title: 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.
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.
authors.affiliation: Department of Medicinal Chemistry, Jacobus Pharmaceutical Company, 37 Cleveland Lane, Princeton, NJ 08540, USA. j_freundlich@jacobuspharm.com
authors.forename: Joel S
authors.initials: JS
authors.lastname: Freundlich
authors.forename: John W
authors.initials: JW
authors.lastname: Anderson
authors.forename: Dimitri
authors.initials: D
authors.lastname: Sarantakis
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Shieh
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Valderramos
authors.forename: Edinson
authors.initials: E
authors.lastname: Lucumi
authors.forename: Mack
authors.initials: M
authors.lastname: Kuo
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.forename: Guy A
authors.initials: GA
authors.lastname: Schiehser
authors.forename: David P
authors.initials: DP
authors.lastname: Jacobus
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D014260:Triclosan / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000962:Antimalarials; D014260:Triclosan; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)