Synthesis and antiviral evaluation of trisubstituted indole N-nucleosides as analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB)

2,5,6-Trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) and 2-bromo-5, 6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (BDCRB) are nucleosides th at exhibit strong and selective activity against human cytomegalovirus (HCM V). Selected polyhalogenated indole nucleosides have now been synthesized a s 3-deaza analogues of the benzimidazole nucleosides using the sodium salt glycosylation method. 2-Benzylthio-1-[2-deoxy-3,5-bis-O-(4-methylbenzoyl)-b eta-D-erythropentofuranosyl]-5,6-dichloroindole (8) was prepared stereosele ctively via the coupling of a 2-deoxyribofuranosyl alpha-chloride derivativ e with the sodium salt of 2-benzylthio-5,6-dichloroindole (5). Compound 8 w as then elaborated into the targeted 2-benzylthio-1-(beta-D-ribofuranosyl)- 5,6-dichloroindole (18) in five steps. 2,5,6-Trichloro-(1-beta-D-ribofurano syl)indole (19) was prepared using the same synthetic route with 2,5,6-tric hloroindole (6) as the starting material. We were subsequently able to prep are 19 in three steps using a modification of the sodium salt glycosylation method. 2-Bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)indole (25) was also prepared using the same procedures. Target compounds were tested for activi ty against HCMV, herpes simplex virus type 1 (HSV-1), and human herpes viru s six (HHV-6) and for cytotoxicity. All of the compounds were less active a gainst HCMV than TCRB and weakly active or inactive against HSV-1 and HHV-6 .