title: Synthesis and antiviral activity of 3-formyl- and 3-cyano-2,5,6-trichloroindole nucleoside derivatives.
abstract: A series of trichlorinated 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 previously reported 3-formyl-2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole (FTCRI) and its 3-cyano homologue (CTCRI) were chemically modified at the 3-position. The formation of hydrazones and oximes of FTCRI was accomplished by a dehydrative addition of the appropriate hydrazine or hydroxylamine derivatives, respectively. A carboxamide oxime and imidate were synthesized from CTCRI by the addition of hydroxylamine or methanol, respectively, to the 3-nitrile substituent. Analogues synthesized from FTCRI generally had less antiviral activity than either FTCRI or CTCRI. However, the derivatives of CTCRI were potent and selective inhibitors of HCMV in vitro. The analogue 2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole-3-carboxamide oxime was especially selective (HCMV IC50 = 0.30 microM, CC50 > 100 microM). None of the analogues had significant activity against HSV-1.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48019, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Williams
authors.forename: Jiong J
authors.initials: JJ
authors.lastname: Chen
authors.forename: John C
authors.initials: JC
authors.lastname: Drach
authors.forename: Leroy B
authors.initials: LB
authors.lastname: Townsend
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D007211:Indoles; D009705:Nucleosides