An analogue of AICAR with dual inhibitory activity against WNV and HCV NTPase/helicase: synthesis and in vitro screening of 4-carbamoyl-5-(4,6-diamino-2,5-dihydro-1,3,5-triazin-2-yl)imidazole-1-beta-D-ribofuranoside.
The title compound (4) was synthesized by the reaction of ethyl 1-(2,3,5-tri-O-benzoyl-beta-d-ribofuranosyl)-5-formylimidazole-4-carboxylate with excess guanidine in ethanol at reflux. Compound 4 was evaluated in vitro against NTPases/helicases of four different viruses of the Flaviviridae family, including the West Nile virus (WNV), hepatitis C virus (HCV), dengue virus (DENV), and the Japanese encephalitis virus (JEV), employing both an RNA and a DNA substrate. The compound showed activity against NTPase/helicase of WNV and HCV with an IC(50) of 23 and 37 microM, respectively, when a DNA substrate was employed, while no activity was observed when an RNA substrate was used. There was no activity against the NTPase/helicase of either DENV or JEV irrespective of whether an RNA or a DNA substrate was employed. Considering that Flaviviridae are RNA viruses, the observed absence of activity against an RNA substrate, but the presence of activity against a DNA substrate is intriguing and somewhat surprising. The preliminary studies show that compound 4 does not form a tight complex with either an RNA or a DNA substrate, suggesting that its mechanism of action may involve direct interaction with the enzyme.
Ujjinamatada
Ravi K
RK
Laboratory for Drug Design and Synthesis, Department of Chemistry and Biochemistry, University of Maryland-Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
Baier
Andrea
A
Borowski
Peter
P
Hosmane
Ramachandra S
RS
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018067:Flaviviridae; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D043583:Nucleoside-Triphosphatase / Q000037:antagonists & inhibitors*; D020365:RNA Helicases / Q000037:antagonists & inhibitors*; D012263:Ribonucleosides / Q000737:chemistry* / Q000494:pharmacology; D012265:Ribonucleotides / Q000737:chemistry / Q000494:pharmacology; D014902:West Nile virus / Q000187:drug effects* / Q000201:enzymology
D000998:Antiviral Agents; D012263:Ribonucleosides; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D043583:Nucleoside-Triphosphatase; D020365:RNA Helicases; C031143:AICA ribonucleotide