Synthesis and antiviral activity of some 2-substituted 3-formyl- and 3-cyano-5,6-dichloroindole nucleosides.
A series of dichlorinated indole nucleosides has been synthesized and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1) and for cytotoxicity. The isopropylidene-protected analogs of the previously reported 3-formyl-2,5,6-trichloro-1-(beta-Dribofuranosyl)indole (FTCRI) and 3-cyano-2,5, 6-trichloro-1-(beta-D-ribofuranosyl)indole (CTCRI) were modified by nucleophilic displacement of the 2-chloro substituent using secondary amines. Deprotection of the intermediates provided 2-substituted analogs of FTCRI and CTCRI in good yield. There was a significant difference in reactivity between the isopropylidene-protected and the fully deprotected FTCRI and CTCRI with respect to nucleophilic displacement of the 2-chloro substituent using dialkylamines. This difference in reactivity was not observed with monoalkylamines or with alkoxides, and the corresponding 2-alkylamino- and 2-methoxy substituted analogs were synthesized from FITCRI and CTCRI directly. None of the synthesized analogs demonstrated potent antiviral activity without some corresponding cytotoxicity.
Williams
John D
JD
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Drach
John C
JC
Townsend
Leroy B
LB
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000254:growth & development*; D018259:Herpesvirus 1, Human / Q000254:growth & development*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D007211:Indoles; D009705:Nucleosides