Phthalimide-containing hydrazides and amides as diketo acid-class HIV-1 integrase inhibitors

MEDI 93

Xue Zhi Zhao1, Elena A. Semenova, Semenovel@mail.nih.gov2, B. Christie Vu, cvu@ncifcrf.gov3, Chenzhong Liao, czliao@helix.nih.gov4, Marc C Nicklaus, mn1@helix.nih.gov1, Stephen H. Hughes, hughes@ncifcrf.gov3, Yves Pommier, pommier@nih.gov2, and Terrence R. Burke Jr., tburke@helix.nih.gov1. (1) Laboratory of Medicinal Chemistry, CCR, NCI, NIH, Frederick, MD 21702, (2) Laboratory of Molecular Pharmacology, CCR, NCI, NIH, Bethesda, MD 20892, (3) HIV Drug Resistance Program, NCI, NIH, Frederick, MD 21702, (4) Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, NIH, DHHS, 376 Boyles Street, Frederick, MD 21702
Integrase (IN) is a crucial enzyme in the life cycle of human immunodeficiency virus type 1 (HIV-1) that has recently been validated as an antiviral target after promising clinical trials of IN inhibitors. Diketo acids (2,4-dioxobutanoic acids, DKAs) were originally reported as a promising class of IN inhibitors that exhibit good antiviral activity. DKAs are often characterized by preferential inhibition of one of the two catalytic functions of IN, strand transfer. Inhibition is thought to involve chelating divalent Mg2+ or Mn2+ ions that are held in the IN active site by a conserved triad of acidic residues D64, D116, E152, termed the “DDE motif”. With the DKAs as a starting point, several generations of highly potent non-acid-containing IN inhibitors have been reported and these are thought to function in similar fashion by chelating the active site divalent metal ions. In the current report we present phthalimide-containing hydrazides and amides that are structurally related to the DKA-class. These compounds inhibit purified IN in vitro; some of the compounds are also active against HIV-1 derived vectors in cell-based assays.
 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007