Synthesis and antimicrobial evaluation of 6-azauracil non-nucleosides

Article abstract of DOI:10.1007/s00706-008-0948-7

The present study describes synthesis and antimicrobial evaluation of a series of novel 6-azauracil non-nucleosides. Reaction of silylated 6-azauracils with the appropriate chloroethers gave the corresponding non-nucleosides. 1-(Allyloxymethy)-6-azauracils and non-nucleosides bearing indanyl, cyclohexenyl, and cyclohexyl moieties were obtained via silylation of 6-azauracils followed by treatment with the appropriate acetals. Selected compounds were tested for their in vitro antimicrobial activity against a panel of standard strains of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Four compounds showed marked inhibitory activity particularly against the tested Gram-positive bacteria.

Full text of DOI:10.1007/s00706-008-0948-7

Monatsh Chem 139, 1483–1490 (2008)
DOI 10.1007/s00706-008-0948-7
Printed in The Netherlands
Synthesis and antimicrobial evaluation of 6-azauracil non-nucleosides
Nasser R. El-Brollosy
Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
Received 17 February 2008; Accepted 31 March 2008; Published online 2 June 2008
# Springer-Verlag 2008
Abstract The present study describes synthesis and herbicidal [1, 2], antiviral [3–6], antimicrobial [7–
antimicrobial evaluation of a series of novel 6- 11], and anti-inflammatory activities [12]. As well
azauracil non-nucleosides. Reaction of silylated 6- as antimalarial [13], anticancer [14, 15], and antiul-
azauracils with the appropriate chloroethers gave the cer [16] activities have been reported.
corresponding non-nucleosides. 1-(Allyloxymethy)-
On the other hand, the chemistry and diverse
6-azauracils and non-nucleosides bearing indanyl, applications of non-nucleoside derivatives have re-
cyclohexenyl, and cyclohexyl moieties were obtained ceived much attention due to their important bio-
via silylation of 6-azauracils followed by treatment logical activity. Several non-nucleosides have been
with the appropriate acetals. Selected compounds reported as reverse transcriptase inhibitors of human
were tested for their in vitro antimicrobial activity immunodeficiency virus type-1 (HIV-1), the causative
against a panel of standard strains of Gram-positive agent of the acquired immunodeficiency syndrome
and Gram-negative bacteria and the yeast-like patho- (AIDS) [17–20]. Non-nucleoside reverse transcrip-
genic fungus Candida albicans. Four compounds tase inhibitors, in contrast to other reverse transcrip-
showed marked inhibitory activity particularly against tase inhibitors, are highly specific as their binding
the tested Gram-positive bacteria.
site is a hydrophobic pocket located approximately
˚
10 A from the polymerase active site. They bind
Keywords 6-Azauracils; 6-Azathymines; 1,2,4-Triazine-3,5-
diones; Non-nucleosides; Antimicrobial activity.
allosterically forcing the reverse transcriptase-subunit
into an inactive conformation [18]. In the present
study, and as a part of interest in the chemistry of
non-nucleosides [21–30], the synthesis and antimi-
crobial evaluation of some novel 6-azauracil non-
nucleosides have been described.
Introduction
6-Azauracils (1,2,4-triazine-3,5(2H,4H)-diones) rep-
resent an important class of heterocyclic compounds.
In recent years, much effort has been done on the
synthesis and biological evaluation of 6-azauracil
derivatives due to their possible applications. Many
6-azauracils have been demonstrated to exhibit
Results and discussions
5-Substituted 6-azauracil derivatives 4a–4d were
prepared via the semicarbazones 3a–3d, by the re-
action of semicarbazide hydrochloride (2) with the
appropriate ꢀ-keto acids 1a–1d, according to lit-
erature procedure [31]. Cyclization of the semi-
carbazones 3a–3d was achieved by treatment with
Correspondence: Nasser R. El-Brollosy, Department of
Pharmaceutical Chemistry, College of Pharmacy, King Saud
University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
E-mail: brollosy@yahoo.com

1484
N. R. El-Brollosy
Scheme 1
aqueous sodium hydroxide to give the correspond-
ing 5-substituted 6-azauracils 4a–4d in good yields
except in the case of 4b, for which the yield
was poor. Sodium ethoxide in ethanol and ethylene
glycol was used instead of aqueous sodium hy-
droxide to afford 4b [5]. 6-Azauracils 4b–4d were
silylated with N,O-bis(trimethylsilyl)acetamide (BSA)
in anhydrous chloroform followed by alkylation
with chloromethyl methyl sulfide, chloromethyl
methyl ether, and=or benzyl chloromethyl ether in
the presence of cesium iodide to give the corre-
sponding non-nucleosides 5a–5g in 51–71% yields
(Scheme 1).
Bis(allyloxy)methane (7a), bis(2-methylallyloxy)-
methane (7b), bis[(E)-2-methyl-3-phenylallyloxy]-
methane (7c), bis(indan-2-yloxy)methane (7d),
bis(3-cyclohexen-1-ylmethoxy)methane (7e), and
bis(2-cyclohexylethoxy)methane (7f) were prepared
from the corresponding alcohols; allyl alcohol (6a),
2-methylallyl alcohol (6b), (E)-2-methyl-3-phenyl-
allyl alcohol (6c), 2-indanol (6d), 3-cyclohexen-1-
methanol (6e), and 2-cyclohexylethanol (6f) were
reacted with dibromomethane using potassium hy-
droxide in anhydrous benzene in the presence of tet-
rabutylammonium bromide according to the method
of Nazaretyan et al. [32].
Silylation of 4a–4d with BSA in anhydrous
acetonitrile followed by treatment with the acetals
¨
7a, 7b, or 7c under the Vorbruggen conditions
[33] using trimethylsilyl trifluoromethanesulfonate
(TMS triflate) as a Lewis acid catalyst afforded
1-allyloxymethyl-6-azauracil (8a), 1-(2-methylallyl-
oxymethyl)-6-azauracils 8b–8e, and 1-[(E)-2-meth-
yl-3-phenylallyloxymethyl]-6-azauracils 8f, 8g in
67%, 54–70%, and 62, 68% yields. Synthesis of
non-nucleosides bearing indanyl, cyclohexenyl, and
cyclohexyl moieties (8h–8m) was investigated.
Compounds 4b and 4c were silylated with BSA in
anhydrous acetonitrile and treated with 7d in the
presence of TMS triflate to give 5-ethyl-1-(indan-2-
yloxymethyl)-6-azauracil (8h) and 1-(indan-2-yloxy-
methyl)-5-phenyl-6-azauracil (8i) in 53 and 61%
yields. Silylation of 5-phenyl-6-azauracil (4c) fol-
lowed by reaction with 7e in the presence of TMS
triflate afforded 1-(3-cyclohexen-ylmethoxymethyl)-
5-phenyl-6-azauracil (8j) in 64% yield. 1-(2-Cyclo-
hexylethoxymethyl)-6-azauracils (8k–8m) were
obtained in 23–54% yields, by treatment of 4a–4c
with the acetal 7f under the same reaction conditions
(Scheme 2).
The acetals 7a–7e were prepared previously [21,
22, 24]. N-1 Alkylation was proved by comparison

Synthesis and antimicrobial evaluation of 6-azauracil non-nucleosides
1485
Scheme 2
with similar NMR data [34, 35]. The N-3 regioiso-
mer was not observed.
testing of 5a–5g, 8a, 8d, 8g–8j, and 8m (200 ꢁg=
disc), the antibacterial antibiotic Ampicillin tri-
hydrate (100 ꢁg=disc), and the antifungal drug
Clotrimazole (100 ꢁg=disc) are shown in Table 1.
In general, the best antibacterial activity was dis-
played by 5a which showed potent inhibitory acti-
vity against the tested Gram-positive bacteria and
medium activity against the tested Gram-negative
bacteria. Meanwhile, 5b, 5e, and 8h were active
against the tested Gram-positive bacteria and almost
inactive against the tested Gram-negative bacteria.
None of the tested compounds was found to be
The newly synthesized non-nucleosides 5a–5g,
8a, 8d, 8g–8j, and 8m were tested for their in vitro
antimicrobial activity against a panel of standard
strains of Gram-positive bacteria (Staphylococcus
aureus IFO 3060 and Bacillus subtilis IFO 3007),
Gram-negative bacteria (Escherichia coli IFO 3301
and Pseudomonas aeuroginosa IFO 3448), and
the yeast-like pathogenic fungus Candida albicans
IFO 0583 using the agar disc-diffusion method
[36]. The results of the preliminary antimicrobial

1486
N. R. El-Brollosy
Table 1 Antimicrobial activity of 5a–5g, 8a, 8d, 8g–8j and
8m (200 ꢁg=8 mm disc), the broad spectrum antibacterial
drug Ampicillin (100 ꢁg=8 mm disc) and the antifungal
drug Clotrimazole (100 ꢁg=8 mm disc) against Staphylococ-
cus aureus IFO 3060 (SA), Bacillus subtilis IFO 3007 (BS),
Escherichia coli IFO 3301 (EC), Pseudomonas aeuroginosa
IFO 3448 (PA), and Candida albicans IFO 0583 (CA)
in anhydrous 20cm3 CHCl3 and the mixture was stirred at
room temperature under nitrogen. After a clear solution was
obtained (20–30min), chloromethyl methyl sulphide, chloro-
methyl ethyl ether, or benzyl chloromethyl ether (1.5mmol)
was added, followed by addition of (0.26 g, CsI 1 mmol). The
reaction mixture was stirred at room temperature under nitro-
gen for 3–4 h. Sat aq NaHCO3 (20 cm3) was added and the
mixture was extracted with 3ꢀ50cm3 CH2Cl2. The organic
phase was collected, dried (MgSO4), and evaporated under
reduced pressure. The residue was chromatographed on silica
gel column using CHCl3 to give 5a–5g.
ꢂ
Comp. no.
Diameter of growth inhibition zone mm
SA
BS
EC
PA
CA
5a
5b
5c
5d
5e
5f
5g
8a
8d
8g
8h
8i
8j
8m
18
18
14
15
18
12
10
14
12
10
17
–
18
16
15
14
24
10
10
10
10
–
19
10
13
10
18
NT
15
11
–
–
12
–
–
–
–
–
10
–
–
–
16
NT
14
–
–
–
–
–
–
–
–
–
–
–
–
–
15
NT
13
–
–
–
–
–
–
–
–
–
–
–
–
–
NT
21
1-Methylthiomethyl-5-phenyl-6-azauracil (5a, C11H11N3O2S)
1
White solid; yield 0.152 g (61%); mp 184–185ꢁC; H NMR
(DMSO-d6, 500MHz): ꢂ ¼ 2.27 (s, 3H, CH3), 5.06 (s, 2H,
CH2), 7.46–7.48, 7.89–7.91 (2ꢀm, 5H, Harom), 12.38 (s,
1H, NH) ppm; 13C NMR (DMSO-d6, 125 MHz): ꢂ ¼ 15.40
(CH3), 54.15 (CH2), 128.57, 128.60, 130.14, 132.42 (Carom),
141.78 (C-5), 148.46 (C-2), 156.92 (C-4) ppm; MS (EI): m=z
(%) ¼ 249 (Mþ, 51), 243 (9), 228 (17), 208 (19), 203 (56), 191
(13), 165 (12), 147 (23), 131 (68), 104 (42), 91 (100).
5-Ethyl-1-ethoxymethyl-6-azauracil (5b, C8H13N3O3)
White solid; yield 0.137 g (69%); mp 76–77ꢁC; 1H NMR
(CDCl3, 500 MHz): ꢂ ¼ 1.21 (t, J ¼ 7.5 Hz, 3H, CH3), 124
(t, J ¼ 7.0 Hz, 3H, CH3), 2.65 (q, J ¼ 7.0 Hz, 2H, CH2), 3.69
(q, J ¼ 7.5 Hz, 2H, CH2), 5.33 (s, 2H, CH2), 9.93 (s, 1H, NH)
ppm; 13C NMR (CDCl3, 125 MHz): ꢂ ¼ 10.36 (CH3), 15.00
(CH3), 23.23 (CH2), 65.70 (CH2), 79.32 (CH2), 148.04 (C-5),
149.09 (C-2), 156.38 (C-4) ppm; MS (EI): m=z (%) ¼ 199
(Mþ, 36), 170 (14), 155 (83), 142 (27), 127 (8), 112 (34),
100 (82), 83 (86) 58 (100).
–
–
19
NT
Ampicillin
Clotrimazole
ꢂ
–:Inactive (inhibition zone <10 mm); NT: Not tested
superior to Clotrimazole against Candida albicans,
only 5a produced weak activity.
1-Ethoxymethyl-5-phenyl-6-azauracil (5c, C12H13N3O3)
1
White solid; yield 0.175 g (71%); mp 122–123ꢁC; H NMR
(CDCl3, 500 MHz): ꢂ ¼ 1.26 (t, J ¼ 7.0 Hz, 3H, CH3), 3.76 (q,
J ¼ 7.0Hz, 2H, CH2), 5.45 (s, 2H, CH2), 7.45–7.48, 8.03–8.05
(2ꢀm, 5H, Harom), 10.08 (s, 1H, NH) ppm; 13C NMR (CDCl3,
125 MHz): ꢂ ¼ 15.03 (CH3), 65.89 (CH2), 79.81 (CH2), 128.35,
128.40, 130.42, 131.13 (Carom), 142.34 (C-5), 148.78 (C-2),
155.97 (C-4) ppm; MS (EI): m=z (%) ¼ 247 (Mþ, 57), 203
(29), 190 (10), 175 (6), 131 (32), 118 (34), 104 (93), 89 (51),
58 (100).
Experimental
NMR spectra were recorded on a Bruker AC 500 Ultra Shield
NMR spectrometer at 500 MHz for 1H and 125 MHz for
13C with TMS as an internal standard. Chemical shifts are
reported in ppm (ꢂ), and signals are expressed as s (singlet),
d (doublet), t (triplet), q (quartet), or m (multiplet). Electron
impact mass spectra were recorded on a Jeol JMS-AX 500
mass spectrometer, melting points were determined on a
Gallenkamp melting point apparatus. Elemental analysis were
alone with a their results agreed favourably with calculated
values. The progress of reactions was monitored by TLC (DC-
alufolio 60 F254) from Merck. For column chromatography
Merck silica gel (0.040–0.063 mm) was used. The bacterial
strains and Candida albicans fungus were obtained from the
Institute of fermentation of Osaka (IFO), Osaka, Japan. The
reference drugs Ampicillin trihydrate (CAS 7177-48-2) and
Clotrimazole (CAS 23593-75-1) were obtained from Sigma-
Aldrich Chemie GmbH, Taufkirchen, Germany.
5-Benzyl-1-ethoxymethyl-6-azauracil (5d, C13H15N3O3)
White solid; yield 0.154 g (59%); mp 96–97ꢁC; 1H NMR
(CDCl3, 500 MHz): ꢂ ¼ 1.23 (t, J ¼ 7.0Hz, 3H, CH3), 3.67
(q, J ¼ 7.0 Hz, 2H, CH2), 3.95 (s, 2H, CH2), 5.32 (s, 2H,
CH2), 7.25–7.36 (m, 5H, Harom), 9.71 (s, 1H, NH) ppm; 13C
NMR (CDCl3, 125 MHz): ꢂ ¼ 15.00 (CH3), 35.92 (CH2),
65.70 (CH2), 79.35 (CH2), 127.02, 128.59, 129.25, 135.75
(Carom), 145.92 (C-5), 148.89 (C-2), 156.04 (C-4) ppm; MS
(EI): m=z (%) ¼ 261 (Mþ, 39), 232 (6), 217 (25), 203 (11),
184 (9), 171 (22), 118 (16), 91 (100).
General procedure for preparation of 6-azauracil non-
nucleosides 5a–5g
N,O-Bis(trimethylsilyl)acetamide (BSA) (0.87 cm3, 3.5 mmol)
was added to a suspension of 1.0 mmol 6-azauracil 4b–4d
1-Benzyloxymethyl-5-ethyl-6-azauracil (5e, C13H15N3O3)
White solid; yield 0.151 g (58%); mp 86–88ꢁC; 1H NMR
(CDCl3, 500 MHz): ꢂ ¼ 1.22 (t, J ¼ 7.0Hz, 3H, CH3), 2.63
(q, J ¼ 7.0 Hz, 2H, CH2), 4.75 (s, 2H, CH2), 5.42 (s, 2H,

Synthesis and antimicrobial evaluation of 6-azauracil non-nucleosides
1487
CH2), 7.29–7.36 (m, 5H, Harom), 9.81 (s, 1H, NH) ppm; 13C
NMR (CDCl3, 125 MHz): ꢂ ¼ 10.32 (CH3), 23.22 (CH2),
72.02 (CH2), 79.03 (CH2), 127.69, 127.89, 128.37, 137.38
(Carom), 148.04 (C-5), 149.07 (C-2), 156.21 (C-4) ppm; MS
(EI): m=z (%) ¼ 261 (Mþ, 11), 244 (3), 232 (6), 181 (4), 155
(47), 147 (16), 107 (31), 91 (100).
rated under reduced pressure. The residue was chromato-
graphed on silica gel column with CHCl3 to afford the
desired non-nucleosides 8a–8g.
1-Allyloxymethyl-5-phenyl-6-azauracil (8a, C13H13N3O3)
1
White solid; yield 0.174 g (67%); mp 101–102ꢁC; H NMR
(CDCl3, 500 MHz): ꢂ ¼ 4.26 (d, J ¼ 5.5Hz, 2H, CH2), 5.24 (d,
J ¼ 10.5 Hz, 1H, CH(Z)¼), 5.35 (d, J ¼ 17.0Hz, 1H, CH(E)¼),
5.48 (s, 2H, CH2), 5.90–5.98 (m, 1H, ¼CH–), 7.28–7.47,
8.03–8.05 (2ꢀm, 5H, Harom), 10.14 (s, 1H, NH) ppm; 13C
NMR (CDCl3, 125 MHz): ꢂ ¼ 71.04 (CH2), 79.26 (CH2),
117.98 (CH2¼), 128.38, 128.40, 130.47, 131.08 (Carom),
133.38 (¼CH–), 142.44 (C-5), 148.89 (C-2), 155.99 (C-4)
ppm; MS (EI): m=z (%) ¼ 259 (Mþ, 14), 228 (5), 202 (28),
190 (21), 175 (4), 160 (6), 131 (43), 115 (17), 104 (100).
1-Benzyloxymethyl-5-phenyl-6-azauracil (5f, C17H15N3O3)
1
White solid; yield 0.195 g (63%); mp 124–125ꢁC; H NMR
(CDCl3, 500 MHz): ꢂ ¼ 4.80 (s, 2H, CH2), 5.53 (s, 2H, CH2),
7.28–8.05 (m, 10H, Harom), 9.92 (s, 1H, NH) ppm; 13C NMR
(CDCl3, 125 MHz): ꢂ ¼ 72.20 (CH2), 79.51 (CH2), 127.02,
127.76, 127.96, 128.36, 128.41, 130.45, 131.12, 137.27
(Carom), 142.40 (C-5), 148.71 (C-2), 155.74 (C-4) ppm; MS
(EI): m=z (%) ¼ 309 (Mþ, 11), 203 (78), 176 (16), 160 (6),
147 (53), 131 (24), 118 (12), 104 (72), 91 (100).
5-Methyl-1-(2-methylallyloxymethyl)-6-azauracil
(8b, C9H13N3O3)
5-Benzyl-1-benzyloxymethyl-6-azauracil (5g, C18H17N3O3)
White solid; yield 0.165 g (51%); mp 73–74ꢁC; 1H NMR
(CDCl3, 500 MHz): ꢂ ¼ 3.94 (s, 2H, CH2), 4.71 (s, 2H, CH2),
5.40 (s, 2H, CH2), 7.30–7.38 (m, 10H, Harom), 9.69 (s, 1H,
NH) ppm; 13C NMR (CDCl3, 125 MHz): ꢂ ¼ 35.89 (CH2),
71.99 (CH2), 78.97 (CH2), 127.07, 127.74, 127.90, 128.37,
128.63, 129.35, 135.73, 137.23 (Carom), 146.01 (C-5),
146.89 (C-2), 155.94 (C-4) ppm; MS (EI): m=z (%) ¼ 323
(Mþ, 13), 232 (10), 217 (65), 204 (7), 161 (43), 131 (19),
118 (7), 91 (100).
White solid; yield 0.118 g (56%); mp 71–72ꢁC; 1H NMR
(CDCl3, 500 MHz): ꢂ ¼ 1.74 (s, 3H, CH3), 2.26 (s, 3H, CH3),
4.08 (s, 2H, CH2), 4.91, 5.00 (2ꢀs, 2H, CH2¼), 5.32 (s, 2H,
CH2), 10.23 (s, 1H, NH) ppm; 13C NMR (CDCl3, 125 MHz):
ꢂ ¼ 16.17 (CH3), 19.32 (CH3), 73.82 (CH2), 78.70 (CH2),
112.80 (CH2¼), 141.20 (C-5), 144.43 (¼C(Me)–), 149.31
(C-2), 156.76 (C-4) ppm; MS (EI): m=z (%) ¼ 211 (Mþ,
15), 196 (8), 141 (9), 127 (5), 112 (6), 85 (11), 70 (29), 42
(100).
5-Ethyl-1-(2-methylallyloxymethyl)-6-azauracil
Bis(2-cyclohexylethoxy)methane (7f, C17H32O2)
(8c, C10H15N3O3)
Colorless viscous oil; yield 0.122g (54%); H NMR (CDCl3,
2-Cyclohexylethanol (6f, 12.8 g, 0.1 mol), 8.79 g (dibro-
momethane 0.0505 mol), and 1.74 g (tetrabutylammonium
bromide 0.00535 mol) were added to 5.66 g (potassium hy-
droxide 0.101 mol) in 30 cm3 anhydrous benzene, and the
suspension was heated under reflux for 5 h. After cooling,
(50 cm3) H2O were added and the resulting solution was
extracted with 3ꢀ50 cm3 ether. The ether phase was dried
with anhydrous MgSO4 and evaporated under reduced pres-
sure to afford 7f as a colorless oil in 55% (7.4g) yield. As
determined from NMR, the desired 7f was contaminated with
the starting material 6f in a 5:2 ratio. The product was used
1
500 MHz): ꢂ ¼ 1.20 (t, J ¼ 7.5 Hz, 3H, CH3), 1.74 (s, 3H,
CH3), 2.65 (q, J ¼ 7.5 Hz, 2H, CH2), 4.09 (s, 2H, CH2),
4.92, 5.01 (2ꢀs, 2H, CH2¼), 5.34 (s, 2H, CH2), 10.17 (s,
1H, NH) ppm; 13C NMR (CDCl3, 125 MHz): ꢂ ¼ 10.31
(CH3), 19.32 (CH3), 23.20 (CH2), 73.86 (CH2), 78.74 (CH2),
112.79 (CH2¼), 141.27 (C-5), 148.06 (¼C(Me)–), 149.22 (C-
2), 156.46 (C-4) ppm; MS (EI): m=z (%) ¼ 225 (Mþ, 24), 196
(5), 155 (13), 154 (61), 141 (16), 112 (4), 85 (7), 70 (19), 56
(100).
1
for further synthesis without purification. H NMR (CDCl3,
500 MHz): ꢂ ¼ 0.90–1.69 (m, 26H, Hhexyl, 2ꢀCH2), 3.59 (t,
J ¼ 6.5 Hz, 4H, 2ꢀCH2), 4.66 (s, 2H, CH2) ppm; 13C NMR
(CDCl3, 125MHz): ꢂ ¼ 26.17, 26.59, 33.38, 34.58 (Chexyl),
37.17 (CH2), 65.70 (CH2), 95.23 (CH2) ppm.
1-(2-Methylallyloxymethyl)-5-phenyl-6-azauracil
(8d, C14H15N3O3)
White solid; yield 0.19 g (70%); mp 125–126ꢁC; H NMR
1
(CDCl3, 500 MHz): ꢂ ¼ 1.77 (s, 3H, CH3), 4.17 (s, 2H, CH2),
4.96, 5.05 (2ꢀs, 2H, CH2¼), 5.47 (s, 2H, CH2), 7.45–7.50,
8.04–8.06 (2ꢀm, 5H, Harom), 10.13 (s, 1H, NH) ppm; 13C
NMR (CDCl3, 125 MHz): ꢂ ¼ 19.38 (CH3), 74.03 (CH2),
79.25 (CH2), 113.00 (CH2¼), 128.38, 128.39, 130.44, 131.12
(Carom), 141.21 (C-5), 142.37 (¼C(Me)–), 148.85 (C-2),
155.98 (C-4) ppm; MS (EI): m=z (%) ¼ 273 (Mþ, 14), 245
(4), 202 (73), 190 (16), 171 (3), 131 (58), 111 (13), 104 (75),
53 (100).
General procedure for preparation of 1-allyloxymethyl-6-
azauracils 8a–8g
Compound 4a–4d (1mmol) was stirred in 15 cm3 anhydrous
CH3CN under nitrogen and 0.87 cm3 (BSA 3.5 mmol) were
added. After a clear solution was obtained (10 min), the reac-
tion mixture was cooled to ꢃ50ꢁC and 0.18cm3 (TMS triflate
1 mmol) were added followed by dropwise addition of 2 mmol
7a–7c appropriate acetal. The mixture was stirred at room
temperature for 4 h. The reaction was quenched with 5 cm3
sat aq NaHCO3 solution and evaporated under reduced pres-
sure. The residue was extracted with 3ꢀ50cm3 ether, the
combined organic fractions were dried (MgSO4), and evapo-
5-Benzyl-1-(2-methylallyloxymethyl)-6-azauracil
(8e, C15H17N3O3)
White solid; yield 0.158 g (55%); mp 76–77ꢁC; 1H NMR
(CDCl3, 500 MHz): ꢂ ¼ 1.73 (s, 3H, CH3), 3.95 (s, 2H,

1488
N. R. El-Brollosy
CH2), 4.07 (s, 2H, CH2), 4.91, 4.97 (2ꢀs, 2H, CH2¼), 5.33 (s,
2H, CH2), 7.25–7.36 (m, 5H, Harom), 9.48 (s, 1H, NH) ppm;
13C NMR (CDCl3, 125 MHz): ꢂ ¼ 19.32 (CH3), 35.90 (CH2),
73.85 (CH2), 78.80 (CH2), 112.82 (CH2¼), 127.05, 128.61,
129.27, 135.69 (Carom), 141.17 (C-5), 145.86 (¼C(Me)–),
148.67 (C-2), 155.89 (C-4) ppm; MS (EI): m=z (%) ¼ 287
(Mþ, 20), 259 (6), 216 (59), 204 (8), 196 (23), 118 (31),
113 (5), 91 (100).
(CH3), 23.28 (CH2), 39.51 (C-10, C-30), 78.10 (C-20), 79.76
(CH2), 124.65, 126.69, 140.35 (Carom), 148.12 (C-5), 148.83
(C-2), 156.18 (C-4) ppm; MS (EI): m=z (%) ¼ 287 (Mþ, 7),
258 (6), 169 (19), 154 (61), 147 (9), 141 (6), 118 (93), 112
(11), 56 (100).
1-(Indan-2-yloxymethyl)-5-phenyl-6-azauracil
(8i, C19H17N3O3)
1
White solid; yield 0.203 g (61%); mp 178–179ꢁC; H NMR
(CDCl3, 500MHz): ꢂ ¼ 3.08 (dd, J ¼ 4.4, 15.9Hz, 2H, I0-H,
30-H), 3.25 (dd, J ¼ 6.5, 15.9Hz, 2H, 10-H, 30-H), 4.73 (m, 1H,
20-H), 5.53 (s, 2H, CH2), 7.17–8.06 (m, 9H, Harom), 9.83 (s,
1H, NH) ppm; 13C NMR (CDCl3, 125 MHz): ꢂ ¼ 39.55 (C-10,
C-30), 78.50 (C-20), 79.91 (CH2), 124.68, 126.66, 126.72,
128.43, 130.51, 131.07, 140.33 (Carom), 142.49 (C-5), 148.64
(C-2), 155.86 (C-4) ppm; MS (EI): m=z (%) ¼ 335 (Mþ,
6), 202 (69), 190 (34), 160 (5), 147 (9), 131 (47), 118 (100),
105 (74).
5-Methyl-1-[(E)-2-methyl-3-phenylallyloxymethyl]-6-
azauracil (8f, C15H17N3O3)
Colorless viscous oil; yield 0.177 g (62%); H NMR (CDCl3,
1
500 MHz): ꢂ ¼ 1.93 (s, 3H, CH3), 2.29 (s, 3H, CH3), 4.24 (s,
2H, CH2), 5.39 (s, 2H, CH2), 6.56 (s, 1H, CH), 7.23–7.38
(m, 5H, Harom), 10.19 (s, 1H, NH) ppm; 13C NMR (CDCl3,
125 MHz): ꢂ ¼ 15.43 (CH3), 16.22 (CH3), 76.17 (CH2), 78.71
(CH2), 126.44, 127.80, 128.14, 130.03, 133.97, 137.59 (Carom
,
CH, ¼C(Me)–), 144.39 (C-5), 149.07 (C-2), 156.58 (C-4)
ppm; MS (EI): m=z (%) ¼ 287 (Mþ, 8), 272 (11), 147 (62),
141 (24), 131 (100), 126 (5), 118 (6), 77 (21).
1-(3-Cyclohexen-1-ylmethoxymethyl)-5-phenyl-6-azauracil
(8j, C17H19N3O3)
5-Phenyl-6-azauracil (4c, 0.189 g, 1 mmol) was stirred in
15cm3 dry acetonitrile under nitrogen and 0.87cm3 (BSA
3.5 mmol) were added. After a clear solution was obtained
(10 min), the mixture was cooled to ꢃ50ꢁC and 0.18 cm3
(TMS triflate 1 mmol) were added followed by the dropwise
addition of 0.472g bis(3-cyclohexen-1-ylmethoxy)methane
(7e) (2mmol). The reaction mixture was stirred at room tem-
perature for 5 h, and worked up as described in preparation of
8h and 8i to give the title 8j.
White solid; yield 0.199g (64%); mp 128–129ꢁC; 1H NMR
(CDCl3, 500MHz): ꢂ ¼ 1.27–2.15 (m, 7H, 3ꢀCH2, CH), 3.60
(dd, J ¼ 3.5, 6.5Hz, 2H, CH2), 5.46 (s, 2H, CH2), 5.64–5.67
(m, 2H, 2ꢀCH¼), 7.28–7.47, 8.03–8.05 (2ꢀm, 5H, Harom),
10.10 (s, 1H, NH) ppm; 13C NMR (CDCl3, 125MHz):
ꢂ ¼ 24.44 (CH2), 25.41 (CH2), 28.27 (CH2), 33.82 (CH),
75.12 (CH2), 80.27 (CH2), 125.73 (CH¼), 127.07 (CH¼),
128.37, 128.41, 130.43, 131.14 (Carom), 142.34 (C-5),
148.80 (C-2), 156.00 (C-4) ppm; MS (EI): m=z (%) ¼ 313
(Mþ, 29), 283 (6), 242 (5), 202 (41), 190 (43), 147 (4), 131
(100), 118 (13), 104 (82).
1-[(E)-2-Methyl-3-phenylallyloxymethyl]-5-phenyl-6-
azauracil (8g, C20H19N3O3)
1
White solid; yield 0.237 g (68%); mp 134–135ꢁC; H NMR
(CDCl3, 500 MHz): ꢂ ¼ 1.94 (s, 3H, CH3), 4.32 (s, 2H,
CH2), 5.53 (s, 2H, CH2), 6.60 (s, 1H, CH), 7.23–8.08 (m,
10H, Harom), 10.29 (s, 1H, NH) ppm; 13C NMR (CDCl3,
125 MHz): ꢂ ¼ 15.48 (CH3), 76.36 (CH2), 79.20 (CH2),
126.68, 128.00, 128.17, 128.40, 128.41, 128.92, 130.47,
131.14, 133.94, 137.18 (Carom, CH, ¼C(Me)–), 142.40 (C-
5), 148.81 (C-2), 155.93 (C-4) ppm; MS (EI): m=z (%) ¼ 349
(Mþ, 6), 203 (36), 190 (7), 160 (15), 147 (66), 131 (100), 115
(24), 104 (49), 91 (56).
1-(Indan-2-yloxy)-6-azauracils 8h and 8i
6-Azauracil (4b, 4c, 1 mmol) was stirred in 15 cm3 dry ace-
tonitrile under nitrogen and 0.87 cm3 (BSA 3.5 mmol) were
added. After a clear solution was obtained (10 min), the
mixture was cooled to ꢃ50ꢁC and 0.18 cm3 (TMS triflate
1 mmol) were added followed by the dropwise addition of
0.56 g bis(indan-2-yloxy)methane (7d) (2 mmol). The reac-
tion mixture was stirred at room temperature for 5 h, and
quenched by addition of 5 cm3 sat aq NaHCO3 solution. The
mixture was evaporated under reduced pressure and the res-
idue was extracted with 3ꢀ50 cm3 ether. The combined
ether fractions were collected, dried (MgSO4), and evapo-
rated under reduced pressure. The residue was purified on a
silica gel column using 1=5 petroleum ether=chloroform to
give 8h and 8i.
1-(2-Cyclohexylethoxymethyl)-6-azauracils (8k–8m)
6-Azauracils (4a–4c, 1 mmol) were stirred in 15cm3 dry ace-
tonitrile under nitrogen and 0.87 cm3 (BSA 3.5 mmol) were
added. After a clear solution was obtained (10 min), the mix-
ture was cooled to ꢃ50ꢁC and 0.18cm3 TMS triflate 1 mmol
were added followed by the dropwise addition of 0.536 g
bis(2-cyclohexylethoxy)methane (7f) (2 mmol). The reac-
tion mixture was stirred at room temperature for 5 h, and
worked up as described in preparation of 8h and 8i to give
8k–8m.
5-Ethyl-1-(indan-2-yloxymethyl)-6-azauracil
(8h, C15H17N3O3)
1
White solid; yield 0.152 g (53%); mp 144–145ꢁC; H NMR
1-(2-Cyclohexylethoxymethyl)-5-methyl-6-azauracil
(8k, C13H21N3O3)
Colorless viscous oil; yield 0.062 g (23%); 1H NMR
(CDCl3, 500 MHz): ꢂ ¼ 0.87–1.68 (m, 16H, Hhexyl, CH2,
CH3), 3.62 (t, J ¼ 6.5 Hz, 2H, CH2), 5.25 (s, 2H, CH2),
10.08 (s, 1H, NH) ppm; 13C NMR (CDCl3, 125 MHz):
(CDCl3, 500 MHz): ꢂ ¼ 1.23 (t, J ¼ 7.5 Hz, 3H, CH3), 2.68 (q,
J ¼ 7.5 Hz, 2H, CH2), 3.03 (dd, J ¼ 4.5, 16.0 Hz, 2H, 10-H, 30-
H), 3.22 (dd, J ¼ 6.5, 16.0Hz, 2H, 10-H, 30-H); 4.65–4.69 (m,
1H, 20-H), 5.42 (s, 2H, CH2), 7.17–7.29 (m, 4H, Harom), 9.51
(s, 1H, NH) ppm; 13C NMR (CDCl3, 125 MHz): ꢂ ¼ 10.41

Synthesis and antimicrobial evaluation of 6-azauracil non-nucleosides
1489
ꢂ ¼ 16.12 (CH3), 26.25, 26.54, 33.23, 34.32 (Chexyl), 36.85
(CH2), 68.05 (CH2), 79.25 (CH2), 144.26 (C-5), 149.20
(C-2), 156.86 (C-4) ppm; MS (EI): m=z (%) ¼ 267 (Mþ,
5), 252 (7), 157 (18), 141 (69), 127 (21), 113 (6), 112
(9), 97 (6), 42 (100).
3. Depelley J, Granet R, Kaouadji M, Krauz P, Pierre S,
Delebassee S, Bosgiraud C (1996) Nucleos Nucleot
15:995
4. Luo MZ, Liu MC, Mozdziesz DE, Lin TS, Dutschman
GE, Gullen EA, Cheng YC, Sartorelli AC (2000) Bioorg
Med Chem Lett 10:2145
5. Maslen HL, Hughes D, Hursthouse M, DeClerq E,
Balzarini J, Simons C (2004) J Med Chem 47:5482
6. Gabrielsen B, Kirsii JJ, Kwong CD, Carter DA, Krauth
CA, Hanna LK, Huggins JW, Monath TP, Kefauver DF,
Blough HA, Rankin JT, Bartz CM, Huffman JH, Smee
DF, Sidwell RW, Shannon WM, Secrist JA (1994) Anti-
viral Chem Chemother 5:209
7. Holla BS, Sarojini BK, Shridhara K, Antony G (1999)
Farmaco 54:149
8. Hozien ZA (2000) J Chem Res Synopses 99:401
9. Kahne D, Kerns R, Fukuzawa S, Ge M, Thompson C
(2000) PCT Int Appl WO:2000004044; Chem Abstr
132:122934
10. El-Brollosy NR (2000) Phosphorus Sulfur Silicon
163:77
11. Holla BS, Shivananda MK (2003) Ind J Heterocyl Chem
13:85
12. Thorwart W, Gebert U, Schleyerbach R, Bartlett
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75574
13. March LC, Bajwa GS, Lee J, Wasti K, Joullie MM (1976)
J Med Chem 19:845
1-(2-Cyclohexylethoxymethyl)-5-ethyl-6-azauracil
(8l, C14H23N3O3)
Colorless viscous oil; yield 0.096 g (34%); H NMR (CDCl3,
1
500 MHz): ꢂ ¼ 0.91–1.66 (m, 16H, Hhexyl, CH2, CH3), 2.63
(q, J ¼ 7.5 Hz, 2H, CH2), 3.64 (t, J ¼ 6.4 Hz, 2H, CH2), 5.29
(s, 2H, CH2), 10.11 (s, 1H, NH) ppm; 13C NMR (CDCl3,
125 MHz): ꢂ ¼ 10.39 (CH3), 23.20 (CH2), 26.20, 26.55, 33.23,
34.35 (Hhexyl), 36.86 (CH2), 79.39 (CH2), 147.92 (C-5),
149.05 (C-2), 156.46 (C-4) ppm; MS (EI): m=z (%) ¼ 281
(Mþ, 7), 252 (8), 171 (13), 155 (84), 141 (26), 127 (9), 112
(4), 97 (6), 56 (100).
1-(2-Cyclohexylethoxymethyl)-5-phenyl-6-azauracil
(8m, C18H23N3O3)
White solid; yield 0.178 g (54%); mp 137–138ꢁC; H NMR
1
(CDCl3, 500 MHz): ꢂ ¼ 0.91–1.53 (m, 13H, Hhexyl, CH2), 3.74
(t, J ¼ 6.5 Hz, 2H, CH2), 5.44 (s, 2H, CH2), 7.45–7.47, 8.04–
8.05 (2ꢀm, 5H, Harom), 10.09 (s, 1H, NH) ppm; 13C NMR
(CDCl3, 125MHz): ꢂ ¼ 26.22, 26.52, 33.27, 34.36 (Chexyl),
36.80 (CH2), 68.38 (CH2), 79.95 (CH2), 128.35, 128.41,
130.41, 131.14 (Carom), 142.32 (C-5), 148.79 (C-2), 155.97
(C-4) ppm; MS (EI): m=z (%) ¼ 329 (Mþ, 14), 219 (12), 203
(91), 189 (25), 175 (7), 160 (8), 131 (41), 104 (83), 53 (100).
14. Fischer H, Moeller H, Budnowski M, Atassi G,
Dumont P, Venditti J, Yoder OC (1984) Arzneim
Forsch 34:663
Determination of in vitro antimicrobial activity
The primary screen was carried out using the agar disc-
15. Mansour A, Eid MM, Khalil NS (2003) Nucleos Nucleot
22:21
¨
diffusion method [36] using Muller-Hinton agar medium.
16. Hirai K, Sugimoto H, Mizushima T (1986) JP:61134389.
(1987) Chem Abstr 106:67353
17. Tanaka H, Takashima H, Ubasawa M, Sekiya K, Inouye
N, Baba M, Shigeta S, Walker RT, DeClercq E, Miyasaka
T (1995) J Med Chem 38:2860
18. Hopkins AL, Ren J, Esnouf RM, Willcox BE, Jones EY,
Ross C, Miyasaka T, Walker RT, Tanaka H, Stammers
DK, Stuart DI (1996) J Med Chem 39:1589
19. Pedersen OS, Pedersen EB (1999) Antiviral Chem
Chemother 10:285
20. Pedersen EP, Jorgensen PT, Dahan B, El-Brollosy NR,
Nielsen C, Doel AM, Vestergaard BF (2003) PCT Int
Appl WO:2003057677; Chem Abstr 139:85591
21. El-Brollosy NR, Jorgensen PT, Dahan B, Boel AM,
Pedersen EB, Nielsen C (2002) J Med Chem 45:5721
22. El-Brollosy NR, Pedersen EB, Nielsen C (2003) Arch
Pharm Pharm Med Chem 336:236
Sterile filter paper discs (8 mm diameter) were moistened
with the compound solution in dimethylsulphoxide of spe-
cific concentration (200 ꢁg=disc), the antibacterial antibiot-
ic Ampicillin trihydrate (100 ꢁg=disc) and the antifungal
drug Clotrimazole (100 ꢁg=disc) were carefully placed on
the agar culture plates that had been previously inoculated
separately with the microorganisms. The plates were incu-
bated at 37ꢁC, and the diameter of the growth inhibition
zones were measured after 24 h in case of bacteria and 48 h
in case of Candida albicans.
Acknowledgements
The author would like to thank Prof. E.E. Habib and Prof.
A.A. El-Emam, Faculty of Pharmacy, Qassim University, Saudi
Arabia, for the antimicrobial screening.
23. El-Essawy FA, El-Brollosy NR, Pedersen EB, Nielsen C
(2003) J Heterocyl Chem 40:213
24. Wamberg M, Pedersen EB, El-Brollosy NR, Nielsen C
(2004) Bioorg Med Chem 12:1141
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