title: Synthesis and biological activity of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 2: 2'-substituted triclosan derivatives.
abstract: 2'-Substituted analogs of triclosan have been synthesized to target inhibition of the key malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of these compounds exhibit good potency (EC50<500 nM) against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite and modest (IC50=1-20 microM) potency against purified PfENR enzyme. Compared to triclosan, this survey of 2'-substituted derivatives has afforded gains in excess of 20- and 30-fold versus the 3D7 and Dd2 strains of parasite, respectively.
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: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Edinson
authors.initials: E
authors.lastname: Lucumi
authors.forename: Mack
authors.initials: M
authors.lastname: Kuo
authors.forename: Han-Chun
authors.initials: HC
authors.lastname: Tsai
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Valderramos
authors.forename: Luchezar
authors.initials: L
authors.lastname: Karagyozov
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: Guy A
authors.initials: GA
authors.lastname: Schiehser
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
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* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004352:Drug Resistance, Microbial; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D004987:Ethers / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014260:Triclosan / Q000031:analogs & derivatives / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D004987:Ethers; D014260:Triclosan; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)