Bicyclic furo pyrimidine nucleosides with aryloxyphenyl and halophenyl substituted side chains as potent and selective varicella-zoster virus inhibitors

Article abstract of DOI:10.1081/NCN-100002492

The discovery of potent and selective inhibitors of VZV based on unusual bicyclic alkyl furo pyrimidine nucleosides has been recently reported. Modifications to the side-chain by addition of a phenyl group were found to further enhance the antiviral potency of these compounds. A series of alkoxyphenyl compounds (5a-5g) and two halophenyl derivatives (5h and 5i) were successfully synthesised and displayed anti-VZV activity at low μM concentrations.

Full text of DOI:10.1081/NCN-100002492

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BICYCLIC FURO PYRIMIDINE NUCLEOSIDES WITH
ARYLOXYPHENYL AND HALOPHENYL SUBSTITUTED
SIDE CHAINS AS POTENT AND SELECTIVE VARICELLA-
ZOSTER VIRUS INHIBITORS
a
b
a
c
Sally Blewett , Christopher McGuigan , Hubert Barucki , Graciela Andrei , Robert
c
c
c
Snoeck , Erik De Clercq & Jan Balzarini
a
Welsh School of Pharmacy, Cardiff University , King Edward VII Avenue, Cardiff, Cf10
XF, United Kingdom
3
b
Welsh School of Pharmacy, Cardiff University , King Edward VII Avenue, Cardiff, Cf10
XF, United Kingdom
3
c
Rega Institute for Medical Research , Minderbroederstraat 10, Leuven, B3000, Belgium
Published online: 07 Feb 2007.
To cite this article: Sally Blewett , Christopher McGuigan , Hubert Barucki , Graciela Andrei , Robert Snoeck , Erik
De Clercq & Jan Balzarini (2001) BICYCLIC FURO PYRIMIDINE NUCLEOSIDES WITH ARYLOXYPHENYL AND HALOPHENYL
SUBSTITUTED SIDE CHAINS AS POTENT AND SELECTIVE VARICELLA-ZOSTER VIRUS INHIBITORS, Nucleosides, Nucleotides and
Nucleic Acids, 20:4-7, 1063-1066, DOI: 10.1081/NCN-100002492
To link to this article: http://dx.doi.org/10.1081/NCN-100002492
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1063–1066 (2001)
BICYCLIC FURO PYRIMIDINE NUCLEOSIDES
WITH ARYLOXYPHENYL AND HALOPHENYL
SUBSTITUTED SIDE CHAINS AS POTENT
AND SELECTIVE VARICELLA-ZOSTER
VIRUS INHIBITORS
1
1,∗
1
Sally Blewett , Christopher McGuigan, Hubert Barucki,
2
2
2
Graciela Andrei, Robert Snoeck, Erik De Clercq,
2
and Jan Balzarini
1Welsh School of Pharmacy, Cardiff University, King Edward VII
Avenue, Cardiff, Cf10 3XF, United Kingdom
2
Rega Institute for Medical Research, Minderbroederstraat 10,
Leuven, B3000, Belgium
ABSTRACT
The discovery of potent and selective inhibitors of VZV based on unusual
bicyclic alkyl furo pyrimidine nucleosides has been recently reported. Modifi-
cations to the side-chain by addition of a phenyl group were found to further
enhance the antiviral potency of these compounds. A series of alkoxyphenyl
compounds (5a–5g) and two halophenyl derivatives (5h and 5i) were success-
fully synthesised and displayed anti-VZV activity at low µM concentrations.
We have recently reported the discovery of potent and selective inhibitors of
Varicella Zoster Virus (VZV) based on unusual bicyclic alkyl furo pyrimidine de-
oxynucleosides (1). The alkyl side chain at the 6-position of the furo ring (1, Fig. 1),
was found to be a prerequisite for anti-viral activity for these types of compounds,
with an optimal chain length of C8–C10. The lead compounds displayed potencies
ca. 300-fold greater than compounds currently used in treatment, such as acyclovir.
∗
Corresponding author.
1
063
Copyright ꢀC 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
1
064
BLEWETT ET AL.
Figure 1.
To investigate modifications to the required alkyl side-chain, extensive
structure-activity relationship (SAR) studies are underway. A series of p-substituted
alkyl phenyl substituted compounds were recently synthesised and found to have
significantly enhanced potency (sub-nanomolar) with selectivity index values ex-
ceeding 500,000 for the most active compound in the series (2, Fig. 1) (2).
Further modifications which contain an alkyl and/or a substituted aromatic
moiety at the 6-position are being investigated. These include a series of compounds
(5a–5g)inwhichanoxygentethersanalkylchaintothephenylringatthe6-position.
It was previously observed that the introduction of an oxygen atom in the alkyl side
chain of the parent compounds enhanced water solubility but was detrimental for
antiviral activity (3). It is anticipated that the alkoxyphenyl series will be more water
soluble than the previously reported alkylphenyl series. Previously, a small series
of ω-substituted compounds were synthesised and the ω-chloro nonyl compound in
particular was observed to be potent and selective (4). The other halogen atoms were
also found to be acceptable. The synthesis of p-halo substituted phenyl derivatives
is currently being undertaken and the results for the chloro- and bromo- derivatives
(5h, 5i) are discussed herein.
Chemistry
The synthetic route for the target compounds involved Pd catalysed cou-
ꢁ
pling of 5-iodo-2 -deoxyuridine (3) with the corresponding terminal alkyne to give
ꢁ
intermediate 5-(2-alkoxyphenyl) ethynyl-2 -deoxyuridines (4a–4i, Scheme 1). As
previously noted (1), these intermediates were cyclised in situ using copper (1)
catalysis (5). Target structures (5a–5i) were characterised by H-1 and C-13 NMR,
high resolution mass spectrometry and microanalysis (6).

ORDER
REPRINTS
BICYCLIC FURO PYRIMIDINE NUCLEOSIDES
1065
Scheme 1.
Table 1.
a
EC50(µM) EC50(µM) EC50(µM) EC50(µM)
CPD VZV OKA VZV YS
TK 07/1 TK YS-R MCC(µM) CC50(µM) Clog Pd
− −
b
c
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
g
h
i
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
0.1
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
0.1
>50
>50
>50
>50
>50
>50
>50
>50
>50
74
>50
>50
>50
>50
>50
>50
>50
>50
>50
125
>50
>50
>50
>50
>50
>50
>50
200
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
0.27
0.80
1.33
1.86
2.39
2.92
3.45
1.07
1.22
−2.30
0.5
2.9
0.5
1.0
50
>200
ACV
>200
a) EC50, effective concentration (µM), the concentration required to reduce virus plaque formation
after 5 days in HEL cell cultures by 50% compared to untreated controls; b) MCC, minimal
cytotoxic concentration (µM), the compound concentration required to cause a microscopically
visible alteration of normal cell morphology; c) CC50, 50% cytotoxic concentration (µM), required
concentration to reduce the cell number by 50% after 5 days in the absence of virus; d) ClogP is the
calculated logarithm of the octanol-water partition coefficient P. n.d., not determined.

ORDER
REPRINTS
1
066
BLEWETT ET AL.
Compounds 5a–5i were evaluated for their ability to inhibit the replication of
VZV according to previously described methods (7). Data are shown in Table 1 for
the activity of 5a–5i versus two strains of thymidine kinase-competent VZV and
−
also two strains of thymidine kinase-deficient (TK ) VZV, with data also included
for the reference anti-herpetic agent acyclovir.
Preliminary data shows that the compounds are more active than ACV. No
cytotoxicity is detectable at the concentration required for antiviral activity. The
absence of antiviral activity against thymidine kinase-deficient VZV strains indi-
cates the requirement for thymidine kinase mediated phosphorylation for antiviral
action as was previously observed for this family of compounds (8).
REFERENCES
1.
McGuigan, C.; Yarnold, C.J.; Jones, G.; Velazquez, S.; Barucki, H.; Brancale, A.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J. Med. Chem., 1999, 42,
4479–4484.
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McGuigan, C.; Barucki, H.; Carangio, A.; Blewett, S.; Andrei, G.; Snoeck, R.;
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Robins, M.J.; Barr, P.J. J. Org. Chem., 1983, 48, 1854–1862.
ꢁ
3-(2 -deoxy-β-D-ribofuranosyl)-6-(4-n-chlorophenyl)-2,3-dihydrofuro-[2,3-d]pyrimi-
1
din-2-one (5i). H-NMR (d6-DMSO; 300MHz); 8.91 (1H, s, H-4), 7.88 (2H, Ha) − 7.57
3
4
(
2H, Hb) (AB system, J = 7.89Hz, J = 2.3Hz), 7.37 (1H, s, H-5), 6.19 (1H, dd,
3 3
3
ꢁ
ꢁ
ꢁ
J = 6.17Hz, H1 ), 5.35 (1H, d, J = 4.1Hz, 3 -OH), 5.24 (1H, t, J = 5.12Hz, 5 -OH),
ꢁ
ꢁ
ꢁ
4
.26 (1H, m, H-3 ), 3.95 (1H, m, H-4), 3.70 (2H, m, H-5 ), 2.41 and 2.13 (2H, m, 2-H a
ꢁ
+
+
+
and 2-H b). MS (ES ) m/e 385 (MNa , 100%), 269 (baseNa , 10%). Accurate mass:
C17H15N2O5ClNa requires: 385.0567; found: 385.0575. Found: C, 56.02%; H, 4.39%;
N, 7.67%. C17H15ClN2O5 requires: C, 56.29%; H, 4.17%, N, 7.72%.
De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maudgal, P.C.
Nature, 1986, 324, 464–467.
7
.
.
8
McGuigan, C.; Brancale, A.; Barucki, H.; Srinivasan, S.; Jones, G.; Pathirana, R.;
Blewett, S.; Alvarez, R.; Yarnold, C.J.; Carangio, A.; Velazquez, S.; Andrei, G.; Snoeck,
R.; De Clercq, E.; Balzarini, J. Drugs of the Future, 2000, in press.

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