Notes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2859
H.; De Clercq, E. Specific anti-HIV-1 “acyclonucleosides” which
cannot be phosphorylated: synthesis of some deoxy analogues
of 1-[-(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J . Med.
Chem. 1991, 34 (4), 1508-1511.
at position 2 are the most potent compounds. The
activity of imidazo[1,2-a]pyrimidine 34 requires the
synthesis of further compounds in this series in order
to make a structure-activity relationship analysis.
Finally, from a comparison of 20 with 28 it appears that
the methyl group at position 5 diminishes the cytotox-
icity.
(4) (a) Gueiffier, A.; Milhavet, J . C.; Blache, Y.; Chavignon, O.;
Teulade, J . C.; Madesclaire, M.; Viols, H.; Dauphin, G.; Chapat,
J . P. Synthesis of 1H-imidazo[1,2-a]pyrazolo[3,4-c]pyridines.
Chem. Pharm. Bull. 1990, 38 (9), 2352-2356. (b) Gueiffier, A.;
Blache, Y.; Viols, H.; Chapat, J . P.; Chavignon, O.; Teulade, J .
C.; Dauphin, G.; Debouzy, J . C.; Chabart, J . C. Carbon-nitrogen
bond formation in cyclisation by deoxygenation, thermolysis or
photolysis of phenylimidazo[1,2-a][1,8]naphthyridine. J . Het-
erocycl. Chem. 1992, 29, 283-287.
(5) Elhakmaoui, A.; Gueiffier, A.; Debouzy, J . C.; Blache, Y.;
Chavignon, O.; Teulade, J . C.; Milhavet, J . C.; Dauphin, G.;
Chapat, J . P. Synthesis of acyclo-C-nucleosides of imidazo[1,2-
a]pyridine as potential antiviral agents; Studies of model
membrane passage. Boll. Chim. Farm. 1995, submitted.
(6) Elhakmaoui, A.; Gueiffier, A.; Milhavet, J . C.; Blache, Y.; Chapat,
J . P.; Chavignon, O.; Teulade, J . C.; Snoeck, R.; Andrei, G.; De
Clercq, E. Synthesis and antiviral activity of 3-substituted
imidazo[1,2-a]pyridine. BioOrg. Med. Chem. Lett. 1994, 4 (16),
1937-1940.
Con clu sion s
The thioether derivatives reported here appear to be
original antiviral agents. The fact that they show
selective activity against CMV and VZV suggests that
they are preferentially metabolized by the virus-infected
cells and/or show a particullary affinity for virus-specific
enzymes. Rationalization of these results using molec-
ular modeling is currently under investigation, while
the synthesis of new compounds is in progress.
(7) Gueiffier, A.; Blache, Y.; Chapat, J . P.; Alhakmaoui, A.; Essassi,
E. M.; Andrei, G.; Snoeck, R.; De Clercq, E.; Chavignon, O.;
Teulade, J . C.; Fauvelle, F. Synthesis and antiviral activity of 2
and 3-substituted imidazo[1,2-a]pyrimidines. Nucleosides Nu-
cleotides 1995, 14 (3-5), 551-554.
Ack n ow led gm en t. This research was supported by
grants from the Direction des Recherches Etudes et
Techniques (93-1000/A000), the Biomedical Research
Programme of the European Community, and the
Belgian Nationaal Fonds voor Wetenschappelijk Onder-
zoek (NFWO). We thank Anita Van Lierde, Anita
Camps, Frieda De Meyer, Patrick Seldeslachts, Anja
Van Cauwenberge, and Ann Absillis for excellent tech-
nical assistance.
(8) Roe, A. M. The thermal condensation of imidazoles with carbonyl
compounds. J . Chem. Soc. 1963, 2195-2200.
(9) Teulade, J . C.; Bonnet, P. A.; Rieu, J . N.; Viols, H.; Chapat, J .
P.; Grassy, G.; Carpy, A. C-3 hydroxylation of some imidazo-
[1,2-a]azines, J . Chem. Res. (M) 1986, 1842-1874.
(10) (a) De Clercq, E.; Descamps, J .; Verhelst, G.; Walker, R. T.;
J ones, A. S.; Torrence, P. F.; Shugar, D. Comparative efficacy
of antiherpes drugs against different strains of herpes simplex
virus. J . Infect. Dis. 1980, 141 (5), 563-574. (b) De Clercq, E.
Antiviral and antimetabolic activities of neplanocins. Antimi-
crob. Agents Chemother. 1985, 28 (1), 84-89. (c) De Clercq, E.;
Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J .; Maudgal, P.
C. A novel selective broad-spectrum anti-DNA virus agents.
Nature 1986, 323 (6087), 464-467. (d) Pauwels, R.; Balarini,
J .; Baba, M.; Snoeck, R.; Schols, D.; Herdewijn, P.; Desmyter,
J .; De Clercq, E. Rapid and automated tetrazolium-based
colorimetric assay for the detection of anti-HIV compounds. J .
Virol. Methods 1988, 20, 309-321. (e) Schols, D.; De Clercq,
E.; Balzarini, J .; Baba, M.; Witvrouw, M.; Hosoya, M.; Andrei,
G.; Snoeck, R.; Neyts, J .; Pauwels, R.; Nagy, M.; Gyo¨rgyi-
Edele´nyi, J .; Machovich, R.; Horvath, I.; Lo¨w, M.; Go¨ro¨g, S.
Sujphated polymers are potent and selective inhibitors of various
enveloped viruses, including herpes simplex virus, cytomega-
lovirus, vesicular stomatitis virus, respiratory synctial virus and
toga-, arena- and retroviruses. Antiviral Chem. Chemother.
1990, 1 (4), 233-240. (f) De Clercq, E. in vitro and ex-viro test
systems to rationalize drug design and delivery. In Minutes
collection; Crommelin, D., Couvreur, P., Ducheˆne, D., Eds.; 1994;
pp 108-125.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures, including 1H and 13C NMR spectral data for
all new compounds (5 pages). Ordering information is given
on any current masthead page.
Refer en ces
(1) De Clercq, E. Recent advances in the search for selective
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