2foi
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Synthesis, Biological Activity, and X-Ray Crystal Structural Analysis of Diaryl Ether Inhibitors of Malarial Enoyl ACP Reductase.
OverviewOverview
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 <, 200 nM. This study has significantly expanded the knowledge base with, regard to the structure-activity relationship (SAR) 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.
About this StructureAbout this Structure
2FOI is a Protein complex structure of sequences from Plasmodium falciparum 3d7 with and as ligands. Active as [acyl-carrier-protein_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number 1.3.1.9 Full crystallographic information is available from OCA.
ReferenceReference
X-ray structural analysis of plasmodium falciparum enoyl acyl carrier protein reductase as a pathway towards the optimization of triclosan antimalarial efficacy., Freundlich JS, Wang F, Tsai HC, Kuo M, Shieh HM, Anderson JW, Nkrumah LJ, Valderramos JC, Yu M, Kumar TR, Valderramos SG, Jacobs WR Jr, Schiehser GA, Jacobus DP, Fidock DA, Sacchettini JC, J Biol Chem. 2007 Jun 13;. PMID:17567585 [[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]
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