Trypanocidal activity of piperazine-linked bisbenzamidines and bisbenzamidoxime, an orally active prodrug.
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.
Huang
Tien L
TL
College of Pharmacy, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA. thuang@xula.edu
Bacchi
Cyrus J
CJ
Kode
Nageswara R
NR
Zhang
Qiang
Q
Wang
Guangdi
G
Yartlet
Nigel
N
Rattendi
Donna
D
Londono
Indira
I
Mazumder
Lakshman
L
Vanden Eynde
Jean Jacques
JJ
Mayence
Annie
A
Donkor
Isaac O
IO
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
D001550:Benzamidines; D010879:Piperazines; D011355:Prodrugs; D014344:Trypanocidal Agents; D000077489:Piperazine