Details

Autor(en) / Beteiligte

• Cannalire, Rolando
• Tarantino, Delia
• Astolfi, Andrea
• Barreca, Maria Letizia
• Sabatini, Stefano
• Massari, Serena
• Tabarrini, Oriana
• Milani, Mario
• Querat, Gilles
• Mastrangelo, Eloise
• Manfroni, Giuseppe
• Cecchetti, Violetta

Titel

Functionalized 2,1-benzothiazine 2,2-dioxides as new inhibitors of Dengue NS5 RNA-dependent RNA polymerase

Ist Teil von

• European journal of medicinal chemistry, 2018-01, Vol.143, p.1667-1676

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Over recent years, many RNA viruses have been “re-discovered”, including life-threatening flaviviruses, such as Dengue, Zika, and several encephalitis viruses. Since no specific inhibitors are currently available to treat these infections, there is a pressing need for new therapeutics. Among the flaviviral proteins, NS5 RNA-dependent RNA polymerase (RdRp) represents a validated target being essential for viral replication and it has no human analog. To date, few NS5 RdRp inhibitor chemotypes have been reported and no inhibitors are currently in clinical development. In this context, after an in vitro screening against Dengue 3 NS5 RdRp of our in-house HCV NS5B inhibitors focused library, we found that 2,1-benzothiazine 2,2-dioxides are promising non-nucleoside inhibitors of flaviviral RdRp with compounds 8 and 10 showing IC50 of 0.6 and 0.9 μM, respectively. Preliminary structure-activity relationships indicated a key role for the C-4 benzoyl group and the importance of a properly functionalized C-6 phenoxy moiety to modulate potency. Compound 8 acts as non-competitive inhibitor and its proposed pose in the so-called N pocket of the RdRp thumb domain allowed to explain the key contribution of the benzoyl and the phenoxy moieties for the ligand binding. [Display omitted] •We have identified 2,2-dioxido-2,1-benzothiazine benzoates as new DENV NS5 RdRp inhibitors.•Compounds 8 and 10 showed sub-micromolar potency (0.6 and 0.9 μM, respectively) against the enzyme.•Kinetic studies indicated a mixed type of inhibition consistent with allosteric inhibition.•An accessible synthesis to prepare this less explored scaffold has been reported.•A plausible binding mode of 8 within the RdRp N pocket was generated.