title: Exploration of larger central ring linkers in furamidine analogues: synthesis and evaluation of their DNA binding, antiparasitic and fluorescence properties.
abstract: The effects of replacing the central furan ring of furamidine with indole and benzimidazole on their DNA binding affinity, antiparasitic activity and fluorescence are reported. The bis-cyanophenylindoles required to make the corresponding amidines were prepared by sequential Stille and/or Suzuki coupling reactions. The bis-cyanophenylbenzimidazoles were obtained by coupling 4-cyanobenzaldehydes with the appropriate cyano substituted phenylenediamine. The bis-nitriles were converted to the diamidines by reaction with LiN[Si(CH(3))(3)](2) or by Pinner methodology. Specifically, we have prepared new series of 2,6- and 2,5-diaryl indoles (6a,b, 12 and 17a-d) and the related benzimidazoles (24, 30 and 35). The new compounds bind in the DNA minor groove in DNA AT base pair sequences and eight of the ten new analogues exhibit ΔT(m) values comparable to or higher than that of furamidine. Six of ten of the new compounds exhibit lower IC(50) values against Trypanosoma brucei rhodesiense (T. b. r.) and eight of ten exhibit lower IC(50) values against Plasmodium falciparum (P. f.) than furamidine. Four of the ten show greater efficacy than furamidine in the rigorous T. b. r. STIB900 mouse model for African trypanosomiasis. Generally, the fluorescence properties of the new analogues are similar to that of DAPI.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Abdelbasset A
authors.initials: AA
authors.lastname: Farahat
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Paliakov
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.forename: Alaa-Eldin M
authors.initials: AE
authors.lastname: Barghash
authors.forename: Fatma E
authors.initials: FE
authors.lastname: Goda
authors.forename: Hassan M
authors.initials: HM
authors.lastname: Eisa
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002942:Circular Dichroism; D003432:Cross-Linking Reagents / Q000737:chemistry; D016054:DNA, Protozoan / Q000187:drug effects* / Q000378:metabolism; D005453:Fluorescence; D006801:Humans; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects / Q000235:genetics
chemical_list: D000977:Antiparasitic Agents; D000981:Antiprotozoal Agents; D001550:Benzamidines; D001562:Benzimidazoles; D003432:Cross-Linking Reagents; D016054:DNA, Protozoan; C033286:furamidine; C031000:benzimidazole