STRUCTURE-ACTIVITY RELATIONSHIP OF NEW GROWTH-INHIBITORS OF TRYPANOSOMA-CRUZI

Several drugs bearing the 4-phenoxyphenoxy skeleton and other closely related structures were designed, synthesized, and evaluated as antipr oliferative agents against Trypanosoma cruzi, the etiologic agent of C hagas' disease. The new class of drugs was envisioned by modifying the nonpolar 4-phenoxyphenoxy moiety replacing selected aromatic protons by different groups via electrophilic aromatic substitution reactions as well as introducing a sulfur atom at the polar extreme. Of the desi gned compounds, sulfur-containing derivatives were shown to be potent antireplicative agents against T. cruzi. Among these drugs, 4-phenoxyp henoxyethyl thiocyanate (compound 56) proved to be an extremely active growth inhibitor of the epimastigote forms of T. cruzi and displayed an IC50 of 2.2 mu M. Under the same assay conditions, this drug was mu ch more active than Nifurtimox, one of the drugs currently in clinical use to control this disease. This thiocyanate derivative was also a v ery active inhibitor against the intracellular form of the parasite at the nanomolar level. Other sulfur derivatives prepared also exhibited very potent antiproliferative action against T. cruzi. The presence o f a sulfur atom at the polar extreme for this family of compounds seem s to be very important for biological action because this atom was alw ays associated with high inhibition values. 4-Phenoxyphenoxyethyl thio cyanate presents very good prospective not only as a lead drug but als o as a potential chemotherapeutic agent.