Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 microM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for inhibition. Herein, we present 1H-benzo[de]isoquinoline-1,3(2H)-diones as a new series of selective inhibitors of HCV NS5B polymerase. The HTS hit 1 shows submicromolar potency in two different HCV replicons (1b and 2b) and displays no activity on other polymerases (HIV-RT, Polio-pol, GBV-b-pol). These inhibitors act during the pre-elongation phase by binding to NS5B non-nucleoside binding site Thumb Site II as demonstrated by crystal structure of compound 1 with the DeltaC55-1b and DeltaC21-2b enzymes and by mutagenesis studies. SAR in this new series reveals inhibitors, such as 20, with low micromolar activity in the HCV replicon and with good activity/toxicity window in cells.

The identification of a new series of P. falciparum growth inhibitors is described. Starting from a series of known human class I HDAC inhibitors a SAR exploration based on growth inhibitory activity in parasite and human cells-based assays led to the identification of compounds with submicromolar inhibition of P. falciparum growth (EC 50 < 500 nM) and good selectivity over the activity of human HDAC in cells (up to >50-fold). Inhibition of parasital HDACs as the mechanism of action of this new class of selective growth inhibitors is supported by hyperacetylation studies.KEYWORDS: Malaria, Plasmodium falciparum, PfHDAC1, 4-arylimidazoles I nfection with malaria parasites such as Plasmodium falciparum remains a devastating cause of death in tropical geographies with 40% of the world population at risk of acquiring the disease. There are approximately 200 million clinical cases of malaria every year leading to an estimated 600,000 deaths.1 The requirement for improved therapies to treat and to cure malaria is an evident medical and humanitarian need that is exacerbated by an alarming rise in parasite resistance to the current standard of care.2,3 Drugs that operate via novel mechanisms of action for which no innately resistant parasites are expected are therefore especially desirable.DNA is tightly packed around histone proteins in the nucleus of eukaryotic cells with its transcription being regulated by chemical modifications to the nucleosomal histone proteins themselves. Histone deacetylases (HDACs) are zinc-dependent enzymes that play crucial roles in modulating mammalian cell chromatin structure, transcription, and gene expression. 4−6HDACs have also been identified as important regulators of transcription in P. falciparum, 7−10 and inhibition of P. falciparum histone deacetylases (Pf HDACs) has been reported to both effectively kill the parasites (Vorinostat, Figure 1) 11−16 and lead to efficacy in animal models of malaria (compound 2).17 Such findings underscore the potential for Pf HDAC inhibitors to be used for malaria therapy. 18−20 Of the five HDAC encoding genes known in P. falciparum one has homology to mammalian class I isoforms (Pf HDAC1), two are similar class II (Pf HDAC2 and 3) mammalian HDACs, while the remaining two are class III HDACs, or silent information regulator 2 (SIR2) proteins. 19 In light of the close sequence homology between Pf HDAC1 and human class I HDACs 21 an

The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compound RGFP966. These compounds are again based on an alternative ZBG with respect to the ortho-anilide that is featured in HDAC3 selective compounds reported to date.

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