Synthesis and Anti-HIV-1 activity of novel new MKC-442 analogues containing alkenyl chains or reactive functionalities in the 6-benzyl group

In an effort to obtain more insight into the anti-HIV efficacy of MKC-442 analogues (1-(alkoxymethyl)-6-benzyluracils), a new series of compounds was synthesized and evaluated for inhibition of HIV-1 replication. The modifications include a reactive center such as an aldehyde or an epoxide substituted at the benzyl group. It was believed that such reactive groups could improve the activity against HIV for the Y181C mutant by forming a covalent bond to the mercapto group in cysteine in the hydrophobic pocket. Unfortunately, only moderate activities were found in cell-based assays for such compounds against wild-type HIV and no activity against the Y181C mutant. However, higher activities were found for a corresponding oxime and the precursor molecules with butenyl and allyloxy substituents in the benzyl group. A few amino-DABO and S-DABO analogues were also synthesized, but they were found inactive against HIV.