Synthesis and anti-HIV activity of new modified 1,2,3-triazole acyclonucleosides

Article abstract of DOI:10.1081/NCN-100108325

The synthesis of 1,2,3-triazole acyclonucleosides 7a-h via 1,3-dipolar cycloaddition of N-9/N-1-propargylpurine/pyrimidine 2a-h with azido-pseudo-sugar 4 is described and none of them had anti-HIV activity.

Full text of DOI:10.1081/NCN-100108325

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SYNTHESIS AND ANTI-HIV ACTIVITY OF NEW MODIFIED
1,2,3-TRIAZOLE ACYCLONUCLEOSIDES
H. B. Lazrek , M. Taourirte , T. Oulih , J. L. Barascut a , J. L. Imbach a , C. Pannecouque b
M. Witrouw b & E. De Clercq b
,
a Université des Sciences et Techniques Montpellier II , Laboratoire de Chimie Bio-Organique,
France
b Rega Institute for Medical Research , K. U. Leuven, Belgium
Published online: 17 Aug 2006.
To cite this article: H. B. Lazrek , M. Taourirte , T. Oulih , J. L. Barascut , J. L. Imbach , C. Pannecouque , M. Witrouw & E.
De Clercq (2001) SYNTHESIS AND ANTI-HIV ACTIVITY OF NEW MODIFIED 1,2,3-TRIAZOLE ACYCLONUCLEOSIDES, Nucleosides,
Nucleotides and Nucleic Acids, 20:12, 1949-1960
To link to this article: http://dx.doi.org/10.1081/NCN-100108325
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(12), 1949–1960 (2001)
SYNTHESIS AND ANTI-HIV ACTIVITY
OF NEW MODIFIED 1,2,3-TRIAZOLE
ACYCLONUCLEOSIDES
H. B. Lazrek,1,* M. Taourirte,2 T. Oulih,1 J. L. Barascut,3
J. L. Imbach,3 C. Pannecouque,4 M. Witrouw,4 and E. De Clercq4
1Laboratoire de Chimie Bio-Organique, Faculte des Sciences
Semlalia, BP S15, Marrakech, Maroc
2Faculte des Sciences et Techniques-Gueliz, BP 618,
Marrakech, Maroc
3Laboratoire de Chimie Bio-Organique, Universite des Sciences et
Techniques Montpellier II, France
4Rega Institute for Medical Research, K. U. Leuven, Belgium
ABSTRACT
The synthesis of 1,2,3-triazole acyclonucleosides 7a-h via 1,3-dipolar
cycloaddition of N-9=N-1-propargylpurine=pyrimidine 2a-h with azido-
pseudo-sugar 4 is described and none of them had anti-HIV activity.
The synthesis and biological evaluation of modified nucleoside analogues
have been a very active research area for a number of years1. In particular,
several acyclonucleosides analogues are, presently, known as potent antiviral
agents, among these ACV, HBG, DHPG2,3, PMEA and HPMPA4 deriva-
tives. Furthermore, the importance of side-chain conformation in the inter-
action of acyclic nucleosides with enzymes has been noted5, and differences in
affinities for the viral thymidine kinase appear to be due to conformational
factors.
*Corresponding author.
1949
Copyright # 2001 by Marcel Dekker, Inc.
www.dekker.com

1950
LAZREK ET AL.
In addition, substances containing a five membered heterocyclic base
are important targets in chemical synthesis because of their pronounced
biological activities. Among them, ribavirin (virazole), which contains a
substituted 1,2,4-triazole ring, represents the most successful one1. For in-
stance, Alvarez et al6. have reported the synthesis and activity of a series of
TSAO analogues, in which the thymine moiety of the lead compound
(TSAO-T) was replaced by a series of 1,2,3-triazole substituted with different
functional groups (amide, esters, . . .) at the position 4 or 5. Several com-
pounds of this class show potent anti-HIV-1 activities in comparison with the
prototype (thymine) derivative, TSAO-T.
Based on these considerations and in continuation of our workon
acyclonucleosides7–9, we prepared a series of modified 1,2,3-triazole acyclo-
nucleosides bearing a nucleobase at the position 4 or 5 of the triazole moiety.
The idea behind these acyclic derivatives comes from a constraint imposed on
side-chain flexibility by incorporation of 4 or 5-methylene-1,2,3-triazole as a
spacer arm which would result in a better conformation for enzyme inter-
action10.
RESULTS AND DISCUSSION
The most common method described in literature for the preparation of
1,2,3-triazole rings is the 1,3-dipolar cycloaddition11,12 between substituted
acetylenes as dipolarophiles and alkyl azide derivatives. Thus, uracil 1a was
treated with propargyl bromide in the presence of K2CO3 in DMF13, after
24 h reaction gave N-1-isomer 2a and the N-1,N-3-dialkylated isomer as side
product. The desired product was obtained via column chromatography in
50% yield (Table 1) (Sch. 1). These conditions were used for the preparation
of 2b-d and 2f-h For the iodouracil derivative 2e solid-liquid phase transfer
Table 1. N-Alkylation of Heterocyclic Bases with Propargyl Bromide
Base
Condition
Time (h)
Yield %a
Thymine
Uracil
K2CO3=DMF
K2CO3=DMF
K2CO3=DMF
3
3
1
1
0.5
1
2
65
50
56
63
62
70
70
72
5-Chlorouracil
5-Bromouracil
5-Iodouracil
5-Fluorouracil
Adenine
K2CO3=DMF
tBuOK=18-Crown=THF
K2CO3=DMF
K2CO3=DMF
N-2-Ac-guanineb
K2CO3=DMF
3
a yield of N-alkylated nucleobases (2a-h).
b ratio N-7:N-9 was 5:5.

ANTI-HIV ACTIVITY OF 1,2,3-TRIAZOLE ACYCLONUCLEOSIDES
1951
Scheme1.
catalysis (tBuOK=18-crown-6=THF)14 gave the desired product in 62% yield
(Table 1).
An alternative route was explored to obtain the products 2c, 2d and 2e
using the N-1-propargyluracil 2a as starting material, followed by halo-
genations at the C-5 position. Treatment of 2a with N-bromo-, N-chloro- or
N-iodosuccinimide in pyridine afforded the corresponding compounds 2c, 2d
and 2e in good yield (Sch. 2).
Scheme 2.
1
The structure of these compounds was confirmed using H NMR, ele-
mental analysis and UV spectroscopy.
Acyclic intermediate 3 was prepared according to the literature15 and it
was easily transformed to the corresponding azido derivative 416 (Sch. 3).
We therefore investigated the cycloaddition of this azide 4 with electron
deficient alkynes 2a-h. It was necessary to select conditions which were
sufficiently mild to avoid the thermal degradation of the azide. Thus
cycloaddition of the azide 4 with 2a-h occurred smoothly in refluxing toluene

1952
LAZREK ET AL.
Scheme 3.
(110 ꢀC) and the triazole acyclonucleosides 5a-h and 6a-h thus formed
(Sch. 4), were separated using column chromatography, as a mixture of
regioisomers. Only the major isomers 5a-h were obtained as pure products.
It has been reported, that addition of azides to unsymmetrical acet-
ylenes is determined by steric and electronic factors. In general, such addition
tends to give mainly the isomers with electron-withdrawing groups at the
4-position and electron releasing groups at the 5-position. On the other hand,
the sterically less hindered isomer tends to be the major isomer7.
The structure of the two isomers was established by comparison of the
chemical shift values for the triazole ring protons with those available from a
known pair of 4- and 5-TSAO 1, 2, 3-triazole derivatives7. In the case of the
4-substituted isomers 5 the signal of H-5 proton appeared at lower field
(7.74–8.23 ppm) than the signal of H-4 proton (6.90–7.75 ppm) in the
5-substituted derivatives 6.
A common feature of many acyclic nucleoside analogues with antiviral
activity, including ACV and HBG, is the presence of a primary alcoholic
group. The later function and the nucleic acid base are essential for the
antiviral activity. For this purpose deprotected products 7a-h were obtained
in good yield by treating compounds 5a-h with ammonia in methanol at
room temperature (Sch. 4).
Scheme 4.

ANTI-HIV ACTIVITY OF 1,2,3-TRIAZOLE ACYCLONUCLEOSIDES
1953
Table 2. 1,3-Dipolar Cycloaddition of N-Propargyl Pyrimidine=Purine
Derivatives with Acyclic Azide 4
Substrate
Yield %
Ratio* 5:6
2a
2b
2c
2d
2e
2f
74
84
70
68
82
76
65
60
91:9
100:0
100:0
78:22
100:0
86:14
74:26
75:25
2g
2h
1
* The ratios were determined from H NMR spectra.
Table 3. Chemical Shifts (d, ppm) of H-5, H-4
Compound
H-5
H-4
5a=6a
5b=6b
5c=6c
5d=6d
5e=6e
5f=6f
7.74
8.06
8.23
8.09
8.09
8.08
8.08
8.00
6.90
–
–
7.73
–
7.70
7.65
7.75
5g=6g
5h=6h
Antiviral Activity
Compounds 2a-h, 5a-f and 7a-h were evaluated for their inhibitory
effect against the cytopathic effect of HIV-1 (IIIB) and HIV-2 (ROD) in MT-
4 cells17. No activity was observed against the replication of these viruses at
compound concentrations up to 100 mg=mL.
EXPERIMENTAL
Melting points (mp) were determined on a electrothermal digital melting
point apparatus and were uncorrected. Ultraviolet spectral (UV) were re-
1
corded with a Cary 219 spectrometer. The H NMR spectra were recorded
using a Brucker AC 250 MHz spectrometer. T (1,2,3-triazole) and B (het-
erocyclic base). Mass spectra (MS) were obtained with JEOL JMS DX 300
instrument using fast atomic bombardment (FABþ). Thin layer chromato-

1954
LAZREK ET AL.
graphy was performed on plates of Kieselgel 60 F254 (Merck) and short-
wave ultraviolet light (254 nm) was used to detect the UV-absorbing spots.
Column chromatography separation was carried out on silica gel (0.063–
0.2 mm, Merck). Elemental analysis was determined by the French Micro-
analytical Central Service.
Preparation of N-1/N-9-propargylpyrimidine=Purine
Method A: To a suspension of heterocylic base (4 mmol) and anhydrous
potassium carbonate (4 mmol) in 50 mL of DMF, was added 12 mmol of
propargyl bromide. The mixture was stirred at room temperature for the
required time. Removal of the solvent and column chromatography on silica
gel afforded the pure product.
Method B: To a solution of 2b (2 mmol) in pyridine (30 mL) was added
N-halogenosuccinimide (NCS, NBS or NIS) (4 mmol). The mixture was
stirred for 30 min at 100 ꢀC and then a saturated aqueous NaHCO3 solution
(50 mL) was added. The mixture was extracted with CHCl3 (3650 mL). The
organic phase was dried (MgSO4) and concentrated. The residue was purified
by column chromatography.
Method C: To a solution of of 18-crown-6 (1 mmol) in dry THF
(40 mL) under nitrogen atmosphere was added potassium tert-butoxide
(10 mmol). Then the heterocyclic base (10 mmol) was added, and the reac-
tion mixture was stirred at room temperature for 15 min. At this time
propargyl bromide (10 mmol) was added dropwise with stirring. When the
addition was finished, the mixture was stirred at 25 ꢀC for 3 h. The residue
was then filtered and evaporated to dryness in vaccuo and chromato-
graphed on silica gel column.
N-1-Propargylthymine 2a
Method A: Eluent 99=1, v=v CH2Cl2=MeOH; yield 56%; mp 154–156ꢀC
(CH2Cl2=ether); 1H NMR (DMSO-d6) d 1.76 (s, 3H, CH3), 3.40 (t, 1H, CH,
J ¼ 2.2 Hz), 4.46 (d, 2H, CH2-N, J ¼ 2.1 Hz), 7.56 (s, 1H, H-6), 11.4 (s, 1H,
NH); UV (MeOH) lmax 271 nm; FAB-MS m=z 165 (MþH).þ
N-1-Propargyluracil 2b
Method A: yield 50%; 1H NMR (DMSO-d6) d 3.41 (t, 1H, CH,
J ¼ 2.3 Hz), 4.51 (d, 2H, CH2-N, J ¼ 2.3 Hz), 5.62 (d, 1H, H-5, J ¼ 7.8 Hz),
7.7 (d, 1H, H-6, J ¼ 7.8 Hz), 11.3 (s, 1H, NH); UV (MeOH) lmax 261 nm; mp
154–166ꢀC (CH2Cl2=ether); FAB-MS m=z 151 (MþH).þ

ANTI-HIV ACTIVITY OF 1,2,3-TRIAZOLE ACYCLONUCLEOSIDES
1955
N-1-Propargyl-5-chlorouracil 2c
Method A: yield: 46%; Method B: yield 92%; mp 168–170ꢀC
1
(CH2Cl2=ether); H NMR (DMSO-d6) d 3.46 (t, 1H, CH, J ¼ 2,4 Hz), 4.50
(d, 2H, CH2-N, J ¼ 2,4 Hz), 8.20 (s, 1H, H-6), 11.86 (s, 1H, NH); UV(-
MeOH) lmax 276 nm; FAB-MS m=z 185 (MþH).þ
N-1-Propargyl-5-bromouracil 2d
Method A: yield 42%; Method B: yield 97%; mp 172–174ꢀC
1
(CH2Cl2=ether); H NMR (DMSO-d6) d 3.45 (t, 1H, CH, J ¼ 2,4 Hz), 4.51
(d, 2H, CH2-N, J ¼ 2,4 Hz), 8.26 (s, 1H, H-6), 11.91 (s, 1H, NH); UV
(MeOH) lmax 278 nm; FAB-MS m=z 230 (MþH).þ
N-1-Propargyl-5-iodouracil 2e
ꢀ
Method A: yield 62%; Method B: yield 50%; mp 179–181 C
1
(CH2Cl2=ether); H NMR (DMSO-d6) d 3.42 (t, 1H, CH, J ¼ 2,6 Hz), 4.58
(d, 2H, CH2-N, J ¼ 2,6 Hz), 8.28 (s, 1H, H-6), 12,02 (s, 1H, NH), UV
(MeOH) lmax 282 nm; FAB-MS m=z 273 (M þH).þ
N-1-Propargyl-5-fluorouracil 2f
Method A: yield 52%; mp 146–148 ꢀC (CH2Cl2=ether); 1H NMR
(DMSO-d6) d 3.46 (t, 1H, CH, J ¼ 2,4 Hz), 4.60 (d, 2H, CH2-N, J ¼ 2,4 Hz),
8.25 (d, 1H, H-6, J ¼ 6,6 Hz), 11.96 (s, 1H, NH); UV (MeOH) lmax 270 nm;
FAB-MS m=z 169 (MþH).þ
N-9-Propargyl-N-2-acetylguanine 2h
Method A: yield 35%; mp 285–286 ꢀC (CH2Cl2=ether); 1H RMN
(DMSO-d6) d 2.00 (s, 3H, CH3CON), 3.55 (t, 1H, CH, J ¼ 2.5 Hz), 4.95 (d,
2H, CH2-N, J ¼ 2.5 Hz), 7.35(bs, 2H, NH2), 8.08 (s, 1H, H-8); UV (H2O)
lmax 259, 280 nm; FAB-MS m=z 233 (MþH).þ
N-9-Propargyladenine 2g13
Method A: yield 80%; 1H NMR DMSO-d6) d 3.55 (t, 1H, CH,
J ¼ 2.5 Hz), 5.07 (d, 2H, CH2-N, J ¼ 2.5 Hz), 7.35 (sl, 2H, NH2), 8.20 and
8.25 (2s, 2H, H-2 and H-8); UV (MeOH) lmax 260 nm; mp 213–214 ꢀC
(CH2Cl2=MeOH); FAB-MS m=z 174 (MþH).þ

1956
LAZREK ET AL.
General Procedure for the Synthesis of Compounds 5a-h
A solution of 12.5 mmol alkylazide and 2.5 mole of N-1=N-9-pro-
pargylpyrimidine=purine in anhydrous toluene (40 mL) were heated under
reflux for 2 to 3 days (see Table 1). Evaporation of the solvent furnished a
1
mixture of compounds 5 and 6. Ratio of 5=6 was determined by H NMR
based on the integration of triazole protons H-4 (1,5-isomer) and H-5 (1,4-
isomer), after purification by silica gel column chromatography.
1-[[1-((4-Acetoxyethoxy)methyl) -1,2,3-triazol-4-yl] methyl]thymine 5a.
1
Yield 60% as a white solid; H NMR (CDCl3) d 1.91 (s, 3, CH3), 2.06 (s, 3,
CH3CO), 3.74 (t, 2, CH2, J ¼ 4.6 Hz), 4.18 (t, 2, CH2), 4.99 (s, 2, T-CH2-B),
5.71 (s, 2, O-CH2-N), 7.35 (s, 1, H6), 7.92 (s, 1, H-50), 9.28 (s, 1, NH); MS (EI)
m=z 323 (Mþ); UV (MeOH) lmax 272 nm, mp 152–154 ꢀC (EtOH-ether),
Anal. calcd. for C13H17N5O5: C, 48.30; H, 5.30; N, 21.66. found, C, 48.18;
H, 5.27; N, 21.85.
1-[[1-((4-Acetoxyethoxy)methyl)-1,2,3-triazol-4-yl] methyl]uracil 5b.
1
Yield 63%; H NMR (CDCl3) d 2.06 (s, 3, CH3CO), 3.74 (t, 2, CH2,
J ¼ 4.0 Hz), 4.18 (t, 2, CH2), 5.01 (s, 2, T-CH2-B), 5.72 (s, 2, O-CH2-N),
5.74 (d, 1, H5, J ¼ 7.5 Hz), 7.51 (d, 1, H-6), 7.91 (s, 1, H-50), 9.26 (s, 1,
NH); MS (EI) m=z 309 (Mþ); UV (MeOH) lmax 265 nm; mp 148–150 ꢀC;
Anal. calcd. for : C12H15N5O5: C, 46.60; H, 4.89; N, 22.64; found, C,
46.02; H, 4.89; N, 22.75.
1-[[1-((4-Acetoxyethoxy)methyl)-1,2,3-triazol-4-yl] methyl] 5-chlorouracil
1
5c. Yield 57%; H NMR (CDCl3) d 2.05 (s, 3, CH3CO), 3.74 (t, 2, CH2,
J ¼ 4.5 Hz), 4.17 (t, 2, CH2, J ¼ 4.5 Hz), 5.00 (s, 2, T-CH2-B), 5.72 (s, 2, O-
CH2-N), 7.80 (s, 1, H-6), 7.95 (s, 1, H-50), 9.88 (s, 1, NH); MS (EI) m=z
343 (Mþ); UV (MeOH) lmax 278 nm; mp102–104 ꢀC (EtOH-ether); Anal.
calcd. for C12H14N5O5Cl: C, 41.93; H, 4.11; N, 20.37; found, C, 42.18; H,
4.09; N, 20.53.
1-[[1-((4-Acetoxyethoxy)methyl)-1,2,3-triazol-4-yl] methyl] bromouracil
1
5d. Yield 45%; H NMR (CDCl3) d 2.06 (s, 3, CH3CO), 3.75 (t, 2,
CH2CH2, J ¼ 4.6 Hz), 4.18 (t, 2, AcOCH2), 5.03 (s, 2, T-CH2-B), 5.72 (s, 2,
O-CH2-N), 7.89 (d, 1, H-50), 7.90 (s,1, H-6), 9.04 (s, 1, NH); MS (EI) m=z
387 (Mþ); UV (MeOH) lmax 279 nm; mp 143–145 ꢀC (EtOH=ether); Anal.
calcd. for C12H14N5O5Br : C, 37.13; H, 3.64; N, 18.04, found, C, 37.18; H,
3.53; N; 18.11.
1-[[1-((4-Acetoxyethoxy)methyl)-1,2,3-triazol-4-yl] methyl]iodouracil
1
5e. Yield 67%; H NMR (DMSO-d6) d 2.0 (s, 3, CH3CO), 3.60 (t, 2,
CH2, J ¼ 4.6 Hz), 4.15 (t, 2, CH2, J ¼ 4.6 Hz), 5.0 (s, 2, T-CH2-B), 5.80 (s, 2,

ANTI-HIV ACTIVITY OF 1,2,3-TRIAZOLE ACYCLONUCLEOSIDES
1957
O-CH2-N), 8.30 (s, 1, H-6), 8.38 (s 1, H-50), 11.8 (s, 1, NH); MS (EI) m=z 435
(Mþ); UV (MeOH) lmax 282 nm; mp 147–149 ꢀC (EtOH=ether), Anal. calcd.
for C12H14N5O5I.: C, 33.12; H, 3.24; N, 16.09; found, C, 32.97; H, 3.26; N,
16.31.
1-[[1-((4-Acetoxyethoxy)methyl)-1,2,3-triazol-4-yl] methyl]fluorouracil
1
5f. Yield 54%, H NMR (CDCl3) d 2.06 (s, 3, CH3CO), 3.75 (t, 2, CH2,
J ¼ 4.6 Hz), 4.18 (t, 2, CH2), 5.00 (s, 2, T-CH2-B), 5.73 (s, 2, O-CH2-N),
7.65 (d, 1, H-6), 7.93 (s, 1, H-50), 9.71 (s, 1, NH); MS (EI) m=z 327 (Mþ);
UV (MeOH) lmax 269 nm; mp 124–126 ꢀC (EtOH); Anal. calcd. for
C12H14N5O5F: C, 44.07; H, 4.31; N, 1.41; found, C, 44.23; H, 4.26; N, 21.52.
9-[[1-((4-Acetoxyethoxy)methyl)-1,2,3-triazol-4-yl] methyl]adenine 5g.
Yield 47%, 1H NMR (DMSO-d6) d 1.9 (s, 3, CH3COO), 3.6 (t, 2, OCH2), 4.0
(t, 2, OCH2), 5.4 (t, 2, T-CH2-B), 5.65 (s, 2, O-CH2-N), 7.15 (bs, 2, NH2),
8.08 (s, 1, H-50), 8.14 and 8.19 (2s, 2, H-2 þ H-8); UV (EtOH): lmax
261 nm; FAB-MS m=z 333 (M þH).
9-[[1-((4-Acetoxyethoxy)methyl)-1,2,3-triazol-4-yl]methyl]N-2-acetyl
1
guanine 5h. Yield 42%, H NMR (CDCl3) d 2.1 (s, 3, CH3COO), 2.4 (s, 3,
CH3CON), 3.7 (t, 2, OCH2), 4.2 (t, 2, OCH2), 5.65 (t, 2, T-CH2-B), 5.75 (s, 2,
OCH2N), 8.0 (s, 1, H-50), 8.1 (s, 1, H-8); UV (H2O) lmax ¼ 256, 274 nm; FAB-
MS m=z 391 (M þH).þ
Deprotection Method
To 1 mole of the acetylated acyclonucleoside was added 45 mL of me-
thanol saturated with ammonia at 0 ꢀC. The flaskwas stopped tightly and the
solution was stirred for 24 h at room temperature. Thin-layer chromato-
graphy indicated that complete deprotection of acyclonucleoside had oc-
curred. Volatile materials were evaporated and the residue was purified by
chromatography.
1-[1-[(4-Hydroxyethoxy)methyl]-1,2,3-triazol-4-yl] methyl] thymine 7a.
1
Yield 87%, H NMR (DMSO-d6) d 3.46 (m, 4, CH2CH2), 4.57 (m, 1, OH),
4.91 (s, 2, T-CH2-B), 5.69 (s, 2, OCH2N), 7.62 (s, 1, H-6), 8.21 (s, 1, H-50),
11.31 (s, 1, NH); MS (EI) m=z 281(Mþ); UV (MeOH) l 270 nm (e 9400);
mp 164–166 ꢀC (EtOH); Anal. calcd. for C11H15N5O4.: C, 46.97; H, 5.38;
N, 24.90, found, C, 46.96; H, 5.14; N, 24.94.
1-[1-[(4-Hydroxyethoxy)methyl]-1,2,3-triazol-4-yl] methyl] uracil 7b.
Yield 92%, 1H NMR (DMSO-d6) d 3.40 (m, 2, CH2), 3.74 (m, 2,
CH2OH), 4.67 (m, 1, OH), 4.95 (s, 2, T-CH2-B), 5.70 (s, 2, OCH2N), 7.75

1958
LAZREK ET AL.
(d, 1, H-6, J ¼ 7.4 Hz), 8.21 (s, 1, H-50), 11.29 (s, 1, NH); MS (EI) m=z 267
(Mþ); UV (MeOH) lmax 262 nm (e 12200); mp 224–226 ꢀC (EtOH), Anal.
calcd. for C10H13N5O4.: C, 44.94; H, 4.90; N, 26.21; found, C, 44.73; H,
4.94; N, 26.48.
1-[1-[(4-Hydroxyethoxy)methyl]-1,2,3-triazol-4-yl] methyl] 5-chlorouracil
1
7c. Yield 79%, H NMR (DMSO-d6) d 3.46 (m, 4, CH2CH2), 4.74 (m, 1,
OH), 4.96 (s, 2, T-CH2-B), 5.69 (s, 2, OCH2N), 8.25–8.26 (2s, 2, H-50, H-
6), 11.86 (s, 1, NH); MS (EI) m=z 301(Mþ); UV (MeOH) lmax 277 nm (e
10000), mp 144–146 ꢀC (EtOH); Anal. calcd. for C10H12N5O4Cl : C, 39.81;
H, 4.01; N, 23.21;. found, C, 39.85; H, 4.13; N, 23.22.
1-[1-[(4-Hydroxyethoxy)methyl]-1,2,3-triazol-4-yl] methyl] 5-bromouracil
1
7d. Yield 82%, H NMR (DMSO-d6) d 3.47 (m, 4, CH2CH2), 4.70 (m, 1,
OH), 4.96 (s, 2, T-CH2-B), 5.70 (s, 2, OCH2N), 8.25 (s, 1, H-6), 8.35 (s, 1,
H-50), 11.83 ( s,1,NH ); MS (EI) m=z 346 (Mþ); UV (MeOH) lmax 280 nm
(e 9800); mp 217–219 ꢀC (EtOH); Anal. calcd. for C10H12N5O4Br: C, 34.70;
H, 3.49; N, 20.23;. found, C, 34.59; H, 3.52; N, 20.22.
1-[1-[(4-Hydroxyethoxy)methyl]-1,2,3-triazol-4-yl] methyl] 5-iodouracil
1
7e. Yield 82%, H NMR (DMSO-d6) d 3.50 (m, 4, CH2CH2), 4.74 (m, 1,
OH), 4.99 (s, 2, T-CH2-B), 5.73 (s, 2, OCH2N), 8.27 (s, 1, H-6), 8.36 (s, 1,
H-50), 11.72 (s, 1, NH); MS (EI) m=z 394 (Mþ); UV (MeOH) lmax 282 nm
(e 4900); mp 160–162 ꢀC (EtOH); Anal. calcd. for C10H12N5O4I.: C, 30.55;
H, 3.08; N, 17.81; found, C, 30.61; H, 3.06; N, 17.86.
1-[1-[(4-Hydroxyethoxy)methyl]-1,2,3-triazol-4-yl] methyl] 5-fluorouracil
1
7f. Yield 74%, H NMR (DMSO-d6) d 3.46 (m, 4, CH2CH2), 4.72 (m, 1,
OH), 4.91 (s, 2, T-CH2-B), 5.70 (s, 2, OCH2N), 8.21 (d, 1, H-6), 8.25 (s, 1,
H-50), 11.84 (s, 1, NH); MS (EI) m=z 286 (Mþ); UV (MeOH) lmax 269 nm
(e 8200); mp 125–127 ꢀC (EtOH); Elem. Anal. calcd for C10H12N5O4F: C,
42.14; H, 4.24; N, 24.57. found, C, 42.26; H, 4.35; N, 24.29.
9-[1-[(4-Hydroxyethoxy)methyl]-1,2,3-triazol-4-yl] methyl]adenine 7g.
1
Yield 74%, H NMR (DMSO-d6) d 3.4 (m, 4, CH2CH2), 4.65 (sl, 1, OH),
5,45 (s, 2, T-CH2-B), 5.7 (s, 2, OCH2N), 7.22 (bs, 2, NH2), 8.05 (s, 1, H-
50), 8.20 and 8.25 (2s, 2, H-2 þ H-8); UV (0.1N HCl) lmax 260 nm; FAB-
MS m=z 291 (MþH);þ Anal. calcd. For C11H14N8O2: C, 45.51; H, 4.86; N,
38.60; found, C, 45.58; H, 4.97; N, 38.74.
9-[1-[(4-Hydroxyethoxy)methyl]-1,2,3-triazol-4-yl] methyl]guanine 7h.
1
Yield 65%, H NMR (DMSO-d6) d 3.5 (m, 4, CH2CH2), 4.65 (sl, 1, OH),
5.55 (s, 2, T-CH2-B), 5.7 (s, 2, OCH2N), 6.3 (bs, 2, NH2), 8.0 (s, 1, H-5),
8.2 (s, 1, H-8); UV (H2O) lmax 256; 278 nm, FAB-MS m=z 307 (MþH).þ

ANTI-HIV ACTIVITY OF 1,2,3-TRIAZOLE ACYCLONUCLEOSIDES
1959
Anal. calcd. for C11H14N8O3: C, 43.13; H, 4.61; N, 36.58; found, C, 43.24; H,
4.75; N, 36.64.
ACKNOWLEDGMENTS
This workwas supported by CNRS (France), DFG (Germany) and
CNR (Morocco) and the inter-universities cooperation (AI 1141=96). We
thankProf. J. L. Abbud Mas of the C.S.I.C., Madrid, Spain, and Prof.
W. Pfleiderer, University of Konstanz, Konstanz, Germany for their help
and their interest in this work. We thank Kristien Etven for excellent tech-
nical assistance.
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Received 16 May 2000
Accepted 25 September 2001