Synthesis and biological activity of some new pyrazoline and pyrimidine derivatives

Abstracts

New series of pyrazoline 3-aryl-4,5-dihydro-1H-pyrazole-1-carbaldehydes (4-6), (aryl-4,5-dihydro-1H-pyrazol-1-yl)ethanones (9-11) and 3-aryl-4,5-dihydro-1H-pyrazoles (24 and 25) were synthesized by reacting chalcones (1-3) with hydrazine hydrate in either formic acid, acetic acid or ethanol, respectively. Also, new 6-arylpyrimidin-2-amine derivatives (32-34) were synthesized from the same chalcones. The structures of the newly synthesized compounds were established on the basis of IR, ¹H NMR, 13C NMR, mass spectral data and elemental analyses. The compounds were evaluated for their antibacterial and antifungal activities. Three heterocycles showed relevant activity against C. albicans and some compounds also showed activity against E. coli.

chalcones; pyrazoline; pyrimidine; antibacterial; antifungal

Novas séries de pirazolinas, 3-aril-4,5-diidro-1H-pirazol-1-carbaldeídos (4-6), (aril-4,5-diidro-1H-pirazol-1-il)etanonas (9-11) e 3-aril-4,5-diidro-1H-pirazóis (24 e 25) foram sintetizadas pela reação de chalconas (1-3) com hidrato de hidrazina em ácido fórmico, ácido acético ou etanol, respectivamente. Novos derivados de pirimidina 6-arilpirimidina-2-amina (32-34) também foram sintetizados a partir das mesmas chalconas de partida. As estruturas dos novos compostos sintetizados foram estabelecidas através do estudo dos espectros de IV, ¹H RMN, 13C RMN e análise elementar. Todos os compostos foram avaliados quanto as suas atividades antibacteriana e antifúngica. Dentre estes compostos, três mostraram atividade relevante contra C. albicans e outros também apresentaram atividade contra E. coli.

ARTICLE

Synthesis and biological activity of some new pyrazoline and pyrimidine derivatives

Seham Y. Hassan^*

Department of Chemistry, Faculty of Science, University of Alexandria, PO Box 426, 21321 Ibrahimia, Alexandria, Egypt

ABSTRACT

New series of pyrazoline 3-aryl-4,5-dihydro-1H-pyrazole-1-carbaldehydes (4-6), (aryl-4,5-dihydro-1H-pyrazol-1-yl)ethanones (9-11) and 3-aryl-4,5-dihydro-1H-pyrazoles (24 and 25) were synthesized by reacting chalcones (1-3) with hydrazine hydrate in either formic acid, acetic acid or ethanol, respectively. Also, new 6-arylpyrimidin-2-amine derivatives (32-34) were synthesized from the same chalcones. The structures of the newly synthesized compounds were established on the basis of IR, ¹H NMR, ¹³C NMR, mass spectral data and elemental analyses. The compounds were evaluated for their antibacterial and antifungal activities. Three heterocycles showed relevant activity against C. albicans and some compounds also showed activity against E. coli.

Keywords: chalcones, pyrazoline, pyrimidine, antibacterial, antifungal

RESUMO

Novas séries de pirazolinas, 3-aril-4,5-diidro-1H-pirazol-1-carbaldeídos (4-6), (aril-4,5-diidro-1H-pirazol-1-il)etanonas (9-11) e 3-aril-4,5-diidro-1H-pirazóis (24 e 25) foram sintetizadas pela reação de chalconas (1-3) com hidrato de hidrazina em ácido fórmico, ácido acético ou etanol, respectivamente. Novos derivados de pirimidina 6-arilpirimidina-2-amina (32-34) também foram sintetizados a partir das mesmas chalconas de partida. As estruturas dos novos compostos sintetizados foram estabelecidas através do estudo dos espectros de IV, ¹H RMN, ¹³C RMN e análise elementar. Todos os compostos foram avaliados quanto as suas atividades antibacteriana e antifúngica. Dentre estes compostos, três mostraram atividade relevante contra C. albicans e outros também apresentaram atividade contra E. coli.

Introduction

Chalcones are well known intermediates for the synthesis of various heterocyclic compounds. Compounds with the chalcone backbone have been informed to possess various biological activities.¹ Chalcones have been reported to possess antimicrobial,² anti-inflammatory,^2,3 antioxidant and anticancer properties.⁴ They were also found to exhibit analgesic,⁵ platelet antiaggregation,⁶ antiulcerative,⁷ antimalarial,⁸ antiviral,⁹ antileishmanial,10 antitubercular¹¹ and antihyperglycemic properties,¹² as well as to inhibit the enzymes tyrosinase,¹³ and aldose reductase.⁹

Much attention has been paid to the synthesis of heterocyclic compounds bearing nitrogen-containing rings, like pyrazoline and pyrimidine systems, mainly due to their potential pharmacological activity.^14-31

Pyrazolines are well known and important nitrogencontaining 5-membered heterocycles, which were found to possess a broad spectrum of biological activities such as anti-inflammatory,¹⁴ herbicidal,¹⁵ antimicrobial,¹⁶ antifungal,¹⁷ antidepressant,¹⁸ anticonvulsant,19 antitumor,²⁰ antitubercular,21 insecticidal,²² antimycobacterial,²³ molluscicidal,²⁴ and antinociceptive.²⁵ A classical synthesis of 2-pyrazolines involves the base catalyzed²⁶ Claisen- Schmidt condensation of appropriate ketones with suitable aldehydes in the presence of potassium hydroxide in aqueous ethanolic solution at room temperature to give chalcones,²⁷ which undergo a subsequent cyclization reaction with hydrazines.28 Several alternatives are available for this condensation,²⁹ including under acidic²⁸ or basic³⁰ conditions. On the other hand, pyrimidines have also been reported to show a variety of biological activities.³¹

Based on the interest in the above biological activities exhibited by the pyrazoline and pyrimidine compounds, we report here the synthesis of a new series of pyrazoline and pyrimidine compounds.

Results and Discussion

Chemistry

The sequence leading to the formation of the title compounds is outlined in Schemes 1 and 2. The desired chalcones (1-3) were prepared by the reaction of anthracene-9-carbaldehyde with different ketones (p-chloro acetophenone, p-methyl acetophenone or 2-acetylfuran) in the presence of aqueous ethanolic KOH. The IR spectra of 1-3 exhibited a band due to the unsaturated carbonyl group at 1651-1660 cm^-1. Their ¹H NMR spectra showed a signal at δ 7.45-7.83 ppm attributed to the =CH-2 proton adjacent to C=O with a coupling constant 16 Hz, and a doublet at the range δ 8.60-8.79 ppm due to the =CH-3 proton with the same coupling constant, which confirmed the presence of chalcones in the trans form. The ¹³C NMR of 3-(anthracen9-yl)-1-(4-chlorophenyl)prop-2-en-1-one (1) as a prototype for the prepared chalcones showed a signal at 188.5 ppm corresponding to the C=O group.

The compounds 1-3 were converted into the corresponding 5-(anthracen-9-yl)-3-aryl-4, 5-dihydro1H-pyrazole-1-carbaldehydes (4-6) by treatment with hydrazine hydrate in formic acid. The IR spectra of aldehydes 4-6 showed the C=O band at 1666-1674 cm^-1, and their proton NMR spectra showed three signals within the ranges δ 3.28-3.42 , 3.85-4.09, and 6.40-6.96 ppm due to H₄, H_4' and H₅ of the pyrazoline ring, respectively, in addition to a singlet signal in the range δ 8.84-9.00 ppm due to the CHO proton.

Reaction of compounds 4 and 5 with benzoyl hydrazine gave rise to the corresponding benzoylhydrazides 7 and 8, respectively. Their IR spectra showed the NH bands at 3255, 3267, and the carbonyl absorption bands at 1659, 1662 cm^-1, respectively. Further, in their proton NMR spectra, it were observed the appearance of signals in the ranges δ 3.38-3.59, 3.85-4.53 and 6.71-7.86 ppm, due to H₄, H_4' and H₅ of the pyrazoline ring, respectively, a singlet at δ 8.04 and 8.41 ppm due to the N₁CH=N protons, and a singlet at δ 10.48 and 10.47 ppm, corresponding to the NH protons respectively.

The 1-(5-(anthracen-9-yl)-3-aryl-4, 5-dihydro1H-pyrazol-1-yl)ethanones 9-11 were synthesized by cyclization of chalcones 1-3 with hydrazine hydrate in acetic acid. Their structures were confirmed by IR spectra, which showed their carbonyl band in the range 1655-1667 cm^-1. On the other hand, their proton NMR showed a new singlet in the range δ 2.15-2.37 ppm, attributable to the CH₃ protons, three doublets of doublets in the range δ 3.27-3.48, 3.85-4.03, and 6.66-6.85 ppm corresponding to H₄, H_4' and H₅ of the pyrazoline ring, respectively.

Treatment of the methyl ketones 9 and 10 with benzaldehyde in alkaline medium at room temperature afforded the corresponding α,β-unsaturated ketones 12 and 13, respectively, the IR spectra of which showed the carbonyl group at 1650 and 1652 cm^-1. Their proton NMR spectra showed the disappearance of the CH₃ signals and exhibited pairs of signals at δ 7.40, 8.67 and 7.28, 8.70 ppm, respectively, as doublets, due to the olefinic protons (H_1', H_2').

The desired Schiff's bases 14-19 were prepared by heating the methyl ketones 9-11 with aryl hydrazines (phenyl hydrazine, p-nitrophenyl hydrazine) or hydrazine hydrate in ethanol. Their IR spectra showed a new absorption peak at 3285-3372 cm^-1 due to the NH group, while their ¹H NMR spectra displayed the CH₃ protons as singlets in the range δ 2.14-2.19 ppm. In addition, a broad singlet was observed in the range δ 9.20-10.61 ppm, corresponding to the NH moiety. In case of compound 19, the signal of the NH₂ group appeared at δ 7.22 ppm.

Heating the substituted 4,5-dihydro-1H-pyrazole derivative 14 with acetic anhydride afforded the corresponding tetrazole 20, which evidenced disappearance of NH signals in its IR and proton NMR spectra.

Treatment of the 3-(anthracen-9-yl)-1-arylprop-2en-1-ones 1 or 2 with p-bromophenyl-or 2-naphthyl hydrazine hydrochloride afforded the corresponding 1,3,5-trisubstituted pyrazolines (21-23). Their ¹H NMR spectra showed three multiplets in the ranges δ 2.99-3.39, 3.78-4.09 and 6.86-6.98 ppm due to the pyrazoline protons, in addition to aromatic protons at δ 7.03-8.54 ppm.

Cyclization of the chalcones 1 and 2 with hydrazine hydrate in ethanol gave the 5-(anthracen-9-yl)-3-aryl-4, 5-dihydro-1H-pyrazoles 24 and 25, respectively. Their IR spectra exhibited a NH absorption peak in the range 3254-3284 cm^-1. On other hand, their ¹H NMR showed two multiplets at δ 3.42-4.11 and 6.60-6.74 ppm, due to the pyrazoline protons. The NH protons were observed at δ 8.56 and 9.63 ppm, respectively.

Furthermore, the disubstituted pyrazolines 24 and 25 were allowed to react with sodium nitrite, phenylisothiocyanate, and p-toluenesulfonyl chloride to correspondingly furnish 5-(anthracen-9-yl)-3-aryl-1nitroso-4,5-dihydro-1H-pyrazoles 26 and 27, 5-(anthracen9-yl)-3-aryl-N-phenyl-4,5-dihydro-1H-pyrazole-1carbothioamides 28 and 29 and 5-(anthracen-9-yl)-3-aryl1-tosyl-4,5-dihydro-1H-pyrazoles 30 and 31, respectively, in 74-89% yield.

On the other hand, the reaction of chalcones 1-3 with an alcoholic solution of guanidine carbonate containing aqueous NaOH produced the corresponding 2-amino-4, 6-diarylpyrimidines 32-34 (Scheme 2). This transformation might proceed either by 1,4-addition or 1,2-addition of the guanidine to the chalcones, followed by cyclization of the intermediate, which undergoes proton shift and aromatization to yield the 2-aminopyrimidines.³² The infrared spectra of the products showed two bands in the ranges 3054-3147 and 3323-3366 cm^-1 corresponding to the NH₂ group. Furthermore, their 1H NMR showed a D₂O exchangeable signal at δ 5.97-6.26 ppm due to the NH₂ protons. A singlet at δ 7.35-7.91 ppm was observed due to the pyrimidine-H₅.

Acetylation of the 2-aminopyrimidines 32 and 33 with Ac₂O yielded the monoacetylated compounds 35 and 36, respectively. Their infrared spectra showed peaks at 3260 and 3218 cm-1 corresponding to the NH group and strong sharp peaks at 1667 and 1669 cm^-1, respectively, due to the C=O group. On the other hand, their ¹H NMR showed the CH₃ protons as singlets at δ 2.25 and 2.29 ppm, in addition to the NH protons at δ 10.77 and 10.47 ppm respectively.

Evaluation of the biological activity

Four test organisms representing different groups of microorganisms were used to evaluate the bioactivity of the designed products. The inhibition zone and minimal inhibitory concentration results are given in Table 1.

From the data, it stems that compounds 1, 3, 7, 20, 23, 31 and 34 were the most active against E. coli, while compounds 18, 28 and 30 were found to be active against C. albicans. Some chlorinated compounds exhibited activity against C. albicans (28 and 30) and against E. coli (1, 7 and 20). In addition, some sulfur-containing compounds exhibited activity against C. albicans (28 and 30) and against E. coli (31). It was noticed that furan derivatives also showed activity against C. albicans (18), and against E. coli (3 and 34). No systematic variation was observed in the antibacterial and antifungal activities for the rest of the compounds. All tested compounds showed poor biological activity against P. aeruginosa and S. aureus.

Conclusions

In summary, new series of anthracenylpyrazolines and anthracenylpyrimidines were synthesized from 3-(anthracen-9-yl)-1-aryl-prop-2-en-1-one derivatives, and spectroscopically characterized. The biological activity of the compoundswasevaluatedagainst E. coli, P. aeruginosa, S. aureus and C. albicans by the agar diffusion method. The potency of compounds 18, 28 and 30 as antifungics against C. albicans is about 50% of that of Clotrimazole. On the other hand, the potency of compounds 1, 3, 7, 20, 23, 31 and 34 as antibacterials against E. coli is about 50% of that of Ampicillin.

Experimental

Chemistry

General experimental considerations

Reagent quality solvents were used without purification. Melting points were obtained in open capillary tubes by using a MEL-Temp II melting point apparatus and are uncorrected. Infrared spectra (IR) were recorded on a Perkin-Elmer 1600 series Fourier transform instrument with the samples as KBr pellets. ¹H NMR and ¹³C NMR spectra were recorded on JEOL 500 MHz spectrometers at ambient temperature using tetramethylsilane as an internal reference. Mass spectra were recorded on a JEOL JMS AX-500 spectrometer by using electron impact ionization at 70 eV. Elemental analyses were carried out by the University of Cairo Microanalytical Laboratories. The antimicrobial tests were carried out at the Pharmaceutical Department, Faculty of Pharmacy, Alexandria University. ChemDraw-Ultra-11.0 has been used for the nomenclature of the prepared compounds.

General procedure for the preparation of compounds 1-3

An equimolar mixture of anthracene-9-carbaldehyde (2.06 g, 0.01 mol) and the substituted ketone (1.54 g 4-chloro acetophenone, 1.34 g 4-methyl acetophenone or 1.10 g 2-acetylfuran) in 2% ethanolic KOH (20 mL) was stirred at r.t. for 4 h. The solid product was cooled, collected by filtration, washed with ethanol, dried and recrystallized from chloroform/ethanol.

3-(Anthracen-9-yl)-1-(4-chlorophenyl)prop-2-en-1-one (1)

Yield: 90%, orange-yellow crystals, mp 124-125 ºC. IR (KBr) V_max/cm^-1: 1593 (C₂=C₃), 1656 (C=O); ¹H NMR (CDCl₃) δ 7.45-7.51 (m, 7H, =CH-2 and 6 ArH), 8.00 (d, 4H, J 8 Hz, ArH), 8.27 (d, 2H, J 8 Hz, ArH), 8.42 (s,1H, H_anth-10), 8.79 (d, 1H, J 16 Hz, =CH-3); ¹³C NMR (DMSO-d₆) δ 125.2, 125.4, 125.5, 125.6, 126.6, 126.7, 128.7, 128.8, 129.0, 129.2, 129.3, 129.5, 129.7, 130.0, 130.1, 130.3, 130.6, 131.4, 136.3, 139.7, 142.5, 142.6, 188.5 (C=O). Anal. Calc. for C₂₃H₁₅ClO (342.08): C, 80.58; H, 4.41. Found: C, 80.63; H, 4.57%.

3-(Anthracen-9-yl)-1-p-tolylprop-2-en-1-one (2)

Yield: 86%, yellow crystals, mp 111-112 ºC. IR (KBr) V_max/cm^-1: 1601 (C₂=C₃), 1660 (C=O); ¹H NMR (DMSO-d₆) δ 2.19 (3H, s, p-CH₃), 6.94 (d, 2H, J 8.0 Hz, ArH), 7.31 (d, 2H, J 8.0 Hz, ArH;), 7.49-7.54 (m, 4H, ArH), 7.83 (d, 1H, J 16 Hz, =CH-2), 8.03 (t, 2H, J 7.0 Hz, ArH;), 8.31 (d, 2H, J 7.0 Hz, ArH), 8.47 (s, 1H, H_anth-10), 8.79 (d, 1H, J 16 Hz, =CH-3). Anal. Calc. for C₂₄H₁₈O (322.40): C, 89.41; H, 5.63. Found: C, 89.60; H, 5.70%.

3-(Anthracen-9-yl)-1-(furan-2-yl)prop-2-en-1-one (3)

Yield: 87%, yellow crystals, mp 140-141 ºC. IR (KBr) V_max/cm^-1: 1594 (C₂=C₃), 1651 (C=O); ¹H NMR (DMSO-d₆) δ 6.75 (t, 1H, J 8.0 Hz, ArH), 7.50-7.58 (m, 5H, =CH-2 + 4 ArH), 7.74 (d, 1H, J 3.0 Hz, ArH), 8.12 (d, 3H, J 8.0 Hz, ArH) 8.20 (d, 2H, J 8.0 Hz, ArH), 8.60 (d, 1H, J 16 Hz, =CH-3), 8.66 (s, 1H, H_anth-10). Anal. Calc. for C₂₁H₁₄O₂ (298.33): C, 84.54; H, 4.73. Found: C, 84.65; H, 4.81%.

General procedure for the preparation of compounds 4-6

A mixture of 3-(anthracen-9-yl)-1-(aryl)prop-2-en1-one (1-3, 0.001 mol) and hydrazine hydrate (3 mL) in formic acid (15 mL) was heated under reflux for 8 h. The reaction mixture was poured onto crushed ice, the precipitated product was filtered, washed with water, dried and recrystallized from chloroform/ethanol.

5-(Anthracen-9-yl)-3-(4-chlorophenyl)-4, 5-dihydro-1Hpyrazole-1-carbaldehyde (4)

Yield: 85%, buff crystals, mp 225-226 ºC. IR (KBr) V_max/cm^-1: 1674 (C=O); ¹H NMR (DMSO-d₆) δ 3.36-3.39 (m, 1H, pyrazoline-H₄), 3.85-4.09 (m, 1H, pyrazoline-H_4'), 6.86-6.96 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H₅), 7.48 (dd, 2H, J 3, 7.0 Hz,ArH), 7.56 (d, 2H, J 7.6 Hz,ArH), 7.69 (d, 2H, J 7.0 Hz, ArH), 7.91(d, 2H, J 7.0 Hz, ArH), 8.05 (dd, 2H, J 3.0, 7.0 Hz, ArH), 8.11 (d, 2H, J 7.6 Hz, ArH), 8.53 (s, 1H, H_anth-10), 8.84 (s, 1H, CHO). Anal. Calc. for C₂₄H₁₇ClN₂O (384.86): C, 74.90; H, 4.45; N, 7.28. Found: C, 74.65; H, 4.23; N, 7.49%.

5-(Anthracen-9-yl)-3-p-tolyl-4,5-dihydro-1H-pyrazole-1carbaldehyde (5)

Yield: 81%, brown crystals, mp 199-200 ºC. IR (KBr) V_max/cm^-1: 1666 (C=O); ¹H NMR (DMSO-d₆) δ 2.19 (3H, s, p-CH₃), 3.15-3.30 (1H, m, pyrazoline-H₄), 4.08 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4'), 6.88 (t, 1H, J 7.0, 12 Hz, pyrazoline-H₅), 7.37-7.58 (m, 6H, ArH), 7.67 (d, 1H, J 8.0 Hz, ArH), 7.86 (d, 2H, J 7.6 Hz, ArH), 8.00 (d, 2H, J 8.0 Hz, ArH), 8.56-8.58 (m, 2H, ArH), 9.00 (s, 1H, CHO). Anal. Calc. for C₂₅O (364.44): C, 82.39; H, ^H20^N25.53; N, 7.69. Found: C, 82.15; H, 5.33; N, 7.90%.

5-(Anthracen-9-yl)-3-(furan-2-yl)-4, 5-dihydro-1Hpyrazole-1-carbaldehyde (6)

Yield: 78%, buff crystals, mp 204-205 ºC. IR (KBr) V_max/cm^-1: 1670 (C=O); ¹H NMR (DMSO-d₆) δ 3.28-3.42 (m, 1H, pyrazoline-H₄), 3.98-4.07 (m, 1H, pyrazoline-H_4'), 6.40-6.48 (m, 1H, pyrazoline-H₅), 6.54 (d, 1H, J 3.0 Hz, ArH), 6.70 (t, 1H, J 8.0 Hz, ArH), 6.86 (d, 2H, J 7.0 Hz, ArH), 7.05 (d, 2H, J 7.0 Hz, ArH), 7.20 (d, 1H, J 8.0 Hz, ArH), 7.44 (dd, 2H, J3.0, 7.0Hz,ArH),8.03 (dd,2H, J3.0, 7.0 Hz,Ar-H), 8.52 (s, 1H, H_anth-10), 8.59 (s, 1H, CHO).Anal. Calc. for C₂₂H₁₆N₂O₂(340.37): C, 77.63; H, 4.74; N, 8.23. Found: C, 77.69; H, 4.83; N, 8.04%.

General procedure for the preparation of compounds 7 and 8

To a solution of 5-(anthracen-9-yl)-3-aryl-4, 5-dihydro-1H-pyrazole-1-carbaldehyde 4 (3.84 g, 0.01 mol) or 5 (3.64 g, 0.01 mol) in ethanol (30 mL) was added benzoyl hydrazine (1.63 g, 0.012 mol) and two drops of acetic acid. The reaction mixture was heated under reflux for 6 h, partially concentrated and cooled. The separated solid product was filtered, washed with ethanol, dried and crystallized from ethanol.

N'-((5-(Anthracen-9-yl)-3-(4-chlorophenyl)-4,5-dihydro1H-pyrazole-1-yl)methylene) benzoylhydrazide (7)

Yield: 77%, buff crystals, mp 207-208 ºC. IR (KBr) V_max/cm^-1: 1659 (C=O), 3255 (NH); ¹H NMR (DMSO-d₆) δ 3.38-3.59 (m, 1H, pyrazoline-H₄), 4.51-4.53 (m, 1H, pyrazoline-H_4'), 6.71-6.86 (m, 1H, pyrazoline-H₅), 7.31-7.37 (m, 4H, ArH), 7.47-7.62 (m, 2H, ArH), 7.71-7.83 (m, 5H, ArH), 7.89-7.96 (m, 4H, ArH), 8.04 (s, 1H, N₁CH=N), 8.17-8.32 (m, 2H, ArH), 8.52 (s, 1H, H_anth-10), 10.48 (s, 1H, NH; D₂O exchangeable). Anal. Calc. for C₃₁H₂₃ClN₄O (502.99): C, 74.02; H, 4.61; N, 11.14. Found: C, 74.24; H, 4.85; N, 11.00%.

N'-((5-(Anthracen-9-yl)-3-p-tolyl-4,5-dihydro-1Hpyrazole-1-yl)methylene)benzoylhydrazide (8)

Yield: 74%, buff crystals, mp 181-182 ºC. IR (KBr) V_max/cm^-1: 1662 (C=O), 3267 (NH); ¹H NMR (CDCl₃) δ 2.18 (3H, s, p-CH₃), 3.46 (dd, 1H, J_1,2 9, J_1,3 18 Hz, pyrazoline-H₄), 3.85 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4'), 6.86 (dd, 1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅), 7.34-7.46 (m, 10H, ArH), 7.73-7.81 (m, 4H, ArH), 8.00-8.10 (m, 3H, ArH), 8.41 (s, 1H, N₁CH=N), 8.50 (s, 1H, H_anth-10), 10.47 (s, 1H, NH; D₂O exchangeable).Anal.Calc.forC₃₂H₂₆N₄O(482.58):C,79.64; H, 5.43; N, 11.61. Found: C, 79.41; H, 5.60; N, 11.83%.

General procedure for the preparation of compounds 9-11

A mixture of 3-(anthracen-9-yl)-1-(aryl)prop-2-en1-one (1-3, 0.001 mol) and hydrazine hydrate (3 mL) in acetic acid (15 mL) was heated under reflux for 8 h. The reaction mixture was poured onto crushed ice, the precipitated product was filtered, washed with water, dried and recrystallized from chloroform/ethanol.

1-(5-(Anthracen-9-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (9)

Yield: 84%, buff crystals, mp 239-240 ºC. IR (KBr) V_max/cm^-1: 1655 (C=O); ¹H NMR (CDCl₃) δ 2.35 (s, 3H, COCH₃), 3.46 (dd, 1H, J_1,2 9, J_1,3 18 Hz, pyrazoline-H₄), 3.85 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4'),6.85 (dd,1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅), 7.33-7.48 (m, 5H, ArH), 7.55 (t, 1H, J 7.6 Hz, ArH), 7.74 (dd, 3H, J 2, 9 Hz, ArH), 8.01 (dd, 2H, J 3, 7.6 Hz, ArH), 8.41 (s, 1H, H_anth-10), 8.49 (d, 1H, J 9Hz,ArH).Anal.Calc.forC₂₅H₁₉ClN₂O(398.88):C, 75.28; H, 4.80; N, 7.02. Found: C, 75.08; H, 4.65; N, 7.21%.

1-(5-(Anthracen-9-yl)-3-p-tolyl-4,5-dihydro-1-Hpyrazol-1-yl)ethanone (10)

Yield: 78%, buff crystals, mp 194-195 ºC. IR (KBr) V_max/cm^-1: 1667 (C=O); ¹H NMR (CDCl₃) δ 2.37 (s, 3H, COCH₃), 2.43 (s, 3H, p-CH₃), 3.48 (dd, 1H, J_1,2 9, J_1,3 18 Hz, pyrazoline-H₄), 3.89 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4') 6.85 (dd, 1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅), 7.27 (t, 2H, J 7.6 Hz, ArH), 7.32-7.41 (m, 2H, ArH), 7.49 (t, 1H, J 7.6 Hz, ArH), 7.54-7.57 (m, 1H, ArH), 7.72 (d, 2H, J 7.6 Hz, ArH), 7.79 (d, 1H, J 8 Hz, ArH), 8.01 (d, 2H, J 8.0 Hz, ArH), 8.42 (s, 1H, H_anth-10), 8.52 (d, 1H, J 8.0 Hz, ArH). Anal. Calc.for C₂₆H₂₂N₂O (378.47): C, 82.51; H, 5.86; N, 7.40. Found: C, 82.72; H, 5.98; N, 7.19%.

1-(5-(Anthracen-9-yl)-3-(furan-2-yl)-4,5-dihydro-1-Hpyrazol-1-yl)ethanone (11)

Yield: 80%, buff crystals, mp 200-201 ºC. IR (KBr) V_max/cm^-1: 1657 (C=O); ¹H NMR (DMSO-d₆) δ 2.15 (3H, s, COCH₃), 3.27 (dd, 1H, J_1,2 9, J_1,3 18 Hz, pyrazoline-H₄), 4.03 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4'), 6.66-6.67 (m, 1H,ArH), 6.84 (dd, 1H, J_1,2 9, J_1,3 13 Hz pyrazoline-H₅), 6.99 (d, 1H, J 3.0 Hz, ArH), 7.42 (t, 2H, J 8.0 Hz, ArH), 7.51 (t, 1H, J 7.0 Hz, ArH), 7.56 (t, 1H, J 7.0 Hz, ArH), 7.68 (d, 1H, J 3.0 Hz, ArH),7.90 (s, 1H, H_anth-10), 8.07 (d, 2H, J 7.0 Hz, ArH), 8.55-8.56 (m, 2H, ArH). Anal. Calc. for C₂₃H₁₈N₂O₂(354.40): C, 77.95; H, 5.12; N, 7.90. Found: C, 77.73; H, 5.32; N, 7.99%.

General procedure for the preparation of compounds 12 and 13

An equimolar mixture of 1-(5-(anthracen-9-yl)-3aryl-4, 5-dihydro-1H-pyrazol-1-yl)ethanone 9 (3.98 g, 0.01 mol) or 10 (3.78 g, 0.01 mol) and benzaldehyde (1.06 g, 0.01 mol) in 2% ethanolic KOH (20 mL) was stirred at r.t. for 4 h. The solid product was cooled, collected by filtration, washed with ethanol, dried, and recrystallized from chloroform/ethanol.

1-(5-(Anthracen-9-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-3-phenyl-prop-2-en-1-one (12)

Yield: 71%, off white needles, mp 259-260 ºC. IR (KBr) V_max/cm^-1: 1650 (C=O); ¹H NMR (DMSO-d₆) δ 3.33-3.37 (m, 1H, pyrazoline-H₄), 4.07 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H₄'), 6.88 (dd, 1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅), 7.40 (d, 1H, J 6.0 Hz, =CH-1_'), 7.42-7.47 (m, 4H, ArH), 7.50-7.58 (m, 5H, ArH), 7.67 (d, 2H, J 8 Hz, ArH), 7.86 (d, 2H, J 7.6 Hz, ArH), 7.96 (d, 2H, J 8 Hz, ArH), 8.08 (d, 2H, J 7.6 Hz, ArH), 8.55 (s, 1H, H_anth-10), 8.67 (d, 1H, J 6.0 Hz, =CH-2). Anal. Calc. for C₃₂H₂₃ClN₂O 486.99): C, 78.92; H, 4.76; N, 5.75. Found: C, 79.00; H, 4.82; N, 5.58%.

1-(5-(Anthracen-9-yl)-3-p-tolyl-4,5-dihydro-1H-pyrazol-1-yl)-3-phenylprop-2-en-1-one (13)

Yield: 73%, off white needles, mp 225-226 ºC. IR (KBr) V_max/cm^-1: 1652 (C=O); ¹H NMR (DMSO-d₆) δ 2.33 (3H, s, p-CH₃), 3.27-3.38 (m, 1H, pyrazoline-H₄), 4.07 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4'), 6.86 (dd, 1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅), 7.28 (d, 1H, J 6 Hz, =CH-1), 7.35 (t, 2H, J 7.6 Hz, ArH), 7.41 (t, 2H, J 7.0 Hz, ArH), 7.50-7.58 (m, 5H, ArH), 7.70 (d, 2H, J 7.0 Hz, ArH), 7.77 (d, 2H, J 7.6 Hz, ArH), 8.08 (d, 2H, J 8.0 Hz, ArH), 8.55 (s, 1H, H_anth-10), 8.58 (d, 2H, J 8.0 Hz, ArH), 8.70 (d, 1H, J 6.0 Hz, =CH-2). Anal. Calc. for C₃₃H₂₆N₂O (466.57): C, 84.95; H, 5.62; N, 6.00. Found: C, 84.70; H, 5.90; N, 6.27%.

General procedure for the preparation of compounds 14-19

To a solution of 1-(5-(anthracen-9-yl)-3-aryl-4, 5-dihydro-1H-pyrazol-1-yl)ethanone (9-11, 0.01 mol) in ethanol (25 mL) was added hydrazine hydrate or aryl hydrazine (0.012 mol) and two drops of acetic acid. The reaction mixture was heated under reflux for 8 h, partially concentrated and cooled. The separated solid product was filtered, washed with ethanol, dried and crystallized from ethanol.

5-(Anthracen-9-yl)-3-(4-chlorophenyl)-1-(1-(2-phenylhydrazono)ethyl)-4,5-dihydro-1H-pyrazole (14)

Yield: 77%, buff crystals, mp 270-271 ºC. IR (KBr) V_max/cm^-1: 3295 (NH); ¹H NMR (DMSO-d₆) δ 2.19 (3H, s, N=C-CH₃), 3.22-3.40 (m, 1H, pyrazoline-H₄), 4.07 (m, 1H, pyrazoline-H_4'), 6.89 (dd, 1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅), 7.37 (t, 2H, J 8 Hz, ArH), 7.42 (t, 2H, J 7.0 Hz, ArH), 7.52-7.58 (m, 5H, ArH), 7.66 (d, 2H, J 8.0 Hz, ArH), 7.87 (d, 4H, J 8.0 Hz, ArH), 8.06 (d, 2H, J 7.0 Hz, ArH), 8.56 (s, 1H, H_anth-10), 9.58 (s, 1H, NH; D₂O exchangeable). Anal. Calc.for C₃₁H₂₅ClN₄ (489.01): C, 76.14; H, 5.15; N, 11.46. Found: C, 76.31; H, 5.26; N, 11.19%.

5-(Anthracen-9-yl)-1-(1-(2-phenylhydrazono)ethyl)-3-p-tolyl-4,5-dihydro-1H-pyrazole (15)

Yield: 78%, reddish brown crystals, mp 89-90 ºC. IR (KBr) V_max/cm^-1: 3297 (NH); ¹H NMR (DMSO-d₆) δ 2.19 (3H, s, N=C-CH₃), 2.34 (3H, s, p-CH₃), 3.33-3.39 (m, 1H, pyrazoline-H₄), 4.08 (m, 1H, pyrazoline-H_4'), 6.87 (dd, 1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅), 7.21-7.77 (m, 12H, ArH), 8.09 (d, 2H, J 8.0 Hz, ArH), 8.18-8.20 (m, 2H, ArH), 8.56-8.60 (m, 2H, ArH), 10.61 (s, 1H, NH; D₂O exchangeable). Anal. Calc.for C₃₂(468.59): C, 82.02; H, 6.02; N, ^H28^N4 11.96. Found: C, 82.25; H, 5.88; N, 12.20%.

5-(Anthracen-9-yl)-3-(4-chlorophenyl)-1-(1-(2-(4-nitrophenyl)hydrazono)ethyl)-4,5-dihydro-1H-pyrazole (16)

Yield: 79%, pale brown crystals, mp 180-181 ºC. IR (KBr) V_max/cm^-1: 3285 (NH); ¹H NMR (DMSO-d₆) δ 2.19 (s, 3H, N=C-CH₃), 3.26-3.33 (m, 1H, pyrazoline-H₄), 4.08 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4'), 6.88 (dd, 1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅),7.43-7.52 (m, 4H, ArH), 7.55 (d, 2H, J 9.0 Hz, ArH), 7.66 (d, 2H, J 9.0 Hz, ArH), 7.69-7.74 (m, 2H, ArH), 7.87 (d, 2H, J 8.0 Hz, ArH;), 7.97 (d, 2H, J 7.6 Hz, ArH), 8.08 (d, 2H, J 7.6 Hz, ArH), 8.57 (s, 1H, H_anth-10), 9.22 (s, 1H, NH; D₂O exchangeable). Anal. Calc. for C₃₁H₂₄ClN₅O₂(534.01): C, 69.72; H, 4.53; N, 13.11. Found: C, 69.79; H, 4.80; N, 12.97%.

5-(Anthracen-9-yl)-1-(1-(2-(4-nitrophenyl)hydrazono) ethyl)-3-p-tolyl-4,5-dihydro-1H-pyrazole (17)

Yield: 80%, pale brown crystals, mp 85-86 ºC. IR (KBr) V_max/cm^-1: 3300 (NH); ¹H NMR (DMSO-d₆) δ 2.19 (3H, s, N=C-CH₃), 2.33 (3H, s, p-CH₃), 3.30-3.40 (m, 1H, pyrazoline-H₄), 4.08 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4'), 6.86 (dd, 1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅), 7.28 (d, 2H, J 8.0 Hz, ArH), 7.34-7.43 (m, 3H, ArH), 7.50-7.58 (m, 3H, ArH), 7.69-7.82 (m, 4H, ArH), 8.12 (d, 2H, J 8.0 Hz, ArH), 8.55 (s, 1H,H_anth-10 ), 8.58 (d, 2H, J 8.0 Hz, ArH), 9.20 (s, 1H, NH; D₂O exchangeable), MS m/z: 513 (M). Anal. Calc.for C₃₂H₂₇N₅O₂ (513.59): C, 74.83; H, 5.30; N, 13.64. Found: C, 74.60; H, 5.09; N, 13.85%.

5-(Anthracen-9-yl)-3-(furan-2-yl)-1-(1-(2-(4-nitrophenyl) hydrazono)ethyl)-4,5-dihydro-1H-pyrazole (18)

Yield: 81%, brown crystals, mp 120-121 ºC. IR (KBr) V_max/cm^-1: 1323, 1502 (NO₂), 3372 (NH); ¹H NMR (DMSO-d₆) δ 2.14 (3H, s, N=C-CH₃), 3.26 (dd, 1H, J_1,2 9, J_1,3 18 Hz, pyrazoline-H₄), 4.03 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4'), 6.84 (dd, 1H, J_1,2 9, J_1,3 13 Hz pyrazoline-H₅), 6.98 (d, 1H, J 3.0 Hz, ArH), 7.42 (t, 3H, J 3.8 Hz, ArH), 7.50-7.56 (m, 4H, ArH), 7.67 (d, 1H, J 10 Hz, ArH), 7.93 (s, 1H, H_anth-10), 8.07 (d, 4H, J 7.6 Hz, ArH), 8.54-8.56 (m, 2H, ArH), 9.20 (s, 1H, NH; D₂O exchangeable). Anal. Calc. for C₂₉H₂₃N₅O₃ (489.52): C, 71.15; H, 4.74; N, 14.31. Found: C, 71.33; H, 4.51; N, 14.05%.

5-(Anthracen -9-yl) -3-(4 -chlorophenyl) -1-(1-hydrazonoethyl)-4, 5-dihydro-1H-pyrazole (19)

Yield: 85%, pale yellow needles, mp 275-276 ºC. ¹H NMR (DMSO-d₆) δ 2.19 (3H, s, N=C-CH₃), 3.38 (m, 1H, pyrazoline-H₄), 4.08 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4'), 6.91 (dd, 1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅), 7.22 (s, 2H, NH₂; D₂O exchangeable), 7.37-7.43 (m, 2H, ArH), 7.51-7.57 (m, 4H, ArH), 7.67 (d, 2H, J 7.0 Hz, ArH), 7.88 (d, 2H, J 8.0 Hz, ArH), 8.09 (d, 2H, J 8.0 Hz, ArH), 8.57 (s, 1H, H_anth-10). Anal. Calc. for C₂₅H₂₁ClN₄ (412.91): C, 72.72; H, 5.13; N, 13.57. Found: C, 72.63; H, 4.95; N, 13.73%.

5-(Anthracen-9-yl)-7-(4-chlorophenyl)-3-methyl-1-phenyl-1, 5-dihydropyrazolo[1,2-a]tetrazole (20)

A mixture of 4,5-dihydro-1H-pyrazole derivative 14 (0.49 g, 0.001 mol) and acetic anhydride (10 mL) was heated on a boiling water bath for 5 h. The reaction mixture was poured onto crushed ice, the precipitated product was filtered, washed with water, dried and recrystallized from ethanol/chloroform, furnishing 20.

Yield: 65%, buff crystals, mp 169-170 ºC. ¹H NMR (DMSO-d₆) δ 2.32 (3H, s, CH₃), 4.34-4.38 (m, 1H, pyrazoline-H₄), 4.50-4.53 (m, 1H, pyrazoline-H₅), 7.27 (t, 2H, J 7.6 Hz, ArH), 7.37-7.51 (m, 3H, ArH), 7.68 (d, 2H, J 8.0 Hz, ArH), 7.90-7.91 (m, 2H, ArH), 7.99 (d, 2H, J 8.0 Hz, ArH), 8.04 (d, 2H, J 7.6 Hz, ArH), 8.12 (d, 2H, J 7.6 Hz, ArH), 8.17-8.19 (m, 2H, ArH), 8.68 (s, 1H, H_anth-10). ¹³C NMR (DMSO) δ 22.16, 56.88, 122.93, 123.11, 124.36, 126.79, 127.04, 128.07, 128.30, 128.95, 129.11, 129.47, 129.69, 130.07, 130.38, 130.51, 130.58, 131.44, 131.95,132.94,135.62,154.09.Anal.Calc.forC₃₁H₂₃ClN₄ (486.99): C, 76.46; H, 4.76; N, 11.50. Found: C, 76.53; H, 4.81; N, 11.41%.

General procedure for the preparation of compounds 21-23

To a solution of 3-(anthracen-9-yl)-1-(aryl)prop-2-en-1-one (1, 0.34 g, 0.001 mol or 2, 0.32 g, 0.001 mol) in absolute ethanol (20 mL) was added the proper aryl hydrazine hydrochloride (0.0012 mol). The reaction mixture was heated under reflux for 4 h. A solid product was obtained after concentration and cooling. The precipitated product was filtered, washed with ethanol, dried, and recrystallized from ethanol/chloroform.

5-(Anthracen -9-yl) -1-(4 -bromophenyl) -3-(4-chlorophenyl)-4, 5-dihydro-1H-pyrazole (21)

Yield: 70%, buff crystals, mp 299-300 ºC. ¹H NMR (DMSO-d₆) δ 3.12-3.39 (1H, m, pyrazoline-H₄), 3.94-4.06 (1H, m, pyrazoline-H_4'), 6.86-6.94 (1H, m, pyrazoline-H₅), 7.03-7.15 (m, 4H, ArH), 7.30 (d, 2H, J 7.6 Hz, ArH), 7.41 (t, 2H, J 7.6 Hz, ArH), 7.48 (t, 2H, J 7 Hz, Ar-H), 7.71 (d, 2H, J 8.0 Hz, ArH), 7.91 (d, 2H, J 8.0 Hz, ArH), 8.05 (d, 2H, J 8.0 Hz, ArH), 8.53 (s, 1H, H_anth-10). Anal. Calc. for C₂₉H₂₀BrClN₂ (511.84): C, 68.05; H, 3.94; N, 5.47. Found: C, 68.27; H, 4.09; N, 5.22%.

5-(Anthracen-9-yl)-1-(4-bromophenyl)-3-p-tolyl)-4,5dihydro-1H-pyrazole (22)

Yield: 73%, brown crystals, mp 130-131 ºC. ¹H NMR (DMSO-d₆) δ 2.17 (s, 3H, p-CH₃), 3.34 (dd, 1H, J_1,2 9, J_1,3 18 Hz, pyrazoline-H₄), 4.09 (dd, 1H, J_1,2 13, J_1,3 18 Hz, pyrazoline-H_4'), 6.86 (dd, 1H, J_1,2 9, J_1,3 13 Hz, pyrazoline-H₅), 7.34 (t, 2H, J 7.6 Hz,ArH), 7.41 (t, 2H, J 7.6 Hz, ArH), 7.49-7.58 (m, 5H, Ar-H), 7.62 (d, 2H, J 9.0 Hz, ArH), 7.85 (d, 2H, J 8.0 Hz, ArH), 8.08 (d, 2H, J 8.0 Hz, ArH), 8.54-8.56 (m, 1H, ArH). Anal. Calc. for C₃₀H₂₃BrN₂ (491.42): C, 73.32; H, 4.72; N, 5.70. Found: C, 73.59; H, 4.61; N, 5.51%.

5-(Anthracen-9-yl)-1-(naphthalene-2-yl)-3-p-tolyl-4, 5-dihydro-1H-pyrazole (23)

Yield: 77%, pale brown crystals, mp 160-161 ºC. ¹H NMR (DMSO-d₆) δ 2.44 (3H, s, p-CH₃), 2.99-3.39 (m, 1H, pyrazoline-H₄), 3.78-4.04 (m, 1H, pyrazoline-H_4'), 6.92-6.98 (m, 1H, pyrazoline-H₅), 7.21-7.27 (m, 4H, ArH _.), 7.29 (dd, 2H, J 7.6, 13 Hz, ArH), 7.39-7.43 (m, 2H, ArH), 7.57-7.79 (m, 4H, ArH), 7.81 (dd, 1H, J 3.0, 5.0 Hz, ArH), 7.97 (dd, 2H, J 7.6, 13 Hz), 8.20-8.28 (m, 2H, ArH), 8.31 (dd, 1H, J 3.0, 5.0 Hz, ArH), 8.50 (s, 1H, ArH), 8.52 (s, 1H, ArH). Anal. Calc. for C₃₄H₂₆N₂ (462.58): C, 88.28; H, 5.57; N, 6.06. Found: C, 88.05; H, 5.43; N, 6.24%.

General procedure for the preparation of compounds 24 and 25

A mixture of 3-(anthracen-9-yl)-1-(aryl)prop-2-en-1-one (1, 0.34 g, 0.001 mol or 2, 0.32 g, 0.001 mol) and hydrazine hydrate (3 mL) in ethanol (20 mL) was heated under reflux for 4 h. The solid product was obtained after concentration and cooling, the precipitated product was filtered, washed with ethanol, dried and recrystallized from ethanol.

5-(Anthracen-9-yl)-3-(4-chlorophenyl)-4, 5-dihydro-1H-pyrazole (24)

Yield: 74%, pale brown crystals, mp 230-231 ºC. IR (KBr) V_max/cm^-1: 3254 (NH); ¹H NMR (DMSO-d₆) δ 3.60-4.11 (m, 2H, pyrazoline-H₄,H_4'), 6.71-6.74 (m, 1H, pyrazoline-H₅), 7.01-7.11 (m, 2H, ArH), 7.25-7.40 (m, 2H, ArH), 7.50-7.71 (m, 4H, ArH), 7.83-7.91 (m, 4H, ArH), 8.18 (s, 1H, H_anth-10), 8.56 (s, 1H, NH; D₂O exchangeable), MS m/z: 356, 358 (M). Anal. Calc. for C₂₃H₁₇ClN₂ (356.85): C, 77.41; H, 4.80; N, 7.85. Found: C, 77.60; H, 4.60; N, 7.63%.

5-(Anthracen-9-yl)-3-p-tolyl-4, 5-dihydro-1H-pyrazole (25)

Yield: 71%, reddish brown crystals, mp 145-146 ºC. IR (KBr) V_max/cm^-1: 3284 (NH); ¹H NMR (DMSO-d₆) δ 2.44 (s, 3H, p-CH₃), 3.42-4.08 (m, 2H, pyrazoline-H₄,H_4'), 6.60-6.73 (m, 1H, pyrazoline-H₅), 7.17 (d, 2H, J 8.0 Hz, ArH), 7.64 (d, 2H, J 7.6 Hz, ArH), 7.70 (d, 2H, J 7.6 Hz, ArH), 7.90 (dd, 2H, J 3.0, 5.0 Hz, ArH), 8.12 (d, 2H, J 8.0 Hz, ArH), 8.18 (dd, 2H, J 3.0, 5.0 Hz, ArH), 8.47 (s, 1H, H_anth-10), 9.63 (s, 1H, NH; D₂O exchangeable). Anal. Calc. for C₂₄H₂₀N₂ (336.43): C, 85.68; H, 5.99; N, 8.33. Found: C, 85.60; H, 5.79; N, 8.52%.

General procedure for the preparation of compounds 26 and 27

To an ice cold solution of 5-(anthracen-9-yl)-3-aryl-4,5-dihydro-1H-pyrazole 24 (0.35 g, 0.001 mol) or 25 (0.33 g, 0.001 mol) in hydrochloric acid (50%, 15 mL) was added NaNO₂ (0.07 g, 0.001 mol) and the reaction mixture was stirred for 3 h. The separated solid product was filtered, washed with ethanol, dried and recrystallized from ethanol.

5-(Anthracen-9-yl)-3-(4-chlorophenyl)-1-nitroso-4,5-dihydro-1H-pyrazole (26)

Yield: 89%, pale brown crystals, mp 150-151 ºC. ¹H NMR (DMSO-d₆) δ 3.28 (dd, 1H, J_1,2 13.8, J_1,3 16.8 Hz, pyrazoline-H₄), 3.67 (dd, 1H, J_1,2 13.8, J_1,3 16.8 Hz, pyrazoline-H_4'), 6.39 (t, 1H, J13.8 Hz, pyrazoline-H₅), 7.43-7.52 (m, 6H,ArH), 7.69 (d, 2H, J 8.0 Hz,ArH), 8.06 (d, 2H, J 7.6 Hz, ArH), 8.41 (d, 2H, J 8.0 Hz, ArH), 8.55 (s, 1H, H_anth-10). Anal. Calc. for C₂₃H₁₆ClN₃O (385.85): C, 71.59; H, 4.18; N, 10.89. Found: C, 71.70; H, 4.32; N, 10.70%.

5-(Anthracen-9-yl)-1-nitroso3-p-tolyl-4,5-dihydro-1H-pyrazole (27)

Yield: 84%, buff crystals, mp 129-130 ºC. ¹H NMR (DMSO-d₆) δ 2.43 (3H, s, p-CH₃), 3.25-3.44 (m, 1H, pyrazoline-H₄), 3.69-4.09 (m, 1H, pyrazoline-H_4'), 7.00-7.24 (m, 1H, pyrazoline-H₅), 7.18 (d, 2H, J 9 Hz, ArH), 7.39 (d, 2H, J 9.0 Hz, ArH), 7.59 (t, 2H, J 8.0 Hz, ArH), 7.69 (d, 2H, J 8.0 Hz, ArH), 7.82 (t, 2H, J 8 Hz, ArH), 7.88 (d, 2H, J 8.0 Hz, ArH), 8.17 (s, 1H, H_anth-10). Anal. Calc. for C₂₄H₁₉N₃O (365.43): C, 78.88; H, 5.24; N, 11.50. Found: C, 78.75; H, 4.98; N, 11.74%.

General procedure for the preparation of compounds 28 and 29

To a solution of 5-(anthracen-9-yl)-3-aryl-4,5-dihydro-1H-pyrazole (24, 0.35 g, 0.001 mol or 25, 0.33 g, 0.001 mol) in dry ether (20 mL) was added an equal amount of phenylisothiocyanate (0.14 g) and the reaction mixture was stirred for 6 h. The solid product obtained was filtered, washed with ethanol, dried and recrystallized from ethanol.

5-(Anthracen-9-yl)-3-(4-chlorophenyl)-N-phenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide (28)

Yield: 82%, pale grey crystals, mp 250-251 ºC. IR (KBr) V_max/cm^-1: 949, 1143, 1346, 1552 (NCS amide I, II, III, IV respectively), 3260 (NH); ¹H NMR (DMSO-d₆) δ 3.29-3.31 (m, 1H, pyrazoline-H₄), 3.82-3.95 (m, 1H, pyrazoline-H_4'), 7.10-7.25 (m, 1H, pyrazoline-H₅), 7.30-7.35 (m, 2H, ArH), 7.39-7.45 (m, 3H,ArH), 7.48-7.54 (m, 2H,ArH), 7.58-7.64 (m, 2H, ArH), 7.69-7.73 (d, 2H, J 8.0 Hz, ArH), 7.78-7.86 (d, 2H, J 7.0 Hz, ArH), 7.90-7.97 (m, 2H, ArH), 8.08-8.17 (m, 2H, ArH), 8.17 (s, 1H, H_anth-10), 11.10 (s, 1H, NH; D₂O exchangeable). Anal. Calc. for C₃₀H₂₂ClN₃S (492.03): C, 73.23; H, 4.51; N, 8.54. Found: C, 73.40; H, 4.62; N, 8.30%.

5-(Anthracen-9-yl)-N-phenyl-3-p-tolyl-4,5-dihydro-1H-pyrazole-1-carbothioamide (29)

Yield: 85%, buff crystals, mp 215-216 ºC. IR (KBr) V_max/cm^-1: 938, 1168, 1327, 1588 (NCS amide I, II, III, IV respectively), 3243 (NH); ¹H NMR (DMSO-d₆) δ 2.44 (s, 3H, p-CH₃), 3.34-3.69 (m, 1H, pyrazoline-H₄), 3.80-4.03 (m, 1H, pyrazoline-H_4'), 7.28-7.33 (m, 2H,ArH), 7.36-7.41 (m, 2H, ArH), 7.44-7.49 (m, 3H, ArH), 7.51-7.58 (m, 1H, pyrazoline-H₅), 7.62-7.68 (d, 2H, J 9 Hz, ArH) 7.70-7.75 (m, 2H, ArH), 7.79-7.83 (d, 2H, J 8.0 Hz, ArH), 7.86-7.90 (m, 2H,ArH), 8.04-8.10 (m, 2H,ArH), 8.39 (s, 1H, H_anth-10), 11.15 (s, 1H, NH; D₂O exchangeable). Anal. Calc. for C₃₁H₂₅N₃S (471.62): C, 78.95; H, 5.34; N, 8.91. Found: C, 78.76; H, 5.12; N, 9.00%.

General procedure for the preparation of compounds 30 and 31

To a solution of 5-(anthracen-9-yl)-3-aryl-4, 5-dihydro-1H-pyrazole 24 (0.35 g, 0.001 mol) or 25 (0.33 g, 0.001 mol) in dry pyridine (10 mL) was added an equivalent amount of p-tosyl chloride (0.19 g). The reaction mixture was heated on a boiling water bath for 3 h, cooled and then poured onto crushed ice. The solid product separated was filtered, washed with water, dried and recrystallized from ethanol.

5-(Anthracen-9-yl)-3-(4-chlorophenyl)-1-tosyl-4,5-dihydro-1H-pyrazole (30)

Yield: 76%, buff crystals, mp 135-136 ºC. ¹H NMR (DMSO-d₆) δ 2.44 (3H, s, CH₃), 3.42-4.02 (m, 2H, pyrazoline-H₄, H_4'), 6.60-6.67 (m, 1H, pyrazoline-H₅), 7.35 (d, 2H, J 7.6 Hz, ArH), 7.43 (d, 2H, J 8 Hz, ArH), 7.56 (t, 2H, J 8.0 Hz,ArH), 7.76 (d, 2H, J 8.0 Hz,ArH), 7.91 (t, 2H, J 8.0 Hz, ArH), 8.01 (m, 2H, ArH), 8.13 (d, 2H, J 7.6 Hz, ArH), 8.51 (m, 2H, ArH), 8.57 (s, 1H, H_anth-10). Anal. Calc. for C₃₀H₂₃ClN₂O₂S (511.03): C, 70.51; H, 4.54; N, 5.48. Found: C, 70.32; H, 4.45; N, 5.69%.

5-(Anthracen-9-yl)-3-p-tolyl-1-tosyl-4,5-dihydro-1H-pyrazole (31)

Yield: 74%, buff crystals, mp 200-201 ºC. ¹H NMR (DMSO-d₆) δ 2.41 (s, 3H, CH₃), 2.44 (s, 3H, CH₃), 3.40-4.00 (m, 2H,pyrazoline-H₄,H_4'),6.60-6.64(m, 1H,pyrazoline-H₅), 7.05 (d, 2H, J 3 Hz, ArH), 7.22 (d, 2H, J 8 Hz, ArH), 7.29 (t, 2H, J 8 Hz, ArH), 7.33 (d, 2H, J 7.0 Hz, ArH), 7.38 (d, 2H, J 15.0 Hz, ArH), 7.67 (d, 2H, J 7.0 Hz, ArH), 7.89 (d, 2H, J 15.0 Hz,ArH), 7.90 (t, 2H, J 3.0 HzArH), 8.47 (s, 1H, H_anth-10). Anal. Calc. for C₃₁H₂₆N₂O₂S (490.62): C, 75.89; H, 5.34; N, 5.71. Found: C, 75.70; H, 5.22; N, 5.89%.

General procedure for the preparation of compounds 32-34

A mixture of 3-(anthracen-9-yl)-1-(aryl)prop-2-en-1-one 1-3 (0.01 mol) and guanidine carbonate (1.21 g, 0.01 mol) in ethanol (50 mL) was heated under reflux, while a 5 mol L^-1 solution of sodium hydroxide (10 mL) was added portion-wise during one hour. Refluxing was continued for a further 10 h, when the reaction mixture was concentrated, diluted with water and extracted with benzene. The solid product was obtained after concentration and cooling; the precipitated product was filtered, dried and recrystallized from chloroform.

4-(Anthracen-9-yl)-6-(4-chlorophenyl)pyrimidin-2-amine (32)

Yield: 83%, buff crystals, mp 310-311 ºC. IR (KBr) V_max/cm^-1: 3054, 3358 (NH₂); ¹H NMR (DMSO-d₆) δ 5.97 (s, 2H, NH₂; D₂O exchangeable), 7.17 (d, 2H, J 8.0 Hz, ArH;), 7.35 (s, 1H, pyrimidine-H₅), 7.44 (t, 2H, J 8.0 Hz, ArH), 7.59 (t, 2H, J 8 Hz, ArH), 7.98 (d, 2H, J 8.0 Hz, ArH), 8.05 (d, 2H, J 9.0 Hz, ArH), 8.18 (d, 2H, J 9.0 Hz, ArH), 8.68 (s, 1H, H_anth-10). Anal. Calc. for C₂₄H₁₆ClN₃ (381.86): C, 75.49; H, 4.22; N, 11.00. Found: C, 75.21; H, 4.00; N, 11.26%.

4-(Anthracen-9-yl)-6-p-tolylpyrimidin-2-amine (33)

Yield: 81%, buff crystals, mp 210-211 ºC. IR (KBr) V_max/cm^-1: 3142, 3366 (NH₂); ¹H NMR (DMSO-d₆) δ 2.25 (s, 3H, p-CH₃), 6.07 (s, 2H, NH₂; D₂O exchangeable), 7.46-7.52 (m, 4H, ArH), 7.57-7.59 (m, 4H, ArH), 7.63-7.65 (d, 2H, J 9.0 Hz, ArH), 7.71-7.86 (d, 2H, J 8.0 Hz, ArH), 7.91 (s, 1H, pyrimidine-H₅), 8.18 (s, 1H, H_anth-10). Anal. Calc. for C₂₅H₁₉N₃(361.44): C, 83.08; H, 5.30; N, 11.63. Found: C, 83.29; H, 5.56; N, 11.42%.

4-(Anthracen-9-yl)-6-(furan-2-yl)pyrimidin-2-amine (34)

Yield:78%, buff crystals, mp 263-264 ºC. IR (KBr) V_max/cm^-1: 3147, 3323 (NH₂); ¹H NMR (DMSO-d₆) δ 6.26 (s, 2H, NH₂; D₂O exchangeable), 7.53 (s, 1H, pyrimidine-H₅), 7.60-7.64 (m, 1H, ArH), 7.73-7.80 (m, 1H, ArH), 7.85-7.89 (m, 1H, ArH), 7.98 (dd, 2H, J 3.0, 6.0 Hz, ArH), 8.06-8.08 (m, 4H, ArH), 8.17 (dd, 2H, J 3.0, 6.0 Hz, ArH), 8.33 (s, 1H, H_anth-10). Anal. Calc. for C₂₂H₁₅N₃O (337.37): C, 78.32; H, 4.48; N, 12.46. Found: C, 78.56; H, 4.27; N, 12.25%.

General procedure for the preparation of compounds 35 and 36

A mixture of 4-(anthracen-9-yl)-6-arylpyrimidin-2-amine (32, 0.38 g, 0.001 mol or 33, 0.36 g, 0.001 mol) and acetic anhydride (10 mL) was heated on boiling water bath for 2 h. The reaction mixture was poured onto cold water and the precipitated product was filtered, washed with water, dried and recrystallized from ethanol/chloroform.

N-(4-(Anthracen-9-yl)-6-(4-chlorophenyl)pyrimidin-2-yl) acetamide (35)

Yield: 83%, buff crystals, mp 130-131 ºC. IR (KBr) V_max/cm^-1: 1667 (C=O), 3260 (NH); ¹H NMR (DMSO-d₆) δ 2.25 (s, 3H, NCOCH₃), 7.28 (t, 2H, J 8.0 Hz, ArH), 7.47 (t, 2H, J 6.0 Hz, ArH), 7.61 (d, 2H, J 7.6 Hz, ArH), 7.89 (d, 2H, J 6.0 Hz, ArH), 8.00 (s, 1H, pyrimidine-H₅), 8.06 (d, 2H, J 8.0 Hz, ArH), 8.17 (d, 2H, J 7.6 Hz, ArH), 8.70 (s, 1H, H_anth-10), 10.77 (s, 1H, NH; D₂O exchangeable). Anal. Calc. for C₂₆H₁₈ClN₃O (423.89): C, 73.67; H, 4.28; N, 9.91. Found: C, 73.89; H, 4.01; N, 9.75%.

N-(4-(Anthracen-9-yl)-6-p-tolylpyrimidin-2-yl)acetamide (36)

Yield: 78%, buff crystals, mp 119-120 ºC. IR (KBr) V_max/cm^-1: 1669 (C=O), 3218 (NH); ¹H NMR (DMSO-d₆) δ 2.29 (s, 3H, NCOCH₃), 2.36 (s, 3H, p-CH₃), 7.30-7.63 (m, 4H, ArH), 7.90-7.92 (m, 4H, ArH), 8.17-8.19 (m, 4H, ArH), 8.37 (s, 1H, pyrimidine-H₅), 8.74 (s, 1H, H_anth-10), 10.47 (s, 1H, NH; D₂O exchangeable). Anal. Calc. for C₂₇H₂₁N₃O (403.48): C, 80.37; H, 5.25; N, 10.41. Found: C, 80.56; H, 5.01; N, 10.23%.

Biological activity assay

Measurement of the inhibition zone (IZ)

Compounds 1-36 were evaluated in vitro for antimicrobial activity against Escherichia coli ATCC8739 and Pseudomonas aeruginosa ATCC 9027 as gram-negative bacteria, Staphylococcus aureus ATCC 6538P as an example of gram-positive bacteria and Candida albicans ATCC 2091 as yeast-like fungus. The agar-diffusion method³³ was used for the determination of antibacterial and antifungal activity. From 1 mg mL^-1 solutions of each of the test compounds in N,N-dimethylformamide (DMF), 75 µL was placed in a 6 mm diameter well in an agar plate seeded with the appropriate test organism in triplicates.Ampicillin trihydrate (10 µg per disc), Ciprofloxacin (5 µg per disc), Imipenem (10 µg per disc) and Clotrimazole (100 µg per disc) were used as standard antibacterial and antifungal agents, respectively. The plates were incubated at 37 ºC for 24 h. The results were recorded for each tested compounds as the average diameter of inhibition zone of bacterial growth in mm (Table 1). DMF alone (control) showed no inhibition zone.

Minimal inhibitory concentration (MIC)

The microdilution susceptibility test in Muller-Hinton broth (oxoid) and Sabouraud liquid medium (oxoid) were used for the determination of antibacterial and antifungal activity with the same test organisms. The MIC measurements³⁴ were carried out for compounds that showed significant inhibition zones using the two-fold serial dilution technique with solutions in the concentration range 500-15.63 µg mL^-1. Suspensions of the microorganisms at 10⁶ CFU mL^-1 (Colony Forming Units mL^-1) were used to inoculate the prepared test compounds in the above mentioned serial dilution broth. The culture tubes were incubated at 37 ºC for 24-48 h. At the end of the incubation period the growth of bacteria was observed in the form of turbidity. The MIC is defined as the lowest concentration that showed no bacterial growth (Table 1).

Supplementary Information

Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file.

References

1. Szliszka, E.; Czuba, Z. C.; Mazur, B. M.; Sedek, L.; Paradysz,A.; Krol, W.; Int. J. Mol. Sci. 2010,11,1.

2. Mokle, S. S.; Sayeed, M. A.; Kothawar, C.; Int. J. Chem. Sci. 2004,2,96; Rajendra, P. Y.; Lakshmana Rao, A.; Rambabu, R.; E-J. Chem. 2008,5,461; Bhasker,N.; Krishna, B.; Raghava, K. R.; Komal, M. R.; Rasayan J. Chem. 2009,2,139; Zangade, S. B.; Jadhav, J. D.; Lalpod; Vibhute, Y. B.; Dawane, B. S.; J. Chem. Pharm. Res. 2010,2,310.

3. Rojas, J.; Payá, M.; Domínguez, J. N.; Ferrándiz, M. L.; Bioorg. Med. Chem. Lett. 2002,12,1951.

4. Echeverría, C.; Santibañez, J. S.; Donoso-Tauda, O.; Escobar, C. A.; Ramírez-Tagle, R.; Int. J. Mol. Sci. 2009,10,221; Nowakowska, Z. A.; Eur. J. Med. Chem. 2007,42,125; Shah, A.; Khan, A. M.; Qureshi, R.; Ansari, F. L.; Nazar, M. F.; Shah, S. S.; Int. J. Mol. Sci. 2008,9,1424; Boumendjel, A.; Ronot, X. B.; Curr. Drug Targets 2009,10,363; Katsori, A. M.; Hadjipavlou-Latina, D.; Curr. Med. Chem. 2009,16,1062.

5. Viana, G. S.; Bandeira, M. A.; Matos, F.; J. Phytomedicine 2003,10,189.

6. Zhao, L. M.; Jin, H. S.; Sun, L. P.; Piao, H. R.; Quan, Z. S.; Bioorg. Med. Chem. Lett. 2005,15,5027.

7. Li-Ping, G.; Nan, J.-X.; Jin, X.-J.; Jin, Q.-H.; Kwak, K.-C.; Chai, K.-Y.; Quan, Z.-S.; Arch. Pharm. Res. 2005,28,81.

8. Mishra, N.; Arora, P.; Kumar, B.; Mishra L. C.; Bhattacharya, A.; Awasthi, S. K.; Bhasin, V. K.; Eur. J. Med. Chem. 2008,43,1530; Valla, A.; Valla, B.; Cartier, D.;Le Guillou, R.; Labia, R.; Florent, L.; Charneau, S.; Schrevel, J.; Potier, P.; Eur. J. Med. Chem. 2006,41,142.

9. Jamal, H.; Ansari, W. H.; Rizvi, S. J.; Biol. Med. 2009,1,107.

10. Rizvi, S. U. F.; Siddiqui, H. L.; Parvwez, M.; Ahmad, M.; Siddiqui, W. A.; Yasinzai,M. M.; Chem. Pharm. Bull. 2010,58,301; Mei, L.; Prapon, W.; Simon, L. C.; Bioorg. Med. Chem. 2003,11,2729.

11. Sivakumar, P. M.; Geetha, B. S. K.; Mukesh, D.; Chem. Pharm. Bull. 2007,55,44.

12. Satyanarayana, M.; Priti, T.; Brajendra, K. T.; Srivastava, A. K.; Ram, P.; Bioorg. Med. Chem. 2004,12,883.

13. Khatib,S.;Nerya,O.;Musa,R.;Shmuel,M.;Tamir,S.;Vaya,J.; Bioorg. Med. Chem. 2005,13,433; Nishida, J.; Gao, H.; Kawabata, J.; Bioorg. Med. Chem. 2007,15,2396.

14. Drabu, S.; Rana, A.; Harish, K.; Indian J. Heterocycl. Chem. 2007,16,399; Amir, M.; Kumar, S.; Indian J. Chem. 2005,44B,2532; Adnan, A. B.; Hayam, M. A. A.; Aida, A. G.; Arch. Pharm. 2005,338,167.

15. Verma, B. L.; Singhal, M.; Indian J. Heterocycl. Chem. 2007,14,343.

16. Karthikeyan, M. S.; Holla, B. S.; Suchetha, N.; Eur. J. Med. Chem. 2007,42,30; Kaplancikli, Z. A.; Turan-Zitouni, G.; Ozdemir, A.; Revial, G.; Guven, K.; Phosphorus, Sulfur, Silicon Relat. Elem. 2007,182,749; Ahmet, Ö.; Gülhan, T. Z.; Zafer, A. K.; Gilbert, R.; Kiymet, G.; Eur. J. Med. Chem. 2007,42,403; Susant, S. K.; Mrityunjay, B.; Sagar, M. K.; Raj, M. K.; Prasanna, P. K.; Prafulla, M. K.; Acta Pol. Pharm. Drug Res. 2007,64,121; Anjani,S.; Sejal, S.; Ghanshayam, P.; Rasayan J. Chem. 2008,1,581.

17. Shekarchi, M.; Pirali-Hamedani, B. L.; Navidpour, N.; Adib, Shafiee, A.; J. Iran. Chem. Soc. 2008,5,150.

18. Rajendra, P. Y.; Lakshmana, R. A.; Prasoona, L.; Murali, K.; Ravikumar, P.; Bioorg. Med. Chem. Lett. 2005,15,5030; Ruhogluo, O.; Ozdemir, Z.; Calis, U.; Gumusel, B.; Bilgin, A. A.; Arzneimittelforschung 2005,55,431.

19. Ozdemir, Z.; Kandilici, H. B; Gumusel, B.; Calis, U.; Bilgin, A. A.; Eur. J. Med. Chem. 2007,42,373.

20. Brzozwski, Z.; Czewski, F. S.; Gdaniec, M.; Eur. J. Med. Chem. 2000,35,1053.

21. Harinadha, B. V.; Manna, S. K.; Sneha; Srinivasan, K. K.; Varadaraj, B. G.; Indian J. Heterocycl. Chem. 2004,13,253.

22. Kristopher, S. S.; David, M. S.; Pestic. Biochem. Physiol. 2005,81,136.

23. Suresh, K.; Sandhya, B.; Sushma, D.; Rajiv, K.; Himanshu, G.; Recent Pat. Anti-Infect. Drug Discovery 2009,4,154; Shaharyar, M.; Siddiqui, A. A.; Ali, M. A.; Sriram, D.; Yogeeswari, P.; Bioorg. Med. Chem. Lett. 2006,16,3947.

24. Flora, F. B.; Hanaa, M. H.; Adel, S. G.; Bioorg. Med. Chem. 2006,14,3929.

25. Shafiee, A.; Bagheri, M.; Shekarchi, M.; Mohammad, A.; J. Pharm. Pharm. Sci. 2003,6,360.

26. Funiss, B. S.; Hannford, A. J.; Smith, P. W. G.; Tatchell, A. R.; Vogel's Textbook of Practical Organic Chemistry, 5^th ed., Prentice-Hall: Englewood Cliffs, NJ, 1996, p.1032; Morrison, R. T.; Boyd, R. N.; Organic Chemistry, 6^th ed., Prentice-Hall: Englewood Cliffs, NJ, 1992, p.971.

27. Revanasiddappa, B. C.; Nagendra, Rao, R.; Subrahmanyam, E. V. S.; Satyanarayana, D.; E-J. Chem. 2010,7,295; Jadhav, S. B.; Shastri, R. A.; Gaikwad, K. V.; Gaikwad, S. V.; E-J. Chem. 2009,6,S183; Ahmet, O. Z. R.; Gülhan, T. Z.; Zafer, A. K.; Turk. J. Chem. 2008,32,529; Ragini, G.; Neetu, G.; Anshu, J.; Indian J. Chem. 2010,49b, 351; Chetana, B. P.; Mahajan, S. K.; Suvarna, A. K.; J. Pharm. Sci. Res. 2009,3,11.

28. Chimenti, F.; Bizzarri, B.; Manna, F.; Boalsco, A.; Secci, D.; Chimenti, P.; Granese, A.; Rivanera, D.; Lilli, D.; Scaltrito, M. M.; Brenciaglia, M. I.; Bioorg. Med. Chem. Lett. 2005,15,603; Levai, A.; Jeko, J.; Brahmbhatt, D. I.; J. Heterocycl. Chem. 2005,42,1231; Levai, A.; J. Heterocycl. Chem. 2005,39,1; Levai, A.; Jeko, J.; J. Heterocycl. Chem. 2006,43,111; Adnan, A. B.; Tarek, A. A.; Bioorg. Med. Chem. 2004,12,1935.

29. Ali, M. A.; Siddiqui, M. S. A. A.; Eur. J. Med. Chem. 2007,42,268; Amir, M.; Kumar, H.; Khan, S. A.; Bioorg. Med. Chem. Lett. 2008,18,918.

30. Vimesh, M. P.; Kishor, R. D.; Arkivoc 2004, I, 123.

31. Kamal, A.; Laxma Reddy, K.; Devaiah, V.; Shankaraiah, N.; Shiva, M. K.; Suresh, G. K. R.; Lett. Drug Des. Discovery 2005,2,55; Nagaraj,A.; Reddy, S. C.; J. Iran. Chem. Soc. 2008,5,262; Vyas, R.; Choudhary, P. C.; Sharma, H.; Verma, B. L.; Indian J. Heterocycl. Chem. 2008,17,237; Amir, M.; Javed, S. A.; Acta Pharm. 2008,58,467; Arvind, G. M.; Avnish, A. P.; E-J. Chem. 2009,6,S406.

32. El-Rayyes, N. R.; J. Heterocycl. Chem. 1982,19,415.

33. Abou-Elela, G. M.; Ibrahim, H. A.; El-Helow, E.; Sabry, S.; World Appl. Sci. J. 2009,7,748.

34. Cruickshank, R.; Duguid, J. P.; Marmion, B. P.; Swam, H. A.; The Practice of Medical Microbiology; 12^th ed., Churchill Livingstone, London, 1975.

Submitted: November 21, 2010

Published online: March 11, 2011

Supplementary Information

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Publication Dates

• Publication in this collection
  22 July 2011
• Date of issue
  July 2011

History

• Accepted
  11 Mar 2011
• Received
  21 Nov 2010