Discovery of novel and potent benzhydryl-tropane trypanocides highly selective for Trypanosoma cruzi

G A Holloway; J P Parisot; P M Novello; K G Watson; T Armstrong; R C A Thompson; I P Street; J B Baell

doi:10.1016/j.bmcl.2010.02.022

Discovery of novel and potent benzhydryl-tropane trypanocides highly selective for Trypanosoma cruzi

Bioorg Med Chem Lett. 2010 Mar 15;20(6):1816-8. doi: 10.1016/j.bmcl.2010.02.022. Epub 2010 Feb 8.

Authors

G A Holloway¹, J P Parisot, P M Novello, K G Watson, T Armstrong, R C A Thompson, I P Street, J B Baell

Affiliation

¹ Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

PMID: 20185305
DOI: 10.1016/j.bmcl.2010.02.022

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Drug Discovery*
Rats
Structure-Activity Relationship
Trypanocidal Agents / chemistry
Trypanocidal Agents / pharmacology*
Trypanosoma cruzi / drug effects*

Substances

Trypanocidal Agents