title: Discovery of 3-acetyl-4-hydroxy-2-pyranone derivatives and their difluoridoborate complexes as a novel class of HIV-1 integrase inhibitors.
abstract: HIV-1 integrase (IN) has emerged as an important therapeutic target for anti-HIV drug development. Its uniqueness to the virus and its critical role in the viral life cycle makes IN suitable for selective inhibition. The recent approval of Raltegravir (MK-0518) has created a surge in interest and great optimism in the field. In our ongoing IN drug design research, we herein report the discovery of substituted analogs of 3-acetyl-4-hydroxy-2-pyranones and their difluoridoborate complexes as novel IN inhibitors. In many of these compounds, complexation with boron difluoride increased the potency and selectivity of IN inhibition. Compound 9 was most active with an IC(50) value of 9 microM and 3 microM for 3'-processing and strand transfer inhibition, respectively.
authors.affiliation: Department of Pharmacology & Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Room 304, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
authors.forename: Kavya
authors.initials: K
authors.lastname: Ramkumar
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Tambov
authors.forename: Rambabu
authors.initials: R
authors.lastname: Gundla
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Manaev
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Manaev
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarovenko
authors.forename: Valery F
authors.initials: VF
authors.lastname: Traven
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000465:Algorithms; D001483:Base Sequence; D001896:Boron Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D005459:Fluorides / Q000138:chemical synthesis / Q000494:pharmacology*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D011753:Pyrones / Q000138:chemical synthesis / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D000068898:Raltegravir Potassium; D013329:Structure-Activity Relationship
chemical_list: D001896:Boron Compounds; D019428:HIV Integrase Inhibitors; D011753:Pyrones; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D005459:Fluorides