title: Dicationic DNA-targeted antiprotozoal agents: naphthalene replacement of benzimidazole.
abstract: A series of naphthalene analogues of highly active benzimidazole diamidines were synthesized using sequential Stille and Suzuki coupling reactions for preparation of the bis-nitrile intermediates. All of the diamidines showed strong DNA affinities as judged by high DeltaTm values with poly(dA-dT). The dicationic compounds were quite active in vitro versus Trypanosoma brucei rhodesiense (T. b. r.) exhibiting IC50 values ranging from 4 to 98 nM. These compounds were also active versus Plasmodium falciparum (P. f.) giving IC50 values ranging from 4 to 33 nM. Two of the compounds showed good activity in vivo in the STIB900 model for acute African trypanosomiasis; one gave 3/4 cures and the other gave 4/4 cures on ip dosage of 20 mg/kg for 4 days. The amidoxime prodrugs of the naphthalene analogues were essentially ineffective.
authors.affiliation: Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303-3083, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chackal-Catoen
authors.forename: Yi
authors.initials: Y
authors.lastname: Miao
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry*; D002413:Cations, Divalent / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D002413:Cations, Divalent; D009281:Naphthalenes; C031721:naphthalene; D004247:DNA; C031000:benzimidazole