Design, synthesis and anti flaviviridae activity of N(6)-, 5',3'-O- and 5',2'-O-substituted adenine nucleoside analogs.
During a random screening of representative libraries of nucleoside analogues we discovered that the adenine derivatives FEVB28 and FEG118 were Flaviviridae inhibitors endowed with potency comparable, if not superior, to that of ribavirin. Those studies prompted us to design a new class of protected nucleoside analogs, reported herein, which displays interesting anti-bovine viral diarrhea virus (BVDV) activity and low cytotoxicity in cell-based assays (4, 23, 29 EC(50): 14, 11, 26 microM respectively, CC(50)>100 microM) and appreciable activity in enzyme assays against the RNA dependent RNA polymerase (RdRp) of BVDV (4, 23, 29, RdRp inhibition activity 27, 16, 15 microM respectively). A molecular modeling study was also carried out to highlight the possible interactions between this compounds class and the corresponding hepatitis C virus (HCV) enzyme.
Angusti
Angela
A
Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
Manfredini
Stefano
S
Durini
Elisa
E
Ciliberti
Nunzia
N
Vertuani
Silvia
S
Solaroli
Nicola
N
Pricl
Sabrina
S
Ferrone
Marco
M
Fermeglia
Maurizio
M
Loddo
Roberta
R
Secci
Barbara
B
Visioli
Anna
A
Sanna
Tiziana
T
Collu
Gabriella
G
Pezzullo
Margherita
M
La Colla
Paolo
P
D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002417:Cattle; D002460:Cell Line; D002855:Chromatography, Thin Layer; D003198:Computer Simulation; D006224:Cricetinae; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D019277:Entropy; D018067:Flaviviridae / Q000187:drug effects*; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D007202:Indicators and Reagents; D013778:Tetrazolium Salts; D013844:Thiazoles; D012324:RNA-Dependent RNA Polymerase; C022616:thiazolyl blue