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.

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