THIOSEMICARBAZONES AND THIAZOLIDINONES, SAR-STUDIES AND ANTI-EXTRA AND INTRACELLULAR PARASITIC ELIMINATION OF LEISHMANIA AMAZONENSIS

Laís P. De Carvalho*, Rebeca C. C. Pereira, Helena C. Castro, Marco Antonio G. B. Gomes,
Rodrigo R De Oliveira, Edmilson J. Maria and Edésio J. T. De Melo*

ABSTRACT

Leishmaniasis has a high prevalence in under-developed and developing countries and can be lethal if untreated. Nonetheless, the available treatments, including pentavalent antimonials or second-line drugs, can cause a wide variety of drawbacks, or the drug activity can stop. Considering the prominent role of the thiosemicarbazones and thiazolidinones as therapeutic agent candidates due to their versatility in production and activity, these compounds were tested against Leishmania amazonensis. To verify their capacity to eliminate extra and intracellular parasites as well as the structure-activity relationship using an in silico approach. Initially, proliferative promastigotes were incubated at different times and concentrations. Thereafter, infected macrophages with proliferative intracellular amastigotes were subjected to the same conditions. The antiparasitic analyses showed the elimination of both extra and intracellular forms with 24 hours of incubation. The morphological/ultrastructural studies revealed both parasite forms with progressive internal organelles disorganization including promastigotes with rounded shape, dense nucleus and loss of flagellum whereas amastigotes were at different stage without plasma membrane rupture. No effect was observed against host cells with a selective index higher than 10 times when analysing the amastigotes effects. The SAR studies indicate that lower values of Energy of HOMO and number of hydrogen bond acceptors (nOHNH-HBD) and higher values of Energy of LUMO, hydrogen bond donors (nON-HBA), Dipole, Area, Volume, and PSA lead to the safer compounds represented by thiazolidinone group. These data pointed these compounds as good antiparasite prototypes for further studies as they affected both L. amazonensis forms.

Keywords: amastigotes; Leishmania amazonensis; promastigotes; SAR-studies; Thiazolidinones; Thiosemicarbazones.