NEW POTENT INHIBITORS OF TRYPANOTHIONE REDUCTASE FROM TRYPANOSOMA-CRUZI IN THE 2-AMINODIPHENYLSULFIDE SERIES

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 energ y and therefore inhibiting potency. These compounds appeared to be mix ed competitive TR inhibitors and their inhibition profile could be exp lained when their aggregation in solution was taken into consideration . A bis-amino-diphenylsulfide with an IC50 of 0.55 mu M was revealed t o be the best TR inhibitor described so far.