Design, Synthesis, and Antiviral Activity of α-Nucleosides: d- and l-Isomers of Lyxofuranosyl- and (5-Deoxylyxofuranosyl)benzimidazoles

Several 2-substituted α-d- and α-l-lyxofuranosyl and 5-deoxylyxofuranosyl derivatives of 5,6-dichloro-2-(isopropylamino)-1-(β-l-ribofuranosyl)benzimidazole (1263W94) and 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole (TCRB) were synthesized and evaluated for activity against two herpesviruses (HSV-1 and HCMV) and for their cytotoxicity against HFF and KB cells. Condensation of 1,2,3,5-tetra-O-acetyl-l-lyxofuranose (2a) with 2,5,6-trichlorobenzimidazole (1) yielded the α-nucleoside 3a. The 2-bromo derivative and 2-methylamino derivative were prepared by treatment of 3a with HBr followed by deprotection or from methylamine, respectively. Compound 3a was deprotected and the resultant nucleoside used to prepare the 2-cyclopropylamino and 2-isopropylamino derivatives. The 2-alkylthio nucleosides were prepared by condensing 2a with 5,6-dichlorobenzimidazole-2-thione followed by deprotection. Alkylation of this adduct gave the 2-methylthio and 2-benzylthio derivatives. Condensation of 5-deoxy-1,2,3-tri-O-ace...