Design and synthesis of inhibitors of noroviruses by scaffold hopping

Abstract

A scaffold hopping strategy was employed to identify new chemotypes that inhibit noroviruses. The replacement of the cyclosulfamide scaffold by an array of heterocyclic scaffolds lead to the identification of additional series of compounds that possessed anti-norovirus activity in a cell-based replicon system.

Figure 1

Norovirus inhibitor scaffold hopping strategy.

Scheme 1

Reaction conditions: i) CDI/1,4-dioxane; ii) BrCH₂COOC(CH₃)₃/DMF/0°C to rt; iii) TFA; iv) SOCl₂/CH₃OH; v) LiBH₄/THF/EtOH; vi) MsCl/TEA/CH₂Cl₂; vii) 1eq morpholine or 0.5 eq piperazine, NaHCO₃/95% EtOH/reflux.

Scheme 2

Reaction conditions: i) NaBH₄/MeOH; ii) NH₂SO₄NH₂/pyridine/reflux 16h; iii) CDI/1,4-dioxance

Scheme 3

Reaction conditions: i) NBS/AIBN/CCl₄; ii) NaN₃/DMSO; iii) R¹C≡ CH/Sodium ascorbate/CuSO₄/t-BuOH:H₂O(1:1) or CuI/DMSO; iv) TBAF/THF; v) NaCN/DMSO; vi) NaN₃/NH₄Cl/DMF/100 °C; vii) CH₃I/TEA/ACN; viii) CDI/THF/ACN.

Scheme 4

Reaction conditions: i) Gly-OCH₃(HCl)/TEA/NaBH₄/CH₃OH; ii) a) ClSO₂NCO/t-BuOH/CH₂Cl₂, b) TEA/CH₂Cl₂; iii) TFA; iv) NaH/THF.