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. 2012 Jan;47(1):59-64.
doi: 10.1016/j.ejmech.2011.10.019. Epub 2011 Oct 20.

Cyclosulfamide-based derivatives as inhibitors of noroviruses

Dengfeng Dou  1 , Sivakoteswara R Mandadapu, Kevin R Alliston, Yunjeong Kim, Kyeong-Ok Chang, William C Groutas
Affiliations

Cyclosulfamide-based derivatives as inhibitors of noroviruses

Dengfeng Dou et al. Eur J Med Chem. 2012 Jan.

Abstract

An optimization campaign focused on improving pharmacological activity and physicochemical properties of a recently-identified class of cyclosulfamide-based norovirus inhibitors has been carried out. Dimeric compound 4 was found to be a ∼10-fold more potent norovirus inhibitor (ED(50) 0.4 μM) compared to the original hit, however, isonipecotic acid ester derivatives 7e and 10a were shown to have superior therapeutic indices.

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Figures

Figure 1
Figure 1
Structure optimization of norovirus inhibitor (I).
Scheme 1
Scheme 1
Reaction conditions: i) NaH/DMF, then BrCH2CH2Br; ii) piperazine/K2CO3/DMF.
Scheme 2
Scheme 2
Reaction conditions: i) NaH/DMF, then BrCH2COOCH3; ii) LiBH4/THF/EtOH; iii) MsCl/TEA/CH2Cl2; iv) HN(CH2CH2)2X/TEA/DMF; v) H2/10%Pd-C/MeOH; vi) ROH/EDCl/DMF or RCl/TEA/DMF; vii) 1M LiOH/dixone; viii) 4M HCl/MeOH.
Scheme 3
Scheme 3
Reaction conditions; i) EDCl/DMF, then methyl isonipecotate or ethyl piperazine; ii) 1 M LiOH/1,4-dioxane.
See this image and copyright information in PMC

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