title: Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Pinar
authors.initials: P
authors.lastname: Iyidogan
authors.affiliation: Department of Pharmacology, School of Medicine, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Sullivan
authors.affiliation: Chemin Pharma , New Haven, Connecticut 06511, United States.
authors.forename: Mahendra D
authors.initials: MD
authors.lastname: Chordia
authors.affiliation: Department of Pharmacology, School of Medicine, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Frey
authors.affiliation: Department of Pharmacology, School of Medicine, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
keywords: HIV; NNRTI; nucleoside H-phosphonate; reverse transcriptase; synthesis