Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers

  • ACS Med Chem Lett. 2014 Oct 13;5(11):1259-62. doi: 10.1021/ml5003713.
Won-Gil Lee  1 ,  Kathleen M Frey  2 ,  Ricardo Gallardo-Macias  1 ,  Krasimir A Spasov  2 ,  Mariela Bollini  1 ,  Karen S Anderson  2 ,  William L Jorgensen  1
Affiliations
  • 1. Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.
  • 2. Department of Pharmacology, Yale University School of Medicine , New Haven, Connecticut 06520-8066, United States.
PMID: 25408842 DOI: 10.1021/ml5003713
Abstract

Catechol diethers that incorporate a 6-cyano-1-naphthyl substituent have been explored as non-nucleoside inhibitors of HIV-1 Reverse Transcriptase (NNRTIs). Promising compounds are reported that show midpicomolar activity against the wild-type virus and sub-20 nM activity against viral variants bearing Tyr181Cys and Lys103Asn mutations in HIV-RT. An X-ray crystal structure at 2.49 Å resolution is also reported for the key compound 6e with HIV-RT.

Keywords
Anti-HIV agents; NNRTIs; protein crystallography.