title: Synthesis and anti-HIV-1 activity of new MKC-442 analogues with an alkynyl-substituted 6-benzyl group.
abstract: Synthesis and antiviral activities are reported of a series of 6-(3-alkynyl benzyl)-substituted analogues of MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyluracil), a highly potent agent against HIV. The 3-alkynyl group is assumed to give a better stacking of the substituted benzyl group to reverse transcriptase (RT) and this was believed to improve antiviral activity against HIV-1. The bromo derivatives, 5-alkyl-6-(3-bromo-benzyl)-1-ethoxymethyl derivatives 7a, b and 5-alkyl-6-(3-bromobenzyl)-1-allyloxymethyl derivatives 9a, b, showed activity against HIV on the same level as their corresponding analogues 10a-d with a 3-trimethylsilylalkynylbenzyl substituent and their desilylated analogues 11a-d. However, they all showed activity against HIV-1 wild type in the range of more than 10fold lower than the one of MKC-442. Moderate activity against Y181C and Y181C + K103N mutated strains was also observed and, in some cases, they were marginally better than those found for MKC-442. A few amino-DABO and S-DABO analogues were also synthesized but they were found to be inactive against HIV.
authors.affiliation: Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, Odense M, Denmark.
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Aly
authors.forename: Erik B
authors.initials: EB
authors.lastname: Pedersen
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009154:Mutation; D013329:Structure-Activity Relationship; D014498:Uracil / Q000819:agonists / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D014498:Uracil; C083858:emivirine