title: Synthesis and antiviral evaluation of 6-(trifluoromethylbenzyl) and 6-(fluorobenzyl) analogues of HIV drugs emivirine and GCA-186.
abstract: The present study describes the synthesis and antiviral evaluation of a series of novel 6-(3-trifluoromethylbenzyl) and 6-(fluorobenzyl) analogues of the HIV drugs emivirine and GCA-186. The objective was to investigate whether the fluoro or trifluoromethyl substituents could lead to an improved antiviral activity against HIV-1 wild type and mutants resistant to non-nucleoside RT inhibitors. The biological test results showed that the most of theses compounds showed good activity against wild type HIV-1. Among them, compound 1-(ethoxymethyl)-6-(3-fluorobenzyl)-5-isopropyluracil (9i) showed the largest inhibitory potency (EC(50) = 0.02 microM), resulting equally potent than emivirine against wild type HIV-1. Furthermore, compound 9i showed marginal better activity against resistant mutants than emivirine. The key steps in the synthesis of the target compounds were either reaction of an appropriate beta-keto ester with thiourea or a cross-coupling reaction of 6-chloro-2,4-dimethoxypyrimidines with benzylic Grignard reagents.
authors.affiliation: Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, Odense M, Denmark.
authors.forename: Nasser R
authors.initials: NR
authors.lastname: El-Brollosy
authors.forename: Esben R
authors.initials: ER
authors.lastname: Sørensen
authors.forename: Erik B
authors.initials: EB
authors.lastname: Pedersen
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sanna
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* / Q000494:pharmacology; D002460:Cell Line; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C510377:6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil; D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; C083858:emivirine