Facile access to 4′-(N-acylsulfonamide) modified nucleosides and evaluation of their inhibitory activity against SARS-CoV-2 RNA cap N7-guanine-methyltransferase nsp14

Abstract

N-acylsulfonamides possess an additional carbonyl function compared to their sulfonamide analogues. Due to their unique physico-chemical properties, interest in molecules containing the N-acylsulfonamide moiety and especially nucleoside derivatives is growing...

N-Arylsulfonamide-based adenosine analogues to target RNA cap N7-methyltransferase nsp14 of SARS-CoV-2

“…In two earlier studies, we developed N 7-MTase competitive bisubstrates composed of an adenosine or its analogues occupying the SAM methyl donor binding pocket, linked to an N -arylsulfonamide scaffold that mimics the guanine moiety of the cap structure in the cap binding site of nsp14. 23,26 N -Arylsulfonamides, known to be ubiquitous functional scaffolds among medicinally interesting molecules, proved to be here a key component in explaining the inhibitors' high affinity for SARS-CoV-2 nsp14 (tens of nanomolar inhibition) in our work 23,26,29 and that of others. 24,28 In these potent inhibitors, the N -arylsulfonamide moieties were directly attached to the C5′ ribose atom of adenosine or its derivatives (Fig.…”

3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors

“…SAM structure consists of amino acid moiety and adenosine. A rational design of nsp14 bisubstrate inhibitors was reported, where methionine was substituted with various N -alkyl-benzenesulfonamides to target both SAM and RNA substrate-binding pockets ( 1a , Figure 1 ) [ 17 , 18 , 19 ]. Other research groups focused on substituted 7-deazaadenosine derivatives resulting in nanomolar nsp14 inhibitors 1b [ 20 , 21 ].…”

Structure-guided optimization of adenosine mimetics as selective and potent inhibitors of coronavirus nsp14 N7-methyltransferases

“…Indeed, this N -ethyl arylsulfonamide motif likely accounts for the compounds'high affinity for SARS-CoV-2 nsp14, which results in a double-digit nanomolar inhibition [ 23 ]. When the sulfonamide linker was replaced by an amide or an N -acylsulfonamide linker, we showed that the inhibitory activity of the nucleoside analogues was lost [ 15 , 30 ]. In addition, a recent report confirmed the importance of the sulfonamide linker between the adenosine and the aromatic moiety, a 2-naphtalene in this case, to reach nanomolar inhibition of nsp14 [ 24 ].…”