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).  Trypanosomatids have a unique antioxidant metabolism in which the enzyme, trypanothione reductase (TR), plays a central role.  This enzyme catalyzes the NADPH reduction of the 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 polyamines, 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 <i>N</i>-carboxamidine spermine and spermidine derivatives and inhibiting effects on <i>Trypanosoma cruzi</i> trypanothione reductase

243rd National Meeting (2012)

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Synthesis of N-carboxamidine spermine and spermidine derivatives and inhibiting effects on Trypanosoma cruzi trypanothione reductase