title: Anti-herpes simplex virus and cytostatic activity of some new 5-substituted 1-(4-hydroxybutyl)-and 1-(2-hydroxyethoxymethyl) uracil nucleoside analogues.
abstract: Two series of 5-substituted acyclic uracil nucleoside analogues (5-X-acyclo-U) were evaluated for their inhibitory effects against three herpes simplex virus type 1 (HSV-1) strains and one type 2 (HSV-2) strain in a plaque inhibition assay on human embryonic lung fibroblast (HELF) cell cultures as well as for their ability to inhibit the proliferation of baby hamster kidney cells in suspension (BHK-S) culture. Acyclovir [9-(2-hydroxyethoxymethyl)guanine; ACV] and (S)-9-(2,3-dihydroxypropyl)adenine [(S)-DHPA] were used as reference compounds. Only two derivatives, 1-(4-hydroxybutyl)-5-(2,2-dibromovinyl)uracil (Br2V-HBU) and 1-(2-hydroxyethoxymethyl)-5-(2,2-dibromovinyl)-uracil (Br2V-HEMU) proved active, but only at high concentrations (57-350 mumol/l) and without selectivity of anti-herpes activity, whereas ACV showed strong inhibition of HSV-1 and HSV-2 and a low cytostatic effect on BHK-S cells (50% inhibitory concentrations are 0.25-0.73, 2.1, and 240 mumol/l for HSV-1, HSV-2, and BHK-S, respectively), demonstrating a high antiherpes selectivity. In contrast, all other 5-X acyclo-U analogues [X = methyl, ethyl, propyl, butyl, vinyl, and 2-bromovinyl; acyclo = 1-(4-hydroxybutyl) and 1-(2-hydroxyethoxymethyl)] as well as the reference compound (S)-DHPA were inactive at concentrations up to 0.5-1 mmol/l. Some structure to activity relationships of acyclic pyrimidine and purine nucleoside analogues are discussed.
authors.forename: J
authors.initials: J
authors.lastname: Reefschläger
authors.forename: G
authors.initials: G
authors.lastname: Herrmann
authors.forename: H
authors.initials: H
authors.lastname: Jennrich
authors.forename: N
authors.initials: N
authors.lastname: Frost
mesh_terms: D000212:Acyclovir / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites; D000998:Antiviral Agents; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D006224:Cricetinae; D006801:Humans; D018139:Simplexvirus / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000963:Antimetabolites; D000998:Antiviral Agents; C016391:9-(2,3-dihydroxypropyl)adenine; D000225:Adenine; D014529:Uridine; D000212:Acyclovir