Two series of fenarimols for the treatment of Chagas disease

Chagas disease | 2008-2011

 

Partners

DNDi lead optimization consortium (Epichem, Murdoch University, CDCO)

 

Context

Fenarimol, a plant fungicide, was found to be a potent inhibitor of Trypanosoma cruzi, the parasite which causes Chagas disease, and was chosen as a starting point for lead optimisation to improve its activity. A large number of very active and selective inhibitors of T.cruzi were easily synthesized in large quantities and a “scaffold-hopping” exercise created new opportunities, leading to the discovery of an extensive family of novel inhibitors with high oral bioavailability, long half-life and high efficacy.

We have previously released data pertaining to 751 compounds. This second release includes data on a further 84 compounds from the two more advanced series of fenarimols which include the preclinical candidates EPL-BS0967 and EPL-BS1246, both of which are T.cruzi CYP51 inhibitors.

 

Scientific Articles

Two analogues of fenarimol show curative activity in an experimental model of Chagas disease by Keenan, M et al. J Med Chem, December 2013

Complexes of Trypanosoma cruzi sterol 14alpha-demethylase (CYP51) with two pyridine-based drug candidates for Chagas disease: Structural basis for pathogen-selectivity by Hargrove, TY et al. J. Biol. Chem, September 2013

Design, structure-activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi by Keenan, M et al. Bioorganic & Medicinal Chemistry, January 2013

Analogues of fenarimol are potent inhibitors of Trypanosoma cruzi and are efficacious in a murine model of Chagas disease by Keenan, M et al. J. Med. Chem, April 2012

 

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