5-(Acylethynyl)uracils, 5-(Acylethynyl)-2'-deoxyuridines and 5- (Acylethynyl)-1-(2-hydroxyethoxy)methyluracils. Their synthesis, antiviral and cytotoxic activities

Article abstract of DOI:10.1016/S0223-5234(99)80088-9

5-(acylethynyl)uracils 4 were synthesized from 5-iodo-2,4- dimethoxypyrimidine 1 through a palladium-catalyzed reaction with acetylenic carbinols 5, subsequent oxidation with manganese dioxide in dichloromethane, demethylation with 6 N hydrochloric acid, followed by treatment with sodium hydroxide in 95% ethanol. The corresponding 5-acylethynyl-2'-deoxyuridines 9 and 5-acylethynyl-1-(2hydroxyethoxy-methyl)uracils 13 were synthesized following a similar procedure. The 5-acylethynyluracils 4 were cytotoxic against murine L1210 and human T-lymphocyte (Molt 4/C8, CEM) cells. The 2'- deoxyuridine derivatives 9 were less cytotoxic; however the acyclonucleosides 13 were as active as the free bases 4. The compounds did not have antiviral activities at subtoxic concentrations.

Full text of DOI:10.1016/S0223-5234(99)80088-9

Eur. J. Med. Chem. 34 (1999) 389−398
© Elsevier, Paris
389
Original article
5-(Acylethynyl)uracils, 5-(Acylethynyl)-2´-deoxyuridines
and 5-(Acylethynyl)-1-(2-hydroxyethoxy)methyluracils.
Their synthesis, antiviral and cytotoxic activities1
Nitya G. Kundua*, Jyan S. Mahantya, Chinmay Chowdhurya, Swapan K. Dasguptaa,
Biswajit Dasa, Colin Paul Spearsb,
Jan Balzarinic, Erik De Clercqc
aDepartment of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Calcutta-700 032, India
bCancer Research Laboratory, University of Southern California, Los Angeles, California 90033, USA
cRega Institute for Medical Research, Katholieke, Universiteit Leuven, B-3000 Leuven, Belgium
(Received 17 August 1998; revised 9 December 1998; accepted 10 December 1998)
Abstract – 5-(acylethynyl)uracils 4 were synthesized from 5-iodo-2,4-dimethoxypyrimidine 1 through a palladium-catalyzed reaction with
acetylenic carbinols 5, subsequent oxidation with manganese dioxide in dichloromethane, demethylation with 6 N hydrochloric acid, followed
by treatment with sodium hydroxide in 95% ethanol. The corresponding 5-acylethynyl-2≠-deoxyuridines 9 and 5-acylethynyl-1-(2-
hydroxyethoxy-methyl)uracils 13 were synthesized following a similar procedure. The 5-acylethynyluracils 4 were cytotoxic against murine
L1210 and human T-lymphocyte (Molt 4/C8, CEM) cells. The 2≠-deoxyuridine derivatives 9 were less cytotoxic; however the
acyclonucleosides 13 were as active as the free bases 4. The compounds did not have antiviral activities at subtoxic concentrations. © Elsevier,
Paris
5-(Acylethynyl)uracils / 5-(Acylethynyl)-2≠-deoxyuridines / 5-(Acylethynyl)-1-(2-hydroxyethoxy)methyluracils
1. Introduction
human lymphoblastoid cells, HT-29 colon carcinoma
cells and L1210 mouse leukaemia cells [23]. They were
also found to inhibit thymidylate synthase. We have also
reported [24] on the synthesis of the 2≠-deoxyri-
bonucleosides of (I), e.g. 5-(Acylethynyl)-2≠-deoxy-
uridines (III).
In this paper we report on the synthesis of a number of
new 5-(Acylethynyl)uracils, their derivatives, and the
antiviral and cytotoxic activities of 5-(Acylethynyl)-
uracils 4, 5-(Acylethynyl)-2≠-deoxyuridines 9, and
5-(Acylethynyl)-1-(2-hydroxyethoxy) methyl uracils 13.
In view of the importance of 5-substituted derivatives
of uracil in cancer chemotherapy [2], as antiviral
agents [3–8] and the development of a series of
5-substituted uracil derivatives which have cytotoxic
and/or antiviral properties [9–18], we became interested
in the synthesis of novel 5-substituted uracils. With that
objective we have synthesized 5-(Acylethynyl)-
uracils [19, 20]. These compounds were shown to have
strong anti-tumour properties and to act as inhibitors of
thymidylate synthase [21, 22], a critical enzyme needed
for cellular proliferation.
2. Chemistry
The related vinyl analogues, e.g. [E]-5-(2-
acylvinyl)uracils (II) have also been synthesized by us
and were found to be weakly cytotoxic to CCRF-CEM
We have developed three different procedures for the
synthesis of the 5-(Acylethynyl)uracils (i) a silicon me-
diated procedure [19], (ii) a Grignard procedure [20] and
(iii) a palladium-catalyzed procedure [24]. Palladium-
catalyzed reactions [25–38] have been extensively uti-
*Correspondence and reprints
1
Part 25 of our series of studies on uracil derivatives and
analogues. For part 24, see [1]

390
Scheme 1. (i) HC≡C-CH(OH)Ar 5, (PPh3)2PdCl2, CuI, Et3N,
55 °C; (ii) MnO2, CH2Cl2; (iii) 6N HCl; (iv) NaOH in 95%
EtOH.
I, II and III
the 5-(Acylethynyl)uracils 4 in 55–79% yields. The
compounds were characterized by their IR, UV and NMR
spectra.
lized for C–C bond formation in aromatic and heterocy-
clic systems. We have found the palladium-catalyzed
procedure to be the most convenient and have utilized it
to synthesize a number of 5-(Acylethynyl)uracils (4a–4g)
as shown in scheme 1.
The reaction of the acetylenic carbinols 5 with 5-iodo-
2,4-dimethoxypyrimidine 1 in the presence of bis(triph-
enylphosphine)palladium (II) chloride and cuprous iodide
in triethylamine at 55 °C yielded the 5-(3-aryl-3-
hydroxyprop-1-ynyl)-2,4-dimethoxypyrimidines 2 in ex-
cellent yields (88–98%). These were then oxidized with
manganese dioxide in dichloromethane to the
5-(Acylethynyl)-2,4-dimethoxypyrimidines 3 in 87–96%
yields. The latter were demethylated by refluxing with
6 N hydrochloric acid and subsequent treatment of the
products with sodium hydroxide in 95% ethanol yielded
The synthesis of 5-(Acylethynyl)-2≠-deoxyuridines
was accomplished starting from 5-iodo-3≠, 5≠-di-O-(p-
toluoyl)-2≠-deoxyuridine
6
through
a
palladium-
catalyzed reaction according to scheme 2 [24].
The acyclonucleosides, e.g. 5-(Acylethynyl)-1-(2-
hydroxyethoxy)methyluracils 13 were synthesized [39]
from 1-(2-acetoxyethoxy)methyl-5-iodouracil 10 in three
steps following the procedure in scheme 3 where 1-(2-
acetoxyethoxy)methyl-5-(3-aryl-3-hydroxy-prop-1-ynyl)-
uracils 11 and 1-(2-acetoxy ethoxy)methyl-5-(acyl ethy-
nyl)uracils 12 were the intermediates. All the compounds
were characterized by their IR, UV and 1H NMR spectra.

391
Scheme 3. (i) HC≡C-CH(OH)Ar 5, (PPh3)2PdCl2, CuI, DMF,
Et3N, 55 °C; (ii) PCC, CH2Cl2; (iii) NaOMe in MeOH.
(FM3A) cells, the 5-(Acylethynyl)uracils were generally
found to be 4–5-fold less cytostatic than against L1210
cells.
The 2≠-deoxyribose derivatives of 4, e.g., 5-(Acyl-
ethynyl)-2≠-deoxyuridines 9 were surprisingly less cyto-
static than the corresponding bases against murine leu-
kaemia (L1210), murine mammary carcinoma (FM3A)
and human T-lymphocyte (Molt 4/C8, CEM) cell lines.
These results are in contrast to the behaviour of
5-ethynyluracil (5-EU) [9] and the corresponding 2≠-
deoxyuridine derivative(EydU) [13] where the 2≠-
deoxyuridine derivative was a much more potent cyto-
static agent than the parent base. However, the
5-(Acylethynyl)-2≠-deoxyuridines 9 (entries 8–10), al-
though less active than 5-ethynyl-dUrd (entry 17), were
much more active than 5-iodo-2≠-deoxyuridine (entry 19)
and 5-(phenylethynyl)-2≠-deoxyuridine (entry 20) and
other 5-alkynyl-2≠-deoxyuridines reported [13].
Scheme 2. (i) HC≡C-CH(OH)Ar 5, (PPh3)2PdCl2, CuI, DMF,
Et3N, 55 °C; (ii) PCC, CH2Cl2; (iii) NaOMe in MeOH.
3. Biological results
5-(Acylethynyl)uracils 4, 5-(Acylethynyl)-2≠-deoxy-
uridines 9 and 5-(Acylethynyl)-1-(2-hydroxy-ethoxy)
methyluracils 13 were tested for their biological activities
in various tumour cell lines and viral test systems
according to the previously published procedures [40–42,
48, 49]. As can be seen from table I, 5-(Acyl-
ethynyl)uracils 4 proved highly cytotoxic against murine
leukaemia (L1210) and human T-lymphocyte (Molt 4/C8;
CEM) cells. It is noteworthy that these compounds
showed a similar cytostatic profile against L1210/0 and
CCRF-CEM cells as 5-fluorouracil [19]. Also, they were
significantly more active than 5-ethynyluracil against
L1210 cells [9]. Against murine mammary carcinoma
The acyclonucleosides of 4, e.g. 5-(Acylethynyl)-1-(2-
hydroxyethoxy)methyl uracils 13 were also tested against
murine leukaemia (L1210), murine mammary carcinoma
(FM3A) and human T-lymphocyte (Molt 4/C8, CEM)

392
Table I. Inhibitory effects of 5-(Acylethynyl)uracils 4, 5-(Acylethynyl)-2≠-deoxyuridines 9 and 5-(Acylethynyl)-1-(2-hydroxyethoxy)-
methyluracils 13 on the proliferation of Murine Leukaemia (L1210), Murine Mammary Carcinoma (FM3A) and Human T-lymphocyte (Molt
4/C8, CEM) cells.
IC50 (µg/ml)a
Entry
Compound
L1210
FM3A
Molt 4/C8
CEM
5-(Acylethynyl)uracils 4 (5-AEUs)
1
2
3
4
5
6
7
5-Benzoyl EU 4a
5-o-Toluoyl EU 4b
5-m-Toluoyl EU 4c
5-p-Toluoyl EU 4d
5-o-Anisoyl EU 4e
5-m-Anisoyl EU 4f
5-p-Anisoyl EU 4g
1.7 ± 0.04
2.8 ± 0.12
1.7 ± 0.98
1.9 ± 0.20
2.5 ± 0.83
2.5 ± 0.52
2.8 ± 0.28
6.3 ± 3.20
14 ± 12.3
23 ± 2.7
12 ± 2.2
20 ± 9.9
19 ± 7.5
22 ± 9.9
3.1 ± 0.10
2.5 ± 0.02
2.1 ± 0.42
3.3 ± 0.24
2.6 ± 0.04
2.5 ± 0.20
4.2 ± 0.76
1.5 ± 0.13
2.4 ± 0.08
2.0 ± 0.04
1.9 ± 0.27
2.4 ± 0.14
1.9 ± 0.54
3.4 ± 0.48
5-Acylethynyl-2’-deoxyuridines 9 (5-AEdUrds)
8
9
10
5-Benzoyl dUrd 9a
5-p-Toluoyl dUrd 9b
5-p-Anisoyl dUrd 9c
8.4 ± 4.4
21 ± 13.7
14 ± 5.5
119 ± 39
86 ± 6.4
103 ± 12
17 ± 0.6
16 ± 3.8
15 ± 1.9
21 ± 8.7
14 ± 6.5
12 ± 5.5
5-(Acylethynyl)-1-(2-hydroxyethoxy)methyluracils 13 (5-AE-1-HEMUs)
11
12
13
14
15
5-Benzoyl-1-HEMU 13a
5-o-Toluoyl-1-HEMU 13b
5-m-Toluoyl-1-HEMU 13c
5-p-Tolyoyl-1-HEMU 13d
5-p-Anisoyl-1-HEMU 13e
10 ± 0.4
16 ± 0.9
13 ± 2.8
15 ± 0.3
13 ± 3.6
13 ± 4.1
3.9 ± 0.63
3.4 ± 1.00
1.5 ± 1.57
3.4 ± 0.51
3.3 ± 0.22
7.3 ± 2.1
3.7 ± 0.32
3.8 ± 0.37
3.5 ± 0.10
3.5 ± 0.25
3.1 ± 0.36
3.6 ± 0.12
2.1 ± 0.92
2.8 ± 0.38
Reference compounds
> 14(> 10-4 µM) [9]
0.09 [13]
61 [13]
16
17
19
20
5-Ethynyluracil(5-EU)
5-Ethynyl-dUrd(EyDU)
5-Iodo-dUrd(IDU)
5-(Phenylethynyl)dUrd
494 [13]
a50% inhibitory concentration, or compound concentration required to inhibit tumour cell proliferation by 50%.
cells. They were found to be significantly cytotoxic,
particularly against the L1210 and human T-lymphocyte
cells. As a matter of fact they were almost as active as the
parent bases except for compound 13a. We have, how-
ever, previously noted [39] that the acyclonucleosides
were somewhat more active than the corresponding bases
against CCRF-CEM human lymphoblastoid and L1210
murine leukaemia cell lines. This observation that the
acyclonucleosides are as active as the parent bases was
somewhat surprising since 1-(2-hydroxyethoxy)methyl-
5-fluorouracil has an IC50 value of at least 1.7 × 10–5
M [43] when tested against L1210 cells in culture, as
compared to an IC50 value of 0.3 µM for 5-FU [19].
The antiviral activities of 5-(Acylethynyl)uracils 4,
not inhibit virus-induced cytopathogenicity at a concen-
tration that was lower than the cytotoxic concentration
(10 µg/mL for compounds 4a, 4b, 4g and 13c, 40 µg/mL
for compounds 9b, 13a, 13b, 13d and 13e and 100 µg/mL
for 9a and 9c). Similarly, they did not show any specific
activity against other viruses, e.g. VSV, Coxsackie, res-
piratory syncytial virus in HeLa cells and parainfluenza-3
virus, reovirus-1, Sindbis virus, Coxsackie virus B4 and
Punta Toro virus in Vero cell cultures (minimum cyto-
toxic concentration being 40–400 µg/mL and minimum
inhibitory concentration being 10–200 µg/mL) (detailed
data not shown). Also, the compounds 4, 9 and 13 were
tested for their antiviral activities against varicella zoster
virus (VZV) (strain OKA, YS and the thymidine kinase
deficient 07/1 and YS/R strains) and cytomegalovirus
(CMV) (strains AD-169 and Davis) in human embryonic
lung cells (IC50s being 2–50 µg/mL). Again, no specific
inhibitory effects on CMV or VZV were noted with any
of the compounds at subtoxic concentrations (data not
shown).
5-(Acylethynyl)-2≠-deoxyuridines
9
and 5-(Acyl-
ethynyl)-1-(2-hydroxyethoxy)methyluracils 13 were de-
termined against HSV-1, HSV-2, vaccinia virus (VV),
vesicular stomatitis virus (VSV) and HSV-1 TK– strains
in E6SM cell cultures (table II). The compounds did not
exhibit an appreciable antiviral selectivity, i.e. they did

393
Table II. Antiviral activities of 5-(Acylethynyl)uracils 4, 5-(Acylethynyl)-2≠-deoxyuridines 9 and 5-(Acylethynyl)-1-(2-hydroxyethoxy)
methyl uracils 13 in E6SM cell cultures.
Minimum Inhibitory Concentrationb (µg/ml)
Entry
Compound
Minimum
cytotoxic
conc.a
HSV-1
(KOS)
HSV-2 (G) VV
VSV
HSV-1/TK- HSV-1/TK-
(B2006)
(VMW1837)
(µg/ml)
5-Acylethynyluracils 4 (5-AEUs)
1
2
3
5-Benzoyl EU 4a
5-p-Toluoyl EU 4b
5-p-Anisoyl EU 4g
10
10
10
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
> 4
5-Acylethynyl-2≠-deoxyuridines 9 (5-AEdUrds)
4
5
6
5-Benzoyl dUrd 9a
5-p-Toluoyl dUrd 9b
5-p-Anisoyl Durd 9c
100
40
100
> 40
> 10
> 40
> 40
> 10
> 40
> 40
> 10
> 40
> 40
> 10
> 40
> 40
> 10
> 40
> 40
> 10
> 40
5-Acylethynyl-1-(2-hydroxyethoxy)methyl uracils 13 5-(AE-1-HEMUs)
7
8
9
10
11
5-Benzoyl-1-HEMU 13a
5-o-Toluoyl-1-HEMU 13b
5-m-Toluoyl-1-HEMU 13c
5-p-Toluoyl-1-HEMU 13d
5-p-Anisoyl-1-HEMU 13e
40
40
10
40
40
> 10
> 10
> 4
> 10
> 10
> 10
> 10
> 4
> 10
> 10
> 10
> 10
> 4
> 10
> 10
> 10
> 10
> 4
> 10
> 10
> 10
> 10
> 4
> 10
> 10
> 10
> 10
> 4
> 10
> 10
Reference compounds
Brivudin
Ribavirin
Ganciclovir
Acyclovir
5-Ethynyl-dUrd
≥ 400
> 400
>100
400
0.02
4
0.0007
0.02
0.5
> 200
70
0.002
0.04
1
2
20
> 100
> 200
0.1
> 200
10
> 100
> 200
10
2
0.1
40
100
20
0.02
2
aRequired to cause a microscopically detectable alteration of normal cell morphology.
bRequired to reduce virus-induced cytopathogenicity by 50%. Abbreviations: HSV-1, herpes simplex virus type 1; HSV-2, herpes simplex
virus type 2; VV, vaccinia virus; VSV, vesicular stomatitis virus.
5-(Acylethynyl)uracils 4, their 2≠-deoxyribonucleo-
sides 9 and the acyclonucleosides 13 were also tested
against the human immunodeficiency viruses type-1 and
type-2 in human T-lymphocyte (CEM) cells and the
results are shown in table III.
As can be seen from table III, the 5-(Acylethynyl)
uracils 4, their 2≠-deoxyribonucleosides 9 and the acy-
clonucleosides were not effective against HIV at concen-
trations lower than the cytotoxic concentrations.
group led to the 5-(Acylethynyl)uracils 4 which were
more cytotoxic than the 5-ethynyluracils themselves. The
cytotoxic activities were retained in the N1-(2-
hydroxyethoxy) methyl derivatives 13. However, the
corresponding 2≠-deoxyuridines, e.g. compounds 9 were
found to be less cytotoxic than the free bases, e.g.
compounds 4 and 5-ethynyl-2’-deoxyuridine. The antivi-
ral potencies of these compounds were not found to be
significant. We have shown that 5-(Acylethynyl)uracils 4
act as inhibitors of thymidylate synthase [19]. It is con-
jectured that the acyclonucleosides 13 have a mechanism
of action different from those of the parent bases. They
could act as Michael acceptors [44].
4. Conclusions
5-(Acylethynyl)uracils 4 were found to be strongly
cytotoxic against the murine leukaemia (L1210) and
human T-lymphocyte (Molt 4/C8, CEM) cells, they were
less active against murine mammary carcinoma (FM3A)
cells.
It appears that the substitution of the terminal hydrogen
of the ethynyl group of 5-ethynyl uracil with an acyl
5. Experimental protocols
Melting points were determined on a Reichert
(28590)(Austria) melting point bath(> 170 °C) and in
open capillaries in a sulphuric acid bath (< 170 °C) and

394
Table III. Anti-HIV-1 and -HIV-2 activity and cytotoxic properties of 5-(Acylethynyl)uracils 4, 5-(Acylethynyl)-2≠-deoxyuridines 9 and
5-(acylethynyl)-1-(2-hydroxyethoxy)methyluracils 13 in human T-lymphocyte (CEM) cells.
a
b
Entry
Compound
EC50 (µg/ml)
IC50 (µg/ml)
HIV-1(IIIB)
HIV-2(ROD)
5-Acylethynyluracils 4
1
2
3
5-BenzoylEU 4a
5-p-ToluoylEU 4d
5-p-AnisoylEU 4g
> 0.32
> 0.32
> 1.6
> 0.32
> 0.32
> 1.6
1.5 ± 0.13
1.9 ± 0.27
2.4 ± 0.21
5-Acylethynyl-2’-deoxyuridines 9
4
5
6
5-BenzoyldUrd 9a
5-p-ToluoyldUrd 9b
5-p-AnisoyldUrd 9c
> 1.6
> 1.6
> 1.6
> 1.6
> 1.6
> 1.6
13 ± 9.9
8.5 ± 6.4
8.0 ± 5.7
5-Acylethynyl-1-(2-hydroxyethoxy)methyluracils 13
7
8
9
10
11
5-Benzoyl-1-HEMU 13a
5-o-Toluoyl-1-HEMU 13b
5-m-Toluoyl-1-HEMU 13c
5-p-Toluoyl-1-HEMU 13d
5-p-Anisoyl-1-HEMU 13e
> 1.6
> 1.6
> 1.6
> 1.6
> 1.6
> 1.6
> 1.6
> 1.6
> 1.6
> 1.6
5.5 ± 3.5
3.3 ± 0.14
2.9 ± 0.07
4.2 ± 1.7
4.1 ± 0.9
b
a50% effective concentration, or compound concentration required to protect CEM cells against the cytopathicity of HIV by 50%; 50%
inhibitory concentration or compound concentration required to inhibit CEM cell proliferation by 50%.
are uncorrected. The ultraviolet (UV) spectra were re-
corded on a Hitachi 200-20 spectrometer in spectro-
photometric-grade ethanol (Baker). The infrared (IR)
spectra were taken on a Perkin-Elmer instrument, as KBr
plates for solids and as thin film (neat) for liquid samples.
The proton magnetic resonance spectra (1H NMR) (re-
ported in δ) were recorded on a Varian XL-200 spectrom-
eter, a Varian EM-360L 60 MHz spectrometer and a Jeol
FX-100 spectrometer in solvents as indicated with tet-
ramethylsilane as internal reference. Silica gel TLC was
performed on 60F-254 precoated sheets (E. Merck,
Darmstad, Germany) and column chromatography was
carried out on silica gel (60–120 mesh). Elemental
analyses were performed on Perkin-Elmer Elemental
Analyzer 240C and were within ± 0.4% of the calculated
values. 5-Iodo-2,4-dimethoxypyrimidine 1 was synthe-
sized according to the procedure of Das and Kundu [45].
The acetylenic carbinols e.g. 1-arylprop-2-yn-1-ols 5a,
5c, 5d and 5g have been reported [23]. The other com-
pounds 5b, 5e, and 5f were synthesized according to the
published procedures [23, 46, 47].
5.2. 1-o-Anisylprop-2-yn-1-ol (5e)
Yield 76%; light yellow oil; IR (neat): νmax 3 290,
1
2 120 (w), 1 600 cm–1; H NMR (CDCl3 200 MHz): δ
2.59 (d, 1H, J = 2Hz, HC≡C), 3.78 (s,3H, Ar-OCH3),
3.84 (bs, 1H, OH), 5.71 (bs, 1H, CHOH), 6.79–7.02 (m,
2H, Ar H), 7.20–7.34 (m, 1H, Ar H), 7.58 (dd, 1H, J = 8
Hz, 2 Hz, Ar H).
5.3. 1-m-Anisylprop-2-yn-1-ol (5f)
Yield 65%; colourless oil; IR(neat): νmax 3 290, 2 120
(w), 1 600 cm–1; 1H NMR (CDCl3 200 MHz): δ 2.67 (d,
1H, J = 2 Hz, HC(C), 3.45 (bs, 1H, OH), 3.78 (s, 3H,
Ar-OCH3), 5.40 (d, 1H, J = 2 Hz, CHOH), 6.83–6.94 (m,
1H, Ar H), 7.08–7.18 (m, 2H, Ar H), 7.24–7.38 (m, 1H,
Ar H).
Synthesis of 5-(3-Aryl-3-hydroxyprop-1-ynyl)-2,
4-dimethoxypyrimidines 2b, 2c, 2e and 2f;
5-(Acylethynyl)-2, 4-dimethoxypyrimidines 3b, 3c, 3e
and 3f, and 5-Acylethynyluracils 4b, 4c, 4e and 4f were
accomplished according to our previous procedures [24].
5.1. 1-o-Tolylprop-2-yn-1-ol (5b)
5.4. 5-[(3-Hydroxy-3-o-tolyl)prop-1-ynyl]-2, 4-dime-
Yield 52%; colourless oil; IR (neat): νmax 3 290, 2 120
(w), 1 605 cm–1; 1H NMR (CCl4 60 MHz): δ 2.30 (s, 3H,
Ar-CH3), 2.38 (d, 1H, J = 2 Hz, HC≡C), 3.43 (bs, 1H,
OH), 5.32 (d, 1H, J = 2 Hz, CHOH), 6.93–7.23 (m, 3H,
Ar-Hm,p), 7.33–7.70 (m, 1H, Ar-Ho).
thoxypyrimidine (2b)
Yield 98%; white solid; m.p. 106 °C [petroleum ether
(40–60)]; IR(KBr): νmax 3 320(b), 1 605, 1 550 cm–1;
UV(EtOH) λmax 282.4 nm (loge = 4.09), 251.2 nm (loge

395
1
= 4.37); H NMR (CDCl3 200 MHz): δ 2.48 (s, 3H,
5.9. 2, 4-Dimethoxy-5-(m-toluoylethynyl)pyrimidine (3c)
Ar-CH3), 3.98 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 5.86
(s, 1H, CHOH), 7.16–7.40 (m, 3H, Ar Hm,p), 7.68–7.80
(m, 1H, Ar Ho), 8.36 (s, 1H, C-6H); Anal. (C16H16N2O3)
C, H, N.
Yield 93%; white solid; m.p. 150–151 °C (methanol);
IR(KBr): νmax 2 200, 1 635, 1 590 cm–1; UV(EtOH) λmax
312.0 nm (loge = 4.34), 276.0 nm (loge = 4.19); 1H NMR
(CDCl3, 200 MHz) 2.48 (s, 3H, Ar-CH3), 4.11 (s, 3H,
OCH3), 4.20 (s, 3H, OCH3), 7.40–7.58 (m, 3H, Ar Hm,p),
8.12 (m, 1H, Ar Ho), 8.62 (s, 1H, C-6H); Anal.
(C16H14N2O3) C, H, N.
5.5. 5-[(3-Hydroxy-3-m-tolyl)prop-1-ynyl]-2, 4-dime-
thoxypyrimidine (2c)
Yield 96%; white solid; m.p. 102–103 °C [petroleum
ether (40–60)]; IR(KBr): νmax 3 430(b), 1 640(w),
1 590 cm–1; UV(EtOH) λmax 282.1 nm (loge = 4.00),
5.10. 5-(o-Anisoylethynyl)-2, 4-dimethoxypyrimidine (3e)
1
Yield 96%; white solid; m.p. 140 °C (methanol);
IR(KBr): νmax 2 200, 1 630, 1 595 cm–1; UV(EtOH):
λmax 313.7 nm (loge = 4.28), 275.2 nm (loge = 4.11); 1H
NMR (CDCl3, 60 MHz): δ 3.97 (s, 3H, Ar-OCH3), 4.03
(s, 3H, OCH3), 4.10 (s, 3H, OCH3), 6.87–7.73 (m, 3H, Ar
Hm, p), 8.10 (dd, 1H, J = 8 Hz, 2 Hz, Ar Ho), 8.50 (s, 1H,
C-6H); Anal. (C16H14N2O4) C, H, N.
251.0 nm (loge = 4.27); H NMR (CDCl3 200 MHz): δ
2.40 (s, 3H, Ar-CH3), 3.68 (d, 1H, J = 6 Hz, OH), 4.00 (s,
3H, OCH3), 4.04 (s, 3H, OCH3), 5.71 (d, 1H, J = 6 Hz,
CHOH), 7.14–7.58 (m, 4H, Ar H), 8.40 (s, 1H, C-6H);
Anal. (C16H16N2O3) C, H, N.
5.6. 5-[(3-o-Anisyl-3-hydroxy)prop-1-ynyl]-2, 4-dime-
thoxypyrimidine (2e)
5.11. 5-(m-Anisoylethynyl)-2, 4-dimethoxypyrimidine (3f)
Yield 89%; white solid; m.p. 114 °C [petroleum ether
(40–60)]; IR(KBr): νmax 3 260(b), 1 595 cm–1;
UV(EtOH) λmax 281.7 nm (loge = 4.14), 251.6 nm (loge
= 4.31); 1H NMR (CDCl3 200 MHz): δ 3.28 (d, 1H, J =
6 Hz, OH), 3.95 (s, 3H, Ar-OCH3), 4.03 (s, 3H, OCH3),
4.07 (s, 3H, OCH3), 6.00 (d, 1H, J = 6 Hz, CHOH),
6.94–7.12 (m, 2H, Ar H), 7.30–7.44 (m, 1H, Ar H), 7.70
(dd, 1H, J = 8Hz, 2Hz, Ar H), 8.40 (s, 1H, C-6H); Anal.
(C16H16N2O4) C, H, N.
Yield 91%; white solid; m.p. 151–152 °C (methanol);
IR(KBr): νmax 2 200, 1 630, 1 585 cm–1; UV(EtOH):
λmax 310.6 nm (loge = 4.29), 276.8 nm (loge = 4.07); 1H
NMR (CDCl3, 60 MHz): δ 3.86 (s, 3H, Ar-OCH3), 4.03
(s, 3H, OCH3), 4.10 (s, 3H, OCH3), 6.97–7.97 (m, 4H, Ar
H), 8.52 (s, 1H, C-6H); Anal. (C16H14N2O4) C, H, N.
5.12. 5-(o-Toluoylethynyl)uracil (4b)
Yield 63%; white powder; m.p. > 300 °C (aq. metha-
nol); IR(KBr): νmax 2 210, 1 700, 1 615 cm–1;
UV(EtOH): λmax 329.4 nm (loge = 4.21), 265.0 nm (loge
= 3.98); H NMR (DMSO-d6 100 MHz): δ 2.56 (s, 3H,
Ar-CH3), 7.20–7.72 (m, 3H, Ar Hm,p), 8.16–8.56 (m, 2H,
Ar Ho + C-6H); Anal. (C14H10N2O3) C, H, N.
5.7. 5-[(3-m-Anisyl-3-hydroxy)prop-1-ynyl]-2, 4-dime-
thoxypyrimidine (2f)
1
Yield 93%; white solid; m.p. 121–122 °C [petroleum
ether (40–60)]; IR(KBr): νmax 3 220(b), 1 610,
1 595 cm–1; UV(EtOH) λmax 282.3 nm (loge = 4.18),
1
251.2 nm (loge = 4.345); H NMR (CDCl3 60 MHz): δ
5.13. 5-(m-Toluoylethynyl)uracil (4c)
3.77 (s, 3H, Ar-OCH3), 3.90 (s, 3H, OCH3), 3.97 (s, 3H,
OCH3), 4.90 (d, 1H, J = 6 Hz, OH), 5.67 (d, 1H, J = 6
Hz, CHOH), 6.63–6.93 (m, 1H, Ar H), 6.97–7.40 (m, 3H,
Ar H), 8.23 (s, 1H, C-6H); Anal. (C16H16N2O4) C, H, N.
Yield 60%; white powder; m.p. > 300 °C (aq. metha-
nol); IR(KBr): νmax 2 200, 1 735, 1 670, 1 615 cm–1;
UV(EtOH): λmax 328.8 nm (loge = 4.20), 269.5 nm (loge
1
= 4.00); H NMR (DMSO-d6 100 MHz): δ 2.40 (s, 3H,
5.8. 2,4-Dimethoxy-5-(o-toluoylethynyl)pyrimidine (3b)
Ar-CH3), 7.32–7.72 (m, 3H, Ar Hm,p), 8.04 (s, 2H, Ar
Ho), 8.40 (s, 1H, C-6H), 11.68 (s, 1H, NH), 11.88 (s, 1H,
NH); Anal. (C14H10N2O3) C, H, N.
Yield 88%; white solid; m.p. 142 °C (methanol);
IR(KBr): νmax 2 200, 1 630, 1 590 cm–1; UV(EtOH) λmax
1
319.2 nm (loge = 4.41), 273 nm (loge = 4.20); H NMR
5.14. 5-(o-Anisoylethynyl)uracil (4e)
(CDCl3, 200 MHz) 2.72 (s, 3H, Ar-CH3), 4.10 (s, 3H,
OCH3), 4.16 (s, 3H, OCH3), 7.36–7.60 (m, 3H, Ar Hm,p),
8.40 (app. d, 1H, Ar Ho), 8.60 (s, 1H, C-6H); Anal.
(C16H14N2O3) C, H, N.
Yield 55%, white power; m.p. > 300 °C (aq. metha-
nol); IR(KBr): νmax 2 200, 1 740, 1 695, 1 605 cm–1;
UV(EtOH): λmax 324.9 nm (loge = 4.22), 270.0 nm (loge

396
1
= 3.95); H NMR (DMSO-d6 100 MHz): δ 3.84 (s, 3H,
Ar-OCH3), 6.88–7.36 (m, 2H, Ar H), 7.44–7.84 (m, 1H,
Ar H), 7.98 (dd, 1H, J = 8 Hz, 2 Hz, Ar H) 8.18 (s, 1H,
C-6H), 11.56 (s, 2H, 2(NH); Anal. (C14H10N2O4) C, H,
N.
1H NMR (DMSO-d6 100 MHz): δ 2.00 (s, 3H,
CH3COO), 2.40 (s, 3H, Ar-CH3), 3.60–3.92 (A2B2, 2H,
AcOCH2CH2), 4.00–4.24 (A2B2, 2H, AcOCH2CH2),
5.20 (s, 2H, OCH2N), 7.36–7.68 (m, 2H, Ar Hm,p),
7.96–8.20 (m, 2H, Ar Ho), 8.76 (s, 1H, C-6H), 12.00 (bs,
1H, N-3H); Anal. (C19H18N2O6) C, H, N.
5.15. 5-(m-Anisoylethynyl)uracil (4f)
5.19. 1-[(2-Acetoxyethoxy)methyl]-5-(p-toluoylethynyl)-
uracil (12d)
Yield 79%, white powder; m.p. > 300 °C (aq. metha-
nol); IR(KBr): νmax 2 200, 1 740, 1 690, 1 630,
1 615 cm–1; UV(EtOH): λmax 331.2 nm (loge = 4.13),
272.2 nm (loge = 3.93); 1H NMR (DMSO-d6 100 MHz):
δ 3.84 (s, 3H, Ar-OCH3), 7.20–7.68 (m, 2H, Ar Hm,p),
7.70–8.08 (m, 2H, Ar Ho), 8.40 (s, 1H, C-6H), 11.68 (bs,
2H, 2(NH); Anal. (C14H10N2O4) C, H, N.
Yield 59% (based on 10); white solid; m.p. 165 °C
(benzene); IR(KBr): νmax 3 180, 2 210, 1 720, 1 695,
1 625, 1 605 cm–1; UV(EtOH): λmax 325.2 nm; 1H NMR
(CDCl3 100 MHz): δ 2.08 (s, 3H, CH3COO), 2.42 (s, 3H,
Ar-CH3), 3.72–3.96 (A2B2, 2H, AcOCH2CH2), 4.12–4.36
(A2B2, 2H, AcOCH2CH2), 5.28 (s, 2H, OCH2N), 7.34 (d,
2H, J = 8 Hz, Ar Hm), 7.96 (s, 1H, C-6H), 8.20 (d, 2H, J
= 8 Hz, Ar Ho), 8.80 (bs, 1H, N-3H); Anal. (C19H18N2O6)
C, H, N.
5.16.
1-[(2-Acetoxyethoxy)methyl]-5-(benzoylethynyl)
uracil (12a)
Yield 64% (based on 10); light yellow solid; m.p.
184–185 °C (methanol); IR(KBr): νmax 3 440, 2 200,
1 735, 1 720, 1 690, 1 635, 1 615 cm–1; UV(EtOH): λmax
324.8, 263.4 nm; 1H NMR (CDCl3 100 MHz): δ 2.10 (s,
3H, CH3COO), 3.76–3.96 (A2B2, 2H, AcOCH2CH2),
4.16–4.36 (A2B2, 2H, AcOCH2CH2), 5.28 (s, 2H,
OCH2N), 7.40–7.72 (m, 3H, Ar Hm,p), 7.96 (s, 1H,
C-6H), 8.20–8.40 (m, 2H, Ar Ho), 8.44 (bs, 1H, N-3H);
Anal. (C18H16N2O6) C, H, N.
5.20.
uracil (13a)
5-(Benzoylethynyl)-1-[(2-hydroxyethoxy)methyl]
Yield 89%; white solid; m.p. 181–182 °C (ethanol);
IR(KBr): νmax 3 410(b), 2 200, 1 725, 1 710, 1 680,
1 640, 1 620 cm–1; UV(EtOH): λmax 323.8 nm, 265.4 nm;
1H NMR (DMSO-d6 100 MHz): δ 3.52 (s, 4H,
OCH2CH2O), 4.70 (bs, 1H, OH), 5.20 (s, 2H, OCH2N),
7.44–7.92 (m, 3H, Ar Hm,p), 8.08–8.40 (m, 2H, Ar Ho),
8.76 (s, 1H, C-6H), 11.96 (bs, 1H, N-3H); Anal.
(C16H14N2O5) C, H, N.
5.17.
1-[(2-Acetoxyethoxy)methyl]-5-(o-toluoylethy-
nyl)uracil (12b)
5.21. 1-[(2-Hydroxyethoxy)methyl]-5-(o-toluoylethynyl)-
uracil (13b)
Yield 61% (based on 10); white solid; m.p. 165 °C
(methanol); IR(KBr): νmax 3 200, 2 200, 1 730, 1 715,
1 680, 1 640, 1 620 cm–1; UV(EtOH): λmax 322.2,
Yield 94%; white solid, m.p. 162–163 °C (methanol);
1
266.8 nm; H NMR (CDCl3 300 MHz): δ 2.11 (s, 3H,
IR(KBr): νmax 3 420, 2 200, 1 740, 1 680, 1 640,
1
1 620 cm–1; H NMR (DMSO-d6 100 MHz): δ 2.58 (s,
CH3COO), 2.66 (s, 3H, CH3) 3.81–3.84 (A2B2, 2H,
AcOCH2CH2), 4.22–4.25 (A2B2, 2H, AcOCH2CH2),
5.26 (s, 2H, OCH2N), 7.25–7.47 (m, 3H, Ar Hm,p), 7.92
(s, 1H, C-6H), 8.40–8.43 (m, 1H, Ar Ho), 8.77 (bs, 1H,
N-3H); Anal. (C19H18N2O6) C, H, N.
3H, Ar-CH3), 3.56 (s, 4H, OCH2CH2O), 4.70 (app. t, 1H,
OH), 5.18 (s, 1H, OCH2N), 7.28–7.80 (m, 3H, Ar H),
8.36 (dd, 1H, J = 8 Hz, 2 Hz, Ar H), 8.68 (s, 1H, C-6H),
11.96 (bs, 1H, N-3H); LRMS calcd. for M+
(C17H16N2O5) 328. Found 328; Anal. C, H, N.
Synthesis
of
1-[(2-Acetoxyethoxy)methyl]-5-
(Acylethynyl)uracils (12a–e) and 5-(Acylethynyl)-1-(2-
hydro-xyethoxy)methyluracils (13a–e) were accom-
plished according to the procedure which we have
described before [39].
5.22. 1-[(2-Hydroxyethoxy)methyl]-5-(m-toluoylethynyl)-
uracil (13c)
Yield 89%; white solid; m.p. 176 °C (methanol);
IR(KBr): νmax 3 430, 2 200, 1 700, 1 630, 1 610 cm–1;
UV(EtOH): λmax 329.4 nm, 268.8 nm; NMR (DMSO-
d6 100 MHz): δ 2.48 (s, 3H, Ar-CH3), 3.52 (s, 4H,
OCH2CH2O), 4.64 (app. t, 1H, OH), 5.16 (s, 2H,
OCH2N), 7.36–8.16 (m, 4H, Ar H), 8.72 (s, 1H, C-6H),
11.92 (bs, 1H, N-3H); Anal. (C17H16N2O5) C, H, N.
5.18.
nyl)uracil (12c)
1-[(2-Acetoxyethoxy)methyl]-5-(m-toluoylethy-
Yield 56% (based on 10); white solid; m.p. 160 °C
(benzene); IR(KBr): νmax 3 440(b), 2 200, 1 725, 1 680,
1 635, 1 620 cm–1; UV(EtOH): λmax 324.6 nm, 270.0 nm;

397
5.23. 1-[(2-Hydroxyethoxy)methyl]-5-(p-toluoylethynyl)-
uracil (13d)
cytomegalovirus (strains AD-169 and Davis)] cell cul-
tures, following previously established procedures [48,
49]. Briefly, confluent cell cultures in microtitre trays
were inoculated with 100 CCID50 of virus, 1 CCID50
being the virus dose required to infect 50% of the cell
cultures. After a 1 h virus adsorption period, residual
virus was removed, and the cell cultures were incubated
in the presence of varying concentrations (400, 200, 100,
etc. µg/mL) of the test compounds. Viral cytopathogenic-
ity was recorded as soon as it reached completion in the
control virus-infected cell cultures.
Yield 97%; white solid; m.p. 197–198 °C (methanol);
IR(KBr): νmax 3 360, 2 200, 1 720, 1 680, 1 630,
1 610 cm–1; UV(EtOH): λmax 324.4 nm, NMR (DMSO-
d6 100 MHz): δ 2.42 (s, 3H, Ar-CH3), 3.58 (s, 4H,
OCH2CH2O), 3.68 (bs t, 1H, OH), 5.18 (s, 2H, OCH2N),
7.46 (d, 2H, J = 8 Hz, Ar Hm), 8.10 (d, 2H, Ar Ho), 8.72
(s, 1H, C-6H), 11.94 (bs, 1H, N-3H); Anal. (C17H16N2O5)
C, H, N.
5-(p-Anisoylethynyl)-1-[(hydroxyethoxy)methyl]uracil
(13e). see [39].
Compounds 2(a, d and g), 3(a, d and g), and 4(a, d and
g) have already been described [24].
Synthesis of 5-(Acylethynyl)-2´-deoxyuridines (9a-
c) [24].
1-[(2-Acetoxyethoxy)methyl]-5-(p-anisoylethynyl)uracil
(12e) see [39].
The anti-HIV-1 and -HIV-2 assays were performed as
follows:
Human immunodeficiency virus type 1 [HIV-1 (HTLV-
IIIB)] was kindly provided by Dr. R.C. Gallo (when at the
National Institute of Health, Bethesda, MD). Virus stocks
were prepared from supernatants of HIV-1-infected MT-4
cells. HIV-2 (strain ROD) was provided by Dr. L.
Montagnier (Pasteur Institute, Paris, France) and virus
stocks were prepared from the supernatants of HIV-2-
infected MT-4 cells. CEM cells were obtained from the
American Tissue Culture Collection(Rockville, MD).
4 × 105 CEM cells/mL were infected with HIV-1(IIIB)
or HIV-2(ROD) at ≈ 100 CCID50 (50% cell culture
infective dose) per mL of cell suspension. The 100 µl of
the infected cell suspension was transferred into 96-well-
microtitre plate wells and mixed with 100 µl of the
appropriate dilutions of the test compounds. After 4 to 5 d
incubation of the cell cultures at 37 °C, giant cell forma-
tion was recorded microscopically in the HIV-infected
cell cultures.
6. Biology
6.1. Inhibition of L1210, FM3A, Molt and CEM cell
proliferation
All assays were performed in flat-bottomed 96-well
microtitre plates as previously described [40]. Briefly, the
cells were suspended in growth medium and added to the
microplate wells at a density of 5 × 104 L1210 or FM3A
cells/well (200 µL), or 7.5 × 104 Molt and CEM
cells/well in the presence of varying concentrations of the
test compounds. The cells were then allowed to prolifer-
ate for 48 h (L1210; FM3A) or 72 h (Molt, CEM) at
37 °C in a humidified CO2-controlled atmosphere. At the
end of the incubation period the cells were counted in a
Coulter counter. The IC50 was defined as the compound
concentration that reduced the number of viable cells by
50%.
Acknowledgements
Acknowledgement is made for the financial assistance
received from the Department of Science and Technol-
ogy, Government of India, New Delhi, under a project
(No. SP/SI/G 45/88) to NGK. JSM was a research fellow
in the above project. Partial financial assistance was also
received from the Council of Scientific and Industrial
Research, Government of India, New Delhi, with a
postdoctoral research associateship to SKD. We are also
grateful to Ann Absillis, Frieda De Meyer, Anita Camps,
Lizette van Berckelaer and Anita Van Lierde for excellent
technical assistance and Christiane Callebaut for dedi-
cated editorial help. These investigations were supported
by grants from the Belgian Fonds voor Geneeskundig
Wetenschappelijk Onderzoek(Krediet nr) and the Belgian
Geconcerteerde Onderzoeksacties(Krediet nr. 95/5).
6.2. Antiviral assays
The antiviral assays, except for HIV were based on an
inhibition of virus-induced cytopathicity in either HeLa
(vesicular stomatitis virus, Coxsackie virus B4 and res-
piratory syncytial virus), Vero (parainfluenza-3 virus,
reovirus-1, Sindbis virus, Coxsackie B4 and Punta Toro
virus), E6SM (human embryonic skin-muscle) [herpes
simplex virus type 1 (HSV-1) (strain KOS), HSV-2 (strain
B), vaccinia virus, vesicular stomatitis virus, and the
thymidine kinase-deficient HSV-1 strains B2006 and
VMW 1837] or HEL (human embryonic lung) [varicella-
zoster virus (strains OKA, YS, 07/1 and YS/R) and

398
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