ABSTRACT
In ongoing studies towards novel hepatitisâ C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A.
Subject(s)
Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line , Cell Membrane Permeability/drug effects , Cell Proliferation/drug effects , Dogs , Drug Evaluation, Preclinical , Drug Resistance, Viral , Hepacivirus/metabolism , Humans , Hydrogen Bonding , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
[reaction: see text] A stepwise [3+3] annelation sequence to tetrahydropyridines via addition of the Büchi Grignard to aziridines has been developed. These intermediates can be further functionalized with good regio- and stereocontrol and this methodology has been employed in the stereoselective formal synthesis of (-)-dihydropinidine.
Subject(s)
Piperidines/chemical synthesis , Pyridines/chemical synthesis , Catalysis , Molecular Structure , StereoisomerismABSTRACT
The synthesis of a functionalized spiropiperidine via a tandem ring closing metathesis strategy is described, furthermore, the regio- and stereoselective functionalization of this compound has been achieved through a novel nitrogen-directed epoxidation reaction.
ABSTRACT
A novel [3+2]-cycloaddition reaction of alkynylboronates and nitrile oxides gave the title compound, C(22)H(32)BNO(3), as a single regioisomer. The X-ray crystal structure analysis of this compound shows two independent molecules in the asymmetric unit, each with approximately coplanar isoxazole and boronate rings.
