Synthesis and preliminary biological activity of some new pyrazole derivatives as acyclonucleoside analogues

Article abstract of DOI:10.2174/157018010789869307

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.

Full text of DOI:10.2174/157018010789869307

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 introduc-
tion of modified arm in N1 position of pyrazole moieties has not any impact on the biolgical activity.
Keywords: Pyrazole, Acyclonucleoside, Synthesis, Biological activity.
INTRODUCTION
by cellular enzymes to its triphosphate and incorporated in the ter-
minal 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.
Pyrazole derivatives are well established in the literature as im-
portant biologically active heterocyclic compounds. These deriva-
tives are the subject of many research studies due to their wide-
spread potential biological activities such as anti-inflammatory [1],
antipyretic [2], antimicrobial [3], antiviral [4], antitumour [5, 6],
anticonvulsant [7], antihistaminic [8], antidepressant [9], insecti-
cides [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 het-
erocycles 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].
The structures of the all newly acyclonucleosides were deter-
mined on the basis of the corresponding analytical and spectro-
scopic data.
Biological Activity
Based on the above mentioned research results, the goal of this
study is to synthesize some novel pyrazoles with acyclic substitu-
ents mimetizing individual fragments of the ribose ring for the pur-
pose of synergism and/or increasing the expected biological effects.
The synthesis of target drugs was illustrated in Scheme 1.
The compounds described in this manuscript 9-18 were first
tested in vitro for their activity against two fungal strains (Sac-
charomyces 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.
RESULTS AND DISCUSSION
Chemistry
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.
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 moi-
ety 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
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 acyclic-
chain 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 micro-
organisms such as Saccharomyces cerevisiae, Echerichia coli
and Fusarium oxysporum f.sp albedinis.
*Address correspondence to this author at the Laboratoire de Chimie Organique, Ma-
cromoléculaire et Produits Naturels, Département de Chimie, Faculté des Sciences,
Université Mohamed I, Oujda, Maroc, Fax: 212 536 50 06 03;
E-mail: radi_smaail@yahoo.fr
1570-1808/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

28 Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1
Radi et al.
R
R
Br
AcO
X
1) EtO-Na+
2) Dowex H+
N
CH3
N
CH3
tBuOK/THF
N
N
3
4
X = O
X = CH2
X
HO
X
AcO
5
6
7
8
R = CH3, X = O
R = CH3, X = CH2
R = CO2Et, X = O
R = CO2Et, X = CH2
9
R = CH3, X = O
10 R = CH3, X = CH2
11 R = CO2Et, X = O
12 R = CO2Et, X = CH2
R
R
Br
HO
N
H
CH3
N
CH3
N
tBuOK/THF
N
1
R = CH3
2
R = CO2Et
13
14
R = CH3
R = CO2Et
OH
R
R
OH
H2N
Formol 35%
Ethanol
N
CH3
N
CH3
CH3CN, 25°C
N
N
4 days
HO
H
HO
N
15
16
R = CH3
R = CO2Et
17
18
R = CH3
R = CO2Et
Scheme 1.
EXPERIMENTAL
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).
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).
Ethyl 1-[(2-Acetoxyethoxy) methyl]-5-methyl-1H-pyrazole-3-
carboxylate (7)
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).
General Procedure for the Preparation of Acetyl Com-
pounds 5-8
A mixture of (4.1x10-2 mol) of 1 or 2 and (4.1x10-2 mol) of po-
tassium 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 mix-
ture was filtered, evaporated and the residue was separated on alu-
mina using CH2Cl2 as eluant to give the target acetyl compound as
yellow oil.
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).
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);
1H 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).
General Method: Deacetylation
1-(4-Acetoxybutyl)-3,5-dimethyl-1H-pyrazole (6)
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
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,

Synthesis and Preliminary Biological Activity
Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1 29
crude material was neutralised by Dowex H+ 50x8, filtered, washed
with hot EtOH and purified by silica gel column flash-
chromatography to give the target drugs as colourless viscous oil.
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).
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).
Ethyl 1-(3-Hydroxypropyl)-5-methyl-1H-pyrazole-3-carboxylate
(14)
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).
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).
General Procedure for the Preparation of Compounds 17
and 18
The products 17-18 were prepared by the addition of 2-
aminoethanol to 15 or 16. To a solution of the substituted hy-
droxymethylpyrazole 15 or 16 (10 mmol) in acetonitrile (25 ml)
was added 2-aminoethanol (10 mmol) and the mixture was contin-
ued under stirring at room temperature for 4 days. The crude mate-
rial was evaporated, washed with water and CH2Cl2 and purified by
silica gel column flash-chromatography to give the target product as
colourless viscous oil.
Ethyl 1-[(2-Hydroxyethoxy) methyl]-5-methyl-1H-pyrazole-3-
carboxylate (11)
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 (CD-
Cl3): ꢀ : 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).
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
(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).
Ethyl 1-[(2-Hydroxyethyl amino) methyl]-5-methyl-1H-pyrazole-
3-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 Uni-
versitaire pour le Développement, Belgium) within the framework
of the P3 program. We gratefully acknowledge Prof. A. Hakkou for
the biological results.
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.
REFERENCES
[1]
Tewari, A.K.; Mishra, A. Synthesis and anti-inflammatory activities of
N4,N5-disubstituted-3-methyl-1H-pyrazolo[3,4-c]pyridazines. Bioorg. Med.
Chem., 2001, 9, 715-718.
[2]
[3]
Wiley, R.H.; Wiley, P. Pyrazolones, Pyrazolidones and Derivatives; John
Wiley and Sons: New York, 1964.
Pimerova, E.V.; Voronina, E.V. Antimicrobial activity of pyrazoles and
pyridazines obtained by interaction of 4-aryl-3-arylhydrazono-2,4-
dioxobutanoic acids and their esters with hydrazines. Pharm. Chem. J., 2001,
35, 18-20.
1-(3-Hydroxypropyl)-3,5-dimethyl-1H-pyrazole (13)
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);
[4]
Janus, S.L.; Magdif, A.Z.; Erik, B.P.; Claus, N. Synthesis of triazenopyrazole
derivatives as potential inhibitors of HIV-1. Monatsh. Chem., 1999, 130,
1167-1174.

30 Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1
Radi et al.
[5]
[6]
[7]
Park, H.J.; Lee, K.; Park, S.; Ahn, B.; Lee, J.C.; Cho, H.Y.; Lee, K.I. Identi-
fication of antitumor activity of pyrazole oxime ethers. Bioorg. Med. Chem.
Lett., 2005, 15, 3307-3312.
Bouabdallah, I.; M’barek, L.A.; Zyad, A.; Ramadan, A.; Zidane, I.; Mel-
haoui, A. Anticancer effect of three pyrazole derivatives. Nat. Prod. Res.,
2006, 20, 1024-1030.
Michon, V.; Du Penhoat, C.H.; Tombret, F.; Gillardin, J.M.; Lepagez, F.;
Berthon, L. Preparation, structural analysis and anticonvulsant activity of 3-
and 5-aminopyrazole N-benzoyl derivatives. Eur. J. Med. Chem., 1995, 147-
155.
Yildirim, I.; Ozdemir, N.; Akçamur, Y.; Dinçer, M.; Andaç, O. 4-Benzoyl-
1,5-diphenyl-1H-pyrazole-3-carboxylic acid methanol solvate. Acta Cryst.,
2005, E61, 256-258.
Bailey, D.M.; Hansen, P.E.; Hlavac, A.G.; Baizman, E.R.; Pearl, J.; Defelice,
A.F.; Feigenson, M.E. 3,4-Diphenyl-1H-pyrazole-1-propanamine antidepres-
sants. J. Med. Chem., 1985, 28, 256-260.
Chu, C.K.; Cutler, J. Chemistry and antiviral activities of acyclonucleosides.
J. Heterocycl. Chem., 1986, 23, 289-319.
Arrieta, A.; Carrillo, J.R.; Cossı´o, F.P.; Ortiz, A.D.; Gomez-Escalonilla,
M.J.; de la Hoz, A.; Langa, F.; Moreno, A. Efficient tautomerization hydra-
zone-azomethine imine under microwave irradiation. Synthesis of [4,3ꢀ] and
[5,3ꢀ]bipyrazoles. Tetrahedron, 1998, 54, 13167-13180.
Remy, R.J.; Secrist III, J.A. Acyclic nucleosides other than acyclovir as
potential antiviral agents. Nucleosides Nucleotides, 1985, 4, 411-427.
Shaeffer, H.J.; Beauchamp, L.; De Miranda, P.; Elion, G.B.; Bauer, D.B.,
Collins, P. 9-(2-Hydroxyethoxymethyl) guanine activity against viruses of
the herpes group. Nature (London), 1978, 272, 583-585.
[17]
[18]
Martin, J.C.; Dvorak, C.A; Smee, D.F.; Mattews T.R.; Verheyden, J.P.H. 9-
[(1,3-Dihydroxy-2-propoxy)methyl] guanine: a new potent and selective an-
tiherpes agent. J. Med. Chem.,1983, 26, 759-761.
Ashton, W.T.; Canning, L.D.; Reynolds, G.F.; Tolman, R.L.; Karkas, J.D.;
Liou, R., Davies, M.-E.M.; De Witt, C.M.; Perry H.C.; Field, A.K. Synthesis
and antiherpetic activity of (S)-, (R)-, and (±)-9-[(2,3-dihydroxy-1-
propoxy)methyl]guanine, linear isomers of 2'-nor-2'-deoxyguanosine. J.
Med. Chem., 1985, 28, 926-933.
Lin, T.-S.; Lin, M.-C. Synthesis of 9-(2,3-dihydroxy-1-propoxymethyl)
guanine. A new potential antiviral agent. Tetrahedron Lett. 1984, 25, 905-
906.
Mac Coss, M.; Chen, A.; Tolman, R.L. Syntheses of all four possible di-
astereomers of the acyclonucleoside 9-(1,3,4-trihydroxy-2-butoxymethyl)
guanine from carbohydrate precursors. Tetrahedron Lett., 1985, 26, 4287-
4290.
Vere Hodge, R.A. Famciclovir and penciclovir. The mode of action of fam-
ciclovir including its conversion to penciclovir. Antiviral Chem. Chemother.,
1993, 4, 67-84.
El Ashry, E.S.H.; El Kilany, Y. Acyclonucleosides: Part 1. Seco-
Nucleosides. Adv. Heterocycl. Chem., 1997, 67, 391-438.
El Ashry, E.S.H.; El Kilany, Y. Acyclonucleosides: Part 2. diseco-
Nucleosides. Adv. Heterocycl. Chem., 1997, 68, 1-88.
El Ashry, E.S.H.; El Kilany, Y. Acyclonucleosides, Part III. tri-, tetra-, and
pentaseco-Nucleosides. Adv. Heterocycl. Chem., 1997, 69, 129-215.
Robins, M.J.; Hatfield, P.W. Nucleic acid related compounds. 37. Conven-
ient and high-yield syntheses of N-[2-hydroxyethoxy)methyl]heterocycles as
acrylic nucleoside analogues. Can. J. Chem., 1982, 60, 547-553.
Taha, M.L.; Lazrek, H.B. Synthesis of some 4-substituted 1-(4-
hydroxybutyl)-pyrazolo[3,4-d]pyrimidines analogs of 9-(4-hydroxybutyl)
guanine (HBG). Bull. Soc. Chim. Belg., 1995, 104, 647-652.
Fifani, J.; Ramdani, A.; Tarrago, G. 1,6,11,16-tetraazaporphyrinogen, syn-
thesis and behaviour. New J. Chem., 1977, 1, 521-528.
[19]
[20]
[8]
[9]
[21]
[10]
[11]
[22]
[23]
[24]
[25]
[12]
[13]
[14]
[15]
Agrofoglio, L.A.; Challand, S.R. Acyclic, Carbocyclic and L-Nucleosides;
Kluwer Academic Publishers, USA 1998.
[26]
Ogilvie, K.K.; Cheriyan, U.O.; Radatus, B.K.; Smith, K.O.; Galloway, K.S.;
Kennell, W.L. Biologically active acyclonucleoside analogues. II. The syn-
thesis of 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine (BIOLF-
62). Can. J. Chem., 1982, 60, 3005-3010.
Field, A.K.; Davie, M.E.; Dewitt, C.; Perry, H.C.; Liou, R., Germershausen,
J.I.; Karkas, J.D.; Ashton, W.T.; Johnson, D.B.R.; Tolman, R.C. 9-([2-
hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine: a selective inhibitor of
herpes group virus replication. Proc. Natl. Acad. Sci. USA, 1983, 80, 4139-
4143.
[27]
[28]
[29]
[30]
[31]
Driessen, W. L. Synthesis of some new pyrazole-containing chelating agents.
Recl. Trav. Chim. Pays-Bas, 1982, 101, 441-443.
Evans, I.R.; Szécsényi, K.M.; Leovac V.M. 1-(Hydroxymethyl)-3,5-
[16]
dimethylpyrazole. Acta Cryst., 2005, E61, 625-626.
Touzani, R.; Ramdani, A.; El Kadiri, S.; Gourand, F. 1-Hydroxymethyl-3-
ethoxy-5-methylpyrazole. Molecules, 1999, 4, M116.
Carrod, L.P.; Grady, F.D. Antibiotics and Chemotherapy, 3rd ed.; Churchill
Livingstone: Edin-burgh, 1972, pp. 477.S