Discovery of novel and potent benzhydryl-tropane trypanocides highly selective for Trypanosoma cruzi.
A benzhydryl tropinone oxime that is potently toxic to Trypanosoma cruzi has been previously identified. An SAR investigation determined that no part of the original compound was superfluous and all early SAR probes led to significant drops in activity. The only alteration that could be achieved without loss of activity was replacement of the aryl chloride substituent with chloro homologues. This led to the discovery of a trifluoromethyl-containing analogue with an EC(50) against T. cruzi of 30 nM and a cytotoxicity selectivity index of over 1000 relative to rat skeletal myoblast L-6 cells.
Holloway
G A
GA
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Parisot
J P
JP
Novello
P M
PM
Watson
K G
KG
Armstrong
T
T
Thompson
R C A
RC
Street
I P
IP
Baell
J B
JB
D000818:Animals; D002460:Cell Line; D055808:Drug Discovery; D051381:Rats; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
D014344:Trypanocidal Agents