The photooxidation of benzoylformic acid (la) in benzene gave peroxybenzoic acid, hydrogen peroxide, and phenyl benzoate. The addition of -methylstyrene to the oxidation system afforded the epoxide together with acetophenone as a C-C cleaved product, and the ester yield was significantly increased at the expense of the peracid. The photooxidation of la was not sensitized by methylene blue or other sensitizers, but was efficiently accelerated by pyridine or other weakly basic solvents such as ethers. Pyridine effectively catalyzed the photoepoxidation as well as the photodecarboxylation of la to benzaldehyde.The photoepoxidation gave predominantly trans epoxides, and the relative reactivities of olefins were similar to the photoepoxidation with benzoin (i.e., PhC03•) and quite different from the peracid epoxidation. Similar results were obtained by other a-keto acids or the corresponding esters. These facts suggest that the photoepoxidation proceeds via radical epoxidation by acylperoxy radical, affording trans epoxide predominantly. Contrary to previous reports, the photooxidation of -keto acids via an *02 reaction was not substantiated. The photodecarboxylation of la to afford benzaldehyde was selectively catalyzed by water, and its undissociated form was about tenfold more reactive than the corresponding carboxylate ion.

GS-9190 (Tegobuvir) is a novel imidazopyridine inhibitor of hepatitis C virus (HCV) RNA replication in vitroand has demonstrated potent antiviral activity in patients chronically infected with genotype 1 (GT1) HCV. GS-9190 exhibits reduced activity against GT2a (JFH1) subgenomic replicons and GT2a (J6/JFH1) infectious virus, suggesting that the compound's mechanism of action involves a genotype-specific viral component. To further investigate the GS-9190 mechanism of action, we utilized the susceptibility differences between GT1b and GT2a by constructing a series of replicon chimeras where combinations of 1b and 2a nonstructural proteins were encoded within the same replicon. The antiviral activities of GS-9190 against the chimeric replicons were reduced to levels comparable to that of the wild-type GT2a replicon in chimeras expressing GT2a NS5B. GT1b replicons in which the ␤-hairpin region (amino acids 435 to 455) was replaced by the corresponding sequence of GT2a were markedly less susceptible to GS-9190, indicating the importance of the thumb subdomain of the polymerase in this effect. Resistance selection in GT1b replicon cells identified several mutations in NS5B (C316Y, Y448H, Y452H, and C445F) that contributed to the drug resistance phenotype. Reintroduction of these mutations into wild-type replicons conferred resistance to GS-9190, with the number of NS5B mutations correlating with the degree of resistance. Analysis of GS-9190 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of GS-9190 is different from other nonnucleoside inhibitors. Collectively, these data demonstrate that GS-9190 represents a novel class of nonnucleoside polymerase inhibitors that interact with NS5B likely through involvement of the ␤-hairpin in the thumb subdomain.Hepatitis C virus (HCV) is a major cause of morbidity, affecting approximately 170 million people worldwide with an estimated 3 to 4 million additional new infections occurring each year (36). HCV is a positive-strand RNA virus with six major genotypes that are further divided into multiple subtypes. Due to the error-prone nature of its replication enzyme, a myriad of different viral quasispecies exists within an infected individual (32). With this high degree of viral variability, the current treatment regimen, which consists of weekly injections of pegylated alpha interferon (PEG-IFN) and twice-daily oral doses of ribavirin (RBV), is of limited efficacy and, in addition, carries significant side effects (8, 23). Although the HCV NS3/4A protease inhibitors telaprevir and boceprevir for treatment of chronic HCV infection will soon be available, these compounds will still need to be combined with the current standard of care (PEG-IFN/RBV) to be efficacious and will not cure all infected individuals (10,14,30). Therefore, the development of additional direct antiviral agents with diverse resistance profiles is necessary, with the ultimate goal of developing all-oral antiviral combinations that can achieve superior ...

GS-327073 is a potent in vitro inhibitor of HCV replication either alone or in combination with other selective HCV inhibitors.

A new method for preparing mono-and bis(hexahydro-3,3,5,5,7-pentaalkyl-2H-l,4-diazepin-2-ones) is reported (Schemes I and ). The key step of this synthesis is the final one in which a 1,3-diamine is reacted with a ketone in the presence of sodium hydroxide, chloroform, and a phase-transfer catalyst (PTC). Bis(hexahydro-3,3,5,5,7-pentaalkyl-2H-l,4-diazepin-2-ones) are isolated as a mixture of diastereomers. Of these bis compounds, diastereomers of l,l'-(l,2-ethanediyl)bis(hexahydro-3,3,5,5,7-pentamethyl-2H-l,4-diazepin-2-one) (5a) can be readily separated by a fractional recrystallization, or their diastereomeric distributions can be measured by 13C NMR.

Mittels 31P‐ NMR‐Spektroskopie bei Verwendung von Pr3+ als Verschiebungsreagens wird gezeigt, daß die Phospholipide Dipalmitoylphosphatidylcholin (I), Dilinoleoylphosphatidylcholin (II) und Eilecithine (III) in den organischen Lösungsmitteln Benzol, Chlorbenzol und o‐Dichlorbenzol aggregieren, und zwar mit einer Aggregationszahl von 80‐100, wenn das molare Verhältnis von H2O/Phospholipid 20/1 beträgt.