title: Improving an antitrypanosomal lead applying nucleophilic substitution on a safety catch linker.
abstract: In a joint effort with various laboratories we have been aiming at the structure-based design of glycolysis inhibitors as anti-trypanosomal drugs. 2'-Deoxy-2'-(3-methoxybenzamido)-N(6)-(1-naphtylmethyl)adenosine (1a) was thus revealed as a promising lead structure for the development of selective agents against protozoan parasites. Here we describe the polymer-assisted synthesis of novel amido derivatives of the scaffold 2'-amino-2'-deoxy-N(6)-(1-naphtylmethyl)adenosine (5a) we reported recently. This building block synthesized in solution was treated with an excess of polymer-supported carboxylic acids leading to chemoselective, practically quantitative conversion of the amine to the desired analogous amides. The best compound (1h) from this series was obtained after on-bead nucleophilic substitution of the carboxylic acid equivalent attached to the Kenner safety catch linker and exhibited an improved inhibitory effect on T. b. brucei blood stream forms with an IC(50) of 0.85 microM in vitro
authors.affiliation: Institut für Pharmazie, Abteilung für Pharmazeutische Chemie, Universität Hamburg, Bundesstrasse 45, D-20146, Hamburg, Germany.
authors.forename: Abolfasl
authors.initials: A
authors.lastname: Golisade
authors.forename: Claudia
authors.initials: C
authors.lastname: Herforth
authors.forename: Ludo
authors.initials: L
authors.lastname: Quirijnen
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Andreas
authors.initials: A
authors.lastname: Link
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014345:Trypanosoma / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases