Protozoan parasites that are members of the family Trypanosomatidae cause human diseases including Chagas' disease in South America (Trypanosoma cruzi) and trypanosomiasis in Africa (T. brucei subspecies). The enzyme trypanothione reductase (TR) is pivotal to the unique antioxidant metabolism of these parasites. This enzyme catalyzes the NADPH reduction of a disulfide of trypanothione. Trypanothione is an unusual glutathione-spermidine conjugate (N1,N8-bis(glutathionyl)spermidine) and the reduced (dithiol) form of trypanothione acts as a reducing agent in several vital processes including maintenance of the parasites' cellular thiol redox balance and reduction of tryparedoxin (which is a substrate for ribonucleotide reductase). Thus inhibitors of TR have potential as novel anti-trypanosomal chemotherapeutics. Here we report the syntheses of several novel aryl-guanidino polyamine derivatives and studies of the inhibiting effects of these compounds on recombinant T. cruzi TR. The polyamines investigated were spermidine (N-(3-aminopropyl)-1,4-diaminobutane) and spermine (N,N'-bis(3-aminopropyl)-1,4-diaminobutane) derivatives with N-carboxamidine and aromatic substituents.

Synthesis of aryl-guanidino polyamine conjugates and inhibition of trypanothione reductase

245th National Meeting (2013)

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