title: Synthesis of novel N-1 (allyloxymethyl) analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine) with improved activity against HIV-1 and its mutants.
abstract: This paper reports the synthesis and the antiviral activities of a series of 6-arylmethyl-1-(allyloxymethyl)-5-alkyluracil derivatives, which can be viewed as analogues of the anti-HIV-1 drug emivirine (formerly MKC-442) from which they differ in the replacement of the ethoxymethyl group with variously allyloxymethyl moieties. The most active compounds N-1 allyloxymethyl- and N-1 3-methylbut-2-enyl substituted 5-ethyl-6-(3,5-dimethylbenzyl)uracils (12 and 13) showed activity against HIV-1 wild-type in the picomolar range with selective index of greater than 5 x 10(6) and activity in the submicromolar range against the clinically important Y181C and K103N mutant strains known to be resistant to emivirine. Structure-activity relationship studies established a correlation between the anti-HIV-1 activity and the substitution pattern of the N-1 allyloxymethyl group.
authors.affiliation: Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Odense M Denmark.
authors.forename: Nasser R
authors.initials: NR
authors.lastname: El-Brollosy
authors.forename: Per T
authors.initials: PT
authors.lastname: Jørgensen
authors.forename: Berit
authors.initials: B
authors.lastname: Dahan
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Boel
authors.forename: Erik B
authors.initials: EB
authors.lastname: Pedersen
authors.forename: Claus
authors.initials: C
authors.lastname: Nielsen
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: C470204:1-(allyloxymethyl)-6-(3,5-dimethylbenzyl)-5-ethyluracil; C470205:6-(3,5-dimethylbenzyl)-5-ethyl-1-(3-methylbut-2-enyloxymethyl)uracil; D019380:Anti-HIV Agents; D014498:Uracil; C083858:emivirine