title: Synthesis and in vitro antiprotozoal activity of bisbenzofuran cations.
abstract: Forty three cationic bisbenzofurans were synthesized either by interaction of o-hydroxyaldehydes with alpha-halogenated ketones followed by intramolecular ring closure or by a copper- or palladium-mediated heteroannulation of substituted o-iodophenols with terminal acetylenes. In vitro antiprotozoal activities of compounds 1-43 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and cytotoxicity against mammalian cells were influenced by the position and the type of cationic substituents as well as the length of the carbon linker between aromatic moieties. One bisamidine displayed an antitrypanosomal efficacy comparable to that of pentamidine and melarsoprol. Twenty two compounds were more potent than pentamidine and seven dications were more effective than artemisinin against P. falciparum. Eight bisbenzofurans displayed activity against L. donovani superior to that of pentamidine. Overall, bisamidines connected by two-carbon linkers exhibited the highest efficacies against T. b. rhodesiense, P. falciparum, and L. donovani.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, NC 27599-7525, USA.
authors.forename: Svetlana M
authors.initials: SM
authors.lastname: Bakunova
authors.forename: Stanislav A
authors.initials: SA
authors.lastname: Bakunov
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Todd
authors.initials: T
authors.lastname: Barszcz
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: James Edwin
authors.initials: JE
authors.lastname: Hall
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002412:Cations; D007893:Leishmania donovani / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects
chemical_list: D000962:Antimalarials; D001572:Benzofurans; D002412:Cations; D014344:Trypanocidal Agents