title: Trypanocidal activity of piperazine-linked bisbenzamidines and bisbenzamidoxime, an orally active prodrug.
abstract: A series of 32 piperazine-linked bisbenzamidines (and related analogues) were analysed for their in vitro and in vivo trypanocidal activity against a drug-sensitive strain of Trypanosoma brucei brucei and a drug-resistant strain of Trypanosoma brucei rhodesiense. The compounds showed similar potencies against both strains. The most potent compounds were bisbenzamidines substituted at the amidinium nitrogens with a linear pentyl group (8, inhibitory concentration for 50% (IC(50))=1.7-3.0 nM) or cyclic octyl group (17, IC(50)=2.3-4.6 nM). Replacement of the diamidine groups with diamidoxime groups resulted in a prodrug (22) that was effective orally against T. b. brucei-infected mice. Three compounds (7, 11 and 15) provided 100% cure when administered parenterally. The results indicate that the nature of the substituents at the amidinium nitrogens of bisbenzamidines strongly influence their trypanocidal activity.
authors.affiliation: College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. thuang@xula.edu
authors.forename: Tien L
authors.initials: TL
authors.lastname: Huang
authors.forename: Cyrus J
authors.initials: CJ
authors.lastname: Bacchi
authors.forename: Nageswara R
authors.initials: NR
authors.lastname: Kode
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Guangdi
authors.initials: G
authors.lastname: Wang
authors.forename: Nigel
authors.initials: N
authors.lastname: Yartlet
authors.forename: Donna
authors.initials: D
authors.lastname: Rattendi
authors.forename: Indira
authors.initials: I
authors.lastname: Londono
authors.forename: Lakshman
authors.initials: L
authors.lastname: Mazumder
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Vanden Eynde
authors.forename: Annie
authors.initials: A
authors.lastname: Mayence
authors.forename: Isaac O
authors.initials: IO
authors.lastname: Donkor
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001550:Benzamidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004351:Drug Resistance; D006801:Humans; D051379:Mice; D021261:Parasitic Sensitivity Tests; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology
chemical_list: D001550:Benzamidines; D010879:Piperazines; D011355:Prodrugs; D014344:Trypanocidal Agents; D000077489:Piperazine