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Antimicrobial Agents and Chemotherapy, January 2008, p. 361-364, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00883-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Madurahydroxylactone Derivatives as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and RNase H{triangledown}

Christophe Marchand,1* John A. Beutler,2 Antony Wamiru,2,3 Scott Budihas,4 Ute Möllmann,5 Lothar Heinisch,6 John W. Mellors,7 Stuart F. Le Grice,4 and Yves Pommier1

Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland,1 Molecular Targets Development Program, Center for Cancer Research, National Cancer Institute—Frederick, Frederick, Maryland,2 SAIC—Frederick, Frederick, Maryland,3 HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute—Frederick, Frederick, Maryland,4 Department of Molecular and Applied Microbiology,5 Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany,6 Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania7

Received 5 July 2007/ Returned for modification 20 August 2007/ Accepted 22 October 2007

A series of 29 madurahydroxylactone derivatives was evaluated for dual inhibition of human immunodeficiency virus type 1 (HIV-1) integrase and RNase H. While most of the compounds exhibited similar potencies for both enzymes, two of the derivatives showed 10- to 100-fold-higher selectivity for each enzyme, suggesting that distinct pharmacophore models could be generated. This study exemplifies the common and divergent structural requirements for the inhibition of two structurally related HIV-1 enzymes and demonstrates the importance of systematically screening for both integrase and RNase H when developing novel inhibitors.

* Corresponding author. Mailing address: National Cancer Institute, Center for Cancer Research, 37 Convent Drive, Bldg. 37, Rm. 5060, Bethesda, MD 20892. Phone: (301) 435-2463. Fax: (301) 402-0752. E-mail: marchand{at}nih.gov

{triangledown} Published ahead of print on 29 October 2007.

Antimicrobial Agents and Chemotherapy, January 2008, p. 361-364, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00883-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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