Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase

A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC₅₀ values. The most potent compound exhibited IC₅₀ less than 10 nM against the genotype 1b HCV polymerase and EC₅₀ of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.     

Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase

Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b) <10 nM; EC(50) (1b)=34 nM) as well as good stability towards human liver microsomes (HLM t(1/2) =59 min).     

Advancements in Input‐Output Models and Indicators for Consumption‐Based Accounting

The use of global, multiregional input‐output (MRIO) analysis for consumption‐based (footprint) accounting has expanded significantly over the last decade. Most of the global studies on environmental and social impacts associated with consumption or embodied in international trade would have been impossible without the rapid development of extended MRIO databases. We present an overview of the developments in the field of MRIO analysis, in particular as applied to consumption‐based environmental and social footprints. We first provide a discussion of research published on various global MRIO databases and the differences between them, before focusing on the virtual laboratory computing infrastructure for potentially making MRIO databases more accessible for collaborative research, and also for supporting greater sectoral and regional detail. We discuss work that includes a broader range of extensions, in particular the inclusion of social indicators in consumption‐based accounting. We conclude by discussing the need for the development of detailed nested MRIO tables for investigating linkages between regions of different countries, and the applications of the rapidly growing field of global MRIO analysis for assessing a country's performance toward the United Nations Sustainable Development Goals.