Emtricitabine prodrugs with improved anti-HIV activity and cellular uptake

Mol Pharm. 2013 Feb 4;10(2):467-76. doi: 10.1021/mp300361a. Epub 2012 Sep 4.


Three fatty acyl conjugates of (-)-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC, emtricitabine) were synthesized and evaluated against HIV-1 cell-free and cell-associated virus and compared with the corresponding parent nucleoside and physical mixtures of FTC and fatty acids. Among all the compounds, the myristoylated conjugate of FTC (5, EC(50) = 0.07-3.7 μM) displayed the highest potency. Compound 5 exhibited 10-24 and 3-13-times higher anti-HIV activity than FTC alone (EC(50) = 0.7-88.6 μM) and the corresponding physical mixtures of FTC and myristic acid (14, EC(50) = 0.2-20 μM), respectively. Cellular uptake studies confirmed that compound 5 accumulated intracellularly after 1 h of incubation and underwent intracellular hydrolysis in CCRF-CEM cells. Alternative studies were conducted using the carboxyfluorescein conjugated with FTC though β-alanine (12) and 12-aminododecanoic acid (13). Acylation of FTC with a long-chain fatty acid in 13 improved its cellular uptake by 8.5-20 fold in comparison to 12 with a short-chain β-alanine. Compound 5 (IC(90) = 15.7-16.1 nM) showed 6.6- and 35.2 times higher activity than FTC (IC(90) = 103-567 nM) against multidrug resistant viruses B-NNRTI and B-K65R, indicating that FTC conjugation with myristic acid generates a more potent analogue with a better resistance profile than its parent compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacokinetics
  • Deoxycytidine / pharmacology
  • Emtricitabine
  • Flow Cytometry
  • HIV-1 / drug effects
  • Humans
  • Prodrugs / pharmacokinetics*
  • Prodrugs / pharmacology*


  • Anti-HIV Agents
  • Prodrugs
  • Deoxycytidine
  • Emtricitabine