Improving an antitrypanosomal lead applying nucleophilic substitution on a safety catch linker

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 IC50 of 0.85 muM in vitro (C) 2001 Elsevier Science. Ltd. All rights reserved.