Letters in Drug Design & Discovery, 2010, 7, 27-30
27
Synthesis and Preliminary Biological Activity of Some New Pyrazole Derivatives as Acyclonucleoside Analogues Smaail Radi*, Souad Salhi and Amal Radi
Laboratoire de Chimie Organique, Macromoléculaire et Produits Naturels, Département de Chimie, Faculté des Sciences, Université Mohamed I, Oujda, Maroc Received: May 31, 2009; Revised: September 07, 2009; Accepted: September 07; 2009
Abstract: Some novel pyrazole acyclonucleosides were prepared through binding of pyrazole-3,5-substituted derivatives with acyclic substituents mimetizing individual fragments of the ribose ring such as: 1-[(2-hydroxyethoxy) methyl], 1-[4-(hydroxybutyl)], 1-[3(hydroxypropyl)] and 1-[(2-hydroxyethyl amino) methyl]. Their syntheses were performed from easily accessible starting materials. The prepared compounds were evaluated for their antibacterial activity. Structure-activity relationship studies (SAR) indicate that introduction of modified arm in N1 position of pyrazole moieties has not any impact on the biolgical activity.
Keywords: Pyrazole, Acyclonucleoside, Synthesis, Biological activity. INTRODUCTION Pyrazole derivatives are well established in the literature as important biologically active heterocyclic compounds. These derivatives are the subject of many research studies due to their widespread potential biological activities such as anti-inflammatory [1], antipyretic [2], antimicrobial [3], antiviral [4], antitumour [5, 6], anticonvulsant [7], antihistaminic [8], antidepressant [9], insecticides [10] and fungicides [10]. Until now, the binding of heterocyclic compounds with acyclic sugar moiety forming thus the acyclonucleosides has commanded the world-wide attention of many research groups because of their high potential to exhibit chemotherapeutic activity [11, 12]. In this respect, some acyclic related nucleosides, such as acyclovir [13], HBG [14], DHPG [15-20], iso-NDG [15-20], penciclovir [14] and its oral form famiciclovir [14, 21] have been reported and evaluated as potential antiviral drugs. Thereafter, the discovery of novel heterocycles that are attached to open-chain carbohydrate residues was the aim and subject of many researchers. This is evident from the large number of scientific articles and reviews [22-24].
by cellular enzymes to its triphosphate and incorporated in the terminal position of DNA. Thus, the acetyl groups in the sugar moiety of the newly compounds 5-8 were removed using sodium ethoxide to give respectively 9-12 after treatment with Dowex H+ 50x8 and flash column chromatography. Compounds 13 and 14 were formed by condensation of 3-bromopropanol with pyrazole derivatives 1 and 2 using potassium tert-butoxide as base to yield after 6 hours one isolated major product. The target compounds 17 and 18 were easily prepared from the condensation of one equivalent of 1(hydroxymethyl)-3,5-dimethylpyrazole (15) [28, 29] and ethyl 1(hydroxymethyl)-5-methyl-1H-pyrazole-3-carboxylate (16) [30], respectively, with one equivalent of 2-aminoethanol under gentle conditions (room temperature, atmospheric pressure, 4-7 days), using anhydrous acetonitrile as solvent. The reaction is very slow but selective at room temperature. The structures of the all newly acyclonucleosides were determined on the basis of the corresponding analytical and spectroscopic data.
Based on the above mentioned research results, the goal of this study is to synthesize some novel pyrazoles with acyclic substituents mimetizing individual fragments of the ribose ring for the purpose of synergism and/or increasing the expected biological effects. The synthesis of target drugs was illustrated in Scheme 1.
Biological Activity
RESULTS AND DISCUSSION
The activities were determined by the agar diffusion technique as previously described [31]. The agar media were inoculated with test organisms and a solution of the tested compound in DMSO / EtOH (50 / 50) was added to different concentration in the culture media.
Chemistry Our strategy was to develop a simple, few steps, and high yield procedure to prepare the desired compounds. The condensation of heterocyclic pyrazoles 1 and 2, respectively, with alkylating agents such as [(2-acetoxyethoxy) methyl] bromide 3 [25] “the sugar moiety of ACV” and 4-acetoxybutylbromide 4 [26] “the sugar moiety of HBG” was carried out under solid-liquid phase transfer catalysis to favour the -isomer [27] in case of asymmetrical pyrazole 2. Thus, one isolated major product 5-8 as the -isomer was formed. These major products were also obtained, after 6 hours of refluxing, using potassium tert-butoxide as base and THF as solvent. Thereafter, nucleoside derivatives should have the 5'-OH free to be converted *Address correspondence to this author at the Laboratoire de Chimie Organique, Macromoléculaire et Produits Naturels, Département de Chimie, Faculté des Sciences, Université Mohamed I, Oujda, Maroc, Fax: 212 536 50 06 03; E-mail:
[email protected] 1570-1808/10 $55.00+.00
The compounds described in this manuscript 9-18 were first tested in vitro for their activity against two fungal strains (Saccharomyces cerevisiae and Fusarium oxysporum f.sp albedinis) and against bacterial strains (Echerichia coli). Streptomycin was used as reference compound and better standard in antibacterial assay.
In pharmacological term, all these products, with different open-chain carbohydrate residues, were found to be inactive when compared with the CMI of 0.1 to 4 mg/l of the standard. We can thus conclude that introduction of different arms in N1 position of 3,5-disubstituted pyrazoles has not any impact on the antibacterial activity. Extension antiviral and antitumour activities are under study and will be reported in due course. In conclusion, new pyrazole derivatives drugs with acyclicchain carbohydrate residues were prepared from easily accessible starting materials in few steps. The preliminary in vitro test results of these compounds were negatives against the three studied microorganisms such as Saccharomyces cerevisiae, E ch e r i ch i a coli and Fusarium oxysporum f.sp albedinis. © 2010 Bentham Science Publishers Ltd.
28 Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1
Radi et al. R
AcO
R
Br
X
N
tBuOK/THF 3 X=O 4 X = CH2
1) EtO-Na+
CH3
N
2) Dowex H+
N X
HO X
AcO 5 6 7 8
R = CH3, R = CH3, R = CO2Et, R = CO2Et,
R
N H N 1 2
X=O X = CH2 X=O X = CH2
9 10 11 12
R HO
CH3 N
R = CH3, R = CH3, R = CO2Et, R = CO2Et,
X=O X = CH2 X=O X = CH2
Br
CH3
N tBuOK/THF
CH3 N
R = CH3 R = CO2Et 13 14
OH
R = CH3 R = CO2Et
R
OH
Formol 35% Ethanol
CH3
N N
H2N
N
CH3CN, 25°C 4 days HO
R = CH3 R = CO2Et
CH3 N
H N
HO 15 16
R
17 18
R = CH3 R = CO2Et
Scheme 1.
EXPERIMENTAL Melting points were determined on a Büchi-Tottoli capillary apparatus and are uncorrected. The 1H NMR and 13C NMR spectra were recorded with a 300 MHz Bruker AC-300 spectrometer. Chemical shifts are reported in parts per million () using internal TMS standard. The IR spectra were taken with KBr discs on Perkin-Elmer 1310 spectrometer. Thin-layer chromatography was performed on silica gel 60F-254 plates. Column chromatography was performed on silica gel (0.0063-0.2 mm, Merck). The mass spectrum was obtained on a Jeol JMX-DX. Elemental analyses were performed by Microanalysis Central Service (CNRS).
General Procedure for the Preparation of Acetyl Compounds 5-8 A mixture of (4.1x10-2 mol) of 1 or 2 and (4.1x10-2 mol) of potassium tert-butoxide in 150 ml of THF was stirred under reflux for 30 min. Alkylating agent 3 or 4 (4.1x10-2 mol) in 100 ml of THF was then added slowly. After stirring under reflux for 6 h, the mixture was filtered, evaporated and the residue was separated on alumina using CH2Cl2 as eluant to give the target acetyl compound as yellow oil. 1-[(2-Acetoxyethoxy) methyl]-3,5-dimethyl-1H-pyrazole (5) Yield: 65 %; Rf: 0.39 (CHCl3 / MeOH, 9.5/0.5, V/V in silica); H NMR (CDCl3): : 2.01 (s, 3H, COOCH3); 2.33 (s, 6H, 2CH3); 3.65 (m, 2H, OCH2CH2O); 4.65 (m, 2H, OCH2CH2O); 5.48 (s, 1H, H-Pz); 5.81 (s, 2H, OCH2N); 13C NMR (CDCl3): : 12.60 (CH3); 13.26 (CH3); 21.01, 171.29 (Ac); 61.24 (OCH2N); 64.04, 70.20 (OCH2CH2O); 104.45 (C4); 139.70 (C5); 144.10 (C3); Anal. calcd for C10H16N2O3: C 56.60, H 7.54, N 13.20. Found: C 56.49, H 7.82, N 13.17; m/z : 213 [M+1]+ (FAB>0). 1
1-(4-Acetoxybutyl)-3,5-dimethyl-1H-pyrazole (6) Yield: 50 %; Rf: 0.78 (CH2Cl2 / MeOH, 9/1, V/V in silica); 1H NMR (CDCl3): : 1.51 (m, 2H, CH2CH2OAc); 1.77 (m, 2H,
CH2CH2N); 2.01 (s, 3H, COOCH3); 2.33 (s, 6H, 2CH3); 3.73 (t, 2H, OCH2); 4.12 (t, 2H, CH2N); 5.85 (s, 1H, H-Pz); 13C NMR (CDCl3): : 13.26 (CH3); 14.68 (CH3); 21.01, 169.29 (Ac); 25.39 (CH2CH2N); 27.40 (CH2CH2OAc); 49.45 (CH2N); 64.04 (OCH2); 104.43 (C4); 139.70 (C5); 142.15 (C3); Anal. calcd for C11H18N2O2: C 62.85, H 8.57, N 13.33. Found: C 62.80, H 8.51, N 13.42; m/z : 211 [M+1]+ (FAB>0). Ethyl 1-[(2-Acetoxyethoxy) carboxylate (7)
methyl]-5-methyl-1H-pyrazole-3-
Yield: 62 %; Rf: 0.74 (CH2Cl2 / MeOH, 9/1, V/V in silica); 1H NMR (CDCl3): : 1.30 (t, 3H, CH2CH3); 2.01 (s, 3H, COOCH3); 2.33 (s, 3H, CH3); 3.70 (m, 2H, OCH2); 4.30 (q, 2H, CH2CH3); 4.63 (m, 2H, CH2OAc); 5.60 (s, 2H, OCH2N); 6.61 (s, 1H, H-Pz); 13C NMR (CDCl3): : 11.26 (CH3); 14.70, 61.23 (Et); 21.01, 170.29 (Ac); 63.33 (OCH2N); 64.01, 64.10 (OCH2CH2O); 108.65 (C4); 140.70 (C5); 143.47 (C3); 162.68 (CO2Et); Anal. calcd for C12H18N2O5: C 53.33, H 6.66, N 10.37. Found: C 53.27, H 6.60, N 10.50; m/z : 271 [M+1]+ (FAB>0). Ethyl 1-(4-Acetoxybutyl)-5-methyl-1H-pyrazole-3-carboxylate (8) Yield: 60 %; Rf: 0.58 (CH2Cl2 / MeOH, 9/1, V/V in silica); 1H NMR (CDCl3): : 1.30 (t, 3H, CH2CH3); 1.57 (m, 2H, CH2CH2OAc); 1.86 (m, 2H, CH2CH2N); 2.01 (s, 3H, COOCH3); 2.30 (s, 3H, CH3); 3.85 (m, 2H, OCH2); 4.12 (t, 2H, CH2N); 4.30 (q, 2H, CH2CH3); 6.60 (s, 1H, H-Pz); 13C NMR (CDCl3): : 11.26 (CH3); 14.50, 60.80 (Et); 21.01, 171.29 (Ac); 25.84 (CH2CH2N); 26.87 (CH2CH2OAc); 49.45 (CH2N); 64.04 (OCH2); 108.43 (C4); 139.70 (C5); 142.00 (C3); 162.95 (CO2Et); Anal. calcd for C13H20N2O4: C 58.20, H 7.46, N 10.44. Found: C 58.12, H 7.36, N 10.61; m/z : 269 [M+1]+ (FAB>0).
General Method: Deacetylation To 20 ml of dry ethanol, was added (1 mmole) of sodium metal. After complete hydrogen release, the acetyl compound (1 mmole) was added and the reaction mixture was stirred for 5 hours. The
Synthesis and Preliminary Biological Activity
crude material was neutralised by Dowex H+ 50x8, filtered, washed with hot EtOH and purified by silica gel column flashchromatography to give the target drugs as colourless viscous oil. 1-[(2-Hydroxyethoxy) methyl]-3,5-dimethyl-1H-pyrazole (9) Yield: 96 %; Rf: 0.12 (CH2Cl2 / MeOH, 9/1, V/V in silica); 1H NMR (CDCl3): : 2.33 (s, 6H, 2CH3); 3.70 (s, 1H, OH); 3.65 (m, 2H, CH2O); 4.20 (m, 2H, CH2OH); 5.81 (s, 2H, OCH2N); 5.83 (s, 1H, H-Pz); 13C NMR (CDCl3): : 12.11 (CH3); 13.38 (CH3); 61.24 (OCH2N); 64.04, 70.20 (OCH2CH2O); 104.45 (C4); 139.70 (C5); 144.10 (C3); Anal. calcd for C8H14N2O2: C 56.45, H 8.29, N 16.46. Found: C 56.39, H 8.36, N 16.47; IR (KBr, cm-1): (OH) = 3100, (C=N) = 1635, (C=C) = 1480; m/z : 171 [M+1]+ (FAB>0). 1-(4-Hydroxybutyl)-3,5-dimethyl-1H-pyrazole (10) Yield: 94 %; Rf: 0.48 (CH2Cl2 / MeOH, 9/1, V/V in silica); 1H NMR (CDCl3): : 1.57 (m, 2H, CH2CH2OH); 1.77 (m, 2H, CH2CH2N); 2.33 (s, 6H, 2CH3); 3.73 (t, 2H, CH2OH); 4.08 (t, 2H, CH2N); 4.61 (s, 1H, OH); 5.85 (s, 1H, H-Pz); 13C NMR (CDCl3): : 13.26 (CH3); 14.68 (CH3); 25.39 (CH2CH2N); 29.40 (CH2CH2OH); 49.45 (CH2N); 61.04 (OCH2); 104.86 (C4); 139.70 (C5); 142.10 (C3); Anal. calcd for C9H16N2O: C 64.25, H 9.59, N 16.65. Found: C 64.20, H 9.69, N 16.62; IR (KBr, cm-1): (OH) = 3110, (C=N) = 1640, (C=C) = 1485; m/z : 169 [M+1]+ (FAB>0). Ethyl 1-[(2-Hydroxyethoxy) carboxylate (11)
methyl]-5-methyl-1H-pyrazole-3-
Yield: 90 %; Rf: 0.37 (CH2Cl2 / MeOH, 9/1, V/V in silica); 1H NMR (CDCl3): : 1.30 (t, 3H, CH2CH3); 2.33 (s, 3H, CH3); 3.48 (s, 1H, OH); 3.65 (t, 2H, OCH2); 4.20 (t, 2H, CH2OH); 4.30 (q, 2H, CH2CH3); 5.54 (s, 2H, OCH2N); 6.57 (s, 1H, H-Pz); 13C NMR (CDCl3): : 11.26 (CH3); 14.70, 61.23 (Et); 61.24 (OCH2N); 62.10, 62.38 (OCH2CH2O); 108.65 (C4); 140.70 (C5); 143.47 (C3); 162.68 (CO2Et); Anal. calcd for C10H16N2O4: C 52.62, H 7.07, N 12.27. Found: C 52.55, H 7.16, N 12.30; IR (KBr, cm-1): (OH) = 3100, (C=N) = 1640, (C=C) = 1490, (C=O) =1710; m/z : 229 [M+1]+ (FAB>0). Ethyl (12)
1-(4-Hydroxybutyl)-5-methyl-1H-pyrazole-3-carboxylate
Yield: 92 %; Rf: 0.18 (CH2Cl2 / MeOH, 9/1, V/V in silica); 1H NMR (CDCl3): : 1.30 (t, 3H, CH2CH3); 1.51 (m, 2H, CH2CH2OH); 1.84 (m, 2H, CH2CH2N); 2.30 (s, 3H, CH3); 3.25 (s, 1H, OH); 3.60 (m, 2H, OCH2); 4.08 (t, 2H, CH2N); 4.30 (q, 2H, CH2CH3); 6.60 (s, 1H, H-Pz); 13C NMR (CDCl3): : 11.26 (CH3); 14.50, 60.72 (Et); 26.50 (CH2CH2N); 29.30 (CH2CH2OH); 49.45 (CH2N); 61.61 (OCH2); 108.43 (C4); 139.70 (C5); 142.00 (C3); 162.00 (CO2Et); Anal. calcd for C11H18N2O3: C 58.39, H 8.02, N 12.38. Found: C 58.32, H 8.11, N 12.36; IR (KBr, cm-1): (OH) = 3150, (C=N) = 1640, (C=C) = 1492, (C=O) =1720; m/z : 227 [M+1]+ (FAB>0).
General Procedure for the Preparation of Compounds 13 and 14 A mixture of (4.1x10-2 mol) of heterocyclic pyrazole 1 or 2 and (4.1x10-2 mol) of potassium tert-butoxide in 150 ml of THF was stirred under reflux for 30 min. 3-bromopropanol (4.1x10-2 mol) in 100 ml of THF was then added slowly. After stirring under reflux for 6 h, the mixture was filtered, evaporated and the residue was separated on silica gel using CH2Cl2 as eluant to give the target compound as viscous oil.
Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1
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32.70 (CH2CH2CH2); 45.56 (CH2N); 59.85 (OCH2); 104.35 (C4); 139.75 (C5); 147.67 (C3); Anal. calcd for C8H14N2O : C 62.33, H 9.09, N 18.18. Found: C 62.21, H 9.19, N 18.13; IR (KBr, cm-1): (OH) = 3120, (C=N) = 1640, (C=C) = 1490; m/z : 155 [M+1]+ (FAB>0). Ethyl (14)
1-(3-Hydroxypropyl)-5-methyl-1H-pyrazole-3-carboxylate
Yield: 62 %; Rf: 0.25 (CH2Cl2 / MeOH, 9/1, V/V in silica); 1H NMR (CDCl3): : 1.3 (t, 3H, CH2CH3); 1.96 (m, 2H, CH2CH2CH2); 2.30 (s, 3H, CH3); 3.20 (s, 1H, OH); 3.70 (m, 2H, CH2OH); 4.25 (t, 2H, CH2N); 4.32 (q, 2H, CH2CH3); 6.60 (s, 1H, H-Pz); 13C NMR (CDCl3): : 11.26 (CH3); 14.52, 59.13 (Et); 32.67 (CH2CH2CH2); 46.77 (CH2N); 61.29 (OCH2); 108.50 (C4); 140.32 (C5); 142.67 (C3); 163.20 (COOEt); Anal. calcd for C10H16N2O3: C 56.60, H 7.54, N 13.20. Found: C 56.40, H 7.49, N 13.36; IR (KBr, cm-1): (OH) = 3100, (C=N) = 1640, (C=C) = 1490, (C=O) =1710; m/z : 213 [M+1]+ (FAB>0).
General Procedure for the Preparation of Compounds 17 and 18 The products 17-18 were prepared by the addition of 2aminoethanol to 15 or 16. To a solution of the substituted hydroxymethylpyrazole 15 or 16 (10 mmol) in acetonitrile (25 ml) was added 2-aminoethanol (10 mmol) and the mixture was continued under stirring at room temperature for 4 days. The crude material was evaporated, washed with water and CH2Cl2 and purified by silica gel column flash-chromatography to give the target product as colourless viscous oil. 1-[(2-Hydroxyethyl amino) methyl]-3,5-dimethyl-1H-pyrazole (17) Yield: 60 %; 1H NMR (CDCl3): : 2.33 (s, 6H, 2CH3); 2.70 (m, 2H, CH2CH2OH); 3.60 (m, 2H, CH2OH); 4.83 (s, 2H, CH2N); 5.82 (s, 1H, H-Pz); 13C NMR (CDCl3): : 12.28 (CH3); 13.57 (CH3); 48.25 (CH2CH2OH); 61.20 (CH2OH); 62.05 (NCH2); 104.45 (C4); 139.33 (C5); 148.00 (C3); Anal. calcd for C8H15N3O: C 56.78, H 8.93, N 24.83. Found: C 56.62, H 8.72, N 24.99; m/z : 170 [M+1]+ (FAB>0). Ethyl 1-[(2-Hydroxyethyl amino) methyl]-5-methyl-1H-pyrazole3-carboxylate (18) Yield: 62 %; Rf: 0.25 (CH2Cl2 / MeOH, 9/1, V/V in silica); 1H NMR (CDCl3): : 1.3 (t, 3H, CH2CH3); 2.33 (s, 3H, CH3); 2.74 (t, 2H, CH2CH2OH); 3.40 (s, 1H, OH); 3.65 (t, 2H, CH2OH); 4.30 (q, 2H, CH2CH3); 6.02 (s, 2H, CH2N); 6.57 (s, 1H, H-Pz); Anal. calcd for C10H17N3O3: C 52.85, H 7.54, N 18.49. Found: C 52.80, H 7.45, N 18.39; m/z : 228 [M+1]+ (FAB>0). ACKNOWLEDGEMENT This work was partly supported by the CUD (Commission Universitaire pour le Développement, Belgium) within the framework of the P3 program. We gratefully acknowledge Prof. A. Hakkou for the biological results. REFERENCES [1] [2]
1-(3-Hydroxypropyl)-3,5-dimethyl-1H-pyrazole (13)
[3]
Yield: 70 %; Rf: 0.48 (CH2Cl2 / MeOH, 9/1, V/V in silica); 1H NMR (CDCl3): : 1.96 (m, 2H, CH2CH2CH2); 2.30 (s, 6H, 2CH3); 3.60 (s, 1H, OH); 4.10 (m, 2H, CH2OH); 4.81 (t, 2H, CH2N); 5.80 (s, 1H, H-Pz); 13C NMR (CDCl3): : 11.26 (CH3); 13.40 (CH3);
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