Synthesis and Evaluation of Anti-HIV Activity of Fatty Acyl Conjugates of Tenofovir Alefanamide

The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by intracellular enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent this limitation, several prodrug approaches have been proposed and developed. Herein, we hypothesized that the conjugation of anti-HIV fatty acids with the nucleotide tenofovir alafenamide (TAF) (1) could improve the anti-HIV activity of the nucleotide. Several fatty acyl amide conjugates of TAF were synthesized and evaluated in comparative studies with TAF. The synthesized compounds were evaluated as racemic mixtures for anti-HIV activity in vitro in a single-round HIV-1 infection assay using TZM-bl cells at concentrations ranging from 0.01 to 100 ng/mL. Tetradecanoyl TAF conjugate 10 and palmitoyl TAF conjugate 17 had higher CLogP and displayed comparable activity to TAF (96-99% inhibition at 10–100 ng/mL) but at lower molar concentrations. The IC50 of conjugate 17 (0.65 nM) was lower than that of TAF (1.06 nM); however, this difference was not statistically significant.