New potent inhibitors of trypanothione reductase from Trypanosoma cruzi in the 2-aminodiphenylsulfide series

Summary From a screening assay, 2-aminodiphenylsulfides were selected as leads for trypanothione reductase (TR) inhibition and studied by molecular modelling in the catalytic site of the enzyme. A series of analogues, monomers or bis-derivatives, were synthesized to improve binding energy and therefore inhibiting potency. These compounds appeared to be mixed competitive TR inhibitors and their inhibition profile could be explained when their aggregation in solution was taken into consideration. A bis-aminodiphenylsulfide with an IC 50 of 0.55 μM was revealed to be the best TR inhibitor described so far.