1,2,5-Oxadiazole <i>N</i>-Oxide Derivatives and Related Compounds as Potential Antitrypanosomal Drugs:  Structure−Activity Relationships

The syntheses of a new series of derivatives of 1,2,5-oxadiazole <i>N</i>-oxide, benzo[1,2-<i>c</i>]1,2,5-oxadiazole <i>N</i>-oxide, and quinoxaline di-<i>N-</i>oxide are described. In vitro antitrypanosomal activity of these compounds was tested against epimastigote forms of<i> Trypanosoma </i><i>cruzi</i>. For the most effective drugs, derivatives <b>IIIe </b>and <b>IIIf</b>, the 50% inhibitory dose (ID<sub>50</sub>) was determined as well as their cytotoxicity against mammalian fibroblasts. Electrochemical studies and ESR spectroscopy show that the highest activities observed are associated with the facile monoelectronation of the <i>N</i>-oxide moiety. Lipophilic−hydrophilic balance of the compounds could also play an important role in their effectiveness as antichagasic drugs.