title: 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one-based HIV-1 integrase inhibitors.
abstract: The bis-salicylhydrazides class of HIV-1 integrase (IN) inhibitors has been postulated to function by metal chelation. However, members of this series exhibit potent inhibition only when Mn2+ is used as cofactor. The current study found that bis-aroylhydrazides could acquire inhibitory potency in Mg2+ using dihydroxybenzoyl substituents as both the right and left components of the hydrazide moiety. Employing a 2,3-dihydro-6,7-dihydroxy-1 H-isoindol-1-one ring system as a conformationally constrained 2,3-dihydroxybenzoyl equivalent provided good selectivity for IN-catalyzed strand transfer versus the 3'-processing reactions as well as antiviral efficacy in cells using HIV-1 based vectors.
authors: Laboratory of Medicinal Chemistry and HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
authors: Xue Zhi
authors: XZ
authors: Zhao
authors: Elena A
authors: EA
authors: Semenova
authors: B Christie
authors: BC
authors: Vu
authors: Kasthuraiah
authors: K
authors: Maddali
authors: Christophe
authors: C
authors: Marchand
authors: Stephen H
authors: SH
authors: Hughes
authors: Yves
authors: Y
authors: Pommier
authors: Terrence R
authors: TR
authors: Burke
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D002413:Cations, Divalent; D002460:Cell Line; D045744:Cell Line, Tumor; D005822:Genetic Vectors; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054833:Isoindoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008274:Magnesium / Q000378:metabolism; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D002413:Cations, Divalent; D019428:HIV Integrase Inhibitors; D006834:Hydrazines; D054833:Isoindoles; D008274:Magnesium