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J. Biol. Chem., Vol. 282, Issue 35, 25436-25444, August 31, 2007

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X-ray Structural Analysis of Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase as a Pathway toward the Optimization of Triclosan Antimalarial Efficacy^*

Joel S. Freundlich¹, Feng Wang, Han-Chun Tsai, Mack Kuo, Hong-Ming Shieh, John W. Anderson, Louis J. Nkrumah^¶, Juan-Carlos Valderramos^¶2, Min Yu^¶2, T. R. Santha Kumar^¶, Stephanie G. Valderramos^¶2, William R. Jacobs, Jr^¶||, Guy A. Schiehser, David P. Jacobus, David A. Fidock^¶2, and James C. Sacchettini³

From the Department of Medicinal Chemistry, Jacobus Pharmaceutical Company, Princeton, New Jersey 08540, the Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128, the ^¶Department of Microbiology and Immunology and the ^||Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York 10461

The x-ray crystal structures of five triclosan analogs, in addition to that of the isoniazid-NAD adduct, are described in relation to their integral role in the design of potent inhibitors of the malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of the novel 5-substituted analogs exhibit low micromolar potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite and inhibit purified PfENR enzyme with IC₅₀ values of <200 nM. This study has significantly expanded the knowledge base with regard to the structure-activity relationship of triclosan while affording gains against cultured parasites and purified PfENR enzyme. In contrast to a recent report in the literature, these results demonstrate the ability to improve the in vitro potency of triclosan significantly by replacing the suboptimal 5-chloro group with larger hydrophobic moieties. The biological and x-ray crystallographic data thus demonstrate the flexibility of the active site and point to future rounds of optimization to improve compound potency against purified enzyme and intracellular Plasmodium parasites.

Received for publication, March 1, 2007 , and in revised form, June 5, 2007.

^* This work was supported by funding from the Medicines for Malaria Venture and National Institutes of Health Grants AI060342 and AI43268. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2NQ8, 2FOI, 2OOS, 2OL4, 2OP0, and 2OP1) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1–S7.

² Present address: Depts. of Microbiology and of Medicine, Columbia University, New York, NY 10032.

³ Supported by Robert A. Welch Foundation Grant A-0015.

¹ To whom correspondence should be addressed: Dept. of Chemistry, Princeton University, Frick Chemical Laboratory, Princeton, NJ 08544. Tel.: 609-258-9804; Fax: 609-258-1980; E-mail: joelf{at}princeton.edu.

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