Synthesis and antiviral properties of novel 7-heterocyclic substituted 7-deaza-adenine nucleoside inhibitors of Hepatitis C NS5B polymerase

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…Interestingly, Di Francesco et al 207 found the direct formation of 7-substituted phosphoramidate prodrug 410 from the corresponding parent nucleoside to be problematic and decided to use tetrahydropyranyl (THP) groups to both protect the secondary hydroxyl group and the pyrazole moiety. Thus, key intermediate 409 was obtained in four steps from 408 by 5′-silylation followed by protection of the 3′-hydroxyl, selective desilylation using TBAF, and Suzuki coupling with THP-protected pyrazole boronic acid.…”

Nucleosides and Nucleotides for the Treatment of Viral Diseases

“…7-Heterocyclic substituted 7-deaza-adenine derivatives containing either the 2 0 -F-2 0 -C-methyl or 2 0 -OH-2 0 -C-methyl substitution (65,66) demonstrated modest HCV replicon potency and modest liver triphosphate levels when administered in vivo to rats. 71 In a similar fashion, an extensive series of 6-substituted-7-heteroaryl-7-deazapurine ribonucleosides (68)(69)(70) were studied, but replicon activity was generally correlated with cytotoxicity. 71 In a similar fashion, an extensive series of 6-substituted-7-heteroaryl-7-deazapurine ribonucleosides (68)(69)(70) were studied, but replicon activity was generally correlated with cytotoxicity.…”

“…Another attempt to identify novel base containing HCV nucleos(t)ide inhibitors was inspired by Janus linear tricyclic nucleosides (71)(72)(73). 73 Unfortunately, neither of these nucleosides nor a representative phosphoramidate prodrug demonstrated anti-HCV activity.…”

Quantum Chemical Study of the Relationships Between Electronic Structure and Pharmacokinetic Profile, Inhibitory Strength Toward Hepatitis C Virus Ns5b Polymerase and HCV Replicons of Indole-Based Compounds

“…NS5B has the key function of replicating HCV's RNA by using the viral positive RNA strand as its template, and catalyzes the polymerization of ribonucleoside triphosphates during RNA replication. NS5B has been and remains a major target for the development of HCV-specific drugs [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] (we have included only references from year 2012).…”