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. 2007 May 1;17(9):2470-3.
doi: 10.1016/j.bmcl.2007.02.026. Epub 2007 Feb 13.

Synthesis and biological evaluation of nucleoside analogues having 6-chloropurine as anti-SARS-CoV agents

Masahiro Ikejiri  1 , Masayuki Saijo, Shigeru Morikawa, Shuetsu Fukushi, Tetsuya Mizutani, Ichiro Kurane, Tokumi Maruyama
Affiliations

Synthesis and biological evaluation of nucleoside analogues having 6-chloropurine as anti-SARS-CoV agents

Masahiro Ikejiri et al. Bioorg Med Chem Lett. .

Abstract

Nucleoside analogues that have 6-chloropurine as the nucleobase were synthesized and evaluated for anti-SARS-CoV activity by plaque reduction and yield reduction assays in order to develop novel anti-SARS-CoV agents. Among these analogues, two compounds, namely, 1 and 11, exhibited promising anti-SARS-CoV activity that was comparable to those of mizoribine and ribavirin, which are known anti-SARS-CoV agents. Moreover, we observed several SAR trends such as the antiviral effects of the 6-chloropurine moiety, unprotected 5'-hydroxyl group and benzoylated 5'-hydroxyl group.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Structures of the nucleoside analogues.
Scheme 1
Scheme 1
Reagents and conditions: (a) Me2C(OMe)2, p-TsOH, acetone, rt, 4 h, 91%; (b) BzCl, Et3N, DMAP, CH2Cl2, 0 °C to rt, 2 h, quant; (c) AcOH/water (4:1), 60 °C, 5 h, 61%; (d) Ac2O, DMAP, Pyr, 4 h; (e) t-BuONO, Et4NCl, CCl4, CH2Cl2, 0 °C to 50 °C, 4.5 h, 57% from 2′-deoxyadenosine; (f) 2 M NH3–MeOH, 0 °C, 9 h, 76%.
Scheme 2
Scheme 2
Reagents and conditions: (a) 6-Chloropurine, PPh3, 1,1′-azobis(N,N-dimethylformamide), THF, rt, 2 days; (b) p-TsOH, MeOH, rt, 24 h, 66% from 16; (c) PhC(OMe)3, p-TsOH, MeCN, rt, 4 h, followed by water, rt, 3 h, 67%; (d) TBSCl, Pyr, −20 °C to rt, 18 h, 37%; (e) 6-chloropurine, PPh3, 1,1′-azobis(N,N-dimethylformamide), THF, rt to 45 °C, 18 h, 44% (recovery of 19, 40%); (f) p-TsOH, MeOH, rt, 18 h, 96%.
Figure 2
Figure 2
Inhibitory effect of compounds 1, 2 and 11 on plaque formation of SARS-CoV Frankfurt-1 strain in the plaque reduction assay.
Figure 3
Figure 3
Inhibitory effect of nucleoside analogues 1, 2 and 11 in the yield reduction assay. The same experiment was performed at least three times independently with SARS-CoV Frankfurt-1 strain and Vero E6 cells.
See this image and copyright information in PMC

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