<i>O</i>-Alkoxyamidine Prodrugs of Furamidine: In Vitro Transport and Microsomal Metabolism as Indicators of in Vivo Efficacy in a Mouse Model of <i>Trypanosoma brucei rhodesiense</i> Infection

Abstract

Five O-alkoxyamidine analogues of the prodrug 2,5-bis[4-methoxyamidinophenyl]furan were synthesized and evaluated against Trypanosoma brucei rhodesiense in the STIB900 mouse model by oral administration. The observed in vivo activity of these prodrugs demonstrates that compounds with an O-methoxyamidine or O-ethoxyamidine group effectively cured all trypanosome-infected mice, whereas prodrugs with larger side-chains did not completely cure the mice. Permeability across Caco-2 cell monolayers and microsomal metabolism were used to identify the underlying mechanisms of prodrug efficacy.