6-کلرو-3-نیترو-4-هیدروکسی کینولین-2-(H1)-اون به عنوان یک عامل ضدباکتری کارا و قابل مقایسه
Subject Areas : Biotechnological Journal of Environmental MicrobiologyEnayatollah Moradi Rufchahi 1 *
1 - گروه شیمی، دانشکده علوم پایه ، واحد لاهیجان ، دانشگاه آزاد اسلامی، لاهیجان ایران
Keywords: 4-هیدروکسی کینولین-2-(H1)-اون, نیترودارکردن, اسپکتروسکوپی, خواص ضدباکتری,
Abstract :
در این مطالعه ابتدا 4-کلرو آنیلین در اثر واکنش با دی اتیل مالونات به دی آنیلید مربوطه تبدیل و سپس در دمای 140 تا 150 درجه سانتیگراد از طریق حلقه زایی در پلی فسفریک اسید مذاب به 6 -کلرو-4-هیدروکسی کینولین-2-(H1)-اون تبدیل شد. 6 -کلرو-3-نیترو-4-هیدروکسی کینولین-2-(H1)-اون با موفقیت از 6-کلرو--4-هیدروکسی کینولین-2-(H1)-اون از طریق واکنش نیترودارشدن شناخته شده سنتز شد. ترکیبات سنتز شده از طریق نوبلور کردن در دی متیل فرمامید خالص سازی شدند. این ترکیب از طریق روش های طیف سنجی مادون قرمز و رزونانس مغناطیسی هسته پروتون شناسایی و تعیین ساختار شد. سپس فعالیت ضدباکتری این ترکیب در حلال دی متیل سولفوکسید به روش چاهک در مقابل چهار باکتری استافیلوکوکوس اورئوس، اشیرشیا کولی، پروتیوس ولگاریس و لیستریا مونوسیتوژنز مورد بررسی قرار گرفت. نتایج نشان دادند که ترکیب مورد نظر فعالیت ضد باکتری قابل قبولی در مقایسه با داروی شناخته شده جنتا مایسین از خود نشان می دهد.
F. O’Donnell, T.J.P. Smyth, V.N. Ramachandran, W.F. Smyth, a study of the antimicrobial activity of selected synthetic and naturally occurring quinolones. Int. J. Antimicrob. Agents 35 (2010) 30-38.
[2] M. M. Abdou, Chemistry of 4-Hydroxy-2(1H)-quinolone. Part 1: Synthesis and reactions Arabian Journal of Chemistry 10 (2017), S3324–S3337, http://dx.doi.org/10.1016/j.arabjc.2014.01.012.
[3] G.S. Bisacch, Origins of the quinolone class of antibacterials: an expanded “discovery story”. J. Med. Chem. 58 (2015) 4874–4882, https ://doi.org/10.1021/jm501 881c.
[4] J.P. Michael, Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 20 (2003) 476-493.
[5] A. A. Aly, E. M. El‑Sheref, A.‑F. E. Mourad, M. E. M. Bakheet, S. Bräse, 4‑Hydroxy‑2‑quinolones: syntheses, reactions and fused heterocycles. Molecular Diversity 24 (2020) 477-524, https://doi.org/10.1007/s11030-019-09952-5.
[6] M. D. Ferretti, A. T. Neto, A. F. Morel, T. S. Kaufman, E. L. Larghi, Synthesis of symmetrically substituted 3,3-dibenzyl-4-hydroxy-3,4- dihydro-1H-quinolin-2-ones, as novel quinoline derivatives with antibacterial activityEuropean Journal of Medicinal Chemistry 81 (2014) 253-266.
[7] V. Dolle, E. Fan, C. H. Nguyen, A.M. Aubertin, A. Kirn, M.L. Andreola, G. Jamieson, L.T. Litvak, E. Bisagni, Journal of Medicinal Chemistry 38 (1995) 4679-4686, https://doi.org/10.1021/jm00023a007.
[8] D. Audisio, S. Messaoudi, J.F. Peyrat, J.D. Brion, M. Alami, L. Cegielkowski, D. Methy-Gonnot, C. Radanyi, J. M. Renoir, Discovery and Biological Activity of 6BrCaQ as an Inhibitor of the Hsp90 Protein Folding Machinery. Chem Med Chem 6 (2011) 804-815, https://doi.org/10.1002/cmdc.201000489.
[9] S.X. Cai, Z.L. Zhou, J.C. Huang, E.R. Whittemore, Z.O. Egbuwoku, J.E. Egbuwoku, J.E. Hawkinson, R.M. Woodward, E. Weber, J.F.W. Keana, Structure−Activity Relationships of 4-Hydroxy-3-nitroquinolin-2(1H)-ones as Novel Antagonists at the Glycine Site of N-Methyl-d-aspartate Receptors. Journal of Medicinal Chemistry 39 (1996) 4682-4686, https://doi.org/10.1021/jm960520y.
[10] N.M. Shukla, S.S. Malladi, C.A. Mutz, R. Balakrishna, S.A. David, Structure−Activity Relationships in Human Toll-Like Receptor 7-Active Imidazoquinoline Analogues. Journal of Medicinal Chemistry 53(2010) 4450-4465, https://doi.org/10.1021/jm100358c.
[11] A. Oeveren, M. Motamedi, E. Martinborough, S. Zhao, Y. Shen, S. West, W. Chang, A. Kallel, K.B. Marschke, F.J. Lopez, A. Negro-Vilar, L. Zhi, Novel selective androgen receptor modulators: SAR studies on 6-bisalkylamino-2-quinolinones.Bioorganic & Medicinal Chemistry Letters 17 (2007) 1527-1531, https://doi.org/10.1016/j.bmcl.2007.01.001.
[12] D.R. Buckle, B.C.C. Cantello, H. Smith, B.A. Spicer, 4-Hydroxy-3-nitro-2-quinolones and related compounds as inhibitors of allergic reactions. Journal of Medicinal Chemistry 1975, 18(1975) 726–732, https://doi.org/10.1021/jm00241a01.
[13] https://www.biosynth.com/p/FH159597/15151-57-2-4-hydroxy-3-nitro-21h-quinolinone
6-Chloro-3-nitro-4-hydroxyquinoline-2(1H)-one as an efficient and comparable antibacterial agent
Enayatollah Moradi Rufchahi1
Department of Chemistry, Faculty of Science, Islamic Azad University, Lahijan branch, P.O. Box: 1616, Lahijan, Iran
Abstract
In this study, at first 4-chloro aniline was reacted with diethyl malonate to give corresponding malonodianilide. Then this compound was cyclized to 6-Chloro -4-hydroxyquinolin-2(1H)-one in melted polyphosphoric acid at 140-150 °C. 6-Chloro-3-nitro-4-hydroxyquinoline-2(1H)-one was successfully synthesized from 6-Chloro -4-hydroxyquinolin-2(1H)-one through a tradition nitration process. This compound was characterized by use of forier transfor infrared (FT-IR) and proton nuclear magnetic resonance (1H NMR) spectroscopic techniques. Then, antibacterial activities of the nitration product dissolved in DMSO were evaluated using well diffusion method against Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Proteus vulgaris (ATCC 49132) and Listeria monocytogenes (1298 ATCC) bacterial strains.
Keywords: 4-hydroxy quinolin-2(1H)-one, Nitration, Spectroscopy, Antibacterial activities
1. Introduction
Over the years, interest in quinolin-2-one derivatives has been growing due to their potential biological and chemical benefits [1, 2]. Quinoline-2-one is an important structural component of several synthetic and natural compounds with notable medicinal properties [3, 4]. There are many papers that have reported the synthesis and properties of quinoline-2-ones and a large number of their derivatives [5]. For example, Antimicrobial tests were conducted on a novel series of symmetrically substituted 3,3-dibenzyl-4-hydroxy-3,4-dihydro-1H-quinolin-2-ones. The results showed that the minimum inhibitory concentration (MIC) values of these active heterocycles were even slightly higher than those exhibited by levofloxacin, employed as a comparator medicinal reference [6].
A series of 4-hydroxy-3-nitro-2-quinolones were synthesized and their biological activity were discussed and compared with their related analogs [7-11]. The ability of these antiallergic agents to prevent the rat's homocytotropic antibody-antigen-induced passive cutaneous anaphylactic reaction has been used to measure their antiallergic activity [12].
Similarly, it has been demonstrated that 4-Hydroxy-3-nitro-2(1H)-quinolone (compound 1, Scheme 1), a nitrated derivative of 4-hydroxyquinolin-2(1H)-one, exhibits anticancer action against cancer cells (Scheme 1). It can be applied to the treatment of lung cancer, breast cancer, and colon cancer, among other cancer types. 4-Hydroxy-3-nitro-2(1H)- quinolone is an epidermal growth factor receptor (EGFR) antagonist and blocks epidermal growth factor signaling through its inhibition of EGFR tyrosine kinase activity [13].
Inspired by aforementioned encouraging results, herein we firstly prepared 6-chloro-4-hydroxyquinolin-2(1H)-one (16) and characterized its structure. This compound was then reacted with concentrated nitric acid to obtain corresponding 3-nitro derivative (17) (Scheme 2). Besides, antibacterial activities of the dyes dissolved in DMSO were evaluated using well diffusion method against Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Proteus vulgaris (ATCC 49132) and Listeria monocytogenes (1298 ATCC) bacterial strains.
Scheme1. Some biologically active 3-nitro derivatives of 4-hydroxyquinolin-2(1H)-ones
2. Experimental
2.1. materials and methods
All chemicals and solvents were procured from commercial suppliers, namely Aldrich–Sigma and Merck chemical companies. The FT-IR spectra of the samples were obtained using a Perkin Elmer FT-IR Spectrophotometer, employing pressed KBr discs. NMR spectra were acquired using a Brucker Avance spectrometer in DMSO-d6 with TMS serving as an internal standard. Melting points were determined using a Barnstead Electrothermal 9100 melting point apparatus in open capillary tubes, and the values were left uncorrected.
2.2. Preparation of N, N-Di-(4-chlorophenyl) malonamide 16
A mixture of 4-chloroaniline (100 mmol, 12.8 g) and dimethylmalonate (50 mmol, 5.7 ml) was refluxed for 4 hours in an oil bath. After cooling, the mixture was treated with diethyl ether, filtered by suction, and recrystallized from ethanol. The yield was 95%, resulting in a white solid with a melting point of 218-220 °C (reported as 217 °C [14]).
2.3. Synthesis of 6-chloro-4-hydroxyquinoline-2-(1H)-one 17
N, N′-Di-(4-chlorophenyl) malonamide (0.576 g, 2 mmol) was dissolved in 3.5 ml of methane sulfonic acid containing 10% phosphorus pentoxide and heated in an oil bath at 150°C for 90 minutes. The resulting dark viscous solution was allowed to cool, followed by the addition of water. The precipitated compound was filtered, washed with water, and air-dried. The crude product was then dissolved in 20 ml of 0.1 mol∙L⁻¹ sodium hydroxide solution, and any undissolved material was removed by filtration. The filtrate was neutralized with concentrated hydrochloric acid, and the resulting solid was recrystallized from DMF, yielding 6-chloro-4-hydroxyquinolin-2-(1H)-one as a white powder.
6-Chloro- 4-hydroxyquinoline -2-(1H)-one: white solid; Yield 42%; m.p. >350°C (350°C Ref. [15]); FT-IR(KBr) ν (cm-1) 3420(OH), 3100(NH), 3025(=C-H), 1658(C=O); 1H NMR (400MHz, DMSO-d6) δ ppm 12.01(NH, br), 7.78(1H, d, J=2.4 Hz), 7.60(1H, dd, J= 8.8, 2.4Hz), 7.26(1H, d, J= 8.8 Hz), 5.99(1H, s).
2.4. Synthesis of 6-chloro-3-nitro-4-hydroxyquinoline-2-(1H)-one 18
A suspension of 6-Chloro- 4-hydroxyquinoline -2-(1H)-one 17 (2.0 mmol, 0.39 g) in glacial acetic acid (6 mL) was heated for 10-15 minutes in an oil bath at 70 °C and then treated with nitrating agent prepared from concentrated nitric acid (0.2 mL) and concentrated sulphuric acid (0.25 mL) to start the exothermic reaction. The starting material dissolved and the solution was stirred for an additional 10 min at this temperature. The resulting solution was then poured into ice water (100 mL) and the precipitate was filtered and recrystallized from glacial acetic acid to afford 6-chloro-3-nitro-4-hydroxyquinoline-2-(1H)-one 18 as grey powder. FTIR (KBr): 3371 (OH), 3181 (NH), 3078 (=C–H), 1657 (C=O), 1597 (C=C),1597 (N=O), 1499 (N=O); 1H NMR (400 MHz, DMSO-d6), δ(ppm): 11.12 (1H, OH), 7.89 (1H, d, J = 2.0 Hz), 7.51(1H, dd, J=2, 8.4 Hz), 7.19 (1H, d, J=8.4 Hz).
3. Results and Discussions
3.1. Synthesis and characterization
6-chloro-4-Hydroxyquinolin-2(1H)-one 17 was prepared by modification of the reported procedure [19]. In this method, N, N´-di(4-chlorophenyl) malonamide 16 was synthesized by the reaction of 4-chloroaniline with diethyl malonate under reflux condition. This obtained dianilide was then cyclized to 6-chloro-4-Hydroxyquinolin-2(1H)-one in reaction with polyphosphoric acid under thermal condition at 140-150 °C. The 1H NMR data were used to distinguish the structure of this compound from the starting materials in which, the signal at 5.99 ppm (=CH) confirmed the formation of the desired quinolone ring. The preparation of the 6-chloro-4-Hydroxyquinolin-2(1H)-one and its nitration is illustrated in Scheme 2. Compound 17 was nitrated with concentrated nitric acid in glacial acetic acid at 80 °C for 10 min to afford 6-chloro-3-nitro-4-hydroxyquinolin-2-(1H)-one 18 in a good yield.
Compound 11 possesses a nitro group; therefore the stretching
vibration of N=O linkage shows two bands at 1592 and 1334
cm–1 in its IR spectra. The signal assigned to the olefinic proton
was not observed in the 1H NMR spectrum of this compound.
This compound was reduced with sodium dithionite in alkaline
medium to give 3-amino-4-hydroxybenzo[h]quinolin-2-
(1H)-one 12. Bromination of 3 in acetic acid gave 3-bromo-
4-hydroxy-3-nitrobenzo[h]quinolin-2-(1H)-one 13 structure
of which was identified by 1H NMR spectroscopy.
Scheme 2. Synthetic route to 6-chloro-3-nitro-4-hdroxyquinolin-2(1H)-one.
Figure 1. 1H NMR spectra of the compounds 16 (A), 17 (B) and 18 (C) in DMSO-d6 at ambient temperature.
3.2. Evaluation of Antibacterial Activity
The synthesized nitro derivative of 6-chloro-4-hydroxyquinolin-2(1H)-one was tested for its antibacterial activities by using the well diffusion method on Mueller-Hinton agar (MHA). The compound was dissolved in DMSO and Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Proteus vulgaris (ATCC 49132) and Listeria monocytogenes (1298 ATCC) were used as references for the antibacterial assay and the inhibition zones were reported in millimeter (mm) after 24 hours. The results are depicted in Table 3.(needs to revise)
Table 3. Minimal inhibitory concentrations (MIC, _g/mL) of some synthesised compounds
Microorganism | concentration of the compound (mg/ml) | |||
2 | 4 | 6 | 8 | |
Staphylococcus aureus |
|
|
|
|
Escherichia coli |
|
|
|
|
Proteus vulgaris |
|
|
|
|
Listeria monocytogenes |
|
|
|
|
|
|
|
|
|
The MIC values for some of the synthesized product were tested against the mentioned bacterial and are listed in Table 1. Briefly, the bacterial strains were suspended with a turbidity of 0.5 McFarland (equal to 1.5×108 colony-forming units (CFU)/ml) and cultured on MHA under aseptic conditions. Wells with 6mm in diameter were filled with 2 mg/ml, 4 mg/ml, 6 mg/ml and 8 mg/ml of dye solution and incubated at 37℃ for 24 hours. After the incubation period, the diameter of the growth inhibition zone was measured in mm(needs ti revise ar=nd rewrite.
According to the activity index, the well diffusion results show that the compounds 18 has reasonable antimicrobial activity against the tested microbes, which was confirmed by an inhibition zone (see Figure 2). In conclusion, the aim of the present study was to synthesize and investigate the antimicrobial activities of a new quinolone compound in the hope of discovering new lead structure that serve as potent antimicrobial agents compared to the standard drug Gentamycine. (needs ti revise ar=nd rewrite.
References
[1] F. O’Donnell, T.J.P. Smyth, V.N. Ramachandran, W.F. Smyth, a study of the antimicrobial activity of selected synthetic and naturally occurring quinolones. Int. J. Antimicrob. Agents 35 (2010) 30-38.
[2] M. M. Abdou, Chemistry of 4-Hydroxy-2(1H)-quinolone. Part 1: Synthesis and reactions Arabian Journal of Chemistry 10 (2017), S3324–S3337, http://dx.doi.org/10.1016/j.arabjc.2014.01.012.
[3] G.S. Bisacch, Origins of the quinolone class of antibacterials: an expanded “discovery story”. J. Med. Chem. 58 (2015) 4874–4882, https ://doi.org/10.1021/jm501 881c.
[4] J.P. Michael, Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 20 (2003) 476-493.
[5] A. A. Aly, E. M. El‑Sheref, A.‑F. E. Mourad, M. E. M. Bakheet, S. Bräse, 4‑Hydroxy‑2‑quinolones: syntheses, reactions and fused heterocycles. Molecular Diversity 24 (2020) 477-524, https://doi.org/10.1007/s11030-019-09952-5.
[6] M. D. Ferretti, A. T. Neto, A. F. Morel, T. S. Kaufman, E. L. Larghi, Synthesis of symmetrically substituted 3,3-dibenzyl-4-hydroxy-3,4- dihydro-1H-quinolin-2-ones, as novel quinoline derivatives with antibacterial activityEuropean Journal of Medicinal Chemistry 81 (2014) 253-266.
[7] V. Dolle, E. Fan, C. H. Nguyen, A.M. Aubertin, A. Kirn, M.L. Andreola, G. Jamieson, L.T. Litvak, E. Bisagni, Journal of Medicinal Chemistry 38 (1995) 4679-4686, https://doi.org/10.1021/jm00023a007.
[8] D. Audisio, S. Messaoudi, J.F. Peyrat, J.D. Brion, M. Alami, L. Cegielkowski, D. Methy-Gonnot, C. Radanyi, J. M. Renoir, Discovery and Biological Activity of 6BrCaQ as an Inhibitor of the Hsp90 Protein Folding Machinery. Chem Med Chem 6 (2011) 804-815, https://doi.org/10.1002/cmdc.201000489.
[9] S.X. Cai, Z.L. Zhou, J.C. Huang, E.R. Whittemore, Z.O. Egbuwoku, J.E. Egbuwoku, J.E. Hawkinson, R.M. Woodward, E. Weber, J.F.W. Keana, Structure−Activity Relationships of 4-Hydroxy-3-nitroquinolin-2(1H)-ones as Novel Antagonists at the Glycine Site of N-Methyl-d-aspartate Receptors. Journal of Medicinal Chemistry 39 (1996) 4682-4686, https://doi.org/10.1021/jm960520y.
[10] N.M. Shukla, S.S. Malladi, C.A. Mutz, R. Balakrishna, S.A. David, Structure−Activity Relationships in Human Toll-Like Receptor 7-Active Imidazoquinoline Analogues. Journal of Medicinal Chemistry 53(2010) 4450-4465, https://doi.org/10.1021/jm100358c.
[11] A. Oeveren, M. Motamedi, E. Martinborough, S. Zhao, Y. Shen, S. West, W. Chang, A. Kallel, K.B. Marschke, F.J. Lopez, A. Negro-Vilar, L. Zhi, Novel selective androgen receptor modulators: SAR studies on 6-bisalkylamino-2-quinolinones.Bioorganic & Medicinal Chemistry Letters 17 (2007) 1527-1531, https://doi.org/10.1016/j.bmcl.2007.01.001.
[12] D.R. Buckle, B.C.C. Cantello, H. Smith, B.A. Spicer, 4-Hydroxy-3-nitro-2-quinolones and related compounds as inhibitors of allergic reactions. Journal of Medicinal Chemistry 1975, 18(1975) 726–732, https://doi.org/10.1021/jm00241a01.
[13] https://www.biosynth.com/p/FH159597/15151-57-2-4-hydroxy-3-nitro-21h-quinolinone.
[14] E. Ziegler, R. Wolf, J. Kappe, Monatsch 96 (1965) 418.
[15] Moradi-e-Rufchahi, E.O. Synthesis of 6-chloro and 6-fluoro-4-hydroxyl-2-quinolone and their azo disperse dyes,Chin.Chem. Lett.2010, 21, 542-546.
[1] * Corresponding author: Tel.: +981333515849; fax: +981342228701.
E-mail address: em.Rufchahi@iau.ac.ir, moradierufchahi@liau.ac.ir (E. M. Rufchahi)