SYNTHESIS OF N³,5′-CYCLO-4-(β-D-RIBOFURANOSYL)-VIC-TRIAZOLO[4,5-b]PYRIDIN-5-ONE AND ITS 3′-DEOXYSUGAR ANALOGUE AS POTENTIAL ANTI-HEPATITIS C VIRUS AGENTS

Abstract

We recently discovered a novel compound, identified as N3, 5-cyclo-4-(beta-D-ribofuranosyl)-vic-triazolo[4,5-b]pyridinin-5-one, with anti-hepatitis C virus (HCV) activity in vitro. The structure was confirmed by chemical synthesis from 2-hydroxy-5-nitropyridine. It showed anti-HCV activity with EC50= 19.7 microM in replicon cells. Its 3'-deoxy sugar analogue was also synthesized, but was inactive against HCV in vitro.

Synthesis and Structure−Activity Relationships of Novel Anti-hepatitis C Agents: N3,5‘-Cyclo-4-(β-d-ribofuranosyl)-vic-triazolo[4,5-b]pyridin-5-one Derivatives

“…A more efficient two-step procedure was developed. Treatment of 1 6 with NaN 3 at 110-120 °C in dimethylformamide (DMF) for 3 days afforded the 3,5′-cyclo product 6 in 60% yield. After saponification of 6, compound 8 was obtained in good yield (78%).…”

“…The 5-thiono ( 7), 6-chloro (9a), 6-bromo (9b), 7-amino (10a), 7-methylamino (10b), and 7-methyl ( 16) derivatives exhibited more potent anti-HCV activity than 8. 6 Among them, the 6-bromo and 6-chloro derivatives, 9b and 9a, exhibited the most potent anti-HCV activity with EC 90 values of 1.9 and 2.1 µM, respectively (Table 1). The 7-methylamino derivative (10b) was found to exhibit significant anti-HCV activities with an EC 90 value of 7.4 µM.…”

“…This class of compounds did not inhibit purified HCV RNA-dependent RNA polymerase (NS5B) in vitro when tested in cell-free systems. 6,10 It is not surprising that they do not appear to inhibit HCV RNA-dependent RNA polymerase since there is no 5′-OH present in these compounds. The mode of anti-HCV action is now the subject of further studies.…”

“…The potency of the compounds against HCV replicon is expressed as EC90 (effective concentration to reduce the HCV RNA by 90%). 6,11 MTS was utilized to determine the associated potential toxicity (CC 50) as described previously. 12,13…”

“…Recently, we discovered that the novel molecule N 3 ,5′cyclo-4-(β-D-ribofuranosyl)-vic-triazolo [4,5-b]pyridin-5one (8) exhibited moderate anti-HCV activity in a subgenomic RNA replicon system. 6 In an effort to discover better anti-HCV agents, a series of 6-or 7-substituted derivatives were synthesized and their potency was compared to that of the lead compound, 8. The effect of substitution on the heterocyclic moiety of the molecule on the biological activity was explored, in order to gain some insight into the mode of action.…”