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

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 (<b>11</b>) and the H-phosphonate (<b>10</b>) derivatives inhibited RT polymerization with an IC₅₀ value of 6.0 and 4.3 nM, respectively. Additionally, chimeric nucleoside (<b>9</b>) and H-phosphonate (<b>10</b>) derivatives reduced HIV replication in a cell-based assay with low nanomolar antiviral potencies