ANTI-TRYPANOSOMA CRUZI ACTIVITY OF CANDIMINE ISOLATED FROM HIPPEASTRUM ESCOIPENSE. SYNERGISTIC POTENTIAL WITH BENZNIDAZOLE BY THE CHOU-TALALAY METHOD.

PIÑEIRO, MAURICIO; MARTINEZ-PEINADO, NIEVES; ORTIZ, JAVIER; BARRERA, PATRICIA; SOSA, MIGUEL; ALONSO-PADILLA, JULIO; FERESIN, GABRIELA

Congreso; XL Reunión Científica Anual de la Sociedad de Biología de Cuyo; 2022

Chagas disease, caused by T. cruzi, represents a health threat to 10-20 million people. Current chemotherapy is based on Nifurtimox or Benznidazol (Bzn). Its adverse effects cause 15-20% of patients to discontinue treatment. Recently, evidence has emerged in favor of the use of drug combinations to improve the efficacy and tolerance of treatment.The Hippeastrum genus is endemic to South America and has a typical alkaloids family. In Argentina, this genus comprises ten widely distributed and poorly studied species that range in habitat from tropical to subtropical areas and from sea level to high altitudes. Candimine, isolated from H. morelianum, reported activity against the protozoan Trichomonas vaginalis. The objective of this work was to evaluate the combined activity of candimine with Bzn against T. cruzi by means of the Chou-Talalay method.The Combination Index (CI) and the Dose Reduction Index (DRI) were estimated using CompuSyn software. Compounds were combined in a fixed dose ratio corresponding to 0.25; 0.5; 1; 2 and 4 times that of the individual IC50 values.In epimastigotes, the interaction was synergistic (IC < 1) for the combination of 1.07µM candimine and 2.05 µM Bzn. In tripo+amastigotes, four combinations indicated additivism between Bzn and candimine (0.9 < IC < 1.1) and for 2×IC50 a slight synergism was observed (IC = 0.87). In amastigotes, three combinations showed synergism between Bzn and candimine (IC < 1), highlighting the relationship of 4×IC50 (IC = 0.08). All combinations showed a favorable IRD for Bzn and candimine (DRI > 1). Finally, the compounds combination was tested on Vero and HepG2 cells. In both, all combinations reported antagonism (CI > 1). These results suggest that the interaction of candimine would enhance the trypanocidal effect of Bzn, reducing the dose of both compounds to obtain the same result as individually. At the same time, it would be favorable for mammalian cells, since their overall cytotoxic effect is less. Thus, candimine is proposed as a potential compound to increase the efficacy of Bzn and reduce its adverse effects.