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Antimicrob. Agents Chemother. doi:10.1128/AAC.00883-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Madurahydroxylactone derivatives as dual inhibitors of HIV-1 integrase and RNase H

Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Molecular Targets Development Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD (and SAIC-Frederick for AW); HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD; Department of Molecular and Applied Microbiology and Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Jena, Germany; Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA

^* To whom correspondence should be addressed. Email: marchand{at}nih.gov.

	Abstract

A series of 29 madurahydroxylactone derivatives has been evaluated for dual inhibition of HIV-1 integrase and RNase H. While most compounds exhibit similar potencies for both enzymes, two derivatives show 10 to 100-fold selectivity for each enzyme suggesting that distinct pharmacophore models could be generated. This study exemplifies the common and divergent structural requirements for inhibition of these structurally related HIV-1 enzymes and demonstrates the importance of systematically screening against both enzymes when developing novel inhibitors.