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

• Published in: Bioorganic & medicinal chemistry letters 2015-11, Vol.25 (21), p.4824-4827
• Main Authors: Lee, Won-Gil, Frey, Kathleen M., Gallardo-Macias, Ricardo, Spasov, Krasimir A., Chan, Albert H., Anderson, Karen S., Jorgensen, William L.
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Azabicyclo Compounds - chemical synthesis; Azabicyclo Compounds - chemistry; Azabicyclo Compounds - pharmacology; BASIC BIOLOGICAL SCIENCES; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - pharmacology; Cell Line; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Discovery; Drug solubility; HIV - drug effects; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; HIV-1 reverse transcriptase; Humans; Models, Molecular; Molecular Structure; NNRTI; Protein crystallography; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Solubility; Structure-Activity Relationship; Structure-based drug design; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.06.074

[Display omitted] 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.