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

  • ACS Med Chem Lett. 2013 Oct 15;4(12):1183-8. doi: 10.1021/ml4002979.
Pinar Iyidogan  1 ,  Todd J Sullivan  1 ,  Mahendra D Chordia  2 ,  Kathleen M Frey  1 ,  Karen S Anderson  1
Affiliations
  • 1. Department of Pharmacology, School of Medicine, Yale University , New Haven, Connecticut 06520, United States.
  • 2. Chemin Pharma , New Haven, Connecticut 06511, United States.
PMID: 24900627 DOI: 10.1021/ml4002979
Abstract

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.

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