DESIGN, SYNTHESIS, AND ANTIVIRAL ACTIVITY OF ALPHA-NUCLEOSIDES - D-ISOMER AND L-ISOMER OF LYXOFURANOSYL-BENZIMIDAZOLES AND (5-DEOXYLYXOFURANOSYL)BENZIMIDAZOLES

Several 2-substituted alpha-D- and alpha-L-lyxofuranosyl and 5-deoxyly xofuranosyl derivatives of 5,6-dichloro-2-(isopropylamino)-1- -(beta-L -ribofuranosyl)benzimidazole (1263W94) and ,6-trichloro-1-(beta-D-ribo furanosyl)benzimidazole (TCRB) were synthesized and evaluated for acti vity against two herpesviruses (HSV-1 and HCMV) and for their cytotoxi city 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 or-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 re sultant nucleoside used to prepare the 2-cyclopropylamino and 2-isopro pylamino derivatives. The 2-alkylthio nucleosides were prepared by con densing 2a with 5,6-dichlorobenzimidazole-2-thione followed by deprote ction. Alkylation of this adduct gave the 2-methylthio and 2-benzylthi o derivatives. Condensation of 5-deoxy-1,2,3-tri-O-acetyl-L-lyxofurano syl, prepared from L-lyxose, with 1 or 2-bromo-5,6-dichlorobenzimidazo le (15), followed by deprotection, gave the 2-chloro or 2-bromo-5'-deo xylyxofuranosyl derivative, respectively. The cyclopropylamino derivat ive was prepared from the 2-chloro derivative. All D-isomers were prep ared in an analogous fashion from D-lyxose. Either compounds were inac tive against HSV-1 or weak activity was poorly separated from cytoxici ty. In contrast, the 2-halogen derivatives in both the alpha-lyxose an d 5-deoxy-alpha-lyxose series were active against the Towne strain of HCMV. The 5-deoxy alpha-L analogues were the most active, IC50's = 0.2 -0.4 mu M, plaque assay; IC90's = 0.2-2 mu M, yield reduction assay. A ll of the 2-isopropylamino or 2-cyclopropylamino derivatives were less active (IC50's = 60-100 mu M, plaque assay; IC90's = 17-100 mu M, yie ld reduction assay) and were not cytotoxic. The methylamino, thio, and methylthio derivatives were neither active nor cytotoxic. The benzylt hio derivatives were weakly active, but this activity was poorly separ ated from cytotoxicity. The alpha-lyxose L-isomers were more active in a plaque assay against the AD169 strain of HCMV compared to the Towne strain, thereby providing additional evidence of antiviral specificit y.