Structure-activity study on the in vitro antiprotozoal activity of glutathione derivatives

A series of N-, S-, and COOH-blocked glutathione derivatives were evaluated against the pathogenic parasites Trypanosoma brucei, Trypanosoma cruzi, an d Leishmania donovani in vitro, to identify the determinants necessary for activity and for further development; into an active lead structure. The re sults show that N,S-blocked glutathione diesters are the most effective inh ibitors of T. brucei with structures 14-16 being the most active, 14 having an IG(50) similar to 1.9 mu M. The toxicity effects observed for glutathio ne derivatives 12, 14, and 16 have been correlated to the K562 antileukemic activity of these compounds and their inhibitory effects on the glyoxalase system of the host. Diester compounds based on S-2,4-dinitrophenyl-glutath ione (17-22) were found to be significantly better inhibitors of T. brucei with ED50's in the range 16-0.19 mu M. Compounds 19 and 20 were the two bes t inhibitors, with an ED50 of similar to 1.07 and 0.19 mu M, respectively; however 20 displayed toxicity in parasitic assays. Monoesters, monoamides, and diamides tested generally exhibited low in vitro activity. The compound s did not inhibit glutathionylspermidine synthetase and trypanothione reduc tase enzyme targets in:the unique trypanothione pathway of these parasites. Diester compounds per se were considered to he ineffective inhibitors of t rypanothione metabolism suggesting that these compounds might act as prodru gs, being hydrolyzed in situ into a variety of glutathione derivatives whic h include combinations of monoesters, free acids, and amines, some of which are-inhibitors of trypanothione metabolism.