We studied the effects of two N,N'-
thiophene-substituted
polyamine analogs (
MDL 28302 and
MDL 29431) on the capacities of Trypanosoma cruzi, the etiologic agent of
Chagas' disease, to invade and multiply within a mammalian host cell. Both compounds inhibited infectivity significantly in a time- and concentration-dependent manner. This inhibition resulted from a selective effect on the parasite, because pretreatment of T. cruzi but not host cell cultures with either
MDL 28302 or
MDL 29431 reduced infectivity. The parasite gradually recovered its infective capacity after removal of unincorporated
polyamine analog, denoting the reversible nature of the inhibitory effect. Some biochemical modification of
MDL 28302 and
MDL 29431 appeared to be required for their inhibitory activities to be exerted, since the effects of these drugs on T. cruzi infectivity were abrogated by
MDL 72527, a
drug known to inhibit
polyamine oxidase (PAO) activity specifically. Supporting the notion of that products of
MDL 28302 and
MDL 29431 oxidation by PAO were involved in the activity of these compounds was the finding that PAO competitive substrates (N1-acetylspermine and N1-acetylspermidine) also abolished the inhibition of T. cruzi infectivity mediated by
MDL 28302 or
MDL 29431. However, we can not rule out that
MDL 72527 and the PAO competitive substrates might have altered an alternative mechanism because no significant
polyamine oxidase activity could be demonstrated in preparations of lysed or intact T. cruzi in assays monitoring conversion of [14C]
spermine to [14C]
spermidine. When either
MDL 28302 or
MDL 29431 was added to infected cell cultures, a marked reduction in the rate of intracellular parasite growth ensued.(ABSTRACT TRUNCATED AT 250 WORDS)