title: Structure-activity study of pentamidine analogues as antiprotozoal agents.
abstract: Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC(50) = 4 nM). Nine congeners (2-4, 12, 27, 30, and 64-66) were more active against P. falciparum than artemisinin (IC(50) = 6 nM). Eight compounds (12, 32, 33, 44, 59, 62, 64, and 66) exhibited equal or better antileishmanial activities than 1 (IC(50) = 1.8 microM). Several congeners were more active than 1 in vivo, curing at least 2/4 infected animals in the acute mouse model of trypanosomiasis. The diimidazoline 66 was the most promising compound in the series, showing excellent in vitro activities and high selectivities against T. b. rhodesiense, P. falciparum, and L. donovani combined with high antitrypanosomal efficacy in vivo.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Svetlana M
authors.initials: SM
authors.lastname: Bakunova
authors.forename: Stanislav A
authors.initials: SA
authors.lastname: Bakunov
authors.forename: Donald A
authors.initials: DA
authors.lastname: Patrick
authors.forename: E V K Suresh
authors.initials: EV
authors.lastname: Kumar
authors.forename: Kwasi A
authors.initials: KA
authors.lastname: Ohemeng
authors.forename: Arlene S
authors.initials: AS
authors.lastname: Bridges
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Todd
authors.initials: T
authors.lastname: Barszcz
authors.forename: Susan Kilgore
authors.initials: SK
authors.lastname: Jones
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; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002103:Cadaverine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014352:Trypanosomiasis / Q000188:drug therapy
chemical_list: C540185:1,5-bis(4-(2-imidazolinyl)benzene-1-amino)pentane; D000962:Antimalarials; D007093:Imidazoles; D014344:Trypanocidal Agents; D010419:Pentamidine; D002103:Cadaverine