Antidepressants Used as Chemotherapy for Trypanosoma cruzi Infection: Phenothiazines and Derivative Compounds
Pp. 31-67 (37)
Patricia Paglini Oliva, Silvina Lo Presti and Walter Rivarola
Phenothiazines and derivative compounds are tricyclic drugs used in
psychiatric treatments as antidepressants, anxiolytics and antipsychotics. Among their
different biological activities they have potent antifungal, antibacterial and antiplasmid
activity. Currently, there are numerous phenothiazines derivatives; they all share a
common chemical structure: they present three rings, two of them being benzene joined
by a sulfur atom and a nitrogen atom. A slight variation in the substitution pattern of these
drugs can cause clear differences in their pharmacological activities. One of the most
important properties they have is their liability to oxidation by many oxidizing agents.
We have studied the effect of some phenothiazines and derivative compounds upon
Trypanosoma cruzi, the etiological agent of Chagas disease. The drugs currently used
for the treatment of this disease have high toxicity and parasites often cause resistance.
Phenothiazines have been proved to inhibit trypanothione reductase, an enzyme present
in these tripanosomatides that is essential for their redox defense system and that has
been widely identified as a drug target. These tricyclic drugs also had other trypanocidal
effects upon T. cruzi in culture: anticalmodulin action, mitochondrial disruption and cell
membrane disorganization. These drugs were also effective for the treatment of mice
infected with different T. cruzi strains, since they modified the natural evolution of the
infection; noteworthy is the fact that cardiac function and survival of treated animals
were not different from non-infected controls. Phenothiazines and derivative
compounds should therefore be considered as promising trypanocidal agents for the
treatment of Chagas disease.
Antidepressants, benznidazole, cell membrane disruption,
clomipramine, Chagas disease, Chagas disease treatment, mitochondrial
disruption, phenothiazines and derivative compounds, thioridazine, trypanocidal
effects, tricyclic drugs, trypanothione reductase inhibition.
Medical Biophysics, Faculty of Medicine and INICSA, CONICET, National University of Córdoba, Santa Rosa 1085, Córdoba, Argentina.