Serious diseases are caused by protozoan parasites from the Trypanosomatidae family, including: leishmaniasis (Leishmania major, L. donovani, etc.), African trypanosomiasis (Trypanosoma brucei subspecies) and Chagas disease (T. cruzi). The enzyme trypanothione reductase (TR) is pivotal to the unique antioxidant metabolism of these parasites. 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 and is also responsible for maintaining the parasites’ cellular thiol redox balance. Thus inhibitors of TR have potential as novel anti-trypanosomal chemotherapeutics. Here we report the syntheses of several novel aryl-guanidino polyamine derivatives and initial studies of the inhibiting effects of these compounds on recombinant T. cruzi TR. The polyamines investigated were spermidine derivatives with N4-aryl substituents and mono or bis N1,N8-carboxamidino groups. Additionally, certain spermine derivatives with bis-N4, N8-aryl substituents and mono or bis N1,N12-carboxamidino groups were prepared and inhibiting activities against TR assessed.

Synthesis of guanidino derivatives of aryl-substituted polyamines as inhibitors of Trypanosoma cruzi trypanothione reductase

255th National Meeting (2018)

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