Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase.

Publication Type:

Journal Article

Authors:

Lee, Won-Gil; Frey, Kathleen M; Gallardo-Macias, Ricardo; Spasov, Krasimir A; Chan, Albert H; Anderson, Karen S; Jorgensen, William L

Source:

Bioorg Med Chem Lett, Volume 25, Issue 21, p.4824-4827 (2015)

Keywords:

Anti-HIV Agents, Azabicyclo Compounds, Bridged Bicyclo Compounds, Cell Line, Cell Proliferation, Dose-Response Relationship, Drug, Drug Discovery, HIV, HIV Reverse Transcriptase, Humans, Models, Molecular, Molecular Structure, Reverse Transcriptase Inhibitors, Solubility, Structure-Activity Relationship, Triazines

Abstract:

<p>Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that incorporate a 7-indolizinylamino or 2-naphthylamino substituent on a pyrimidine or 1,3,5-triazine core. The most potent compounds show below 10 nanomolar activity towards wild-type HIV-1 and variants bearing Tyr181Cys and Lys103Asn/Tyr181Cys resistance mutations. The compounds also feature good aqueous solubility. Crystal structures for two complexes enhance the analysis of the structure-activity data. </p>

PDB: 
5C25
Detector: 
Q315
Beamline: 
24-ID-E