ABSTRACT
The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives 2, 3, and 4 targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative 2 presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative 4 also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Influenza A virus/drug effects , Naproxen/analogs & derivatives , A549 Cells , Animals , Binding Sites , Cyclooxygenase 2 Inhibitors/chemistry , Dogs , Drug Design , Drug Repositioning , Drug Resistance, Viral/drug effects , Female , Humans , Influenza A virus/pathogenicity , Influenza, Human/drug therapy , Influenza, Human/pathology , Madin Darby Canine Kidney Cells , Mice, Inbred C57BL , Molecular Docking Simulation , Naproxen/pharmacology , Nucleocapsid Proteins , Oseltamivir/pharmacology , RNA-Binding Proteins/chemistry , RNA-Binding Proteins/metabolism , Surface Plasmon Resonance , Viral Core Proteins/chemistry , Viral Core Proteins/metabolismABSTRACT
The preparation of new chiral biphenylic λ3 -iodane reagents bearing transferable alkynyl ligands is described. These reagents transfer their carbon-based ligands onto ß-ketoesters with an enantiomeric excess (ee) up to 68 %, and most remarkably, enable the dearomative alkynylation of naphthols in good to high yields up to 84 % ee.
ABSTRACT
Two model ortho-quinol acetates were easily prepared by iodane-mediated acetoxylative phenol dearomatization and evaluated for their reactivity toward various aryl-based nucleophiles, i.e., aryl metallic reagents and phenolic derivatives. Novel modes of reactivity, allowing the formation of biaryl linkages, were revealed and here exploited for the synthesis of two natural phenolics.
Subject(s)
Acetates/chemistry , Biological Products/chemical synthesis , Hydroquinones/chemistryABSTRACT
A highly enantioselective method for the catalytic cis-stilbene oxide opening reaction with indole derivatives was developed. The scope of the reaction was studied with a selection of aromatic meso-epoxides and various indoles, and the desired 2-(indol-3-yl)ethanol derivatives were obtained in good to excellent yields with excellent enantioselectivities (from 96 to >99% ee).
