In vitro activity and preliminary toxicity of various diamidine compounds against Trypanosoma evansi.
Trypanosoma evansi is an animal pathogenic protozoan, causing a wasting disease called Surra, which is broadly distributed in a wide range of mammalian hosts. Chemotherapy is the most efficient control method, which depends on four drugs. Unfortunately, with the appearance of resistance to these drugs, their effective use is threatened, emphasising a need to find new drugs. Diamidines bind to the minor groove of DNA at AT-rich sites and exert their anti-trypanosomal activity by inhibiting one or more DNA dependent enzymes or by directly impeding the transcription process. In total, 67 novel diamidine compounds were tested in vitro to determine activity against an animal pathogenic Chinese kinetoplastic T. evansi strain. In comparison, a human pathogenic Trypanosoma brucei rhodesiense strain and a P2 transporter knock out of a Trypanosoma brucei brucei strain were also tested. All diamidine compounds tested in this study against T. evansi produced inhibitory concentration (IC(50)) values below 50 nM. The results demonstrate that these compounds are highly active against T. evansi in vitro. In addition, preliminary in vivo toxicity tests were performed on all 67 diamidines with 69% of the compounds showing no acute toxicity at an intra-peritoneal dose of 100mg/kg.
Gillingwater
Kirsten
K
Parasite Chemotherapy, Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Socinstrasse 57, 4002 Basel, Switzerland.
Kumar
Arvind
A
Ismail
Mohamed A
MA
Arafa
Reem K
RK
Stephens
Chad E
CE
Boykin
David W
DW
Tidwell
Richard R
RR
Brun
Reto
R
D000578:Amidines / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D002478:Cells, Cultured; D004133:Diminazene / Q000633:toxicity; D004351:Drug Resistance; D005260:Female; D020128:Inhibitory Concentration 50; D051379:Mice; D010419:Pentamidine / Q000031:analogs & derivatives / Q000633:toxicity; D011806:Quinolinium Compounds / Q000633:toxicity; D051381:Rats; D013498:Suramin / Q000633:toxicity; D014344:Trypanocidal Agents / Q000633:toxicity*; D014345:Trypanosoma / Q000187:drug effects*; D014352:Trypanosomiasis / Q000188:drug therapy / Q000662:veterinary
D000578:Amidines; D001152:Arsenicals; D011806:Quinolinium Compounds; D014344:Trypanocidal Agents; D013498:Suramin; D010419:Pentamidine; C062789:melaminylthioarsenate; C005707:quinapyramine; D004133:Diminazene