Synthesis and antiviral evaluation of halogenated beta-D- and -L-erythrofuranosylbenzimidazoles

A series of 2-substituted benzimidazole D- and L-erythrofuranosyl nucleosid es were synthesized and tested for activity against herpesviruses and for c ytotoxicity. The D-nucleosides 2,5,6-trichloro-1-(beta-D-erythrofuranosyl)b enzimidazole (8a) and 2-bromo-5,6-dichloro-1-(beta-D-erythrofuranosyl)benzi midazole (8b) were prepared by coupling 1,2,3,-tri-O-acetyl-beta-D-erythrof uranose (D-6) with the appropriate benzimidazole, followed by removal of th e acetyl protecting groups. The 2-isopropylamino (9), 2-cyclopropylamino (1 0), and 2-mercaptobenzyl (11) derivatives were synthesized by nucleophilic displacements of the C-2 chlorine in the benzimidazole moiety of 8a. The D- nucleoside 4-bromo-5,6-dichloro-2-isopropylamino-1-(beta-D-erythrofuranosyl )benzimidazole (17) was prepared by coupling D-6 with the appropriate benzi midazole. The L-erythrofuranosyl derivatives, 5,6-dichloro-2-isopropylamino -1-(beta-L-erythrofuranosyl)benzimidazole (21a), its 2-cyclopropylamine ana logue (21b), and the 2-isopropylamino analogue (4c). In comparison, 8a was 15-fold more active against HCMV than 4a, and 8b was 4-fold more active aga inst HCMV than 4b. The 5,6-dichloro-2-isopropylamino-1-(beta-L-erythrofuran osyl)benzimidazole (21a) was less active than 4c, which is now in clinical trials for HCMV infection. Both 8a,b had comparable HCMV activity to 4c. Mo de of action studies with the D-erythrose analogues established that 8b act ed by inhibition of viral DNA processing whereas 9 and 10 may act via a dif ferent mechanism. The lack of a 5'-hydroxymethyl group in all members of th is series established that antiviral activity occurred without 5'-phosphory lation, a feature required for the activity of most nucleoside analogues.