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

Abstract

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.

• Authors: Rolando Cannalire, Delia Tarantino, Andrea Astolfi, Maria Letizia Barreca, Stefano Sabatini, Serena Massari, Oriana Tabarrini, Mario Milani, Gilles Querat, Eloise Mastrangelo, Giuseppe Manfroni, Violetta Cecchetti
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 143 Pg. 1667-1676 (Jan 01 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29137867 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• RNA-Dependent RNA Polymerase

Topics

• Animals
• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Caco-2 Cells
• Cell Survival (drug effects)
• Chlorocebus aethiops
• Dengue Virus (drug effects, enzymology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Microbial Sensitivity Tests
• Models, Molecular
• Molecular Structure
• RNA-Dependent RNA Polymerase (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Vero Cells