Novel inhibitors of trypanothione biosynthesis: Synthesis and evaluation of a phosphinate analog of glutathionyl spermidine (GSP), a potent, slow-binding inhibitor of GSP synthetase

A phosphinate analog of glutathionyl spermidine (Gsp), 3, has been synthesized and evaluated as an inhibitor of Gsp synthetase (GSPS). In addition, a non-spermidine-containing derivative (4) was synthesized in order to evaluate the role of the polyamine moiety in ligand binding. Compound 4 showed almost no inhibitory activity against E. coli GSPS while 3 was found to be a potent, slow-binding inhibitor of this enzyme, with the collisional E•I complex isomerizing to an E•I* complex with 410-fold higher affinity.