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ACS Med Chem Lett. 2013 Oct 15;4(12):1183-8. doi: 10.1021/ml4002979. eCollection 2013 Dec 12.

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

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Department of Pharmacology, School of Medicine, Yale University , New Haven, Connecticut 06520, United States.
Chemin Pharma , New Haven, Connecticut 06511, United States.


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 H-phosphonate (10) derivatives inhibited RT polymerization with an IC50 value of 6.0 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.


HIV; NNRTI; nucleoside H-phosphonate; reverse transcriptase; synthesis

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