Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase (original) (raw)

2013, ACS Medicinal Chemistry Letters

In a continuing study of potent bifunctional anti-HIV agents, we rationally designed a novel chimeric inhibitor utilizing thymidine (THY) and a TMC derivative (a diarylpyrimidine NNRTI) linked via a polymethylene linker (ALK). The nucleoside, 5-hydrogen-phosphonate (H-phosphonate) and 5-triphosphate forms of this chimeric inhibitor (THY-ALK-TMC) were synthesized and the antiviral activity profiles were evaluated at the enzyme and cellular level. The nucleoside triphosphate (11) and the Hphosphonate (10) derivatives inhibited RT polymerization with an IC 50 value of 6.0 nM and 4.3 nM, respectively. Additionally, chimeric nucleoside (9) and H-phosphonate (10) derivatives reduced HIV replication in a cell-based assay with low nanomolar antiviral potencies.