title: Discovery of N-(2-aminoethyl)-N-benzyloxyphenyl benzamides: New potent Trypanosoma brucei inhibitors.
abstract: A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), led to the identification of N-(2-aminoethyl)-N-phenyl benzamides as a starting point for hit-to-lead medicinal chemistry. Eighty two analogues were prepared, which led to the identification of a set of highly potent N-(2-aminoethyl)-N-benzyloxyphenyl benzamides with the most potent compound 73 having an in vitro EC50=0.001μM. The compounds displayed drug-like properties when tested in a number of in vitro assays. Compound 73 was orally bioavailable and displayed good plasma and brain exposure in mice, cured 2 out of 3 mice infected with Trypanosoma brucei in acute model when dosed orally at 50mg/kg once per day for 4days. Given its potent antiparasitic properties and its ease of synthesis, compound 73 represents a potential lead for the development of drug to treat Human African Trypanosomiasis.
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Andriy
authors.initials: A
authors.lastname: Buchynskyy
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Gillespie
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hulverson
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: McQueen
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Creason
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: Ranae M
authors.initials: RM
authors.lastname: Ranade
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Duster
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: gelb@chem.washington.edu.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address: fbuckner@uw.edu.
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology*; D001682:Biological Availability; D055808:Drug Discovery; D051379:Mice; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014352:Trypanosomiasis / Q000188:drug therapy
chemical_list: D000981:Antiprotozoal Agents; D001549:Benzamides
keywords: Hit-to-lead optimization; Human African Trypanosomiasis; Trypanosoma brucei inhibitor; “Sleeping Sickness”