title: Synthesis and antiprotozoal activities of dicationic bis(phenoxymethyl)benzenes, bis(phenoxymethyl)naphthalenes, and bis(benzyloxy)naphthalenes.
abstract: A series of 37 dicationically substituted bis(phenoxymethyl)benzene bis(phenoxymethyl)naphthalene, and bis(benzyloxy)naphthalene analogues of pentamidine was prepared and evaluated for antiprotozoal activities and cytotoxicity in in vitro. 1,3-Bis(4-amidinophenoxymethyl)benzene (1) was the most active against Trypanosoma brucei rhodesiense (IC(50)=2.1 nM). 1,3-Bis[4-(N-isopropylamidino)phenoxymethyl]benzene (2) was most active against Plasmodium falciparum (IC(50)=3.6 nM) and displayed a selectivity index more than 50 times greater than that of pentamidine. Several other compounds displayed lower antiplasmodial IC(50) values and higher selectivity indices relative to pentamidine. 1,4-Bis(4-amidinophenoxymethyl)benzene (14) was the most active against Leishmania donovani (IC(50)=1.3 microM). Compound 2 displayed the greatest activity against T. b. rhodesiense in vivo, curing three of four infected mice dosed intraperitoneally at 5 mg/kg x 4 days.
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: E V K Suresh
authors.initials: EV
authors.lastname: Kumar
authors.forename: Heidi
authors.initials: H
authors.lastname: Chen
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: Barzcz
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* / Q000627:therapeutic use; D001554:Benzene / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D007893:Leishmania donovani / Q000187:drug effects; D051379:Mice; D032446:Myoblasts / Q000187:drug effects; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D000981:Antiprotozoal Agents; D009281:Naphthalenes; C031721:naphthalene; D001554:Benzene