David Dukhan

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 selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisoster...

Provided herein are compounds, compositions and methods for the treatment of liver disorders, including HCV infections. In one embodiment, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

This invention is directed to a method for treating a host, especially a human, infected with hepatitis C, flavivirus and/or pestivirus, comprising administering to that host an effective amount of an anti-HCV biologically active pentofuranonucleoside where the pentofuranonucleoside base is an optionally substituted 2-azapurine. The optionally subs...

Provided herein are 5,5-fused heteroarylene hepatitis C virus inhibitor compounds, for example, of Formula I, IA, or IB, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.

http://www.journal-of-hepatology.eu/article/S0168-8278(11)60817-9/pdf

The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as a seven-membered ring sugar moiety, namely 9-(5-deoxy-beta-D-allo-septanosyl)-adenine, is reported. This compound was synthesized in 14 steps from the commercially available D-glycero-D-gulo-1,4-lactone. When evaluated in cell culture experiments against a broad...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Three 7-fluoro-7-deaza-2-aminopurine nucleoside derivatives were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).

The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as the sugar moiety was synthesized and evaluated as a potential inhibitor of several virus replication.

A series of novel 4-fluoro-1H-pyrazole-3-carboxamide nucleoside analogues were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).

In search for new antiviral agents, we have been interested in 1'-C-fluoromethyl branched ribonucleosides. In this paper, we describe the synthesis of 1'-C-fluoromethyladenosine via electrophilic fluorination of exo-glycal.

The “unnatural” l ‐nucleoside β‐ l ‐2′‐deoxythymidine (L‐dT) is a potent, specific, and selective inhibitor of the replication of hepatitis B virus (HBV), which is currently in Phase III clinical trials. This unit describes, in detail, a semi‐large‐scale synthesis of l ‐dT. This convenient methodology produces l ‐dT in six steps starting with l ‐ri...

Starting from 2-C-methyl-ribonolactone, 1,2,3,5-tetra-O-acetyl-2-C-methyl-4-thioribofuranose was synthesized and condensed with heterocyclic bases to afford 2-C-methyl-4'-thioribonucleosides.

In order to evaluate their antiviral properties, two imidazo[4,5-d]pyridazine 2'-C-methyl-beta-D-ribofuranonucleoside derivatives have been synthesized.

Coupling suitable sugars (D- or L-ribofuranose, 2' or 3-deoxysugar, branched sugars) with 2-aminoimidazo[1,2-a]-s-triazin-4-one was carried out using the different reaction conditions: 1) condensation in the presence of sodium hydride; or 2) condensation using Vorbrüggen's methods. The 5-aza- 7-deazaguanine nucleoside analogues obtained were evalua...

beta-L-2'-Deoxycytidine (beta-L-dC) is a potent, selective and specific anti-hepatitis B virus (HBV) agent. To improve its oral bioavailability, several derivatives involving sugar or base acylation, as well N4-derivatization with an N,N-(dimethylamino)methylene function, were synthesized. The physicochemical characteristics (including chemical sta...

For Abstract see ChemInform Abstract in Full Text.

Pharmacokinetic studies in woodchucks and monkeys indicated that the disposition of β-L-thymidine (L-dT) is comparable to the pharmacokinetic characteristics of other nucleoside analogs after administration to these animals. Woodchuck is a useful animal model for studying anti-hepatitis B virus (HBV) agents because of many similarities between wood...

L-thymidine (L-dT) is a potent antiviral nucleoside against hepatitis B virus (HBV) replication in cell culture, and it has a favorable in vitro toxicity profile. L-dT is an unsubstituted, unmodified P-L-deoxynucleoside with potent antiviral activity against hepadnaviruses in vitro and in vivo and a favorable pharmacological profile. As part of its...

In order to evaluate their antiviral properties, a series of 4'-C-methyl-beta-D-ribofuranosyl purine and pyrimidine nucleosides has been prepared. Unfortunately, none of these 4'-branched nucleosides showed any antiviral activity or cytotoxcity when tested against HIV, HBV, and Yellow Fever virus.

β-l-Thymidine (l-dT) and β-l-2′-deoxycytidine (l-dC) are potent and highly specific inhibitors of hepatitis B virus (HBV) replication both in vivo and in vitro (50% effective concentrations, 0.19 to 0.24 μM in 2.2.15 cells). The intracellular metabolisms of l-dT and l-dC were investigated in HepG2 cells and primary cultured human hepatocytes. l-dT...

A unique series of simple unnatural L-nucleosides that specifically inhibit hepatitis B virus (HBV) replication has been discovered. These molecules have in common a hydroxyl group in the 3'-position (3'-OH) of the beta-L-2'-deoxyribose sugar that confers antiviral activity specifically against hepadnaviruses. Replacement of the 3'-OH broadens acti...

Three simple, related nucleosides, beta-L-2'-deoxycytidine (LdC), beta-Lthymidine (LdT), and beta-L-2'-deoxyadenosine (LdA), have been discovered to be potent, specific and selective inhibitors of the replication hepatitis B virus (HBV), as well as the closely related duck and woodchuck hepatitis viruses (WHV). Structure-activity relationship analy...

A unique series of simple “unnatural” nucleosides has been discovered to inhibit hepatitis B virus (HBV) replication. Through structure-activity analysis it was found that the 3′-OH group of the β-l-2′-deoxyribose of the β-l-2′-deoxynucleoside confers specific antihepadnavirus activity. The unsubstituted nucleosides β-l-2′-deoxycytidine, β-l-thymid...

The syntheses of furanthiofurin [5β-d-(4‘-thioribofuranosyl)furan-3-carboxamide, 1] and thiophenthiofurin [5β-d-(4‘-thioribofuranosyl)thiophene-3-carboxamide, 2], two C-thioribonucleoside analogues of tiazofurin, are described. Direct trifluoroacetic acid-catalyzed C-glycosylation of ethyl furan-3-carboxylate with 1-O-acetyl-2,3,5-tri-O-benzyl-4-th...

Variable temperature- and pH-dependent 1H NMR conformational analyses of 3JHH coupling constants and NOE enhancements in the 4′-thionucleosides 1–10 in D2O, complemented by ab initio calculations, have given insight into the interplay of anomeric and other stereoelectronic effects that are modulated by the substitution of ring oxygen by sulfur in n...

in the present paper, we describe the synthesis of a modified 9-mer oligonucleotide, 4′-S-r(UGUGCACCU) containing for the first time 4′-thio-guanosine units. This modified 9-mer was found to inhibit in vitro genomic RNA dimerization as well as the wild type RNA.

The synthesis and computational studies of 5-(4-thio-β-D-ribofuranosyl)-furan-3-carboxamide (furanthiofurin) and 5-(4-thio-β-D-ribofuranosyl)thiophene-3-carboxamide (thiophenthiofurin) are reported.