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 that exhibit strong and selective activity against human cytomegalovirus (HCMV). Selected polyhalogenated indole nucleosides have now been synthesized as 3-deaza analogues of the benzimidazole nucleosides using the sodium salt glycosylation method. 2-Benzylthio-1-¿2-deoxy-3, 5-bis-O-(4-methylbenzoyl)-beta-D-erythro-pentofuranosyl-5, 6-dichloroindole (8) was prepared stereoselectively via the coupling of a 2-deoxyribofuranosyl alpha-chloride derivative with the sodium salt of 2-benzylthio-5,6-dichloroindole (5). Compound 8 was 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-ribofuranosyl)indole (19) was prepared using the same synthetic route with 2,5,6-trichloroindole (6) as the starting material. We were subsequently able to prepare 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 activity against HCMV, herpes simplex virus type 1 (HSV-1), and human herpes virus six (HHV-6) and for cytotoxicity. All of the compounds were less active against HCMV than TCRB and weakly active or inactive against HSV-1 and HHV-6.
Chen
J J
JJ
Department of Chemistry, College of Literature, Sciences and Arts, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Wei
Y
Y
Drach
J C
JC
Townsend
L B
LB
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D018259:Herpesvirus 1, Human / Q000187:drug effects; D015654:Herpesvirus 6, Human / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
C111642:2,5,6-trichloro-1-(ribofuranosyl)benzimidazole; D000998:Antiviral Agents; D001562:Benzimidazoles; D007211:Indoles; D012263:Ribonucleosides