Synthesis and biological activity of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 2: 2'-substituted triclosan derivatives.
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.
Freundlich
Joel S
JS
Department of Medicinal Chemistry, Jacobus Pharmaceutical Company, 37 Cleveland Lane, Princeton, NJ 08540, USA. J_Freundlich@jacobuspharm.com
Yu
Min
M
Lucumi
Edinson
E
Kuo
Mack
M
Tsai
Han-Chun
HC
Valderramos
Juan-Carlos
JC
Karagyozov
Luchezar
L
Jacobs
William R
WR
Schiehser
Guy A
GA
Fidock
David A
DA
Jacobus
David P
DP
Sacchettini
James C
JC
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*
D000962:Antimalarials; D004987:Ethers; D014260:Triclosan; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)