The Ugi reaction in the generation of new nucleosides as potential antiviral and antileishmanial agents.
5-Formyl-2'-deoxyuridine-3',5'-diacetate was converted to a small library of 5-substituted pyrimidine nucleoside N-acylamino acid amides by means of a Ugi multicomponent reaction. The reaction allowed introduction of various substituents at the acyl moiety, at the amino acid alpha-amide group, and at the amino acid carboxyl function. Evaluation of these novel 5-substituted nucleosides against vaccinia virus and cowpox virus provided one compound with discernable activity against cowpox virus but five- to eightfold less active than the Cidofovir standard. More promising activity was seen for the inhibition of Leishmania donovani promastigotes. Several synthetic products showed antileishmanial activity in the 10(-5)M range. When compared to earlier studies demonstrating anti-orthopoxviral and antileishmanial activity of 5-substituted pyrimidine nucleosides, these results imply that the 5-(N-acylamino acid amide)-derivatized pyrimidine nucleosides may possess more steric bulk, greater hydrophobicity, and more flexibility than is compatible with these particular biological activities.
Fan
Xuesen
X
Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ 86011-5698, USA.
Zhang
Xinying
X
Bories
Christian
C
Loiseau
Philippe M
PM
Torrence
Paul F
PF
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D015608:Cowpox virus / Q000187:drug effects; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007202:Indicators and Reagents; D007891:Leishmania / Q000187:drug effects*; D013058:Mass Spectrometry; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014616:Vaccinia virus / Q000187:drug effects
C519804:5-formyl-2'-deoxyuridine-3',5'-diacetate; D000981:Antiprotozoal Agents; D000998:Antiviral Agents; D007202:Indicators and Reagents; D009705:Nucleosides; D003857:Deoxyuridine