Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase

摘要

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-ALKTMC) were synthesized and the antiviral activity profiles were evaluated at the enzyme and cellular level. The nucleoside triphosphate (11) and the H-phosphonate (10) derivatives inhibited RT polymerization with an IC_(50) value of 6.0 and 4.3 nM, respectively. Additionally, chimeric nucleoside (9) and Hphosphonate (10) derivatives reduced HIV replication in a cellbased assay with low nanomolar antiviral potencies.