Abstract

Trypanosoma cruzi is the causative agent of Chagas' disease. The thiosemicarbazone moiety as a pharmacophore has been described for inhibition of the essential cysteine protease, cruzipain, of this parasite. Our recent study identified an amidinohydrazone containing benzofuroxan as a hit compound for cruzipain inhibition with trypanosomicidal activity. Structural modification of the amidinohydrazone, thio- and semicarbazone motifs, using benzofuroxan and including a benzimidazole 1,3-dioxide system as new core scaffolds are described. These changes allowed for the identification of new structural motifs with desired antitrypanosomal activity. The new amidinohydrazone, thio-, and semicarbazone derivatives had excellent anti-trypanosomal activity without improved cruzipain-inhibitory activity compared with the parent compounds. Relevant structural features of these derivatives for further modification have also been determined.