ABSTRACT
Cyclodehydration using the Burgess reagent provided a novel approach toward the synthesis of N-bridged 5,6-bicylic pyridines including pyrolo-, imidazo-, and triazolopyridines under mild and neutral conditions. The methodology tolerates acid-sensitive functional groups. A novel addition product was observed between the resulting pyrrolo- or imidazopyridine and an additional equivalent of the Burgess reagent, producing the corresponding sulfonylcarbamate adduct.
Subject(s)
Carbamates/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Pyridines/chemical synthesis , Sulfur Compounds/chemistry , Water/chemistry , Crystallography, X-Ray , Cyclization , Models, Molecular , Molecular Structure , Pyridines/chemistryABSTRACT
The introduction of acidic and basic functionality into the side chains of respiratory syncytial virus (RSV) fusion inhibitors was examined in an effort to identify compounds suitable for evaluation in vivo in the cotton rat model of RSV infection following administration as a small particle aerosol. The acidic compounds 2r, 2u, 2v, 2w, 2z, and 2aj demonstrated potent antiviral activity in cell culture and exhibited efficacy in the cotton rat comparable to ribavirin. In a BALB/c mouse model, the oxadiazolone 2aj reduced virus titers following subcutaneous dosing, whilst the ester 2az and amide 2aab exhibited efficacy following oral administration. These results established the potential of this class of RSV fusion inhibitors to interfere with infection in vivo following topical or systemic administration.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Membrane Fusion/drug effects , Respiratory Syncytial Viruses/drug effects , Respiratory Syncytial Viruses/physiology , Water/chemistry , Amines/chemistry , Animals , Antiviral Agents/adverse effects , Antiviral Agents/chemical synthesis , Benzimidazoles/adverse effects , Benzimidazoles/chemical synthesis , Mice , Molecular Structure , Rats , Sigmodontinae , Solubility , Structure-Activity RelationshipABSTRACT
Structure-activity relationships for a series of benzimidazol-2-one-based inhibitors of respiratory syncytial virus are described. These studies focused on structural variation of the benzimidazol-2-one substituent, a vector inaccessible in a series of benzotriazole derivatives on which 2 is based, and revealed a broad tolerance for substituent size and functionality.
