title: N-3 Hydroxylation of Pyrimidine-2,4-diones Yields Dual Inhibitors of HIV Reverse Transcriptase and Integrase.
abstract: A new molecular scaffold featuring an N-hydroxyimide functionality and capable of inhibiting both reverse transcriptase (RT) and integrase (IN) of Human Immunodeficiency Virus (HIV) was rationally designed based on 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio)-thymine (HEPT) non-nucleoside RT inhibitors (NNRTIs). The design involves a minimal 3-N hydroxylation of the pyrimidine ring of HEPT compound to yield a chelating triad which, along with the existing benzyl group, appeared to satisfy major structural requirements for IN binding. In the mean time, this chemical modification did not severely compromise the compound's ability to inhibit RT. A preliminary structure-activity-relationship (SAR) study reveals that this N-3 OH is essential for IN inhibition and that the benzyl group on N-1 side chain is more important for IN binding than the one on C-6.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455.
authors.forename: Jing
authors.initials: J
authors.lastname: Tang
authors.forename: Kasthuraiah
authors.initials: K
authors.lastname: Maddali
authors.forename: Christine D
authors.initials: CD
authors.lastname: Dreis
authors.forename: Yuk Y
authors.initials: YY
authors.lastname: Sham
authors.forename: Robert
authors.initials: R
authors.lastname: Vince
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Zhengqiang
authors.initials: Z
authors.lastname: Wang