Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 11  |  Issue : 2  |  Page : 116-123

Synthesis of certain new fused pyranopyrazole and pyranoimidazole incorporated into 8-hydroxyquinoline through a sulfonyl bridge at position 5 with evaluation of their in-vitro antimicrobial and antiviral activities


1 Department of Therapeutic Chemistry, National Research Centre, Dokki, Giza, Egypt
2 Department of Chemistry of Natural Compounds, National Research Centre, Dokki, Giza, Egypt
3 Central Laboratory for Evaluation of Veterinary Biologics, Abbassia, Cairo, Egypt

Date of Submission14-Jun-2012
Date of Acceptance09-Sep-2012
Date of Web Publication18-Jul-2014

Correspondence Address:
Eslam R. El-Sawy
Department of Natural Compounds Chemistry, National Research Centre, 12311 Dokki, Giza
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EPJ.0000421482.33940.0b

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  Abstract 

Background and objectives

Heterocyclic systems with a quinoline nucleus display a wide spectrum of biological activities such as antimicrobial and antiviral activities. The aim of the present study was the synthesis of new fused pyranopyrazoles, 5a-e and 6a-e, and pyranoimidazoles, 10a-e and 11a-e, incorporated to 8-hydroxyquinoline through a sulfonyl bridge at position 5 and evaluation of their antimicrobial and antiviral activities.

Methods

The synthesis of the titled quinoline derivatives was achieved through cyclization of 8-hydroxyquinoline-5-sulfonyl chloride (1) with 2º-acetyl-2-cyanoacetohydrazide, 2-cyanoacetic acid hydrazide, and 3-amino-5-pyrazolone to afford 2, 3, and 4, respectively. Moreover, reaction of 1 with glycine gives 7, which on heterocyclization with ammonium thiocyanate yielded the 2-thioxoimidazolidin-2-one derivative 8. Cyclocondensation reaction of 3, 4, 8, and 9 with different arylidene malononitriles afforded fused systems, 5a-e, 6a-e, 10a-e, and 11a-e, respectively. The synthesized compounds were evaluated for their in-vitro antimicrobial activity using the disc diffusion method. In addition, they were evaluated for their in-vitro antiviral activity against avian paramyxovirus type 1 (APMV-1) and laryngotracheitis virus (LTV).

Results and conclusion

In-vitro antimicrobial activity of the newly synthesized compounds included an inhibitory effect toward the growth of Escherichia coli and Pseudomonas aeruginosa (Gram-negative bacteria). Furthermore, of the six selected compounds (2, 3, 4, 7, 8 and 9) tested for their antiviral activity, compounds 2, 3, and 4 at a concentration range of 3–4 µg/ml showed marked viral inhibitory activity for APMV-1 of 5000 tissue culture infected dose fifty (TCID50) and LTV of 500 TCID50 in Vero cell cultures on the basis of their cytopathic effect. Chicken embryo experiments show that compounds 2, 3, and 4 possess high antiviral activity in vitro, with inhibitory concentration fifty (IC50) ranging from 3 to 4 µg/egg against avian APMV-1 and LTV and toxic concentration fifty (CC50) ranging from 200 to 300 µg/egg.

Keywords: antimicrobial, antiviral activities, 8-hydroxyquinoline-5-sulfonyl chloride, pyrano[2,3-c] pyrazole, pyrano[2,3-d]imidazole


How to cite this article:
Kassem EM, El-Sawy ER, Abd-Alla HI, Mandour AH, Abdel-Mogeed D, El-Safty MM. Synthesis of certain new fused pyranopyrazole and pyranoimidazole incorporated into 8-hydroxyquinoline through a sulfonyl bridge at position 5 with evaluation of their in-vitro antimicrobial and antiviral activities. Egypt Pharmaceut J 2012;11:116-23

How to cite this URL:
Kassem EM, El-Sawy ER, Abd-Alla HI, Mandour AH, Abdel-Mogeed D, El-Safty MM. Synthesis of certain new fused pyranopyrazole and pyranoimidazole incorporated into 8-hydroxyquinoline through a sulfonyl bridge at position 5 with evaluation of their in-vitro antimicrobial and antiviral activities. Egypt Pharmaceut J [serial online] 2012 [cited 2020 Nov 26];11:116-23. Available from: http://www.epj.eg.net/text.asp?2012/11/2/116/136959


  Introduction Top


Heterocyclic systems with a quinoline nucleus represent privileged moieties in medicinal chemistry and are ubiquitous substructures associated with biologically active natural products. Quinoline derivatives have been shown to display a wide spectrum of biological activities such as antibacterial 1–3, antifungal 4, 5, antiparasitic 6, and antiviral activities 7,8. Because of their wide range of biological activities, quinoline compounds have been considered to be good starting materials for the search of novel antimicrobial and antiviral agents. Accordingly, the aim of the present work was the synthesis of new fused pyranopyrazoles, 5a-e and 6a-e, and pyranoimidazoles, 10a-e and 11a-e, incorporated into 8-hydroxyquinoline through a sulfonyl bridge at position 5. Moreover, the study includes testing of the target compounds for their expected antimicrobial and antiviral activities.


  Subject and methods Top


Chemistry

Melting points were determined in open capillary tubes, on an Electrothermal 9100 digital melting point apparatus (Büchi, Mount Holly, New Jersey, USA), and were reported uncorrected. Elemental analyses were carried out using the Perkin-Elmer 2400 analyzer (Norwalk, Connecticut, USA) and the results were found to be within ±0.4% of the theoretical values [Table 1]. Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 Fourier transform infrared spectroscope against KBr discs. 1H NMR spectra were measured on a JEOL 270 MHz spectrometer (JEOL, Tokyo, Japan) in dimethyl sulfoxide-d 6 and chemical shifts were recorded in δ ppm relative to tetramethylsilane as an internal standard. Mass spectra (EI) were measured at 70 eV using a JEOL-JMS-AX500 mass spectrometer (JEOL). 8-Hydroxyquinoline-5-sulfonyl chloride 9, 2-cyanoacetic acid hydrazide 10, 3-amino-5-pyrazolone 11, 2º-acetyl-2-cyanoacetohydrazide 12, and arylidene malononitrile 13 were prepared as reported.
Table 1: Physical and analytical properties of the newly synthesized compounds

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1-Acetyl-5-amino-4-[(8-hydroxyquinoline-5-yl)sulfonyl]-1,2-dihydro-pyrazol-3-one (2)

A mixture of 8-hydroxyquinoline-5-sulfonyl chloride (1; 2.4 g, 0.01 mol) and 2º-acetyl-2-cyanoacetohydrazide (1.3 g, 0.01 mol) in dioxane (20 ml) containing triethylamine (1 ml) was refluxed for 3 h. After cooling, the precipitate formed was filtered off, washed with water, air dried, and recrystallized from aqueous ethanol [Scheme 1 [Additional file 1], [Table 1].

5-Amino-1-[(8-hydroxyquinoline-5-yl)sulfonyl]-1,2-dihydropyrazol-3-one (3)

A mixture of 8-hydroxyquinoline-5-sulfonyl chloride (1; 2.4 g, 0.01 mol) and 2-cyanoacetic acid hydrazide (0.99 g, 0.01 mol) in dioxane (20 ml) containing triethylamine (1 ml) was refluxed for 2 h. The hot solid that formed was filtered off, washed with water, air dried, and recrystallized from absolute ethanol [Scheme 1, [Table 1].

3-[(8-Hydroxyquinoline-5-yl)sulfonamido]-1,2-dihydropyrazol-5(4H) one (4)

A mixture of 8-hydroxyquinoline-5-sulfonyl chloride (1; 2.4 g, 0.01 mol) and 3-amino-5-pyrazolone (0.99 g, 0.01 mol) in dioxane (20 ml) containing triethylamine (1 ml) was refluxed for 3 h. After cooling, the precipitate formed was filtered off, washed with water, air dried, and recrystallized from aqueous ethanol [Scheme 1, [Table 1].

General procedure for the synthesis of 4-aryl-3,6-diamino-2,4-dihydro-2-[(8-hydroxyquinoline-5-yl)sulfonyl]pyrano [2,3-c] pyrazole-5-carbonitriles (5a-e)

A solution of the appropriate arylidene malononitriles (0.01 mol) and compound 3 (3.06 g, 0.01 mol) in dioxane (20 ml) containing triethylamine (1 ml) was refluxed for 3–6 h. After cooling, the precipitate formed was filtered off, washed with water, air dried, and recrystallized from absolute ethanol [Scheme 1, [Table 1].

General procedure for the synthesis of 6-amino-4-aryl-3-[(8-hydroxyquinoline-5-yl)sulfonamido]pyrano [2,3-c]pyrazole-5-carbonitriles (6a-e)

A solution of the appropriate arylidene malononitriles (0.01 mol) and compound 4 (3.06 g, 0.01 mol) in dioxane (20 ml) containing triethylamine (1 ml) was refluxed for 3–6 h. After cooling, the precipitate formed was filtered off, washed with water, air dried and recrystallized from absolute ethanol [Scheme 1, [Table 1].

2-(2-(8-Hydroxyquinoline-5-yl)sulfonamido)acetic acid (7)

A suspension of 8-hydroxyquinoline-5-sulfonyl chloride (1; 0.24 g, 0.001 mol) and glycine (0.07 g, 0.001 mol) in a saturated solution of potassium carbonate (5 ml, 1.1 mol/l) was stirred and heated at 50°C for 10 min and then at 100°C for 30 min. After cooling, the reaction mixture was neutralized with diluted hydrochloric acid (1 : 1). The precipitate formed was filtered off and recrystallized from dioxane [Scheme 2 [Additional file 2], [Table 1].

1-[(8-Hydroxyquinoline-5-yl)sulfonyl]-2-thioxoimidazolidin-4-one (8)

A suspension of 2-(2-(8-hydroxyquinoline-5-yl)sulfonamido)acetic acid (7; 3.38 g, 0.012 mol), acetic anhydride (6.3 g, 0.067 mol), anhydrous pyridine (15 ml), and ammonium thiocyanate (1.2 g, 0.015 mol) was heated at 110°C for 1 h. The volatiles were removed in vacuo and the residue was suspended in water (100 ml) and stirred for 1 h. The solid formed was filtered off, air dried, and recrystallized from benzene petroleum ether (60–80°C; Scheme 2, [Table 1].

1-[(8-Hydroxyquinoline-5-yl)sulfonyl]imidazolidin-2,4-dione (9)

A suspension of 1-[(8-hydroxyquinoline-5-yl)sulfonyl]-2-thioxo-imidazolidin-4-one (8) (1.77 g, 0.0055 mol), chloroacetic acid (10 g, 0.1 mol), and water (3 ml) was heated at 120°C for 12 h on a sand bath. The reaction mixture was then diluted with water (50 ml) and set aside in a refrigerator at 5°C. The solid formed was filtered off, air dried, and recrystallized from benzene petroleum ether (60–80°C; Scheme 2, [Table 1].

General procedure for the synthesis of 5-amino-7-aryl-1,2-dihydro-1-[(8-hydroxyquinoline-5-yl)sulfonyl]-2-thioxopyrano [3,2-d]imidazole-6-carbonitriles (10a-e)

A solution of the appropriate arylidene malononitriles (0.01 mol) and 1-[(8-hydroxyquinoline-5-yl)sulfonyl]-2-thioxoimidazolidin-4-one (8; 3.23 g, 0.01 mol) in dioxane (20 ml) containing triethylamine (1 ml) was refluxed for 3–6 h. After cooling, the precipitate formed was filtered off, air dried, and recrystallized from absolute ethanol [Scheme 2, [Table 1].

General procedure for the synthesis of 5-amino-7-aryl-1,2-dihydro-1-[(8-hydroxyquinoline-5-yl)sulfonyl]-2-oxo-pyrano [3,2-d]imidazole-6-carbonitriles (11a-e)

A solution of the appropriate arylidene malononitriles (0.01 mol) and 1-[(8-hydroxyquinoline-5-yl)sulfonyl]imidazolidin-2,4-dione (9; 3.07 g, 0.01 mol) in dioxane (20 ml) containing triethylamine (1 ml) was refluxed for 3–6 h. After cooling, the precipitate formed was filtered off, air dried, and recrystallized from absolute ethanol [Scheme 2, [Table 1].

Biological assay

Antimicrobial evaluation

The antimicrobial activities of the test compounds 2, 3, 4, 5a-e, 6a-e, 8, 9, 10a-e, and 11a-e against a variety of pathogenic microorganisms such as Escherichia coli, Pseudomonas aeruginosa (Gram-negative bacteria), Staphylococcus aureus, Bacillus cereus (Gram-positive bacteria), and one strain of fungi (Candida albicans) were determined in vitro using the disc diffusion method 14. They were isolated from clinical samples and identified to the species level according to different API 20E systems (Analytab Products Inc., New York, USA). The antimicrobial activities of the tested compounds were estimated by placing presterilized filter paper discs (6 mm in diameter) impregnated with different doses of the tested compounds (100, 50, and 25 μg/disc) on Nutrient and MacConky agar media for bacteria and on Sabouraud dextrose agar for the fungus. Dimethyl formamide was used as a solvent for impregnation. The inhibition zones of the tested compounds were measured after 24–48 h of incubation at 37°C for bacteria and after 5 days of incubation at 28°C for fungi. Cefotaxime [a standardized 30 μg cefotaxime disc (BBL, Lot 104026; assayed content of 30 μg/disc) was used in the disc diffusion test; Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey, USA] and Pipracillin (Pipracillin, 100 μg/disc; Bristol-Myers Squibb, Giza, Egypt) were used as reference drugs for bacteria, whereas nystatin (30 U/disc; Bristol-Myers Squibb; European unit=0.04 μg/disc) was used as the reference drug for the fungus (C. albicans).

Antiviral evaluation

Viruses

Live avian paramyxovirus type1 (APMV-1) and laryngotracheitis virus (LTV) were obtained from the Strain Bank of Central Laboratory for Evaluation of Veterinary Biologics, Cairo, Egypt.

Cell line

Vero (normal, African green monkey kidney) cell culture was obtained from Veterinary Vaccines and Serum Research Institute, Cairo, Egypt. Cells were cultured in sterile growth medium (RPMI-1640; Sigma-Aldrich, Germany) supplemented with 10% of heat activated new born calf serum (Sigma-Aldrich Chemie GmeH, Taufkirchen, Germany) and antibiotics (1000 IU/ml penicillin, 100 μg/ml streptomycin, and 25 μg/ml amphotericinB; Gibco, Rockville, Maryland, USA). The cells were maintained at 37°C in a humidified atmosphere with 5% CO2 and were subcultured twice a week. The virus was propagated in Vero cells and the infective titer of the stock solution was 10−7tissue culture infected dose fifty (TCID50) per ml (50% tissue culture infective dose). Viruses were adapted on Vero cells throughout seven successive passages, by which the viruses showed a distant cytopathic effect (degeneration and floatation of the infected cells) on the third day after infection.

Specific-pathogen-free egg

Specific-pathogen-free (SPF) embryonated chicken eggs were obtained from Nile SPF Farm, Koam Oshiem, Fayoum, Egypt.

In-vitro cytotoxicity screening

Cytotoxicity of the tested compounds was determined using the 3-(4,5-dimethylthiazoyl-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay 15. The subconfluent cell cultures were trypsinized and collected. The cells at a concentration of 3×103 cells/ml in 100 µl RPM1-1640 culture medium were incubated for 3 h at 37°C in a 5% CO2 incubator. The seed cells were incubated in the 96-well microplates (3×103 cells/well) at 37°C in a 5% CO2 incubator for 24 h. After 24 h, when the cells became confluent, the supernatant was flicked off and added previously diluted with media of 100 μl of different concentrations of test compounds in microplates and kept for incubation at 37°C in a 5% CO2 incubator for 72 h. The cells were periodically checked for granularity, shrinkage, and swelling. After 72 h, the sample solution in the wells was flicked off and 100 μl of MTT (0.5 mg/ml) was added to each well. The plates were gently shaken and incubated for 4 h at 37°C in a 5% CO2 incubator. The purple crystals that developed were dissolved in 100 μl dimethyl sulfoxide and absorbance was measured using an ELISA microplate reader (Bio-Rad Laboratories, Hercules, California, USA) at a wavelength of 570 nm.

In-vitro antiviral assay

Different nontoxic concentrations of test compounds, that is lower than the CTC50 (concentration required to reduce viability by 50%), were checked for antiviral property using the cytopathic effect assay against a challenge dose of 10 TCID50. Cells were seeded in 96-well microtitre plates at a population of 10 000 cells/well and incubated at 37°C in a 5% CO2 atmosphere for a period of 48 h. The plates were washed with fresh RPMI-1640 medium and then with maintenance medium containing the virus (10 TCID50); thereafter, they were incubated at 37°C for 90 min for adsorption of the virus. After this, the cultures were treated with different dilutions of the test compounds in fresh maintenance medium and incubated at 37°C for 5 days. Observations were made every 24 h and cytopathic effects were recorded. Anti-APMV-1 and anti-LTV activities were determined by the inhibition of the cytopathic effect compared with control – that is the protection offered by the test samples to the cells scored 16.

In Vero cell cultures

These assays were performed in nine 24-well tissue culture plates according to the procedure described by Cox et al. 17. Confluent monolayer’s of Vero cells were infected with 5000 TCID50/0.2 ml/well of APMV-1 or 500 TCID50 of LTV and incubated for 2 h (for virus adsorption); thereafter, inoculum was decanted, followed by addition of different 10-fold concentrations of each test sample separately (from 3 to 5 µg/ml/well of each concentration). Virus infectivity and cytotoxicity of each test compound were controlled. Test plates were incubated at 37°C in a 5% CO2 incubator for 3 days. Cytotoxicity concentration fifty (CC50) of each test compound was defined as the concentration of compounds that induced any deviation in the morphology from that of the normal control cells in 50% of Vero cell monolayers. Antiviral inhibitory concentration fifty (IC50) of test compounds was defined as the concentration of compounds that fully inhibited the cytopathic effect of viruses (100 TCID) in 50% of monolayers. In addition, the therapeutic index of samples was expressed as CC50/IC50 18.

In embryonated chicken eggs

Groups of 9–11-day-old SPF embryonated chicken eggs were inoculated with 500 embryo infective dose fifty (EID50) per 0.2 ml per egg of APMV-1 or 50 EID50 of LTV, immediately followed by injection of different concentrations of each compound (from 2 to 500 μg/0.2 ml/egg) separately. The virus infectivity control and test sample toxicity control were inoculated through the chorioallantoic cavity. Test eggs were incubated for 3–4 days at 37°C and 80% humidity. The CC50, IC50, and therapeutic index values were determined as mentioned before. APMV-1 infectivity in embryonated chicken eggs was detected by haemagglutinating activity of the allantoic fluids of the inoculated eggs, as measured by a microtechnique of the haemagglutination test 19, whereas LTV infectivity was determined on the basis of distension of the abdominal region, mottled necrotic or hemorrhagic liver, and mortality scores in embryos. CC50 and IC50 were calculated by the reported method 18.


  Results and discussions Top


Chemistry

The reaction routes for the synthesis of the title compounds are described in Schemes 1 and 2. Condensation of 8-hydroxyquinoline-5-sulfonyl chloride (1) with 2º-acetyl-2-cyanoacetohydrazide in refluxing dioxane in the presence of triethylamine led to the formation of 1-acetyl-5-amino-4-[(8-hydroxyquinoline-5-yl)sulfonyl]-1,2-dihydropyrazol-3-one (2), Scheme 1. The reaction may be preceded by reaction of the chlorine atom of 1 with the active methylene group of 2º-acetyl-2-cyanoacetohydrazide, followed by intramolecular cyclization to give 2. The structure of 2 was confirmed by its correct elemental analysis, [Table 1] as well as its IR, 1H NMR, and MS spectra [Table 2]. 1H NMR of 2 revealed two singlet signals at 10.45 and 8.01 ppm for the OH and NH group, respectively, multiple signals at 7.20–7.88 ppm for five aromatic protons, and two singlet signals at 4.66 and 2.99 ppm for the amino (NH2) and acetyl (COCH3) group, respectively [Table 2].
Table 2: Spectral characterization of the newly synthesized compounds

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In contrast, reaction of 1 with the amino group of 2-cyanoacetic acid hydrazide and its cyclic form 3-amino-5-pyrazolone in refluxing dioxane in the presence of triethylamine gave 5-amino-1-[(8-hydroxyquinoline-5-yl)sulfonyl]-1,2-dihydropyrazol-3-one (3) and 3-[(8-hydroxyquinoline-5-yl)sulfonamido]-1,2-dihydropyrazol-5(4H) one (4) in 66 and 85% yield, respectively [Scheme 1]. The characteristic features of 3 are the absence of the absorption bands for the Cl atom in the IR spectrum and the presence of absorption bands at 3209, 3163, 1686, 1385 and 1188/cm for NH2, NH, C=O, and SO2, respectively. The 1H NMR spectrum of 3 revealed signals at 10.55 (s, 1H, OH), 9.52 (s, 1H, NH), 9.11 and 8.82 (2d, 2H, H-2, and H-4 quinoline), 7.81 and 6.90 (2d, 2H, H-6 and H-7 quinoline), 7.51 (m, 1H, H-3 quinoline), 5.62 (s, 2H, NH2), and 4.44 ppm (s, 1H, CH-pyrazole; [Table 2].

Cyclocondensation reaction of compounds 3 and 4 with some arylidene malononitriles such as benzylidenemalononitrile, p-chlorobenzylidenemalononitrile, p-nitrobenzylidenemalononitrile, p-methoxybenzylidenemalononitrile, and p-(N,N-dimethylamino) benzylidenemalononitrile in refluxing dioxane in the presence of triethylamine as a catalyst led to the formation of fused systems 4-aryl-3,6-diamino-2,4-dihydro-2-[(8-hydroxyquinoline-5-yl)sulfonyl]pyrano [2,3-c]pyrazole-5-carbonitriles (5a-e) and 6-amino-4-aryl-3-[(8-hydroxyquinoline-5-yl)sulfonamido]pyrano [2,3-c]pyrazole-5-carbonitriles (6a-e), respectively, in 18–34% yields [Scheme 1; [Table 1].

Moreover, reaction of 8-hydroxyquinoline-5-sulfonyl chloride (1) with glycine in the presence of saturated potassium carbonate solution led to the formation of 2-(2-(8-hydroxyquinoline-5-yl)sulfonamido)acetic acid (7; Scheme 2].

Heterocyclization of the latter compound through its reaction with ammonium thiocyanate in acetic anhydride in the presence of anhydrous pyridine gave 1-[(8-hydroxyquinoline-5-yl)sulfonyl]-2-thioxoimidazolidin-4-one (8; Scheme 2]. The IR spectrum of 8 showed absorption bands at 1240/cm for C=S besides those for the sulfonamido group at 1371 and 1136/cm. Its 1H NMR spectrum revealed a singlet signal at 8.76 ppm for NH and at 4.24 ppm for CH2 of the imidazole moiety besides other signals that were located at those positions [Table 2].

Acid hydrolysis of compound 8 using aqueous monochloroacetic acid yielded the corresponding imidazolidin-2,4-dione derivative 9 [Scheme 2]. The IR spectrum of 9 showed the absence of the absorption bands of C=S and the presence of absorption bands at 1705 and 1715/cm for C=O groups [Table 2].

In a manner similar to that used to obtain compounds 5a-e and 6a-e, 1-[(8-hydroxyquinoline-5-yl)sulfonyl]-2-thioxoimidazolidin-4-one (8) and 1-[(8-hydroxyquinoline-5-yl)sulfonyl]- imidazolidin-2,4-one (9) were condensed with the previous arylidine malononitriles to yield the fused systems 5-amino-7-aryl-1,2-dihydro-1-[(8-hydroxyquinoline-5-yl)sulfonyl]-2-thioxopyrano [3,2-d]imidazole-6-carbonitriles (10a-e) and 5-amino-7-aryl-1,2-dihydro-1-[(8-hydroxyquinoline-5-yl)sulfonyl]-2-oxo-pyrano [3,2-d]imidazole-6-carbonitriles (11a-e), respectively, in 18–33 yields [Scheme 2; [Table 1]. The 1H NMR spectra of compounds 10a,c,e and 11a,c,e lack the presence of the CH2 proton of imidazole and revealed new singlet signals for NH2 at 8.99, 9.15, 6.76, 8.87, 8.81 and 8.57 ppm, respectively [Table 2].

Antimicrobial activity

All the newly synthesized compounds were tested for their antimicrobial activity against a variety of pathogenic microorganisms, E. coli, P. aeruginosa (Gram-negative bacteria), S. aureus, B. cereus (Gram-positive bacteria), and one strain of fungi (Candida albicans), at different doses of the tested compounds (100, 50, and 25 μg/disc) [Table 3]. The results showed that compounds 3, 4, 5c, 8, and 9 were the most active of all test compounds with growth inhibition of 28, 27, 22, 22, and 20 mm, respectively, at 100 μg/disc against E. coli when compared with the reference drug cefatoxime (32 mm) at 30 μg/disc. In addition, they showed growth inhibition of 18, 18, 16, 14, and 14 mm, respectively, at 50 μg/disc against E. coli when compared with the reference drug cefatoxime (22 mm) at 30 μg/disc. In contrast, compounds 3, 4, 8, and 9 were found to be the most active of all the test compounds with growth inhibition of 19, 20, 18, and 18 mm, respectively, at 100 μg/disc against P. aeruginosa when compared with the reference drugs cefatoxime (22 mm) at 30 μg/disc and piperacillin (20 mm) at 100 μg/disc. The rest of the tested compounds were inactive against all microorganisms tested.
Table 3: Antimicrobial activity of the newly synthesized compounds

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Antiviral activity

In Vero cell cultures

Six selected compounds were tested for their antiviral activity against avian paramyxovirus type1 (APMV-1) and laryngotracheitis virus (LTV) using the virus cytotoxicity effect inhibitory assay. The results revealed that compounds 2 and 3 as well as 4 were completely inhibited by 5000 TCID50 of APMV-1 and 500 TCID50 of LTV infectivity at concentrations of 3, 4, 3 µg/ml, respectively [Table 4]. Substantial therapeutic indices of 66, 75, and 66 were recorded. A cytotoxicity assay indicated that CC50 of 2, 3, and 4 were greater than 200, 300, and 200 mg/ml, respectively [Table 4]. These results proved that the three compounds possessed antiviral activity in Vero cells with the absence of apparent cytotoxicity.
Table 4: Cytotoxic effect of test compounds on normal Vero cell lines

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In chicken embryos

Studies on the activity of the six selected compounds (2, 3, 4, 7, 8, and 9), as determined by haemagglutinating activity in allantoic fluids and LTV infectivity criterion in embryos, showed that 4, 3, and 4 µg/0.2 ml/egg of compounds 3, 4, and 2 were fully reduced by the infectivities of 500 EID50 of APMV-1 and 50 EID50 of LTV, respectively [Table 5]. The toxicity assays of compounds 3, 4, and 2 in chicken embryos at concentrations of 300, 200, and 200 µg/egg showed 100% survival of the inoculated eggs on the fifth day after inoculation. Thus, the recorded therapeutic indices of the three compounds were 75, 66, and 50, respectively, in the case of APMV-1 and 66, 50, and 50, respectively, in the case of LTV. In conclusion, chicken embryo experiments showed that compounds 3, 4, and 2 had high antiviral activities in vitro, with IC50 ranging from 3 to 4 µg/egg against avian APMV-1 and LTV and toxic CC50 ranging from 200 to 300 µg/egg. The results showed that a concentration range of 3–4 µg/ml of compounds 2, 3, and 4 showed marked viral inhibitory activity for APMV-1 of 5000 TCID50 and LTV of 500 TCID50 in Vero cell cultures on the basis of their cytopathic effect. Chicken embryo experiments show that compounds 2, 3, and 4 had high antiviral activity in vitro, with IC50 ranging from 3 to 4 µg/egg against avian APMV-1 and LTV and toxic CC50 ranging from 200 to 300 µg/egg.
Table 5: Cytotoxic effect of test compounds in embryonated chicken specific-pathogen-free eggs

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  Conclusion Top


A series of 5-substituted sulfonyl-8-hydroxyquinoline derivatives have been prepared. 8-Hydroxyquinolines that were incorporated into rings of pyrazole 2, 3, and 4 and imidazole 8 and 9 through a sulfonyl bridge at position 5 showed inhibition growth towards E. coli and P. aeruginosa (Gram-negative bacteria) and exhibit marked viral inhibitory activity against APMV-1 and LTV.



Acknowledgements

The authors thank Ibrahim Hassan Mohamed Tolba, Department of Agriculture Botany, Faculty of Agriculture, Al-Azher University, Cairo, Egypt, for carrying out the antimicrobial activity screening. The authors are also grateful to the Micro analytical Center, Cairo University, Egypt, for providing permission to carry out elemental analyses and IR, 1H NMR, and mass spectrometry.[19]

 
  References Top

1.Hoemann MZ, Xie RL, Rossi RF, Meyer S, Sidhu A, Cuny GD, Hauske JR. Potent in vitro methicillin-resistant Staphylococcus aureus activity of 2-(1H-indol-3-yl)tetrahydroquinoline derivatives. Bioorg Med Chem Lett. 2002;12:129–132  Back to cited text no. 1
    
2.Lilienkampf A, Jialin M, Baojie W, Yuehong W, Franzblau SG, Kozikowski AP. Structure–activity relationships for a series of quinoline-based compounds active against replicating and nonreplicating Mycobacterium tuberculosis. J Med Chem. 2009;52:2109–2118  Back to cited text no. 2
    
3.Hussein M, Kafafy A-H, Abdel-Moty S, Abou-Ghadir O. Synthesis and biological activities of new substituted thiazoline-quinoline derivatives. Acta Pharm. 2009;59:365–382  Back to cited text no. 3
    
4.Vargas MLY, Castelli MV, Kouznetsov VV, Urbina GJM, López SN, Sortino M, et al. In vitro antifungal activity of new series of homoallylamines and related compounds with inhibitory properties of the synthesis of fungal cell wall polymers. Bioorg Med Chem. 2003;11:1531–1550  Back to cited text no. 4
    
5.Meléndez Gómez CM, Kouznetsov VV, Sortino MA, Álvarez SL, Zacchino SA. In vitro antifungal activity of polyfunctionalized 2-(hetero)arylquinolines prepared through imino Diels–Alder reactions. Bioorg Med Chem. 2008;16:7908–7920  Back to cited text no. 5
    
6.Kouznetsov VV, Méndez LYV, Leal SM, Cruz UM, Coronado CA, Gómez CMM, et al. Target-oriented synthesis of antiparasitic 2-hetaryl substituted quinolines based on imino Diels–Alder reactions. Lett Drug Des Discov. 2007;4:293–296  Back to cited text no. 6
    
7.Jia W, Liu Y, Li W, Liu Y, Zhang D, Zhang P, Gong P. Synthesis and in vitro anti-hepatitis B virus activity of 6H-[1]benzothiopyrano[4,3-b]quinolin-9-ols. Bioorga Med Chem. 2009;17:4569–4574  Back to cited text no. 7
    
8.Chen S, Chen R, He M, Pang R, Tan Z, Yang M. Design, synthesis, and biological evaluation of novel quinoline derivatives as HIV-1 Tat-TAR interaction inhibitors. Bioorg Med Chem. 2009;17:1948–1956  Back to cited text no. 8
    
9.Corson BB. Reactions of alpha, beta-unsaturated dinitriles. J Am Chem Soc. 1928;50:2825–2837  Back to cited text no. 9
    
10.Graham B, Porter HD, Weissberger A. Investigation of pyrazole compounds. VIII. Synthesis and acylation of pyrazolones derived from hydrazine and methylhydrazine. J Am Chem Soc. 1949;71:983–988  Back to cited text no. 10
    
11.Heibron I Dictionary of organic compounds. 19654th ed. New York Oxford University Press  Back to cited text no. 11
    
12.Bankovskis J, Cirule M, Brusilovskii PI, Tsilinskaya IA. Synthesis of 5-alkylthio-8-hydroxyquinolines. Chem Heterocyclic Comp. 1979;15:1205–1207  Back to cited text no. 12
    
13.Callejo MJ, Lafuente P, Martin-León N, Quinteiro M, Seoane C, Soto JL. A convenient preparation of [1,2,4]triazolo[1,5-a]pyridines from acetohydrazide derivatives. Synthetic and mechanistic aspects. J Chem Soc Perkin Trans. 1990;1:1687–1690  Back to cited text no. 13
    
14.Barry AL, Thornsberry CLennette EH, Balows A, HauslerJr WJ, Truant JP. Susceptibility testing: diffusion test procedures. Manual of clinical microbiology. 19803rd ed. Washington, DC American Society for Microbiology  Back to cited text no. 14
    
15.Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63  Back to cited text no. 15
    
16.Meyyanathan SN, Murli KE, Chandrashekhar HR, Godavarthi A, Dhanraj SA, Suresh B. Synthesis of some amino acid incorporated 4(3H)-quinazolinones as possible antiherpes viral agents. Ind Drugs. 2006;43:497–502  Back to cited text no. 16
    
17.Cox S, Buontempo PJ, Wright-Minogue J, DeMartino JL, Skelton AM, Ferrari E, et al. Antipicornavirus activity of SCH 47802 and analogs: in vitro and in vivo studies. Antiviral Res. 1996;32:71–79  Back to cited text no. 17
    
18.Reed LJ, Muench H. The use of spiral loops in serological and virological micro-methods. A simple method of estimating 50 percent end point. Am Ind Hyg Assoc J. 1938;27:493–497  Back to cited text no. 18
    
19.Takatsy GX. The use of spiral loops in serological and virological method. Acta Microbial Hung. 1956;3:191–194  Back to cited text no. 19
    



 
 
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