1ZSN

Synthesis, Biological Activity, and X-Ray Crystal Structural Analysis of Diaryl Ether Inhibitors of Malarial Enoyl ACP Reductase. Part 1:4'-Substituted Triclosan Derivatives

Summary for 1ZSN

• Entry DOI: 10.2210/pdb1zsn/pdb
• Related: 1NHD 1NHG 1NHW 1NNU 1ZW1 1ZXL
• Descriptor: enoyl-acyl carrier reductase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 5-CHLORO-2-(2-CHLORO-4-NITROPHENOXY)PHENOL (3 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum)
• Total number of polymer chains: 2
• Total formula weight: 78118.95

Authors

Freundlich, J.S.,Anderson, J.W.,Sarantakis, D.,Shieh, H.M.,Yu, M.,Lucumi, E.,Kuo, M.,Schiehser, G.A.,Jacobus, D.P.,Jacobs Jr., W.R.,Fidock, D.A.,Sacchettini, J.C. (deposition date: 2005-05-24, release date: 2006-05-30, Last modification date: 2023-08-23)

Primary citation

Freundlich, J.S.,Anderson, J.W.,Sarantakis, D.,Shieh, H.M.,Yu, M.,Valderramos, J.C.,Lucumi, E.,Kuo, M.,Jacobs, W.R.,Fidock, D.A.,Schiehser, G.A.,Jacobus, D.P.,Sacchettini, J.C.
Synthesis, biological activity, and X-ray crystal structural analysis of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 1: 4'-Substituted triclosan derivatives.
Bioorg.Med.Chem.Lett., 15:5247-5252, 2005

PubMed Abstract: A structure-based approach has been taken to develop 4'-substituted analogs of triclosan that target the key malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of these compounds exhibit nanomolar potency against purified PfENR enzyme and modest (2-10microM) potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite. X-ray crystal structures of nitro 29, aniline 30, methylamide 37, and urea 46 demonstrate the presence of hydrogen-bonding interactions with residues in the active site and point to future rounds of optimization to improve compound potency against purified enzyme and intracellular parasites.

PubMed: 16198563
DOI: 10.1016/j.bmcl.2005.08.044

Experimental method

X-RAY DIFFRACTION (2.992 Å)