alexa Design-Syntheses, Characterization and Biological Activity Studies of Azobenzen-P,Pꞌ-Di(3,1-Benzoxazin-4-One-2yl) and Azobenzen-P,Pꞌ-Di[(3- Substituted 3(4H)Quinazolinone-2yl] Derivatives
ISSN: 2150-3494
Chemical Sciences Journal
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Design-Syntheses, Characterization and Biological Activity Studies of Azobenzen-P,Pꞌ-Di(3,1-Benzoxazin-4-One-2yl) and Azobenzen-P,Pꞌ-Di[(3- Substituted 3(4H)Quinazolinone-2yl] Derivatives

Zakaria H Aiube1 and Zainab A Jabarah2*

1Chemistry Department, College of Education for Pure Science, University of Baghdad, Ibn-al-Haitham, Baghdad, Iraq

2Basic Science Division, College of Agriculture, University of Baghdad, Baghdad, Iraq

*Corresponding Author:
Zainab A Jabarah
Basic Science Division, College of Agriculture
University of Baghdad, Baghdad, Iraq
Tel: 009647901300655
E-mail: [email protected]

Received Date: May 22, 2017; Accepted Date: May 24, 2017; Published Date: June 12, 2017

Citation: Aiube ZH, Jabarah ZA (2017) Design-Syntheses, Characterization and Biological Activity Studies of Azobenzen-P,Pꞌ-Di(3,1-Benzoxazin-4-One-2yl) and Azobenzen-P,Pꞌ-Di[(3- Substituted-4(3h)Quinazolinone-2yl] Derivatives. Chem Sci J 8:156. doi: 10.4172/2150-3494.1000156

Copyright: © 2017 Aiube ZH, 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

Sixteen azobenzene-p,pꞌ-di[3-substituted-4(3H)quinazolinone-2yl] were synthesized from reaction of azobenzenp, pꞌ-di(3,1-benzoaxzin-4-one-2yl) with amino-moieties nucleophlies, like hydrazinehydrate, hydroxylamine, p,toluidine, p-aminobenzene sulphonamide, 2-pyrimidine, 5-nitro-2-aminopyridine, ethyleneamine,5-(p-bromo) phenyl-2-aminothiazol, p,pꞌ-diamino diphenyl sulphone, quinidine hydrochloride, urea, thiourea, 3,5-dimethyl- 2-phenyl-4-aminopyrazolin-3-one, N(5-methyl-3-isoxazolyl)-p-aminobenzen sulphonamide, semicarbazide and thiosemicarbazide, in a molar ratio (1:2) respectively. azobenzen-p,pꞌ-di(3,1-benzoaxzin-4-one-2yl), was synthesized by following serial synthetic pathway. Reductive-condensation of p-nitrobenzoic acid in basic media give azobenzenp, pꞌ-dicarboxylic acid, then treated with thionyl chloride to give azobenzen-p,pꞌ-diacid chloride. It condensed with anthranilic acid to give azobenzen-p,pꞌ-[(dibenzoic acid-2yl)dicarboxamide], upon treatment with thionyl chloride give azobenzen-p,pꞌ-di(3,1-benzoaxzin-4-one-2yl). All synthesized compounds characterized by FTIR, 1HNMR, 13CNMR and mass spectral analyses. All synthesized azobenzen-p,pꞌ-di(3,1-benzoaxzin-4-one-2yl), and sixteen azobenzenep, pꞌ-di[3-substituted-4(3H)quinazolinone-2yl] compounds, were examined as antibacterial agents against gm(+ve and –ve) bacteria, and antifungal agents. Results showed abroad extended to moderate effects as antibacterial and antifungal agents.

Keywords

Azobenzene; Benzoxazinone; Quinazolinone; Antibacterial; Antifungal

Introduction

2-substituted-3,1-benzoaxzin-4-one derivatives can be considered as semi-acid anhydrides, which undergo many reactions of true acid anhydrides, but at a slower rate [1]. This special reactivity allows these types of heterocyclic compounds to have broad spectrum in medical, biological and industrial fields [1,2]. This class of compounds, found to be useful as antimicrobial [3], anti-platelet aggregation [4], human leukocyte elastase inhibitors [5], receptor agonist active [6], receptor antagonist active [7], enzyme inhibitor [8], protease inhibitor [9-11], fungicidal [12], pesticidal [7]. Also 2-substituted-3,1-benzoaxzin-4- one derivatives, showed some important industrial applications in syntheses of polymeric material [13], optical bleaching agent [14], and cosmetic [15]. On the other hand, they are used as precursors for syntheses of variety of 2,3-disubstituted quinazolin-4-one derivatives [16-19]. Which are known to have medical and biological properties, through reaction with nitrogen nucleophiles [20]. Quinazolinones are class of fused heterocyclic compounds, of two fused benzene and pyrimidinone rings; they are active compounds, exhibiting a broader spectrum of biological activities in animal, as well as in human [21,22]. Literature studies on quinazolinones have shown, that these derivatives possess a wide variety of biological activities, such as antioxidant [23], antifungal [24], antibacterial [25], anticonvulsant [26], anti-inflammatory [27], antihyperlipidemic [28], anticancer [29], antimalarial [30], antispasmodial [31], analgesic [32], antiviral [33], antitubercular [34] and antimicrobial activities [35]. In our work we design syntheses many of di[(3-substituted-4(3H)quinazolinone-2yl] moieties, substituted at (p,pê)-position of bridged azobenzene molecule, via di(3,1-benzoxazin-4-one-2yl) moiety, substituted at (p,pê)-positions of bridged azobenzene molecule.

Materials and Methods

Synthesis of azobenzene-p,pê-dicarboxylic acid [I]

This compound was obtained by condensation of p-nitrobenzoic acid with itself in basic media in presence of reducing agent like glucose, then upon air-oxidation give azobenzene-p,pê-dicarboxylic acid, yield 48%, m.p. 302, lit. >300°C [36].

Synthesis of azobenzene-p,pê-diacid choride [II]

A mixture of azobenzen-p,pê-dicarboxylic acid (0.27 gm, 0.001mol), excess of thionyl chloride (10 ml), and dry pyridine (3 ml), was refluxed for 2 hours. Reaction mixture was extracted several times with n-hexane, and then rotary evaporated. Resulting residue was washed with dry diethyl ether, recrystallized from petroleum ether to give compound [II]. 0.28 gm, yield 91.2%, m.p. 154°C.

Synthesis of azobenzen-p,pê-[(dibenzoic acid-2yl)di carboxamide] [III]

To a clear stirred solution of azobenzen-p,pê-diacid chloride (0.307 gm, 0.001mol) in dry benzene (50 ml) containing dry pyridine (5 ml), anthranilicacid (0.274 gm, 0.002mol) was added. Reaction mixture was stirred for further 5 hours, until completion of reaction which was monitored by TLC, using ethyl acetate: ethanol [2:3] eluent. A precipitate was formed, filtered, washed with distilled water, recrystallized from benzene, to give compound [III]. 0.4 gm, yield 80.7%, m.p. 288-290°C.

Synthesis of azobenzen-p,pê-di[3,1-benzoxazine-4-one-2yl] [IV]

To a clear solution of azobenzen-p,pê-[(dibenzoic acid-2yl) dicarboxamide] (0.508 gm, 0.001mol) in excess of thionyl chloride (10 ml), dry pyridine (5 ml), was reflux for 2 hours, until completion of reaction which was monitored by TLC, using ethyl acetate : ethanol [2:3] eluent. A solid was formed. Reaction mixture was cooled; solid was formed, filtered and washed with dry diethyl ether, recrystallized from DMF, to give compound [IV]. 0.4 gm, yield 84.74%, m.p. 320°C.

Syntheses of azobenzen-p,pê-di[3-substituted-4(3H)-quinazolinone- 2yl] [Va-Vp]

A mixture of azobenzen-p,pê-di[3,1-benzoxazine-4-one-2yl] (0.472 gm: 0.001 mol), and amino moieties compounds, like hydrazine hydrate, hydroxylamine hydrochloride, quinidine, urea, thiourea, semicarbazide, thiosemicarbazide, aromatic and hetro-aromatic amines, 1,2-diaminoethane dihydrochloride (0.002 mol) (Table 1) in DMF (25 ml), was refluxed for a time (Table 1), until completion of reactions were monitored by TLC using petroleumether : ethyl acetate [3:2] eluent. Solids were separated, filtered and purified by crystallization from suitable solvents (mentioned in Table 1), to give azobenzen-p,pê-di[3-substituted -4(3H)-quinazolinone-2yl] [Va-Vp].

No Amino-moieties Refluxed time No Structure formula Weight of product (gm) Yield% Crystallizing solvent
1 Hydrazine hydrate 8hr Va chemical-sciences-journal 0.53 88 DMF
2 Hydroxylammonium chloride 6hr Vb chemical-sciences-journal 0.4 78 DMF
4 p-toluidine 7hr Vc chemical-sciences-journal 0.3 46 DMSO
5 p-Aminobenzenesulphoneamide 8hr Vd chemical-sciences-journal 0.4 51 DMF
6 2-aminopyrimidine 6hr Ve chemical-sciences-journal 0.48 77 DMSO
7 2-amino-5-nitropyridine 8hr Vf chemical-sciences-journal 0.44 61 DMSO
8 1,2-diaminoethanedihydrochloride 6hr Vg chemical-sciences-journal 0.45 81 DMF
9 2-Amino-5(p-bromo)phenyl-1,3-thiazole 7hr Vh chemical-sciences-journal 0.42 49 DMSO
10 4,4ê-diaminodiphyenylsulphone 8hr Vi chemical-sciences-journal 0.45 52 DMF
11 Quinidine hydrochloride 5hr Vj chemical-sciences-journal 0.47 85 DMF
12 Urea 5hr Vk chemical-sciences-journal 0.43 77 DMF
 13 Thiourea 5hr Vl chemical-sciences-journal 0.42 71 DMSO
14 4-amin-1,5-dimethyl-2-phenyl-3-pyrazolin-5-one(amino antipyrine 10hr Vm chemical-sciences-journal 0.38 46 DMF
15 4-amino-N(5-methyl-3-isoxaly)benzenesulphonamide 10hr Vn chemical-sciences-journal 0.41 43 DMSO
16 Semicarbazide 8hr Vo chemical-sciences-journal 0.4 71 DMF
17 Thiosemicarbazide 8hr Vp chemical-sciences-journal 0.4 69 DMF

Table 1: Reaction of azobenzen-p,pê-di(3,1-benzoaxazin-4-one-2yl)[4], with amino-moieties to give azobenzene-p,pê-di[(3-substituted)-4(3H)quinazolinone-2yl] compounds [5a-5p].

Discussion

Chemistry of benzoxazine, quinazolin, quinazolinone and their derivatives have much considerable attention, due to effective biological and pharmacological importance. Awing to these reasons, we design to synthesis anew benzoaxazin-4-one and quinazolin-4-one derivatives. We design syntheses many of di[(3-substituted-4(3H)quinazolinone- 2yl] moieties, substituted at (p,pê)-position of bridged azobenzene molecule, via di(3,1-benzoxazin-4-one-2yl) moiety, substituted at (p,pê)-positions of bridged azobenzene molecule, according to the following synthetic routes.

chemical-sciences-journal

Synthesis of azobenzene-p,pê-dicarboxylic acid [I] [36]

This compound was synthesized in by reductive-condensation, then air-oxidation of basic solution of p-nitrobenzoic acid. Characterized by CHN-analysis and FTIR-spectral analysis, CHN-analysis was agreed with theoretical data. FTIR-spectrum of this compound [I], showed stretching bands of (-OH broad), (C=O and N=N) groups at (3437- 2544, 1693 and 1693 cm-1) respectively.

Synthesis of azobenzen-p,pê-diacid chloride [II]

chemical-sciences-journal

Heating compound [I] with excess of thionyl chloride in presence of pyridine, give good yield of compound [II], which was characterized by CHN- analysis, FTIR, 1H NMR, 13 CNMR and mass spectral analyses. CHN- analysis was agreed with theoretical data. IR-spectrum of this compound [II], showed stretching bonds vibration of C=O and N=N at 1774 and 1577 cm-1 respectively. While 1H NMR-spectrum showed only aromatic protons (8H,m) at (7.9 - 8.2) ppm. 13C NMR-spectrum showed C=O and aromatic carbons signals at (166 and 122-134) ppm respectively. Mass spectral analysis showed molecular ion (M+2) and (M+2H)+2 ions at m/z 307 and 309 respectively.

Synthesis of azobenzene-p,pÍ´-[(dibenzoicacid-2yl)dicarboxamide] [III]

chemical-sciences-journal

Condensation of compound[II] with anthranilic acid in molar ratio (1:2) in presence of pyridine give compound[III], which was characterized by CHN-analysis, FTIR, 1H NMR, 13C NMR and Mass spectral analysis. CHN- analysis was agreed with calculated data. IRspectrum showed stretching bands of (OH, NH, C=O, and N=N) groups at 3232, 3309 (broad), 3230, 1676 and 1450 cm–1 respectively, beside (C=O), (amide I) and (NH)-bending (amide II) bands at 1608 and 1584 cm–1 respectively. While 1H NMR-spectral analysis showed protons of carboxyl as (2H, s) at (12) ppm, amide NH as (2H,s) at (8.6 ppm) and aromatic as (16H,m) at (7.1-8.5) ppm [37]. But 13C NMRspectrum showed carboxyl and carboxamide carbon as a singlet signals at (169, 164) ppm respectively, beside multiplet signal of aromatic carbons at (120 - 153) ppm. Mass spectrum showed, (M+H)+2 and (M+2H)+2 ions at m/z=(309 and 310) respectively.

Synthesis of azobenzene p,pê-di[3,1-benzoxazine-4-one-2-yl] [IV]

Heating compound [III] with excess of thionyl chloride in presence of pyridine, to give compound [IV], Which was characterized by CHN-analysis, FTIR, 1H NMR, 13C NMR and Mass spectral analysis. CHN-analysis was identical to calculated data. IR-spectrum show C=O cyclic ester), C=N and N=N stretching bands at 1762, 1604, 1570 cm-1 respectively. 1H NMR- spectrum showed only aromatic proton as (16H,m) at (7.5-8.5) ppm. While 13C NMR showed C=O (cyclic ester), C=N carbons as singlet signal at (179, 153 ppm), beside multiplet aromatic carbon at (117 - 150) ppm respectively. Mass spectral analysis does not show molecular ion M+2 at m/z (472), but showed fragmented ions m/z (236), probably obtained from molecular ion decomposition with charge is considered to be localized at azo-nitrogen atoms of synthesized molecule of compound [IV] as in the following fragments:

Synthesisofazobenzen-p,pê-di[3-substituted-4(3H)-quinazolinone- 2yl][Va-Vp]

Heating compound [IV] with amino-moiety compounds, given in Table 1, in molar ratio (1:2) give azobenzen-p,pê-di[3-substituted- 4(3H)-quinazolinone-2yl] [Va-Vp], which were characterized by FTIR spectral analysis, many of them characterized by 1H NMR, 13C NMR, and some of them by mass spectral analyses. IR-spectral analysis of compounds [Va-Vp], showed quinazolin-4-one ring stretching bonds C=O, and C=N, at rang (1680-1620), and (1635-1591) cm-1, azogroup (N=N) stretching bonds at rang (1489-1444) cm-1, as well as to starching of 3-substituted moieties [37] are given in Table 2 [37]. 1H NMR spectrum of compounds [V(a, b, c, g, j, k, l, n, o, p)], showed beside quinazolinone aromatic proton as (16,m) at rang (6.5-9.2) ppm, protons signals of 3-substituted moieties, which were shown in Table 2. 13C NMR- spectral analysis of compounds [V(a, b, c, g, j, k, l, n, o, p)], showed quinazolinone, (aromatic, C=O, C=N) carbon signals at (110-140), (163-180), (152-164) ppm, respectively, beside carbon signals of 3-substituted moieties, which are given in Table 2. Mass spectral analysis of compounds [Va, Vd] showed M+2 ions m/z (500, 780), and [Vb] showed [M-H]+2 ions at m/z (501), compound [Ve] dose not showed (M)+2 ions at m/z (626), but show fragmented ion at m/z (236), probably abstained by decomposition of molecular ion, with charge considered to be localized at azo-nitrigen atoms of this symmetrical compounds to give following fragmented ion:

No. Name of compounds Mean of Inhibition zone Diameter (mm)
Staphylococcusaureus Bacillus Escherichia coli No. Klebsiella pneumonia Aspergillus flavus Penicillium
IV Azobenzen-p,pê-di[3,1-benzoxazine-4-one-2-yl] 22 - 16 10 13 10
Va Azobenzen-p,pê-di[3-amino-4(3H)qunazolinone-2yl] 20 17 8 12 12 -
Vb Azobenzen-p,pê-di[3-hydroxy-4(3H)qunazolinone-2yl] 23 30 8 10 11 13
Vc Azobenzen-p,pê-di[3,p-touldino-4(3H)qunazolinone-2yl] 17 - - 11 8 16
Vd Azobenzen-p,pê-di[3,p-benzenesulfoneamido-4(3H)qunazolinone-2-yl 20 9 8 12 12 25
Ve Azobenzen-p,pê-di[3,p-pyrimidino-4(3H)qunazolinone-2yl] 8 - 8 8 10 12
Vf Azobenzen-p,pê-di[3,5ê-nitro-2ê-pyridin-2êyl-4(3H)qunazolinone-2yl] 9 13 8 8 9 12
Vg Azobenzen-p,pê-di[3-2ê-ethylamino-4(3H)qunazolinone-2yl] 8 8 8 8 - -
Vh Azobenzene-p,pê-di[3,4ê-p-bromophenyl-2ê-(1ê,3ê-thiozolyl)-4(3H)qunazolinone-2yl] 16 15 15 15 11 28
Vi Azobenzen-p,pê-di[3(p-4ê-aminodiphenylsulfone)-4(3H)qunazolinone-2yl] 8 15 8 15 15 16
Vj Azobenzen-p,pê-di[3-imidino-4(3H)qunazolinone-2yl] 8 11 10 10 - -
Vk Azobenzen-p,pê-di[3-carbomido-4(3H)qunazolinone-2yl] 8 8 - 8 - -
Vl Azobenzen-p,pê-di[3-thiocarbomido-4(3H)qunazolinone-2yl] 8 13 10 9 12 9
Vm Azobenzen-p,pê-di[3-(1ê,5ê-dimetyl-2ê-phenyl-3ê-pyrazolinone)-4(3H)qunazolinone-2yl] 8 15 9 8 - -
Vn Azobenzen-p,pê-di[3-(5ê-methyl-3ê-isoxazolyl)benzenesulfoneamido-4(3H)qunazolinone-2yl] 8 8 8 9 14 9
Vo Azobenzen-p,pê-di[3,N-ureido- 4(3H)quinazolinone-2yl] 8 14 8 8 12 -
Vp Azobenzen-p,pê-di[3,N-thioureido- 4(3H)quinazolinone-2yl] 8 11 8 9 12 -

Table 3: Antimicrobial activity of compounds [IV-Vp].

Anti-microbial study

Synthetic compounds [IV, V(a-p)], were examined as antibacterial agents against gm (+ve) Staphylococcus aureus, Bacillus bacteria, and gm (-ve) Escherichia coli, Klesbsiella, Pneumonia bacteria, in comparison with effect of Cephalexin, Amoxicillin, Tetracycline Lincomycin antibiotics. Also these compound [IV, V(a-p)], were examined as agents against Aspergillus flavus and Penicillium, Fungi in comparison with effect of Nystatine and Fluconazole antifungal treatments. According to the results given in Table 3, following observation would be deduced.

• First: compounds [V(a, b, h, i)], were found to have a broadening effect on gram (+ve) Bacillus bacteria in comparison with effect of Cephalexin, Amoxicillin, Tetracycline antibiotitics.

• Second: compounds [V(a, b, c, d)], were found to have moderate to higher antibacterial effect on gram (+ve) Staphylococcus aureus bacteria in comparison with effect of Cephalexin, Amoxicillin, and Tetracycline antibiotics.

• Third: compounds [V(a, d, h, i)], were found to have good to excellent antibacterial effect, against gram (-ve) Klebsilla pneumonia bacteria, in comparison with effect of Tetracycline antibiotics.

• Fourth: compounds [V(a, d, I, l, n, o, p)], were found to have a moderate to excellent antifungal effect on Aspergillus fungi in comparison with the effect of Nystatin and Fluconazole antifungal treatment. But compounds [V(c, d, h, i)], were found to have moderate to excellent antifungal effect on Penicillium fungi in comparison with the effect of Nystatin and Fluconazole antifungal treatments.

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