title: Diphenyl furans and aza analogs: effects of structural modification on in vitro activity, DNA binding, and accumulation and distribution in trypanosomes.
abstract: Human African trypanosomiasis is a devastating disease with only a few treatment options, including pentamidine. Diamidine compounds such as pentamidine, DB75, and DB820 are potent antitrypanosomal compounds. Previous investigations have shown that diamidines accumulate to high concentrations in trypanosomes. However, the mechanism of action of this class of compounds remains unknown. A long-hypothesized mechanism of action has been binding to DNA and interference with DNA-associated enzymes. The fluorescent diamidines, DB75 and DB820, have been shown to localize not only in the DNA-containing nucleus and kinetoplast of trypanosomes but also to the acidocalcisomes. Here we investigate two series of analogs of DB75 and DB820 with various levels of in vitro antitrypanosomal activity to determine whether any correlation exists between trypanosome accumulation, distribution, and in vitro activity. Despite wide ranges of in vitro antitrypanosomal activity, all of the compounds investigated accumulated to millimolar concentrations in trypanosomes over a period of 8 h. Interestingly, some of the less potent compounds accumulated to concentrations much higher than those of more potent compounds. All of the compounds were localized to the DNA-containing nucleus and/or kinetoplast, and many were also found in the acidocalcisomes. Accumulation in the nucleus and kinetoplast should be important to the mechanism of action of these compounds. The acidocalcisomes may also play a role in the mechanism of action of these compounds. This investigation suggests that the extent of accumulation alone is not responsible for killing trypanosomes and that organelle-specific accumulation may not predict in vitro activity.
authors.affiliation: Molecular Pharmaceutics, UNC School of Pharmacy, 3312 Kerr Hall, CB#7360, Chapel Hill, NC 27599, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Mathis
authors.forename: Arlene S
authors.initials: AS
authors.lastname: Bridges
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ismail
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.forename: Iris
authors.initials: I
authors.lastname: Francesconi
authors.forename: Mariappan
authors.initials: M
authors.lastname: Anbazhagan
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Hu
authors.forename: Farial A
authors.initials: FA
authors.lastname: Tanious
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Janelle
authors.initials: J
authors.lastname: Saulter
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
authors.forename: James Edwin
authors.initials: JE
authors.lastname: Hall
mesh_terms: D000818:Animals; D001550:Benzamidines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D016054:DNA, Protozoan / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015388:Organelles / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000378:metabolism
chemical_list: C504229:6-(5-(4-amidinophenyl)furan-2-yl)nicotinamidine; D001550:Benzamidines; D016054:DNA, Protozoan; D005663:Furans; D014344:Trypanocidal Agents; C033286:furamidine