Synthesis and Antiviral Activity of [2-[[4-[3-[(1-Methylethyl)amino]-2-Pyridyl]-1-Piperazinyl]Carbonyl]-1H-Indol-5-yl] (BHAP) Acylsphingosine HIV Reverse Transcriptase Inhibitors

The galactosylceramide lipid is recognized and tightly complexed by the HIV-1 membrane glycoprotein gp120 in the initial step of viral infection of certain cells. The incorporation of an antiviral agent into this lipid offers the opportunity to target, via this recognition, the antiviral to the HIV virion and HIV-infected cell. Substitution of a sphingosinyl and a galactosylsphingosinyl segment on the C-5 indolyl substituent of the Upjohn 1-[3-(alkylamino)-2-pyridinyl]-4-(1H-indol-2-ylcarbonyl)-piperazine (BHAP) HIV-1 reverse transcriptase inhibitor gave a set of ersatz ceramides (exemplified by 8 and 21) in which the antiretroviral agent substitutes at the position of the ceramide fatty acid. These sphingosine conjugates retain the full antiviral activity of the BHAP parent in an acute lymphatic cell culture antiviral assay.