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Synthesis of 2,6-Diaryl-4-Indolylpyridines as Novel 5-LOX Inhibitors

Berihu Tekluu1, Sunanda Kumari Kadiri2 and Siddaiah Vidavalur1*

1Department of Organic Chemistry and FDW, College of Science and Technology, Andhra University, Visakhapatnam, Andhra Pradesh, India

2Department of Microbiology, College of Science and Technology, Andhra University, Visakhapatnam, Andhra Pradesh, India

*Corresponding Author:
Siddaiah Vidavalur
Department of Organic Chemistry and FDW
College of Science and Technology
Andhra University, Visakhapatnam
Andhra Pradesh, India
Tel: 089128 44000
E-mail: [email protected]

Received Date: May 24, 2017 Accepted Date: May 27, 2017 Published Date: May 31, 2017

Citation: Tekluu B, Kadiri SK, Vidavalur S (2017) Synthesis of 2,6-Diaryl-4- Indolylpyridines as Novel 5-LOX Inhibitors. Med Chem (Los Angeles) 7: 894-899. doi: 10.4172/2161-0444.1000449

Copyright: © 2017 Tekluu B, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

A series of 2,6-diaryl substituted -4-indolylpyridines have been synthesized from indole-3-carboxaldehyde and acetophenones and all the compounds characterized by spectroscopic techniques. 5-Lipoxygenase enzyme inhibitory activities were performed for all the compounds. Among the 2, 6-diaryl substituted -4-indolylpyridine derivatives 3ad and 3aa showed good activity.

Keywords

Indolylpyridine; 5-LOX; Indole-3-carboxaldehyde

Introduction

3-Substituted indole is a privileged structural motif found in many biologically active compounds and natural products [1]. 3-Substituted indole derivatives exhibit several biological activities such as antibacterial [2-6], anti-inflammatory [7-10], antitumor [11- 13], anticancer [14-18], anti-hypertensive [19], anti-depressant [20,21] and antiviral [22-25] activities. On the other hand, the molecules having pyridine nucleus possess a large spectrum of biological activities like anti-prion [26], anti-hepatitis B virus [27], antibacterial [28], anticancer [29] and antimalarial [30] activities. Therefore, the combined molecules of 3-Substituted indole and pyridine frame works, indolylpyridines, are the valuable starting material for the synthesis of structurally diverse biologically active agents. Indolylpyridines have been reported to exhibit several biological activities such as anti-cancer and anti-inflammatory activities [31,32]. However, 5-lipoxygenase enzyme inhibitory activity (5-LOX) of indolylpyridines has not been fully explored. 5-Lipoxygenase is the key enzyme for the biosynthesis of leukotrienes, the important mediators for inflammatory, allergic, and obstructive processes. 5-LOX inhibitors have potential in treating asthma and various inflammatory disorders [33,34]. Therefore, herein we report the synthesis of a series of 2,6-diaryl-4-indolylpyridines from substituted acetophenones and 1H-indole-3-carbaldehydes using ammonium acetate as a nitrogen source in the presence of acetic acid and 5-LOX activities of several 2, 6-diaryl-4-indolylpyridines.

Experimental Section

General

All the chemicals used were of synthetic grade procured from Sigma Aldrich. Completion of the reactions was monitored by analytical thin layer chromatography (TLC) using E-Merck 0.25 mm silica gel plates using ethyl acetate/hexane as solvent system, visualization was accomplished with UV light (256 nm) and iodine chamber. Synthesized compounds were purified by column chromatography (silica gel 100- 200 mesh) using a mixture of hexane and ethyl acetate. Melting points were measured in open capillary tubes and were uncorrected; all the 1H and 13C spectra were recorded in CDCl3 solvent (400 MHz for 1H and 100 MHz for 13C) relative to TMS internal standard, proton coupling patterns were described as singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m). The electron ionization mass spectra were recorded on Agilent 1100.

General experimental procedure for the synthesis of 1H-indole-3-carboxaldehydes (1a or 1b)

To a solution of substituted indole (42.6 mmol) (or 5-bromo indole) in dry DMF (187.4 mmol) in an ice-salt bath, POCl3 (47.1 mmol) was subsequently added with stirring over a period of 30 min. After completion of addition, the temperature was raised to 40°C, the syrup was stirred for 1.5 h at same temperature. At the end of the reaction (as indicated by TLC) 25 gms crushed ice was added to the reaction mixture. The obtained solution was transferred into 250 mL RB flask, NaOH (470 mmol) dissolved in 50 mL water was added with constant stirring and the resultant suspension was heated rapidly to the boiling point and allowed to cool to room temperature. The mixture was allowed to stand in refrigerator overnight. The precipitate was filtered off, washed thrice with 100 mL water, yielding 1H-indole-3-carboxaldehydes (1a or 1b).

1H-Indole-3-carboxaldehyde (1a): Brownish yellow solid, Yield: 92%, Mp: 196-198°C, 1H NMR (DMSO-d6, 400 MHz): δ=9.52 (s, 1H), 8.12 (s, 1H), 7.62 (d, 1H), 7.52 (s, 1H), 7.34 (d, 1H), 7.22 (t, 1H), 7.14 (t, 1H). 13C NMR (DMSO-d6, 100 MHz): δ=1882.7, 137.2, 131.82, 127.7, 122.4, 120.5, 119.4, 118.0, 111.4.

Bromo-1H-indole-3-carboxaldehyde (1b): Cream coloured solid, Yield: 90%, Mp: 192°C, 1H NMR (DMSO-d6, 400 MHz): δ=9.94 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.75 (s, 1H), 7.43 (d, 1H), 7.34 (d, 1H). 13C NMR (DMSO-d6, 100 MHz): δ=183.9, 144.4, 136.7, 135.2, 125.6, 123.1, 117.3, 114.8, 113.0.

General experimental procedure for synthesis of 2,6-diaryl- 4-indolylpyridines

A mixture of 1H-indole-3-carboxaldehyde (1) (1.0 mmol) and acetophenone (2) (2.0 mmol) in the presence of AcONH4 (5 mol%) and acetic acid was heated in an oil bath at reflux for about 5 h. After the completion of the reaction (as monitored by TLC), the reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulphate and concentrated under vacuum to afford the crude compound. The crude compound was purified with silica gel column chromatography using hexane/EtOAc as eluents to afford the pure product (3) (Supplementary Figures 1-18).

Characterization of 2,6-diaryl-4-indolylpyridines

3-(2,6-di (Phenylpyridin-4-yl)-1H-indole (3aa): Colorless solid, Yield: 80%, Mp: 178-180°C, 1H NMR (400 MHz, CDCl3): δ=8.71 (d, 1H), 8.23 (d, 4H), 8.08 (d, 1H), 7.99 (s, 2H), 7.60 (d, 1H), 7.55 (m, 4H), 7.48 (d, 3H), 7.31 (t, 2H). 13C NMR (100 MHz, CDCl3): δ=157.3, 145.1, 139.6, 136.9, 129.0, 128.7, 127.2, 125.3, 123.6, 122.9, 121.1, 119.6, 117.1, 116.0, 111.9. HRMS (ESI): m/z [M+H]+ calcd for C25H18N2: found: 347.2.

3-[2,6-di(p-Tolyl)pyridin-4-yl]-1H-indole (3ab): Colorless solid, Yield: 75%, Mp: 218–220°C, 1H NMR (400 MHz, CDCl3): δ=8.63 (d, 1H), 8.24 (d, 4H), 7.91 (d, 1H), 7.82 (d, 1H), 7.35 (s, 2H), 7.28 (d, 4H), 7.22 (d, 1H), 7.16 (t, 2H), 2.3 (d, 6H). 13C NMR (100 MHz, CDCl3): δ=155.6, 144.5, 138.3, 135.5, 135.3, 129.0, 128.1, 126.6, 126.0, 124.5, 120.0, 116.9, 115.5, 112.3, 111.0, 21.3. HRMS (ESI): m/z [M+H]+ calcd for C27H22N2: found: 375.8.

3-[2,6-bis(4-Methoxyphenyl)pyridin-4-yl]-1H-indole (3ac): Colorless solid, Yield: 80%, Mp: 230–232°C, 1H NMR (400 MHz, CDCl3): δ=8.65 (d, 1H), 8.25 (d, 4H), 7.94 (d, 1H), 7.86 (d, 1H), 7.39 (s, 2H), 7.29 (d, 4H), 7.25 (d, 1H), 7.18 (t, 2H), 3.8 (s, 6H). 13C NMR (100 MHz, CDCl3): δ=156.2, 144.1, 137.6, 135.2, 134.9, 130.6, 128.5, 126.8, 125.1, 122.8, 119.6, 115.5, 114.9, 112.7, 111.2, 55.8. HRMS (ESI): m/z [M+H]+ calcd for C27H22N2O2: found: 407.8.

3-[2,6-bis(4-Chlorophenyl)pyridin-4-yl]-1H-indole (3ad): White solid, Yield: 84%, Mp: 186-188°C, 1H NMR (400 MHz, CDCl3): δ=8.61 (d, 1H), 8.21 (d, 4H), 7.93 (d, 1H), 7.88 (d, 1H), 7.40 (s, 2H), 7.32 (d, 4H), 7.29 (d, 1H), 7.21 (t, 2H). 13C NMR (100 MHz, CDCl3): δ=155.8, 144.5, 138.2, 135.4, 135.2, 128.9, 128.3, 126.9, 126.0, 124.2, 120.1, 116.9, 115.8, 112.5, 111.2. HRMS (ESI): m/z [M+H]+ calcd for C25H16N2Cl2: found: 416. 7.

3-[2,6-bis(4-Bromophenyl)pyridin-4-yl]-1H-indole (3ae): Colorless solid, Yield: 82%, Mp: 216–217°C, 1H NMR (400 MHz, CDCl3): δ=8.58 (d, 1H), 8.07 (d, 4H); 7.86 (d, 1H) 7.59 (d, 4H), 7.52 (s, 2H), 7.45 (d, 1H) 7.39 (d, 1H), 7.21 (t, 2H). 13C NMR (100 MHz, CDCl3): δ=156.6, 144.7, 138.6, 134.6, 130.8, 129.1, 125.8, 124.2, 122.8, 119.7, 119.1, 117.3, 118.5, 115.5, 113.4. HRMS (ESI): m/z [M+H]+ calcd for C25H161N2Br2: found: 505.7.

3-(2,6-bis(4-Fluorophenyl)pyridin-4-yl)-1H-indole (3af): White Solid, Yield: 75%, Mp: 175-177°C, 1H NMR (400 MHz, CDCl3): δ=8.51 (d, 1H), 8.22 (d, 4H), 8.19 (d, 1H), 7.95 (s, 2H), 7.65 (d, 1H), 7.52 (d, 1H), 7.33 (t, 2H), 7.29 (d, 4H). 13C NMR (100 MHz, CDCl3): δ=164.8, 156.4, 145.0, 136.8, 135.9, 128.9, 125.2, 123.3, 121.2, 119.6, 116.6, 116.1, 115.7, 115.4, 111.8. HRMS (ESI): m/z [M+H]+ calcd for C25H16N2F2: found: 383.

3-[2,6-di(Pyridin-4-yl)pyridin-4-yl]-1H-indole (3ag): Colorless solid, Yield: 63%, Mp: 378–380°C, 1H NMR (400 MHz, CDCl3): δ=9.24 (d, 1H), 8.77 (d, 4H), 8.42 (d, 4H), 8.40 (s, 2H), 7.93 (s, 1H), 7.61 (d, 1H), 7.50 (m, 1H), 7.22 (m, 2H).13C NMR (100 MHz, CDCl3): δ=155.5, 151.1, 146.4, 145.8, 137.2, 129.7, 127.0, 122.3, 121.1, 120.4, 119.1, 118.1, 113.0, 102.8. HRMS (ESI): m/z [M+H]+ calcd for C23H16N4: found: 349.8.

3-[2,6-di(Furan-2-yl)pyridin-4-yl]-1H-indole(3ah): White solid, Yield: 80%, Mp:153–155°C, 1H NMR (400 MHz, CDCl3): δ=9.38 (d, 1H); 8.15 (m, 1H); 7.90 (s, 2H); 7.62 (s, 1H); 7.56 (m, 2H); 7.45 (m, 1H); 7.30 (m, 2H); 7.21 (d, 2H); 6.56 (m, 2H). 13C NMR (100 MHz, CDCl3): δ=158.9, 156.3, 148.0, 142.3, 135.5, 131.3, 128.2, 122.2, 120.2, 119.4, 118.5, 111.3, 108.1, 105.3, 102.3. HRMS (ESI): m/z [M+H]+ calcd for C21H14N2O2: found: 327.6.

2-[2,6-di(Thiophen-2-yl)pyridin-4-yl]-1H-indole(3ai): Colorless solid, Yield: 70%, Mp: 169–171°C, 1H NMR (400 MHz, CDCl3): δ=9.12 (d, 1H), 8.19 (s, 1H), 8.07 (s, 2H), 7.54 (d, 1H), 7.49 (d, 1H), 7.32 (d, 2H), 7.23 (m, 1H), 7.15 (m, 5H). 13CNMR (100 MHz, CDCl3): δ=152.2, 146.2, 137.4, 135.1, 129.9, 128.7, 128.3, 126.3, 122.9, 121.1, 119.2, 118.7, 111.6, 101.8. HRMS (ESI): m/z [M+H]+ calcd for C21H14N2S2: found: 359. 7.

5-Bromo-3-(2,6-di(Phenylpyridin-4-yl))-1H-indole (3ba): White Solid, Yield: 72%, Mp: 185-187°C, 1H NMR (400 MHz, CDCl3): δ=8.68 (d, 1H), 8.23 (d, 4H), 8.14 (s, 1H), 7.90 (s, 2H), 7.59 (t, 4H), 7.51 (d, 3H), 7.39 (t, 1H), 7.28 (t, 1H).13C NMR (100 MHz, CDCl3): δ=157.6, 144.2, 139.8, 135.4, 129.0, 128.7, 127.2, 127.0, 125.9, 124.4, 122.2, 117.1, 115.9, 114.4, 113.2. HRMS (ESI): m/z [M+H]+ calcd for C25H17N2Br2: found: 426.9.

3-(2,6-bis(4-Methoxyphenyl)pyridin-4-yl)-5-bromo-1Hindole( 3bc): Colorless solid, Yield: 80% Mp: 230–232°C, 1H NMR (400 MHz, CDCl3): δ=8.64 (d, 1H), 8.26 (d, 4H); 7.92 (s, 1H), 7.86 (s, 2H), 7.31 (d, 2H), 7.29 (d, 1H), 7.17 (d, 4H), 3.7 (s, 6H). 13C NMR (100 MHz, CDCl3): δ=156.7, 144.3, 138.2, 135.6, 135.0, 130.6, 129.1, 126.9, 125.4, 123.2, 119.6, 115.8, 115.1, 112.8, 111.5, 55.8. HRMS (ESI): m/z [M+H]+ calcd for C27H21N2O2: found: 486.8.

3-(2,6-bis(4-Chlorophenyl)pyridin-4-yl)-5-bromo-1Hindole( 3bd): White Solid, Yield: 81%, mp 120-122°C, 1H NMR (400 MHz, CDCl3): δ=8.64 (d, 1H), 8.14 (d, 4H), 8.11- 8.09 (s, 1H), 7.85 (s, 2H), 7.57 (d, 1H), 7.42 (d, 4H), 7.40 (d, 2H). 13C NMR (100 MHz, CDCl3): δ=156.4, 144.5, 137.9, 135.4, 135.2, 128.9, 128.3, 126.9, 126.0, 124.4, 122.1, 116.9, 115.6, 114.5, 113.2. HRMS (ESI): m/z [M+H]+ calcd for C25H15N2Cl2Br: found: 494.8.

3-(2,6-bis(4-Bromophenyl)pyridin-4-yl)-5-bromo-1H-indole (3be): White Solid, Yield: 83%, Mp: 225-227°C, 1H NMR (400 MHz, CDCl3): δ=8.57 (d, 1H), 8.10 (d, 4H), 8.05 (s, 1H), 7.87 (s, 2H), 7.67 (d, 4H), 7.59 (d, 1H), 7.43 (d, 1H), 7.41 (d, 1H). 13C NMR (100 MHz, CDCl3): δ=156.5, 144.5, 138.3, 135.4, 131.9, 128.6, 126.9, 126.1, 124.4, 123.6, 122.1, 117.0, 115.7, 114.5, 113.2. HRMS (ESI): m/z [M+H]+ calcd for C25H15N2Br3: found: 584.5.

3-(2,6-bis(4-Fluorophenyl)pyridin-4-yl)-5-bromo-1H-indole (3bf): White Solid, Yield: 73%, Mp: 219-221°C, 1H NMR (400 MHz, CDCl3): δ=8.59 (d, 1H), 8.21 (d, 4H), 8.18 (s, 1H), 7.85 (s, 2H), 7.61 (d, 1H), 7.43 (d, 2H), 7.25 (d, 4H). 13C NMR (100 MHz, CDCl3): δ=164.8, 156.5, 144.4, 135.7, 135.4, 128.9, 126.9, 126.0, 124.3, 122.1, 116.6, 115.9, 115.7, 114.5, 113.2. HRMS (ESI): m/z [M+H]+ calcd for C25H15N2BrF2: found: 462.8.

General experimental procedure for biological activity

5-Lipoxygenase enzyme inhibitory activity: The indolylpyridines were screened for their 5-LOX inhibitory potential using colorimetric method. The assay mixture contained 50 mM phosphate buffer, pH 6.3, 5-lipoxygenase, various concentrations of test substances in dimethylsulfoxide, and linoleic acid (80 mM) in a total volume of 0.5 mL, after 5 min incubation of the above reaction mixture, 0.5 mL ferric xylenol orange reagent (in perchloric acid) was added and absorbance was measured after two minutes at 585 nm on a spectrophotometer. Controls were run along with test in a similar manner, except using vehicle instead of test substance solution. Percent inhibition was calculated by comparing the absorbance values of the test solution with that of control. All the tests were run in triplicate and averaged.

Result and Discussion

Chemistry

1H-Indole-3-carboxaldehyde and 5-bromo-1H-indole-3- carboxaldehyde were prepared from indole using phosphorus oxychloride in DMF. The general synthesis of 2,6-diaryl-4- indolylpyridines (3aa-3bf) is illustrated in Scheme 1. The reaction of indole-3-carboxaldehyde (1a-b) with substituted acetophenones (2a-i) in the presence of ammonium acetate in acetic acid at reflux conditions furnished 2,6-diaryl-4-indolylpyridines (3aa-3bf) in 63-84% yield. Based on this protocol we have prepared 14 derivatives of and all the compounds were purified by column chromatography on silica gel. The chemical structures of the target compounds were confirmed by 1H NMR, 13C NMR, and MS spectra (Table 1).

medicinal-chemistry-indolylpyridines

Scheme 1: Synthesis of substituted 2, 6-diaryl-4-indolylpyridines.

Entry indole ketone product Yield (%) b
1 equation equation equation 80
2 1a equation equation 75
3 1a equation equation 80
4 1a equation equation 84
5 1a equation equation 82
6 1a equation equation 75
7 1a equation equation 63
8 1a equation equation 80
9 1a equation equation 70
10 equation 2a equation 72
11 1b 2c equation 81
12 1b 2d equation 80
13 1b 2e equation 83
14 1b 2f equation 73

Table 1: Synthesis of 2,6-diaryl-4-indolylpyridinesb.

Biological activity

5-Lipoxnase enzyme inhibitory activity: All the synthesized 2,6-diaryl-4-indolylpyridines (3aa-3bf) were screened for their 5-lipoxygenase enzyme inhibitory activity using colorimetric method [35] at different concentrations and found to have significant 5-LOX inhibitory activity with IC50 range 14.40 to 32.78 μg/ml (Table 2). Among all the compounds chloro substituted 2,6-diaryl-4- indolylpyridine (3ad) (IC50; 14.40 μg/ml) and unsubstituted 2,6-diaryl- 4-indolylpyridine (3aa) (IC50; 17.40 μg/ml) showed very good activity whereas the compounds 3bd, 3ba, 3bc, 3be, 3ae, 3bf, 3ab and 3ac showed moderate activity. The compounds 3ag, 3ai and 3ah showed the least activity. In conclusion, we have synthesized a series of 2,6-diaryl substituted -4-indolylpyridine derivatives using commercially available starting materials. 5-Lipoxygenase (5-LOX) enzyme inhibitory activities were performed for all the synthesized compounds. Among the tested compounds 3ad and 3aa showed good 5-lipoxygenase enzyme inhibitory activity.

Entry Compound Test items IC50 µM
1 3aa LNO-17-0001 17.40
2 3ab LNO-17-0002 32.95
3 3ac LNO-17-0003 33.14
4 3ad LNO-17-0004 14.40
5 3ae LNO-17-0005 29.94
6 3af LNO-17-0006 >100
7 3ag LNO-17-0007 34.56
8 3ah LNO-17-0008 42.62
9 3ai LNO-17-0009 38.65
10 3ba LNO-17-0010 24.83
11 3bc LNO-17-0011 25.21
12 3bd LNO-17-0012 21.05
13 3be LNO-17-0013 25.78
14 3bf LNO-17-0014 32.78
Standard * 36.49

Table 2: IC50 values obtained from in vitro 5-lipoxygenase inhibition assay for the compounds (3aa–3bf).

Acknowledgement

The authors thank CSIR, New Delhi for financial assistance (through a project 02(0197)/14/EMR-II) and the Ministry of Education, Ethiopia, for financial support to B. T. G.

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