Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B

Abstract

Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Towards those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition which has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19.

Baseline dasabuvir resistance in Hepatitis C virus from the genotypes 1, 2 and 3 and modeling of the NS5B-dasabuvir complex by thein silicoapproach

“…In order to better understand and study dasabuvir RASs, we predicted the dasabuvir’s binding pose in complex with HCV NS5B polymerase using the in silico molecular docking and MD simulations’ methods. The HCV (GT 1b) NS5B polymerase, PDB ID: 4MKB [25], was used as a receptor to predict the dasabuvir’s binding pose. In the aforementioned PDB file, NS5B was co-crystallized with the compound ‘28V’ (PubChem ID 46220530) that is structurally related to dasabuvir (Figure 1(A,B)).…”

“…The HCV NS5B polymerase (GT 1b, isolate BK) crystal structure with PDB ID: 4MKB [25] was retrieved from the protein data bank (https://www.rcsb.org/pdb/home/home.do). It should be noted that the NS5B sequence from the GT 1b isolate BK already possesses C316N substitution.…”

Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors

“…Non-commercially available aldehydes 10a,b were prepared following reported procedures 19,20 . Piperazines 15,16 were prepared following described procedures 21,22 .…”

“…This latter was converted into the corresponding tosylate and then reacted with amines 15 and 16 providing final compounds 7 and 8, respectively. Amines 15 and 16 were prepared through standard functional group interconversion reactions 21,22 .…”

Synthesis of furo[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazine derivatives and their antibacterial activity

“…Heterocyclic compounds containing five-and six-membered nitrogen heterocyclic rings have also attracted the attention due to the fact that they exhibit many biological interactions 9,10 . In addition, 1,2,4-triazin-6-one is structural system found in numerous natural and synthetic biologically active compounds with a wide range of biological activities including anti-inflammatory, 11 antifungal, 10 antiviral, 12 anti-HIV 13 or anticonvulsant. 14 Among tricyclic 5-5-6 fused ring heterocycles only thieno [3,2-b]pyrrole [3,2- 16 have been synthesized and only these thieno-derivatives were evaluated for their anticancer activity.…”