2′-Chloro,2′-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture

Abstract

Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.

Repurposing Nucleoside Analogs for Human Coronaviruses

“…1). We selected several reported anti-HCV agents, such as 2=-C-methylcytidine (compound 2) (9), sofosbuvir (compound 4), a novel prodrug of sofosbuvir (compound 3) (10), and two 2=-dihalogeno nucleoside prodrugs (compounds 6 and 7) (11,12). We also selected ALS-8112 (compound 5) (13), the active form of lumicitabine, a drug developed until recently for the treatment of respiratory syncytial virus (RSV) (14).…”

The α,α‐Dihalocarbonyl Building Blocks: An Avenue for New Reaction Development in Organic Synthesis

“…In 2017, Schinazi and his co‐workers, developed a novel and efficient route for the preparation of (2 S )‐2‐chloro‐2‐fluorolactone 243 , which was used as a potent non‐toxic pangenotypic anti‐HCV agent (Scheme B). The gem ‐dihaloketone precursor 244 was employed as the key precursor to obtain the product in an extra 30 % overall yield in comparison to the original four‐step synthesis .…”

Phosphorus Pentachloride Promoted gem-Dichlorination of 2′- and 3′-Deoxynucleosides

“…Recently, phosphoramidate prodrugs of β- d -2′-deoxy-2′,2′-dichlorouridine, which were obtained upon 2′- C -modification of uridine with a gem -dichloro (CCl 2 ) functionality, have been shown to have inhibitory activity against hepatitis C virus (HCV) replication ( Figure 1 , 1 ) [ 7 ]. Additionally, Zhou et al reported that the substitution of the 2′-methyl group in sofosbuvir with a chlorine atom generated 2′-chloro-2′-fluoro ribonucleotide prodrugs with pan-genotypic anti-HCV activity ( Figure 1 , 2 ) [ 8 ].…”

“…The glycosylation of 2-deoxy-2,2-dichlorofuranose 1-chloride with N 4 -Bz-cytosine has also been reported towards the synthesis of β- d -2′-deoxy-2′,2′-dichlorouridine [ 7 ]. β-2′-Chloro-α-2′-fluororibonucleoside derivatives were prepared from a β-2-chloro-α-2-fluororibofuranose intermediate, which was in turn obtained from 2-deoxy- d -ribose in five steps using N -chlorosuccinimide (NCS) in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) in the chlorination step [ 8 ].…”