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

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

doi:10.1016/j.bmcl.2015.06.074

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

Journal Article · Thu Jul 09 00:00:00 EDT 2015 · Bioorganic and Medicinal Chemistry Letters

DOI:https://doi.org/10.1016/j.bmcl.2015.06.074· OSTI ID:1225073

Lee, Won-Gil ^[1]; Frey, Kathleen M. ^[2]; Gallardo-Macias, Ricardo ^[1]; Spasov, Krasimir A. ^[2]; Chan, Albert H. ^[2]; Anderson, Karen S. ^[2]; Jorgensen, William L. ^[1]

Yale Univ., New Haven, CT (United States)
Yale Univ. School of Medicine, New Haven, CT (United States)

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. As a result, the compounds also feature good aqueous solubility. Crystal structures for two complexes enhance the analysis of the structure–activity data.

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE; National Inst. of Health

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1225073

Alternate ID(s):: OSTI ID: 1435845

Journal Information:: Bioorganic and Medicinal Chemistry Letters, Journal Name: Bioorganic and Medicinal Chemistry Letters Journal Issue: 21 Vol. 25; ISSN 0960-894X

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
HIV-1 reverse transcriptase
NNRTI
drug solubility
protein crystallography
structure-based drug design

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

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