ABSTRACT
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phaseâ 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.
Subject(s)
Protease Inhibitors/chemistry , Quinoxalines/chemistry , Valine/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Cell Line , Dogs , Drug Evaluation, Preclinical , Drug Resistance, Viral , Half-Life , Hepacivirus/metabolism , Humans , Microsomes, Liver/metabolism , Protease Inhibitors/pharmacokinetics , Quinoxalines/chemical synthesis , Quinoxalines/pharmacokinetics , Rats , Structure-Activity Relationship , Valine/chemical synthesis , Valine/chemistry , Valine/pharmacokinetics , Viral Nonstructural Proteins/metabolismABSTRACT
We report the first application of ionic hydrogenation for the synthesis of upper-rim urea- or carbamate-derived hybrid calix[4]arenes. Subsequent metal-mediated transformations using 4-iodophenylurea calixarenes afforded structurally unique 1,3-di(biaryl)-, 1,3-di(biarylalkyne)-, or 1,3-(biaryl)(biarylalkyne)-derived hybrid calixarenes.
ABSTRACT
We report the application of "click" chemistry for the synthesis of hybrid calixarenes appended on the upper rim with carbohydrate and N,C-protected alpha-amino acids. The chemoselective N- or C-deprotection of the alpha-amino acids and their subsequent transformation into dipeptides is described. The first example of a chemo-enzymatic synthesis on upper rim derived calix[4]arenes using trans-sialidase affords sialylated lactose calix[4]arenes. Our innovative chemo-enzymatic process paves the way for further applications.
Subject(s)
Calixarenes/chemistry , Calixarenes/chemical synthesis , Animals , Calixarenes/metabolism , Carbohydrates/chemistry , Glycoproteins/metabolism , Microwaves , Molecular Structure , Neuraminidase/metabolism , Trypanosoma cruzi/enzymologyABSTRACT
An efficient protocol for the synthesis of structurally diverse (diphenylphosphinoylmethyl)benzenes is described. The reaction employs readily available carboxylic acids, chlorodiphenylphosphine, and water as the reagents. A 97% reduction in the reaction times and substantially higher yields of products result, up to a 60% increase, if the reactions are performed under microwave irradiation. The first examples of transition-metal-catalyzed reactions applied to 4-bromo-1,3-bis(diphenylphosphinoylmethyl)benzene are also reported.