title: Synthesis and antiprotozoal activities of benzyl phenyl ether diamidine derivatives.
abstract: Sixty-two cationic benzyl phenyl ether derivatives (36 amidines and 26 prodrugs) were prepared and assayed for activities in vitro and in vivo against Trypanosoma brucei rhodesiense (STIB900), and in vitro against Plasmodium falciparum (K1) and Leishmania donovani axenic amastigotes. 3-Amidinobenzyl 4-amidino-2-iodo-6-methoxyphenyl ether dihydrochloride (55, IC50 = 3.0 nM) and seven other compounds exhibited IC50 values below 10 nM against T. b. rhodesiense in vitro. The 2-bromo-4,4'-diamidino analogue 19 (IC50 = 4.0 nM) and 12 other analogues were more potent than pentamidine (IC50 = 46 nM) against P. falciparum. The 3',4-diamidino-2,6-diiodo analogue 49 (IC50 = 1.4 μM) and two other compounds were more effective than pentamidine (IC50 = 1.8 μM) against L. donovani. A prodrug, 3',4-bis(N″-methoxy)amidino-2-bromo derivative 38, was the most efficacious against trypanosome infected mice, attaining 4/4 cures in four daily 25 mg/kg oral doses, and the 2-chloro-4,4'-diamidine 18 cured 3/4 mice in four daily 5 mg/kg intraperitoneal doses.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Patrick
authors.forename: Stanislav A
authors.initials: SA
authors.lastname: Bakunov
authors.forename: Svetlana M
authors.initials: SM
authors.lastname: Bakunova
authors.forename: Susan Kilgore
authors.initials: SK
authors.lastname: Jones
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Todd
authors.initials: T
authors.lastname: Barszcz
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007893:Leishmania donovani / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D032446:Myoblasts / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014352:Trypanosomiasis / Q000188:drug therapy* / Q000662:veterinary
chemical_list: D000981:Antiprotozoal Agents; D010647:Phenyl Ethers; D010419:Pentamidine
keywords: 50% inhibition concentration; ATMS; Antileishmanial; Antiplasmodial; Antiprotozoal; Antitrypanosomal; BPE; Benzyl phenyl ether derivatives; CQ; Diamidines; FMD; HAT; IC(50); MLSR; PMD; PPT; Prodrugs; SI; WHO; World Health Organization; artemisinin; benzyl phenyl ether; chloroquine; furamidine; human African trypanosomiasis; melarsoprol; pentamidine; podophyllotoxin; selectivity index