Work

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

Year: 2013

Type: article

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.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/ml4002979

Authors: Pinar Iyidogan, Todd J. Sullivan, Mahendra D. Chordia, Kathleen M. Frey, Karen S. Anderson

Institution: Yale University

Language: English

Topic: HIV/AIDS drug development and treatment

Subfield: Infectious Diseases

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases