POLYAMINE DERIVATIVES AS INHIBITORS OF TRYPANOTHIONE REDUCTASE AND ASSESSMENT OF THEIR TRYPANOCIDAL ACTIVITIES

Trypanothione reductase (TR) occurs exclusively in trypanosomes and le ishmania, which are the etiological agents of many diseases. TR plays a vital role in the antioxidant defenses of these parasites and inhibi tors of TR have potential as antitrypanosomal agents. We describe the syntheses of several spermine and spermidine derivatives and the inhib iting effects of these compounds on T. cruzi TR. All of the inhibiting compounds displayed competitive inhibition of TR-mediated reduction o f trypanothione disulfide. The three most effective compounds studied were N-4,N-8-bis(3-phenylpropyl)spermine (12), N-4,N-8-bis(2-naphthylm ethyl)spermine (14), and N-1,N-8-bis(2-naphthylmethyl)spermidine (21), with K-i values of 3.5, 5.5 and 9.5 mu M, respectively. Compounds 12, 14, and 21 were found to be potent trypanocides in vitro with IC50 va lues ranging from 0.19 to 0.83 mu M against four T. brucei ssp. strain s. However, these compounds did not prolong the lives of mice infected with trypanosomes. This work indicates that certain polyamine derivat ives which target a unique pathway in Trypanosomatidae have potential as antitrypanosomal agents. (C) 1997 Elsevier Science Ltd.