Synthesis of novel MKC-442 analogues with potent activities against HIV-1.
Bis(alken-1-yloxy)methanes 2 were synthesized by reacting 2-cyclohexenol, 3-cyclohexenylmethanol, cinnamyl alcohol and its alpha-methyl analogue with dibromomethane. Condensation of 2 with 5, 6-disubstituted uracil derivatives 1 resulted in the desired MKC-442 analogues 3-6. The most active compounds, N-1 cinnamyloxymethyl- and N-1 2-methyl-3-phenylallyloxymethyl substituted 5-ethyl-6-(3, 5-dimethylbenzyl)uracils (5b and 6b), showed activity against wild-type HIV-1 in the nanomolar range, and against Y181C andY181C+K103N, mutant strains known to be resistant to MKC-442, in the micromolar range.
El-Brollosy
Nasser R
NR
Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark. EBP@Chen.sdu.dk
Pedersen
Erik B
EB
Nielsen
Claus
C
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D014498:Uracil; C083858:emivirine