. 196°C, IR (KBr, cm⁻¹) 1623 (C=N), 1699, 1653 (2C=O) and 3345 (NH₂). ¹H-NMR (500 MHz, DMSO-d₆): δ1.58–1.24 (m, 10H, 5CH₂ cyclohexane); 3.02 (dd, H, CH-N cyclohexane); 4.01, 4.03 (s, 6H, 2OCH₃); 6.67, 6.33 (dd, 2H, J=2.00 Hz, furan ring); 6.54–6.20 (m, 9H, arom.); 8.10 (s, 1H, H₇) and 8.79 (s, 2H, NH₂ exchangeable with D₂O). MS (m/z): M⁺: 565 (11%), 564 (48%), 563 (76%). Anal. for C₃₃H₃₁N₃O₆ (565.62) Calcd: C, 70.07; H, 5.52; N, 7.43, Found: C, 69.78; H, 5.12; N, 7.01.

2.1.5. N-((4,9-Dimethoxy-5-oxo-5H-furo [3,2-g] Chromen-6-yl) (Phenylimino) Methyl)-4-nitro-N-phenylbenzamide (4e)

Product 4e was separated as yellow solid, yield: 66%. m.p. 214°C. IR (KBr, cm⁻¹) 1621 (C=N),1672, 1642 (2C=O). ¹H-NMR (500 MHz, DMSO-d₆): 3.76, 3.77 (ss, 6H, 2OCH₃), 6.54–7.20 (m, 14H, arom); 7.28, 6.56 (dd, 2H, J=2.01 Hz, furan ring); 7.54 (s, 1H, H₇). ¹³C NMR (100 MHz, DMSO-d₆): δ, 177.3 (CO), 174.0 (CO), 164.1 (CN), 156.1, 155.0, 153.7, 151.0, 147.1, 147.0, 146.0, 134.2, 133.1, 132.3, 129.0, 128.7, 127.6, 124.4, 123.3, 122.5, 121.7 (aromatic C-H), 113.1, 112.2, 106.1, 56.1 (OCH₃), 54.6 (OCH₃) MS (m/z): M⁺: 589.15 (76.0%), 588 (32%), 587 (45). Anal. for C₃₃H₂₃N₃O₈ (589.55) Calcd C, 67.23; H, 3.93; N, 7.13, Found: C, 66.77; H, 3.41; N, 5.85.

2.1.6. N-((Cyclohexylimino) (4,9-Dimethoxy-5-oxo-5H-furo [3,2-g] Chromen-6-yl) Methyl)-4-nitro-N-phenylbenzamide (4f)

Product 4f was separated as brown solid, yield: 64%. m.p. 146°C, IR (KBr, cm⁻¹) 1618 (C=N), 1677, 1641 (2C=O). ¹H-NMR (100 MHz, DMSO-d₆): δ, 1.44–1.12 (m, 10H, 5CH₂ cyclohexane); 3.02 (dd, H, CH-N cyclohexane), 3.76, 3.77 (s, 6H, 2OCH₃), 7.11, 6.42 (dd, 2H, J=2.01 Hz, furan ring); 7.00–6.98 (m, 9H, CH arm.); 7.56 (s, 1H, H₇). MS (m/z): M⁺: 595.2 (14%), 593 (36%), 592 (83%), Anal. for C₃₃H₂₉N₃O₈ (595.6). Calcd C, 66.55; H, 4.91; N, 7.06, Found: C, 66.01; H, 4.33; N, 6.84.

2.1.7. N-((4,9-Dimethoxy-5-oxo-5H-furo [3,2-g] Chromen-6-yl) (Phenylimino) Methyl)-N-phenyl Nicotinamide (4g)

Product 4g was separated as brown solid, yield: 64%. m.p. 176°C, IR (KBr, cm⁻¹) 1620 (C=N), 1664, 1634 (2C=O). ¹H-NMR (100 MHz, DMSO-d₆): δ, 3.99, 3.86 (s, 6H, 2OCH₃), 7.54–7.00 (m, 14H, arom); 7.12, 6.33 (dd, 2H, J=2.01 Hz, furan ring); 7.74 (s, 1H, H₇). ¹³C NMR (100 MHz, DMSO-d₆): δ, 177.4 (CO), 174.1 (CO), 164.1 (CN), 156.1, 153.7, 151.0, 150.8, 149.0, 147.4, 146.2, 134.2, 133.1, 132.2, 129.0, 128.8, 127.6, 124.6, 124.3, 121.7 (aromatic C-H), 113.1, 112.3. 112.1, 106.1, 56.5 (OCH₃), 56.3 (OCH₃), MS (m/z): M⁺: 545 (9%), 544 (58%), 543 (60%). Anal. for C₃₂H₂₃N₃O₆ (545.54) Calcd C, 70.45; H, 4.25; N, 7.70, found: C, 70.00; H, 3.87; N, 7.24.

2.1.8. N-(Cyclohexylimino) (4,9-Dimethoxy-5-oxo-5H-furo [3,2-g] Chromen-6-yl) Methyl)-N-phenylnicotinamide (4h)

Product 4h was separated as brown solid, yield: 62%. m.p. 211°C, IR (KBr, cm⁻¹) 1623 (C=N), 1672, 1642 (2C=O). ¹H-NMR (100 MHz, DMSO-d₆): δ, 1.41–1.22 (m, 10H, 5CH₂ cyclohexane); 3.11 (dd, H, CH-N cyclohexane), 3.96, 3.78 (ss, 6H, 2OCH₃), 7.54–6.20 (m, 9H, arom.); 7.54, 6.44 (dd, 2H, J=2.01 Hz, furan ring); 7.23–7.10 (m 9H, CH arm.); 7.34 (s, 1H, H₇). MS (m/z): M⁺: 551.21 (67.0%), 550 (35.2%), 549 (7.5%). Anal. for C₃₂H₂₉N₃O₆ (551.59) C, 69.68; H, 5.30; N, 7.62, Found: C, 69.31; H, 4.80; N, 7.02.

2.1.9. 4,9-Dimethoxy-6-(1,4,5-Triphenyl-1H-imidazol-2-yl)-5H-furo [3,2-g] Chromen-5-One (5a)

Product 5a was separated as brown solid, yield: 63%. m.p. 214°C. IR (KBr, cm⁻¹) 1646 (C=O). ¹H-NMR (100 MHz, DMSO-d₆): δ, 3.97 (s, 6H, 2OCH₃); 6.78, 6.52 (dd, 2H, J=2.01 Hz, furan ring); 7.00 (s, 1H, H₇) and 7.31–7.11 (m, 15H, CH arom.). ¹³C NMR (100 MHz, DMSO-d₆): δ, 174.7 (CO), 158.6, 152.7, 149.8, 147.5, 146.0, 136.9, 137.1 133.1, 132.1, 129.7, 129.2, 128.6, 127.3, 124.6, 123.1, 122.5 (aromatic C-H), 118.3, 113,0, 106.1, 55.8 (OCH₃), 54.8(OCH₃). MS (m/z): M⁺: 539 (10%), 462 (38%), 401 (67%), 387 (73%), 311 (62%), 245 (66%). Anal. for C₃₄H₂₄N₂O₅ (540.56) C, 75.54; H, 4.48; N, 5.18, Found: C, 75.01; H, 4.11; N, 4.66.

2.1.10. 6-(1-Cyclohexyl-4,5-diphenyl-1H-imidazol-2-yl)-4,9-dimethoxy-5H-furo[3,2-g]chromen-5-one (5b)

Product 5b was separated as brown solid, yield: 62%. m.p. 215°C, IR (KBr, cm⁻¹) 1638 (C=O). ¹H-NMR (100 MHz, DMSO-d₆): δ, 1.25–1.34 (m, 10H, 5CH₂ cyclohexane); 3.00 (dd, H, CH-N cyclohexane); 3.89 (s, 6H, 2OCH₃); 6.76, 6.44 (dd, 2H, J=2.01 Hz, furan ring); 7.22–7.90 (m, 10 H, CH arom.); 7.99 (s, 1H, H₇). MS (m/z): M⁺: 546 (78%), 545 (39%), 544 (79%). Anal. for C₃₄H₃₀N₂O₅ (546.61) C, 74.71; H, 5.53; N, 5.12, Found: C, 74.22; H, 5.32; N, 4.88.

2.1.11. 6-(5-(4-Aminophenyl)-1,4-diphenyl-1H-imidazol-2-yl)-4,9-dimethoxy-5H-furo[3,2-g] Chromen-5-One (5c)

Product 5c was separated as brown solid, yield: 64%. m.p. 186°C, IR (KBr, cm⁻¹) 1645 (C=O) and 3346 (NH₂). ¹H-NMR (100 MHz, DMSO-d₆): δ, 3.98 (s, 6H, 2OCH₃); 6.78, 6.11 (dd, 2H, J=2.01 Hz, furan ring); 7.48 (s, 1H, H₇); 7.21–7.00 (m, 14H, CH arom.) and 9.01 (s, 2H, NH₂ exchangeable with D₂O). ¹³C NMR (100 MHz, DMSO-d₆): δ, 175.0 (CO), 158.9, 153.3, 150.7, 148.0, 147.1, 145.8, 139.0, 137.1, 136.8, 132.7, 131.7, 129.2, 129.0, 128.9, 128.0, 127.1, 124.5, 123.0, 122.7, 122.1 (aromatic C-H), 118.0, 116.3, 112.7, 111.6, 105.8, 56.1 (OCH₃), 56.0(OCH₃). MS (m/z): M⁺: 555 (49%), 554 (55%), 553 (67%). Anal. for: C₃₄H₂₅N₃O₅ (555.58) C, 73.50; H, 4.54; N, 7.56, found: C, 73.00; H, 4.12; N, 7.22.

2.1.12. 6-(5-(4-Aminophenyl)-1-cyclohexyl-4-phenyl-1H-imidazol-2-yl)-4,9-dimethoxy-5H-furo[3,2-g]chromen-5-one (5d)

Product 5d was separated as yellow solid, yield: 63%. m.p. 192°CIR (KBr, cm⁻¹) 1648 (C=O) and 3346 (NH₂). ¹H-NMR (100 MHz, DMSO-d₆): δ, 1.55–1.24 (m, 10H, 5CH₂ cyclohexane); 3.11 (dd, H, CH-N cyclohexane); 3.89 (s, 6H, 2OCH₃); 6.67, 6.51 (dd, 2H, J=2.01 Hz, furan ring); 7.23–7.10 (m, 9H, CH arom.); 8.11 (s, 1H, H₇) and 8.87 (s, 2H, NH₂ exchangeable with D₂O. MS (m/z): M⁺: 561 (20%), 560 (57%), 559 (51%). Anal. for C₃₄H₃₁N₃O₅ (561.63), C, 72.71; H, 5.56; N, 7.48, Found: C, 72.71; H, 5.56; N, 7.48.

2.1.13. 4,9-Dimethoxy-6-(5-(4-nitrophenyl)-1,4-diphenyl-1H-imidazol-2-yl)-5H-furo[3,2-]chromen-5-one (5e)

Product 5e was separated as yellow solid, yield: 61%. m.p. 222°C, IR (KBr, cm⁻¹) 1643 (C=O). ¹H-NMR (100 MHz, DMSO-d₆): δ, 3.97 (s, 6H, 2OCH₃); 6.78, 6.52 (dd, 2H, J=2.01 Hz, furan ring); 7.00 (s, 1H, H₇) and 7.31–7.11 (m, 14H, CH arom.). ¹³C NMR (100 MHz, DMSO-d₆): δ, 175.5 (CO), 158.9, 153.7, 151.0, 147.6, 150.1, 145,8, 140.7, 137.8, 137.1, 132.8, 132.2, 129.8, 129.2, 129.0, 128.5, 127.7, 124.6, 123.1, 122.7, 121.5, 118.4, 113.1, 112,0, 105.2 (aromatic C-H), 56.6 (OCH₃), 56.4 (OCH₃). MS (m/z): M⁺: 585 (41%), 584 (66%), 583 (62%), Anal. for C₃₄H₂₃N₃O₇ (585.56), C, 69.74; H, 3.96; N, 7.18, Found: C, 69.21; H, 3.64; N, 6.84.

2.1.14. 6-(1-Cyclohexyl-5-(4-nitrophenyl)-4-phenyl-1H-imidazol-2-yl)-4,9-dimethoxy-5H-furo[3,2-g]chromen-5-one (5f)

Product 5f was separated as brown solid, yield: 73%. m.p. 186°C, IR (KBr, cm⁻¹) 1635 (C=O). ¹H-NMR (100 MHz, DMSO-d₆): δ, 1.55–1.34 (m, 10H, 5CH₂ cyclohexane); 3.11 (dd, H, CH-N cyclohexane); 3.88 (s, 6H, 2OCH₃); 6.60, 6.52 (dd, 2H, J=2.01 Hz, furan ring); 7.23–7.07 (m 9H, CH arom). 8.01 (s, 1H, H₇). MS (m/z): M⁺: 591.2 (22%), 590 (45%), 589 (48%). Anal. for C₃₄H₂₉N₃O₇ (591.61), C, 69.03; H, 4.94; N, 7.10, found: C, 68.76; H, 4.23; N, 6.76.

2.1.15. 4,9-Dimethoxy-6-(1,4-diphenyl-5-(pyridin-4-yl)-1H-imidazol-2-yl)-5H-furo[3,2-g]chromen-5-one (5g)

Product 5g was separated as orange solid, yield: 64%. m.p. 196°C, IR (KBr, cm⁻¹) 1647 (C=O). ¹H-NMR (100 MHz, DMSO-d₆): δ, 3.97 (s, 6H, 2OCH₃); 6.78, 6.52 (dd, 2H, J=2.01 Hz, furan ring); 7.00 (s, 1H, H₇) and 7.31–7.11 (m, 14H, CH arom.). ¹³C NMR (100 MHz, DMSO-d₆): δ, 175.2 (CO), 159.7, 153.0, 150.9, 148.2, 147.6, 145.7, 139.1, 137.3, 136.6, 132.7, 131.8, 129.6, 129.3, 129.2, 128.3, 127.2 124.2, 123.4, 122.5, 122.0 (aromatic C-H), 118.2 116.4, 112.4, 111.1, 105.7, 56.1 (OCH₃), 56.0 (OCH₃). MS (m/z): M⁺: 540 (12%), 464 (44%), 387 (74%), 311 (52%), 245 (73%). Anal. for C₃₃H₂₃N₃O₅ (541.55), C, 73.19; H, 4.28; N, 7.76, Found: C, 73.12; H, 4.24; N, 7.70.

2.1.16. 6-(1-Cyclohexyl-4-phenyl-5-(pyridin-4-yl)-1H-imidazol-2-yl)-4,9-dimethoxy-5H-furo[3,2-g]chromen-5-one (5h)

Product 5h was separated as brown solid, yield: 73%. m.p. 201°C, IR (KBr, cm⁻¹) 1644 (C=O). ¹H-NMR (100 MHz, DMSO-d₆): δ, 1.44–1.21 (m, 10H, 5CH₂ cyclohexane); 3.00 (dd, H, CH-N cyclohexane); 3.88 (s, 6H, 2OCH3); 6.64, 6.56 (dd, 2H, J=2.01 Hz, furan ring); 7.28–7.10 (m, 9H), 7.56 (s, 1H, H₇). MS (m/z): M⁺: 547 (9%), 546 (56%), 545 (64%). Anal. for C₃₃H₂₉N₃O₅ (547.6), C, 72.38; H, 5.34; N, 7.67, Found: C, 72.01; H, 4.82; N, 7.03.

2.2. General Procedure for the Preparation of (7a, b)

A solution of ethyl acetoacetate (1 mmol) and 7-hydroxy-5-methoxy-4-oxo-4H-chromene-6 carbaldehyde 6 (1 mmol) in dichloromethane (3 ml) was stirred, and then phenyl isocyanate/or cyclohexyl isocyanate (1 mmol) was added to the mixture. The reaction mixture was stirred for 24–36 h at room temperature. After completion of the reaction, as indicated by TLC (ethyl acetate/n-hexane, 2 : 1), the solvent was removed under vacuum, and the solid residue was washed with ether and the products 4a, b were obtained and recrystallized from ethanol.

2.2.1. 5-Acetyl-7-methoxy-10-methyl-3-phenylchromeno[6,7-g][1,3]oxazocine-2,4,8 (3H)-trione (7a)

Product 7a was separated as beige solid, yield: 55%. m.p. 215°C, IR (KBr, cm⁻¹): 1775, 1770, 1658, 1587 (4C=O). ¹HNMR (100 MHz, DMSO-d₆): δ, 2.01 (s, 3H, CH₃); 2.47 (s, 3H, COCH₃), 4.06 (s, 3H, OCH₃); 6.74 (s, 1H, CH₁₂); 7.87 (d, 1H, CH=C) and 7.31–7.11 (m, 6H, CH arom.). ¹³C NMR (100 MHz, DMSO-d₆): δ, 198.0 (CO), 181.2 (CO), 164.8 (CO), 164.1 (CO), 160.3, 157.5, 157.2, 152.6, 148.6, 134.3, 133.0, 129.2, 123.3, 121.6 (aromatic C-H), 114.2, 110.4, 108.1, 103.2, 55.2 (OCH₃), 25.4 (COCH₃), 20.1 (CH₃),. MS (m/z): M⁺: 419.10 (66.0%), 418 (43.1%), 417 (54.2%). Anal. for C₂₃H₁₇NO₇ (419.38), Calcd C, 65.87; H, 4.09; N, 3.34 found: C, 65.66; H,, 4.01; N, 3.31.

2.2.2. 5-Acetyl-3-cyclohexyl-7-methoxy-10-methylchromeno[6,7-g][1,3]oxazocine-2,4,8 (3H)-trione (7b)

Product 7b was separated as yellow solid, yield: 60%. m.p. 181°C, IR (KBr, cm⁻¹): 1759, 1720 1658 and 1639 (4C=O). ¹HNMR (100 MHz, DMSO-d₆): δ, 1.01–2.26 (10H, m, 5CH₂ of cyclohexyl); 2.46 (s, 3H, CH₃); 2.47 (s, 3H, COCH₃) 3.32 (H, s, CH–N of cyclohexyl); 4.06 (s, 3H, OCH₃) 6.03 (s, 1H, CH₁₂) and 8.23 (d, 1H, CH=C). ¹³C NMR (100 MHz, DMSO-d₆): δ, 198.1 (CO), 182.0 (CO), 164.8 (CO), 164.1 (CO), 159.8, 157.5, 157.2, 155.2, 146.5, 133.8 (aromatic C-H), 111.1, 110.6, 108.0, 103.0, 55.9 (OCH₃), 30.8 (COCH₃), 28.1, 25.7, 23.0 (CH₂), 21.0 (CH₃). MS (m/z): M⁺: 425.11 (33.0%), 424 (65.1%), 423 (45.5%). Anal. for C₂₃H₂₃NO₇ (425.43), Calcd C, 64.93; H, 5.45; N, 3.29, Found C, 64.23; H, 5.15; N, 3.21.

2.3. Determination of Anticancer Activities

2.3.1. Cell Lines

For anticancer activity screening of the newly synthesized compounds, liver HepG2 and breast MCF-7 cell lines as well as the normal cell line (human normal melanocyte, HFB4) were obtained from National Cancer Institute, Cairo University. The cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM) enhanced with 10% warm inactivated fetal calf serum (GIBCO), penicillin (100 U/ml), and streptomycin (100 μg/ml) at 37°C in humidified air containing 5% CO₂. Cells at a concentration of 0.50 × 10⁶ were grown in a 25 cm² flask in 5 ml of culture medium.

2.3.2. Cell Viability

(1) Fast Screening. Cells were seeded in 96 wells plates. The newly synthesized compounds were applied on the two cell lines to test their anticancer activity. The compounds were tested in two distinct concentrations (0.05 μg/ml and 5 μg/ml). The two working solutions were prepared using the complete medium. Three technical replicates were carried out for each concentration. The treated cells were incubated for 48 h at 37°C and 5% CO₂. Afterwards, cell viability was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). The comparison was performed between the treated cells to the positive control (reference drugs) and the negative control (DMEM). The tests were performed in biological replicates.

(2) IC₅₀ Determination. Cells were seeded in 96-well plates. The synthesized compounds that showed a significant reduction in the cell viability were chosen for further analysis. Each compound was tested on the two cell lines in 4 different concentrations (5, 12.5, 25, and 50 μg/ml). The working solutions were prepared using the complete medium. Three technical replicates were performed for each concentration. The treated cells were incubated for 48 h at 37°C and 5% CO₂. The viability of the cells was determined using MTT test. IC₅₀ (50% inhibitory concentration) values were calculated with a four-parameter logistic function and presented in a mean. The test was performed in biological replicates.

2.3.3. MTT Assay

The cells were washed with 50 μL of PBS and then the PBS was discarded [30]. Afterwards, 50 μL of MTT working solution was applied to each well and the cells were incubated for 15–30 min at 37°C and 5% CO₂. The cells were examined microscopically for formazan (black precipitate) development. The supernatant was discarded from each well and the formazan was dissolved using DMSO. The absorbance of the developed color was measured using an automated plate reader at 570 nm with a background wavelength of 670 nm. The results were presented in percentage to the values obtained from untreated cells (negative control).

2.4. Molecular Docking Studies

Promising biological evaluation of new furochromone and oxazocine derivatives 4a–h, 5a–h, and 7a, b encourages us to study their interaction mechanism into the active site of EGFR (PDB ID: 5CAV) by molecular docking technique [31] using MOE 2008.10 program.

2.4.1. Preparation of Receptor

Binding sites were generated from co-crystallized ligand within crystal protein (PDB codes: 5CAV). Water molecules were removed from the complex. Then, the crystallographic disorders and protein energy was minimized by applying CHARMM and MMFF94 force fields. By applying fixed atom constraint, the rigid binding site of protein structure was obtained. The protein essential amino acids are defined and prepared for docking process. 2D structures of tested compounds were drawn using Chem. Bio. Draw Ultra14. 3D structures were protonated, and energy was minimized by applying 0.05 RMSD kcal/mol. CHARMM force field. Then, the minimized structures were prepared for docking using prepared ligand protocol [32].

2.4.2. Molecular Docking Process

Docking process was carried out using CDOCKER protocol, by employing CHARMM-based molecular dynamics (MD) scheme to dock ligands into a receptor binding site. The receptor was held rigid while the ligands were allowed to be flexible during the refinement, where each molecule was allowed to produce seven different interaction poses with the protein and then docking scores (CDOCKER interaction energy) of the best-fitted poses with the active site at (EGFR, PDB codes: 5CAV).

We use all the mentioned processes to predict the proposed binding mode affinity, preferred orientation of each docking pose, and binding free energy (∆G) of the tested compounds with EGFR. The calculated interaction energies for the tested compounds were in complete agreement with experimental results which showed that our compounds are potent inhibitors against EGFR.

3. Results and Discussion

3.1. Chemistry

Highly substituted chromone derivatives 4a–h and 5a–h were synthesized via a one-pot, four-component reaction of aniline, furochromone carbaldehyde 1, acid derivatives 3a–d, namely, benzoic acid/or 4-amino-, 4-nitrobenzoic acid/or nicotinic acid, and phenyl isocyanate/or cyclohexyl isocyanate (Scheme 1). The structures of 4a–h were elucidated from their elemental and spectroscopic analyses (IR, ¹H NMR, and ¹³C NMR) together with mass spectra which prove the structures via getting molecular ion peaks at appropriate m/z values. ¹H NMR spectra of 4a as example revealed characteristic doublet peaks for furan ring protons at δ = 6.22, 6.60 ppm, while aromatic protons appeared at 7.00–7.31 ppm as multiples. ¹³C NMR spectrum of 4a showed 26 distinct resonances characteristic for carbon atoms 55.0 (OCH₃), 54.5 (OCH₃), 176.2 (CO), and 173.7 (CO) ppm. IR spectra of 4a–h showed disappearance of the aldehydic group.

The mechanism of the formation of compounds 4a–h is depicted in Scheme 2. Intermediate (A) in situ is formed between acid and isocyanate. Also, nucleophilic attack of amine toward the most active site of aldehydic carbon afforded the amine intermediate (B). Intermediate (A) attacks intermediate (B) to form oxadiazine ring (D) over expulsion of carbon dioxide molecule with rearrangement to afford the desired products 4a–h (Scheme 2).

In the same manner, furochromone carbaldehyde 1 reacted in one-pot reaction at room temperature in methanol with beneylamine together with isocyanate derivatives 2a, b with benzoic acid derivatives 3a–d to give imidazole derivatives of furochromone 5a–h in a good yield (Scheme 3). The structures of the novel compounds are elucidated via elemental and spectroscopic analysis (cf. Experimental). IR spectra showed disappearance of the aldehydic group. The ¹³C NMR spectrum of 5a showed 21 distinct resonances characteristic for carbon atoms.

The mechanism of formation of compounds 5a–h is cited in Scheme 4, and it revealed similarity with formation mechanism of compounds 4a–h with cyclization of intermediate due to expulsion of water and carbon dioxide molecules to give the final products (Scheme 4).

Synthesis of new derivatives of oxazocine 7a, b at one-pot three-component reaction is studied. Visnagine carbaldehyde 6, ethyl acetoacetate, and isocyanate derivatives 2a, b under mild conditions to afford derivatives 7a, b in a good yield (Scheme 5). The structures of new compounds 7a, b were confirmed based on analytical and spectral data. IR spectra showed disappearance of the characteristic band of (CHO) group and it exhibited 4C=O groups. ¹HNMR (DMSO-d₆) spectra of compounds (7a, b) showed a doublet around δ7.87, 8.23 ppm, respectively, for CH=C group. ¹³C-NMR for compound 7a as example was showed 21 signals characteristic for carbon atoms 198.0 (CO), 181.2 (CO), 164.8 (C0), 164.1 (CO) 55.2 (OCH₃), 25.4 (COCH₃), and 20.1 (CH₃).

3.2. Antitumor Activity

It has been proved that chromones have various kinds of biological activities, including antitumor, antimicrobial, antiviral, anti-inflammatory, antioxidant, and so on. Cytotoxicity refers to cell death, cell lysis, and the inhibition on cell proliferation induced by some substances. In vitro, most of chromones’s cytotoxicity against tumor cells has been tested to confirm their antitumor activity. Cell toxicity is generally evaluated using the MTT (microculture tetrazolium) or SRB (sulforhodamine B) assay. Chromones demonstrate cell toxicity against a quantity of cell lines from a great variety of tumors, including cervical epithelioid carcinoma, breast adenocarcinoma [33], hepatoma carcinoma, lung cancer, leukemia cancer, and colon cancer [34, 35].

3.2.1. Cell Viability

(1) Fast Screening. Quick screening was performed to determine the newly synthesized derivatives which demonstrated a significant reduction in the cell viabilities against the two cell lines: hepatocellular carcinoma (HepG2) and breast carcinoma (MCF7). The impact of the newly derivatives on the breast carcinoma cell line (MCF7) after 48 hrs, as an example, is illustrated in (Figure 1).

Most of the compounds exhibited a distinct reduction in the cell viability of at least one of the two cell lines. Therefore, all the compounds were further analyzed to determine their IC₅₀ values.

(2) IC₅₀ Determination. The data calculated as the concentration of the tested samples needed to inhibit half of the cancer cells population IC₅₀ values were calculated for each compound separately and, mean values ± SD are presented Table 1.

The results stated in Table 1 reveal that many compounds showed good antiproliferative activity against breast cancer cell line (MCF7) with no toxicity on normal cell line. According to National Cancer Institute guidelines, the compound with an IC₅₀ value < 30 μg/mL is active [36]. Therefore, as almost all compounds showed inhibition of cell growth, all the compounds were further analyzed to determine their IC₅₀. MTT test for the investigated compounds showed that most of them expressed the IC₅₀ ranging from 18 to 64 μg/ml compared with the standard drugs in used range of concentration, and they have low toxicity on the normal cell line (Table 1). From the all tested derivatives on these two cancer cell lines, compound 5a–h had the lowest IC₅₀ ranging from 18–26 μg/ml against breast carcinoma cell line (MCF7) (Figure 2).

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

The abovementioned results showed that different cell lines varied greatly in their response against different synthesized compounds. This correlates well with previously reported results [37, 38], where this can be attributed to the inherent different cells in their specific membrane structure and organization.

3.3. Molecular Docking Studies

3.3.1. Reference Ligand and Docking in EGFR Domain

The binding mode of 4ZQ exhibits an energy binding of −24.81, for RMSD (1.67). 4ZQ formed a hydrogen bond with H-bond with (Lys 745) at bond distance 3.13°A, (Met 793) at bond distance of 2.95°A and (Thr 854) at 2.79°A. Docking results of the newly synthesized compounds 4a–h, 5a–h, and 7a, b which docked with EGFR protein (PDB ID: 5CAV) active site (Table 2).

The results revealed that compounds 5a–h showed better docking score ranging from −30.07 to −25.15 kJ/mol, compared to the co-crystallized ligand (4QZ) of −24.81 kJ/mol and root-mean-square deviation value of 1.67 (Table 2). Also, compounds 5a–h showed good binding interaction to the protein active site via formation of hydrogen bonds with the same amino acid residue (Lys 745) as the co-crystalline ligand (Table 2). The results of anticancer activity and docking studies for compounds 5c and 5e were compatible. Compounds 5c and 5e showed potent anticancer activity against MCF-7 cell line (IC₅₀ value 19 and 18 μg/ml) compared to reference drug 5-fluorouracil (IC₅₀ 13 μg/ml), and also exhibited better docking score (−30.07 and −26.11 kJ/mol) and good binding interaction via formation of one hydrogen bond with amino acid residue Lys 745 (2.59 Å and 3.43 Å) and Pi interaction with amino acid residue Phe 723 compared to co-crystallized ligand of docking score −24.81 kJ/mol and three hydrogen bonds with Lys 745, Met 793, and Thr 854 (Figures 3–5).

(a)

(b)

(a)

(b)

(a)

(b)

4. Conclusion

The newly synthesized furochromone and oxazocine derivatives seemed to be preferred for pharmaceutical studies. The results obtained from the synthesized compounds showed reasonable medical indices especially potent activities and, besides this, their lower possible side effects due to no or weak action on normal cell lines. Compounds 5a–h exhibited good antiproliferative potency against breast cancer cell line with week or no effect on normal cell lines. Their activities exceeded the tested standard drugs themselves. These findings may be used to design more effective and less harmful derivatives as potential anticancer agents.

The binding mode of the newly synthesized compounds 4a–h, 5a–h, and 7a, b was assessed by docking with the active site of EGFR protein (PDB ID: 5CAV). Our results exhibited that compounds 5c and 5e demonstrated better binding energy (−30.07 and −26.11 kJ/mol) and good fitting inside the active site of the protein molecular surface in comparison with the co-crystallized ligand, which agrees well with the biological results. In this way, they may be viewed as great inhibitors of EGFR protein and consequently have a high anticancer activity.

Data Availability

The data supporting the findings of the study are already given within the article.

Conflicts of Interest

The author declares no conflicts of interest.

Acknowledgments

The author would like to appreciate Jazan University. The author also thanks Prof. Magdy Sayed Aly for carrying out the biological activity of this work at Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt. The author would also like to thank Dr. Heba M. Abo-Salem, National Research Centre, Dokki, Cairo, Egypt, for performing molecular design.

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Copyright © 2020 Rita M. Borik. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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